Protocol. This trial protocol has been provided by the authors to give readers additional information about their work.

Transcription

1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Langendonk JG, Balwani M, Anderson KE, et al. Afamelanotide for erythropoietic protoporphyria. N Engl J Med 2015;373: DOI: /NEJMoa

2 Robert J. Desnick, PhD, MD Dean for Genetic and Genomic Medicine Professor and Chairman Emeritus Department of Genetics and Genomic Sciences The Mount Sinai Medical Center One Gustave L. Levy Place, Box 1498 New York, NY T F robert.desnick@mssm.edu This supplement contains the following items: 1. Original protocol, final protocol, summary of changes of all versions. 2. Original statistical analysis plan, final statistical analysis plan, summary of changes

3 A Phase III, Multicentre, Double-Blind, Randomized, Placebo- Controlled Study to Confirm the Safety and Efficacy of Subcutaneous Bioresorbable Afamelanotide Implants in Patients with Erythropoietic Protoporphyria (EPP). [Short Title: Multicentre Phase III EPP Study 3] Protocol No: CUV039 Version 1: March 16, 2012 SPONSOR 30 Broad Street Level 14, Suites 1407 and 1408 New York, NY Clinuvel Pharmaceuticals Limited Level 14, 190 Queen Street Melbourne, Victoria 3000 Australia (Phone) (Fax) This study will be conducted in compliance with Good Clinical Practices (GCP) and ICH guidelines, and all patient study documents will be archived by Clinuvel Pharmaceuticals Limited. CONFIDENTIAL Part or all of the information in this protocol may be unpublished material. Accordingly, this protocol is to be treated as confidential and restricted to its intended use. If any portion of this material is required for purposes of publication, authorization must be obtained from Clinuvel Pharmaceuticals Limited and must not be disclosed or used except as authorized in writing by Clinuvel Pharmaceuticals Limited. This material is the property of Clinuvel Pharmaceuticals Limited and must not be disclosed or used except as authorized in writing by Clinuvel Pharmaceuticals Limited. CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

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5 Clinuvel Inc. Confidential Page 2 of 37 PROTOCOL SYNOPSIS Name of company: Clinuvel Inc. Name of finished product: Afamelanotide Name of active ingredient: Nle 4 -D-Phe 7 -α-msh Title of study: A Phase III, Multicentre, Double-Blind, Randomized, Placebo-Controlled Study to Confirm the Safety and Efficacy of Subcutaneous Bioresorbable Afamelanotide Implants in Patients with Erythropoietic Protoporphyria (EPP) Study number: CUV039 Phase of development: III Study period: Approximately 8 months at each study center (including a 2 month recruitment period) Objectives: Primary objectives Determine whether afamelanotide can enable EPP patients to expose themselves to sunlight without incurring pain and phototoxic reactions. Secondary objectives Determine whether afamelanotide can: improve the quality of life of EPP patients reduce the susceptibility to provocation with a standardized light source (minimum symptom dose) in patients with EPP Evaluate the safety and tolerability of afamelanotide implants by measuring TEAEs in patients with EPP and investigate the reversibility of afamelanotide-induced increase in dermal pigmentation. Methodology: This is a randomized placebo-controlled study to be conducted in two parallel study arms for a six month period (three doses). Between 75 and 100 eligible patients will be enrolled. To determine eligibility for study inclusion, patients will undergo a screening evaluation up to 14 days prior to commencement. Patients will receive afamelanotide (16 mg implants) or placebo according to the following dosing regimen: - Group A will be administered afamelanotide implants on Days 0, 60 and 120, or - Group B will be administered placebo implants on Days 0, 60 and 120. The number and severity of phototoxic reactions, the type and duration of sun exposure, treatment-emergent adverse events and the use of concomitant medication will be recorded by patients in study diaries between Days 0 and 180. Quality of life will be measured using the DLQI and EPP-QoL at Days 0, 60, 120 and 180. Participants will visit the clinic on Days 60, 120 and 180 for assessments of adverse events. A subset of patients will be photoprovoked on the lower back and dorsal surface of the hand and the minimal symptom dose (MSD) will be determined on Days 0, 30, 60, 90 and 120. Three months after completion of the efficacy assessment, patients will return to the study site CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

6 Clinuvel Inc. Confidential Page 3 of 37 for a full safety assessment, including an evaluation of the reversibility of pigmentation. At this time an additional questionnaire will be administered and an inventory of activities taken. No. of participants planned: Up to 75 participants in total. Treatment: Afamelanotide (16 mg implants). Diagnosis and main criteria for entry: To be eligible to enter the study, patients must meet the following inclusion criteria: - Male or female subjects with characteristic symptoms of EPP phototoxicity and a biochemically-confirmed diagnosis of EPP. - Aged 18 years old and above (inclusive). - Able to understand and sign the written Informed Consent Form. - Willing to take precautions to prevent pregnancy until completion of the study (Day 180). To be eligible to enter the study, patients must not meet any of the following exclusion criteria: - Any allergy to afamelanotide or the polymer contained in the implant or to lidocaine or other local anesthetic to be used during the administration of the study medication - EPP patients with significant hepatic involvement - Personal history of melanoma or dysplastic nevus syndrome. - Current Bowen s disease, basal cell carcinoma, squamous cell carcinoma, or other malignant or premalignant skin lesions. - Any other photodermatosis such as PLE, AP, DLE, CAD or SU. - Any evidence of clinically significant organ dysfunction or any clinically significant deviation from normal in the clinical or laboratory determinations. - Acute history of drug or alcohol abuse (in the last 6 months). - Patient assessed as not suitable for the study in the opinion of the Investigator (e.g. noncompliance history, allergic to local anesthetics, faints when given injections or giving blood). - Participation in a clinical trial for an investigational agent within 30 days prior to the screening visit. - Prior and concomitant therapy with medications which may interfere with the objectives of the study, including drugs that cause photosensitivity or skin pigmentation. - Female who is pregnant (confirmed by positive serum β-hcg pregnancy test prior to baseline) or lactating. - Females of child-bearing potential (pre-menopausal, not surgically sterile) not using adequate contraceptive measures (i.e. oral contraceptives, diaphragm plus spermicide, intrauterine device). Test product: Afamelanotide (16 mg/implant) contained in a poly(d,l-lactide-co-glycolide) implant core. Dose: Release of 16 mg of afamelanotide over 7 to 10 days Mode of administration: Subcutaneous implantation Reference therapy: Poly(D,L-lactide-co-glycolide) implants. CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

7 Clinuvel Inc. Confidential Page 4 of 37 Criteria for evaluation: Efficacy Endpoints: Primary: Duration of direct sunlight exposure between 10:00 and 18:00 hours on days when no pain was experienced (pain score of 0). Secondary: Combined sun exposure and phototoxic pain Duration of direct sunlight exposure between 10:00 and 18:00 hours on days when no or mild pain was experienced (Likert scores of 0 to 3). Sun exposure Duration of direct sunlight exposure between 10:00 and 18:00 hours during the study. Quality of life Assessed by the DLQI and EPP-QoL measured at baseline and on Days 60, 120 and 180. Photoprovocation A subset of patients will be photoprovoked on the lower back and dorsal surface of the hand to determine the minimum symptom dose on Days 0, 30, 60, 90 and 120. Phototoxicity phototoxic pain The maximum and total pain severity scores (Likert scale) for phototoxic episodes. The number of phototoxic episodes reported from Day 0 to Day 180. Safety and Tolerability Endpoints: Treatment-emergent adverse events (coded as MedDRA Preferred Terms). Changes in hematology, serum chemistry, urinalysis, physical examination and vital sign measurements from Screening to Study Days 60, 120, 180, and at Early Termination Visit, if applicable. Statistical Methods: Efficacy analyses: The primary efficacy endpoint of this study is: - The sunlight exposure for days without pain is calculated for each patient as the mean duration of daily direct sunlight exposure between 10:00 and 18:00 hours on study days when patients report not experiencing phototoxicity-associated pain (Likert score of 0). H 0 : there is no difference in the duration of sunlight exposure on days without pain between active and placebo groups. The difference between the groups will be assessed using the Kruskal-Wallis test. Secondary efficacy endpoints: Combined sun exposure and phototoxic pain The difference in the patient s average daily duration of direct sunlight exposure between 10:00 and 18:00 hours on days when no or mild pain was experienced (Likert scores of 0 to 3) between the treatment groups will be assessed using the Kruskal-Wallis test. Sun exposure The difference in average daily duration of direct sunlight exposure between 10:00 and 18:00 hours during the study between the groups will be assessed using the Kruskal-Wallis test. CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

8 Clinuvel Inc. Confidential Page 5 of 37 Quality of life The difference in quality of life as assessed by the DLQI and EPP-QoL measured at baseline and on Days 60, 120 and 180 between the groups will be assessed using the Kruskal-Wallis test. Photoprovocation A subset of patients will be photoprovoked on the lower back and dorsal surface of the hand to determine the minimum symptom dose on Days 0, 30, 60, 90 and 120. The difference between the groups in changes from baseline will be assessed using the Kruskal-Wallis test. Phototoxicity phototoxic pain - The maximum and total pain severity scores (Likert scale) for phototoxic episodes. - The number of phototoxic episodes reported from Day 0 to Day 180. The differences between the median results for the treatment groups will be assessed using the Kuuskal-Wallis test. Safety Analyses: The number of participants with treatment-emergent adverse events (TEAEs, including and clinically significant changes in laboratory parameters) will be summarized by MedDRA preferred term and body system for each treatment group. TEAEs will be further summarized by intensity, seriousness, outcome and relationship to study drug. CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

9 Clinuvel Inc. Confidential Page 6 of 37 TABLE OF CONTENTS Page No. SIGNATURES OF AGREEMENT FOR PROTOCOL AND AMENDMENTS... 1 PROTOCOL SYNOPSIS... 2 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ETHICS Institutional Review Board (IRB) Ethical Conduct of the Study Participant Information and Informed Consent Protocol Amendments Confidentiality STUDY PERSONNEL AND STUDY ADMINISTRATION INTRODUCTION AND STUDY RATIONALE STUDY OBJECTIVES Primary Objective Secondary Objectives INVESTIGATIONAL PLAN Overall Design and Plan of the Study Selection of Study Population Inclusion Criteria Exclusion Criteria Withdrawals and Replacement of Participants Study Medication Description of Study Medication Method of Assigning Participants to Treatment Group Dosage and Administration of Study Medication Packaging and Labeling of Study Medication Storage and Accountability Compliance CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

10 Clinuvel Inc. Confidential Page 7 of Prior and Concomitant Therapy Prior Therapy Concomitant Therapy Study Procedures Description of Study Days Study Procedures Flowchart Methods of Assessment Data Quality Assurance Data Collection, Monitoring and Auditing Database Management and Quality Control Statistical Methods and Determination of Sample Size Statistical and Analytical Plans Efficacy Assessment Safety Assessment Sample Size Analysis Plan Early Termination of the Study STUDY REPORT, PUBLICATION POLICY & STUDY DOCUMENTATION ARCHIVING STUDY TIMETABLE REFERENCES APPENDICES APPENDIX 1: STUDY FLOWCHART APPENDIX 2: MEDICAL PHOTOGRAPHY APPENDIX 3: PATIENT DIARY (EXTRACT) APPENDIX 4: EPP QUESTIONNAIRE APPENDIX 5: PHOTOPROVOCATION METHODOLOGY CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

11 Clinuvel Inc. Confidential Page 8 of 37 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS α-msh Alpha - Melanocyte stimulating hormone AE Adverse event ALT Alanine transaminase AST Aspartate transaminase BMI Body Mass Index BUN Blood urea nitrogen CFR Code of Federal Regulations CK Creatine kinase (creatine phosphokinase) CRF Case report form CRO Contract research organization cm Centimeter DLE Discoid lupus erythematosus DLQI Dermatology Life Quality Index EPP Erythropoietic protoporphyria EPP-QoL EPP-Specific Quality of Life Questionnaire FDA Food and Drug Administration GCP Good clinical practice β-hcg β-human chorionic gonadotrophin ICH International Committee on Harmonization IRB Institutional Review Board ITT Intention-to-treat kg Kilogram LDH Lactic dehydrogenase MedDRA Medical Dictionary for Regulatory Activities MC1-R Melanocortin 1 receptor mg Milligram ml Milliliter nm Nanometer PCV Packed cell volume PLE Polymorphic light eruption PUVA Phototherapy with psoralen and ultraviolet A radiation RBC Red blood cell (count) SAE Serious adverse event TEAE Treatment-emergent adverse event UV Ultraviolet UVB Ultraviolet light B radiation WBC White blood cell (count) WMA World Medical Association CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

12 Clinuvel Inc. Confidential Page 9 of ETHICS 1.1 Institutional Review Board (IRB) An appropriate Institutional Review Board will approve the protocol and the Participant Information and Informed Consent Form before the study is initiated at each center. Documentation of this approval will be provided to the Sponsor and/or the Sponsor s designee. The Principal Investigator(s) will have the following responsibilities: Obtain IRB approval of the protocol, informed consent documentation and any advertising material to recruit subjects; Obtain IRB approval for any protocol amendments and informed consent documentation revisions before implementing the changes; Provide the IRB with any information requested before or during the study; Submit progress reports to the IRB, as required, during the conduct of the study; Request review and approval of the study as needed; provide copies of all IRB re-approvals and relevant communication to the Sponsor; and, Notify the IRB as required of all serious and unexpected adverse events related to the study medications that occur or are reported by the Sponsor. 1.2 Ethical Conduct of the Study This study will be conducted in accordance with the Declaration of Helsinki, its revisions (Scotland, October 2000 and incorporating Notes of Clarification - Washington, 2002, Tokyo, 2004 and Seoul 2008) and ICH guidelines for Good Clinical Practice (GCP) governing the conduct of studies, and all applicable local regulations. The Principal Investigator will ensure that the study is conducted in accordance with prevailing local laws and regulations. The Principal Investigator is responsible for reporting to the Sponsor, the authorities and the IRB any modifications, safety updates, amendments, and violations of the protocol that impact on subject safety. 1.3 Participant Information and Informed Consent Prior to any study specific screening procedures, the Principal Investigator or nominee will explain to each participant and/or to his/her legal representative, if necessary, the nature of the study, its purpose, procedures to be performed, the necessity for withdrawal of prohibited medication, expected duration, CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

13 Clinuvel Inc. Confidential Page 10 of 37 and the benefits and risks of study participation. After this explanation and before any study specific procedures are performed, the subject must voluntarily sign an informed consent statement in the presence of a witness. The inclusion and exclusion criteria will be reviewed at Screening prior to study medication administration. 1.4 Protocol Amendments Changes in any portion of this protocol that affect subject safety and welfare or that alters the efficacy parameters will be documented in the form of a revision, signed by the appropriate Clinuvel Inc personnel and the Principal Investigator, and approved by the study center's IRB and relevant Competent Authority (where applicable) before the revision is implemented. The IRB Chairperson may approve minor changes or may designate one or more members of the IRB to approve changes. Clarification or interpretation of the study protocol or changes in the methods of statistical analysis may be documented in the form of an administrative change. Administrative changes do not require the Principal Investigator s signature or IRB approval. Administrative changes will be transmitted to the Principal Investigator and a copy provided to the IRB for completeness. 1.5 Confidentiality All information provided to the Principal Investigator (and delegated study site staff) by the Sponsor, including clinical observations at the investigative center, are held strictly confidential and confined to the clinical personnel involved in conducting the study, under the supervision of the Principal Investigator. This includes, but is not limited to preclinical data, protocols, CRFs and verbal or written communications. This information is related in confidence to the IRB or other committees functioning in a similar capacity. A coded number will identify all reports, subject samples, and data published or submitted to third parties in order to maintain subject confidentiality. CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

14 Clinuvel Inc. Confidential Page 11 of STUDY PERSONNEL AND STUDY ADMINISTRATION Each Principal Investigator participating in this study will meet the following criteria: Accessible, interested, and well-organized support staff; Availability of diagnostic facilities to support study data requirements; Availability of physician emergency response at all times; The Principal Investigator will sign the Investigator agreement form and protocol which incorporates the Declaration of Helsinki. By signing the protocol, the Principal Investigator agrees to: 1. Conduct the study in accordance with the protocol and only make changes after notifying the Sponsor, except when required to protect the safety, rights, or welfare of subjects; 2. Personally conduct or supervise the study (or investigation); 3. Inform any subjects that the drug is being used for investigational purposes; 4. Ensure that the requirements relating to obtaining informed consent and IRB review and approval meet ICH-GCP guidelines and the Code of Federal Regulations (21 CFR Parts 50 and 56); 5. Report to the Sponsor any AEs that occur in the course of the study, in accordance with the protocol; 6. Read and understand the Investigator Brochure, including potential risks and side effects of the drug; 7. Ensure that all associates, colleagues and employees assisting in the conduct of the study are informed about their obligations in meeting the above commitments; 8. Maintain adequate and accurate records and make those records available for inspection by the Sponsor, the Sponsor s designated representative, or any agency authorized by law; 9. Ensure that the IRB that complies with the requirements of the ICH-GCP and the Code of Federal Regulations (21 CFR Part 56) will be responsible for initial and continuing review and approval of the clinical study; 10. Promptly report to the IRB and the Sponsor all changes in the research activity and all unanticipated problems involving risks to subjects or others (to include amendments); 11. Make no changes in the research study without approval, except when necessary to eliminate hazards to the subjects; and, 12. Comply with all other requirements regarding the obligations of the clinical investigators and all other pertinent requirements listed in the ICH-GCP guidelines. 13. Ensure any sub-investigator(s) or other delegates are accountable for adherence to GCP guidelines, the study protocol and other study-related documentation. CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

15 Clinuvel Inc. Confidential Page 12 of INTRODUCTION AND STUDY RATIONALE Erythropoietic protoporphyria (EPP) is a genetic disorder in which impaired ferrochelatase activity results in the accumulation of its substrate, protoporphyrin IX. There are two main clinical manifestations of raised protoporphyrin IX levels: cutaneous phototoxicity and hepatobiliary disease. Phototoxicity is the more common of these and it usually presents in early childhood as intolerance to sun-exposure with patients experiencing severe burning pain most often on the face and hands. It may last for several days and may be accompanied by swelling and redness on sun exposed areas 1-3. Accumulation of protoporphyrin IX is responsible for cutaneous phototoxicity leading to (i) pain, (ii) swelling, (iii) formation of ulcers 1 and (iv)discrete scarring. In the presence of light at 410 nm, protoporphyrin IX generates reactive oxygen species resulting in the typical phototoxic reactions. Protoporphyrin IX is eliminated exclusively via the liver. When the capacity of the biliary excretion pathway is exceeded, excess protoporphyrin IX may result in the formation of gallstones or cholestatic liver damage 4. Available treatment modalities for patients with EPP are limited. Avoidance of strong sunlight, either from direct exposure or through windows glass and the use of protective clothing is essential to prevent phototoxic reactions 1-3. Systemic β-carotene has been shown to be of benefit in the treatment of EPP although good efficacy data are lacking 2. The clinical benefits of other treatments such as PUVA, UVB, oral cysteine 5, cholestyramine and combinations thereof remain to be proven. The most effective measures are reflecting sunscreens containing titanium dioxide 6. Afamelanotide is a potent analogue of α-msh which stimulates the production of eumelanin in the skin (epidermis) without the specific cell damage that usually occurs when melanin production is stimulated by UV radiation 11,12. Melanin, in the form of eumelanin, is a photoprotective agent. The mechanisms proposed for photoprotection include, but are not limited to, the absorption and scattering of UV light, free radical scavenging and quenching of UV light 7,8. There is also increasing evidence that melanogenesis represents a major antioxidant defense mechanism in melanocytes, neutralizing the deleterious effects of free radicals and active oxygen species 9. Eumelanin acts as a neutral density filter and, unlike most sunscreens, reduces all wavelengths of light equally so that the photoprotection provided by epidermal melanin pigmentation is essentially independent of wavelength 10. CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

16 Clinuvel Inc. Confidential Page 13 of 37 Following a pilot study conducted in Switzerland 13, three placebo controlled studies have been completed in patients with EPP, two in Europe and one in the United States. Overall these studies demonstrated that afamelanotide: enabled patients to experience more direct sunlight exposure without suffering the consequences of the deep burning pain they would normally experience following such exposure was safe and well tolerated, with no noteworthy changes or trends in adverse events, vital signs, physical exam results or laboratory test parameters 14. This study aims to extend knowledge of the photoprotective effects of afamelanotide in EPP patients. 4.0 STUDY OBJECTIVES 4.1 Primary Objective The primary objective of this study is to determine whether afamelanotide can enable EPP patients to expose themselves to sunlight without incurring pain and phototoxic reactions. 4.2 Secondary Objectives Determine whether afamelanotide implants can: improve the quality of life of EPP patients reduce the susceptibility to provocation with a standardized light source (minimum symptom dose) in patients with EPP Evaluate the safety and tolerability of afamelanotide by measuring treatment-emergent adverse events (TEAEs) and investigate the reversibility of afamelanotide-induced increase in dermal pigmentation. 5.0 INVESTIGATIONAL PLAN 5.1 Overall Design and Plan of the Study This is a randomized placebo-controlled study to be conducted in two parallel study arms for a six month period (three doses). Between 75 and 100 eligible patients will be enrolled. To determine eligibility for study inclusion, patients will undergo a screening evaluation up to 14 days prior to commencement. Patients will be randomized to receive afamelanotide (16 mg implants) or placebo according to the following dosing regimen: CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

17 Clinuvel Inc. Confidential Page 14 of 37 - Group A will be administered afamelanotide implants on Days 0, 60 and 120, or - Group B will be administered placebo implants on Days 0, 60 and 120. The number and severity of phototoxic reactions, the type and duration of sun exposure, treatmentemergent adverse events and the use of concomitant medication will be recorded by patients in study diaries between Days 0 and 180. Quality of life will be measured using the EPP-QoL and DLQI at Days 0, 60, 120 and 180. Participants will visit the clinic on Days 60, 120 and 180 for assessments of adverse events. A subset of patients will be photoprovoked on the lower back and dorsal surface of the hand and the minimal symptom dose (MSD) will be determined on Days 0, 30, 60, 90 and 120. Three months after completion of the efficacy assessment, patients will return to the study site for a full safety assessment, including an evaluation of the reversibility of pigmentation of the epidermis. At this time an additional questionnaire will be administered and an inventory of activities taken. 5.2 Selection of Study Population The target population consists of male and female patients with EPP who experience phototoxic reactions. Patients at each center will have a biochemically-confirmed diagnosis of EPP. The following inclusion and exclusion criteria must be met by each patient before enrollment in the study Inclusion Criteria The participants have to fulfill all of the following criteria for study participation: Male or female subjects with characteristic symptoms of EPP phototoxicity and a biochemicallyconfirmed diagnosis of EPP. Aged 18 years old and above (inclusive). Able to understand and sign the written Informed Consent Form. Willing to take precautions to prevent pregnancy until completion of the study (Day 180) Exclusion Criteria Any of the following criteria will exclude the patient from the study: Any allergy to afamelanotide or the polymer contained in the implant or to lidocaine or other local anesthetic to be used during the administration of study medication CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

18 Clinuvel Inc. Confidential Page 15 of 37 EPP patients with significant hepatic involvement Current Bowen s disease, basal cell carcinoma, squamous cell carcinoma, or other malignant or premalignant skin lesions. Personal history of melanoma or dysplastic nevus syndrome. Any other photodermatosis such as PLE, DLE or solar urticaria. Any evidence of clinically significant organ dysfunction or any clinically significant deviation from normal in the clinical or laboratory determinations. Acute history of drug or alcohol abuse (in the last 6 months). Patient assessed as not suitable for the study in the opinion of the Principal Investigator or delegate (e.g. noncompliance history, allergic to local anesthetics, faints when given injections or giving blood). Participation in a clinical trial of an investigational agent within 30 days prior to the screening visit. Prior and concomitant therapy with medications which may interfere with the objectives of the study, including drugs that cause photosensitivity or skin pigmentation. Female who is pregnant (confirmed by positive serum β-hcg pregnancy test prior to baseline) or lactating. Females of child-bearing potential (pre-menopausal, not surgically sterile) not using adequate contraceptive measures (i.e. oral contraceptives, diaphragm plus spermicide, intrauterine device) Withdrawals and Replacement of Participants A discontinuation occurs when a patient does not complete the study as required by the study protocol. Participants will be free to discontinue their participation in this trial at any time for any reason. In addition, participants may be withdrawn from the trial at the discretion of the Principal Investigator or medically qualified nominee. A patient may withdraw for any reason, for example: Informed consent withdrawn by the patient Unacceptable level of patient non-compliance with protocol requirements Patient experienced an adverse event requiring study discontinuation When the Investigator s or nominee s best professional judgment would indicate that it would be in the patient s best interest to be withdrawn Violation of inclusion/exclusion requirements. The reasons for withdrawal or discontinuation of a patient will be recorded in the patient s medical notes and the CRF. If an AE is the reason for discontinuation, the event must be followed up and CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

19 Clinuvel Inc. Confidential Page 16 of 37 documented as described in the present protocol. If the patient discontinued for any reason after the enrolment into the study, a study termination visit as described in the present protocol should be performed at the time of study discontinuation, or as soon as possible after discontinuation. These will be documented in the patient s medical notes and the CRF. Any patient(s) withdrawn from the trial prior to their completion for any reason may be replaced, provided the replacement is able to complete the study before the start of winter. Data compiled to the point of discontinuation will be used. Participants violating any of the inclusion and exclusion criteria will be described as protocol violators. The way in which protocol violators will be handled in the statistical analysis is described in Section 5.7 of the protocol. 5.3 Study Medication Description of Study Medication The active implant is a sterile biodegradable and biocompatible poly(dl-lactide-co-glycolide) polymer excipient containing 16 mg of afamelanotide. The implants contain no other excipients and are sterile. The placebo implants are identical in size and contain only poly(dl-lactide-co-glycolide) polymer. Both sets of implants are manufactured by SurModics Pharmaceuticals, Birmingham, Alabama, USA Method of Assigning Participants to Treatment Group A computer generated randomization list for each study site will be used to assign each patient to a treatment arm. For each study site, patients who satisfy the inclusion/exclusion criteria will be allocated patient randomization numbers sequentially and chronologically, based on the timing of their attendance at the clinic for the first study implant Dosage and Administration of Study Medication Implants (afamelanotide or placebo) will be administered following application of a local anaesthetic on the designated study days. The implant will be administered subcutaneously via a 14G catheter needle into the fat above the anterior portion of the iliac crest. Any patient who experiences any severe adverse event(s) will be closely monitored. If the adverse event(s) is/are considered related to the drug and persists for more than 24 hours, the patient will be offered the opportunity to have the implant removed. CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

20 Clinuvel Inc. Confidential Page 17 of Packaging and Labeling of Study Medication The outer packaging for each implant is an amber glass vial contained in a plastic pouch with full labeling details affixed. The label will include information in compliance with the local regulatory requirements for clinical trial / investigational medicinal products Storage and Accountability Study medications will be maintained in a safe and secure (restricted access) drug storage refrigerator and maintained at 2-8 C. The Principal Investigator and delegate will agree not to supply study drug to any persons other than those enrolled in the study. Current and accurate inventory and dispensing records will be kept for all study drugs and, upon study completion, a final inventory of all clinical supplies will be compiled. A copy of the drug receipt, inventory and drug accountability documentation will be retained in the Investigator s files. Records will be kept on a drug inventory and dispensing record form provided by Clinuvel Inc or on equivalent forms used by the pharmacy at the study site. After completion of the study, all unused study drugs will be returned to Clinuvel Inc or designee. Empty vials (following implant use) are to be retained. The Clinical Monitor will provide instructions to the center for drug shipment after checking the details of the shipment with the authorities and the Sponsor Compliance Data related to the administration of the study drug will be recorded in the patient s medical notes and the CRF. Case report forms will be completed and available for review and retrieval by Clinuvel Inc personnel or their representative. The Principal Investigator or delegate will review the CRFs for completeness and accuracy and sign and date the set of CRFs where indicated. Clinuvel Inc personnel or their representatives will review case report forms periodically for completeness, legibility and acceptability. The Principal Investigator or delegate will retain the completed Treating Physician s copy of the CRF for their files and forward the other copies to Clinuvel Inc or its representative according to instructions. CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

21 Clinuvel Inc. Confidential Page 18 of Prior and Concomitant Therapy Prior Therapy All subjects will be instructed to advise the Principal Investigator or delegate of any prescribed medicines, over-the-counter medications, dietary supplements or nutraceuticals that are being used. Medications should not be used for the seven days preceding treatment administration on Day 0 until study completion, except those which have been pre-approved by the Principal Investigator or delegate. Medications, which in the opinion of the Principal Investigator or delegate may interfere with the objectives of the study, whether prescribed or not, should not be taken from seven days prior to dosing until the end of the study Concomitant Therapy The Principal Investigator or delegate must be informed as soon as possible about any medication taken from the time of screening until the end of the study and these will be fully documented in the patient s medical notes and the CRF. In the event that a subject has taken a medication which has not been preapproved, the Principal Investigator or delegate will make a decision to continue or discontinue the subject, based whether the medication may interfere with the objectives of the study. These include drugs that cause photosensitivity or skin pigmentation. Reflecting sunscreens (e.g. containing titanium dioxide or zinc oxide) are permissible during this study and their continued use is advised if recommended by the physician. During the study, contraceptive therapy must not be changed. 5.5 Study Procedures This will be an outpatient study (see flowchart in Appendix 1). Participants will attend the clinic for a total of 5 visits, including the screening visit plus a follow up visit three months after completion of Visit 4. In a subset of participants undergoing photoprovocation, a maximum of 7 clinic visits will be required, including the screening visit Description of Study Days Screening Period CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

22 Clinuvel Inc. Confidential Page 19 of 37 Screening (up to 14 days prior to study commencement) The Principal Investigator or delegate will assess eligibility for the study after the following procedures are performed: Signed, informed consent obtained prior to the performance of any study-specific procedures Review of inclusion and exclusion criteria Demographic information, including sex, date of birth, race and Fitzpatrick skin type Complete medical history Complete the standard questions to obtain details of skin cancer risk factors General physical examination Ophthalmic examination including retinal screening by an ophthalmologist Examination of the skin and oral mucosa by a dermatologist Full body anterior and posterior high resolution photography to provide a baseline, including suspicious, pre-existing skin lesions and sun-damaged fields (see Appendix 2). Vital signs Weight measurement Height measurement Blood sample for clinical laboratory evaluations (chemistry and hematology) Urinalysis specimen taken Serum β-hcg pregnancy test for females Introduction to the use of the diary to record the number and severity of phototoxic reactions Review of concomitant medication use Study period Visit 1 (Day 0) After confirming all inclusion and exclusion criteria have been fully met, the following evaluations will be performed: Vital signs Measurement of quality of life assessment with EPP-QoL and DLQI questionnaires Completion of the baseline EPP questionnaire (see Appendix 4). Pregnancy test (urine dipstick) CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

23 Clinuvel Inc. Confidential Page 20 of 37 Issue patient with study diary In a subset of patients, susceptibility to phototoxic reactions - assessment of minimum symptom dose on the lower back and dorsal surface of hands. Review of adverse events and concomitant medication use Implant administered (after all other evaluations have been completed). Visits 2 and 3 (Days 60 ± 5 and 120 ± 5) The following will be undertaken at these visits unless otherwise specified: Examination of the skin and oral mucosa by a dermatologist Vital signs Measurement of quality of life assessment with EPP-QoL and DLQI questionnaires Blood sample for clinical laboratory evaluations (chemistry and hematology) Urinalysis specimen taken Review of diary for adverse events and concomitant medication use Review of diary for phototoxic reactions Issue patient with new study diary Pregnancy test by urine dipstick prior to administration of the implant In a subset of patients, susceptibility to phototoxic reactions - assessment of minimum symptom dose on the lower back and dorsal surface of hands. Study drug implant administered after all other evaluations have been completed Visits 1b and 2b (Days 30 ± 5 and 90 ± 5) (Only applicable for subset of patients undergoing photoprovocation) Susceptibility to phototoxic reactions - assessment of minimum symptom dose on the lower back and dorsal surface of hands. Visit 4 (Day 180 ± 5 days) The following will be undertaken at these visits unless otherwise specified (please refer to flow chart): Ophthalmic examination including retinal screening by an ophthalmologist Examination of the skin and oral mucosa by a dermatologist General physical examination CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

24 Clinuvel Inc. Confidential Page 21 of 37 Full body anterior and posterior high resolution photography, including suspicious pre-existing skin lesions and sun-damaged fields (see Appendix 2). Vital signs Weight measurement Blood sample for clinical laboratory evaluations (chemistry and hematology) Urinalysis specimen taken Review of diary for adverse events and concomitant medication use Review of diary for phototoxic reactions Measurement of quality of life assessment with EPP-QoL and DLQI questionnaires Pregnancy test by urine dipstick Early termination When a patient s participation in the study is early terminated by either the patient or the Principal Investigator or delegate, the following evaluations should be performed: Ophthalmic examination including retinal screening by an ophthalmologist Examination of the skin and oral mucosa by a dermatologist General physical examination Full body anterior and posterior high resolution photography, including suspicious pre-existing skin lesions and sun-damaged fields (see Appendix 2) Vital signs Weight measurement Blood sample for clinical laboratory evaluations (chemistry and hematology) Urinalysis specimen taken Review of diary for adverse events and concomitant medication use Review of diary for phototoxic reactions Measurement of quality of life assessment with EPP-QoL and DLQI questionnaires. Pregnancy test by urine dipstick CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

25 Clinuvel Inc. Confidential Page 22 of Safety Follow Up Approximately three months after completion of the study, patients will return to the study site for examination of the skin and oral mucosa by a dermatologist. At this follow up visit, patients will complete an end of study EPP questionnaire (see Appendix 4) Study Procedures Flowchart Please refer to Appendix 1 for the full study flowchart Methods of Assessment Assessment of Efficacy Variables Direct sunlight exposure Patients will record exposure times in a study-specific diary. Please refer to Appendix 3 for a copy of the patient diary page for recording reactions to light and time spent outdoors Phototoxic reactions EPP sufferers regularly tolerate pain with Likert scale severity scores of 3 and below without an adverse effect on their lifestyle. Moderate to severe pain (Likert scale scores 4 to 6 and 7 and above, respectively) do interfere with the life of an EPP sufferer and these scores will be used to determine the presence and severity of a phototoxic reaction. A phototoxic reaction will be deemed to have occurred if a reaction results in a patient reporting a Likert scale severity score of 4 and above for one or more consecutive days. The days on which the patient experiences pain as a result of phototoxic reactions (caused by exposure to natural light) will be recorded in a study diary. On each day such a reaction occurs, the patient will score their level of pain using an 11 point Likert Pain Intensity Scale. The total severity of an individual phototoxic reaction will be determined by adding the Likert scale severity scores for all days in an individual phototoxic reaction. The maximum severity of a phototoxic reaction will be determined by the highest daily Likert scale score that occurs during that phototoxic reaction. The number of phototoxic reactions will be determined by counting the number of episodes on which patients report a Likert scale score of 4 or more for one or more consecutive days. CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

26 Clinuvel Inc. Confidential Page 23 of Quality of life measurement The quality of life will be determined using the EPP-QoL and DLQI questionnaire. Both questionnaires will be completed at the site on Days 0, 60, 120 and Photoprovocation (subset of patients) An area of approximately 33 mm in diameter will be irradiated with light filtered to transmit radiation between 400 nm and 650 nm up to a maximum irradiation dose of 300 J/cm 2 using a standardized and calibrated light source. Irradiation from the light source can vary over time so it is calibrated before the test is performed. The time it takes for the patient to first experience symptoms together with the radiation output from the light source is used to calculate the Minimum Symptom Dose. See Appendix 5 for methodology Safety Variables Clinical Laboratory Evaluations A blood sample of approximately 15 ml will be taken for monitoring of safety at Screening, Days 60, 120 and 180, and at Early Termination Visit, if applicable. In addition to blood sampling, a urine sample will be collected for analysis at Screening, Days 60, 120 and 180, and at Early Termination Visit, if applicable. For women of childbearing potential, a pregnancy test will be performed on the serum sample collected at Screening and with dipstick at Days 0, 60, 120 and 180, and at Early Termination Visit, if applicable. The following laboratory tests will be performed using a local laboratory. Hematology Hemoglobin Red Blood Cell Count (RBC) Packed Cell Volume (PCV) Platelets White Blood Cell Count (WBC) Neutrophils Lymphocytes Monocytes Eosinophils Basophils CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

27 Clinuvel Inc. Confidential Page 24 of 37 Biochemistry Sodium Potassium Chloride Glucose Urea Creatinine Alkaline Phosphatase (ALP) Phosphate Total Calcium Albumin Protein Total Bilirubin Gamma Glutamyl Transferase (GGT) Serum Iron Ferritin Transferrin Alanine Aminotransferase (ALT) Aspartate Aminotransferase (AST) Lactate Dehydrogenase (LDH) Creatine Kinase (CK) Glomerular Filtration Rate Total Cholesterol Urinalysis Protein Blood Bilirubin Specific Gravity Glucose Ketones ph Nitrites (Microscopic examination to be undertaken if Dipstick results show any abnormality) All laboratory test results will be reviewed by the Principal Investigator or delegate. The Principal Investigator or delegate will sign and date all laboratory reports and evaluate clinical significance of all values outside the reference range and will document this within the laboratory report. If a laboratory value is outside the reference range and felt to represent a clinically significant change from the baseline value this will be reported as an adverse event on the Adverse Event CRF page. An assessment will be made regarding the relationship of the event to the study drug Physical Examination A general physical examination will be performed at Screening and Day 180, or at Early Termination Visit, if applicable. An ophthalmology examination is part of the general physical examination. Any changes from baseline examination will be evaluated and noted on the Case Report Form. The results of the physical examination at Screening will be classified for each site as normal, abnormal or not done. Changes will be indicated at Day 180, or at Early Termination Visit, if applicable. CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

28 Clinuvel Inc. Confidential Page 25 of 37 In addition, at Screening, any suspicious pre-existing skin lesions and sun damaged fields will be photographed. These will be re-photographed at Day 180, or at Early Termination Visit, if applicable (see Appendix 2) Weight/Height Weight (in kg) will be recorded at Screening, Day 180, or at Early Termination Visit, if applicable. Height (in cm) will also be measured at Screening to allow calculation of BMI Vital Signs Measurements Vital signs (blood pressure, temperature and pulse rate) will be recorded at all visits in a standardized manner, i.e. after the patient has rested in a sitting position for 5 minutes. These will be measured at Screening, Days 60, 120 and 180, or at Early Termination Visit, if applicable Adverse Events An adverse event is defined as any untoward medical event (clinical or laboratory) experienced by a patient during the course of a clinical trial, whether or not it is related to the investigational product. An adverse event may be a symptom, sign, or abnormal finding or test result. Whenever possible, the Principal Investigator or delegate will group together into a single term, signs and symptoms that constitute a single diagnosis. For example, cough, rhinitis and sneezing might be grouped together as "upper respiratory tract infection. Expected phototoxic symptoms due to environmental sun exposure will not be documented as Adverse Events. The Principal Investigator or delegate will monitor each patient closely for the development of adverse events, and any adverse experience spontaneously reported by or elicited from the patient or observed by the Investigators (physician or study staff) from Day 0 onwards will be recorded on the appropriate Adverse Events page of the Case Report Form. Reporting of adverse events by participants will be elicited by nonspecific questions such as Have you noticed any problems? or Do you feel different in any way? Participants will be encouraged to report adverse events at their onset. The Principal Investigator or delegate will record the adverse event(s) on the Case Report Form and provide the date and time of onset, severity, seriousness, relationship to study medication, date of resolution (or the fact that the event is still continuing), action taken, and outcome. A causality assessment will be made for every adverse event. If a laboratory value is outside the normal range, the Principal Investigator or delegate must comment on the findings in the laboratory report. For any clinical laboratory abnormality, the Principal Investigator or delegate will make a judgment as to clinical significance. All clinically significant laboratory abnormalities will be recorded on the Adverse Events page of the CRF. All adverse events CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

29 Clinuvel Inc. Confidential Page 26 of 37 will be followed up in accordance with good clinical practice. Adverse events will be graded for severity as defined below: Mild - The adverse event is transient and easily tolerated by the patient. Specific action is optional. Moderate - The adverse event causes the patient discomfort and interrupts the patient s usual activities. Severe - The adverse event causes considerable interference with the patient s usual activities and may be incapacitating or life-threatening. Outcome of the event must be described as one of the following: Resolved without sequelae Resolved with sequelae Continuing The Principal Investigator or delegate will be asked to document his/her opinion of the relationship of the event to the study drug as follows: None - The event can be readily explained by the patient's underlying medical condition or concomitant therapy and no temporal relationship exists between the study drug and the event. Unlikely - The temporal relationship between the event and the administration of the study drug is uncertain and it is likely that the event can be explained by the patient's medical condition or other therapies. Possible - There is some temporal relationship between the event and the administration of the study drug and the event is unlikely to be explained by the patient's medical condition or other therapies. Probable - The temporal relationship between the administration of the study drug is compelling, and the event cannot be explained by the patient's medical condition or other therapies. Definite The event follows a reasonable temporal sequence from administration of the medication, follows a known or suspected response pattern to the medication, is confirmed by improvement upon stopping or reducing the dosage of the medicine (dechallenge) and reappears upon repeated exposure (rechallenge). Serious Adverse Events A Serious Adverse Event (SAE) is any adverse event occurring at any dose that results in any of the following outcomes: CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

30 Clinuvel Inc. Confidential Page 27 of 37 Death Is life-threatening Requires inpatient hospitalization or a prolongation of an existing hospitalization Results in a persistent or significant disability/incapacity Is a congenital anomaly/birth defect. Important medical events that may not be immediately life threatening, result in death or require hospitalization but may be considered a serious adverse event when, based upon appropriate medical judgment, they may jeopardize the patient or may require medical or surgical intervention to prevent one of the outcomes listed in the definition above. Reporting: Any serious adverse event, including death due to any cause, which occurs during this study will be reported immediately by telephone (by the end of the next business day) to the appropriate Safety Department (telephone number of Clinuvel is (646) or ). In addition to the initial telephone report, all SAEs will be recorded on the Adverse Events page of the CRF, and a Serious Adverse Event form will be completed and sent via facsimile immediately to the appropriate Safety Department (fax number of Clinuvel: (212) or ). All SAEs require telephone notification and a written SAE report within 24 hours. The responsible Principal Investigator or delegate will determine whether the seriousness of the event warrants removal of any patient from the study. The Principal Investigator or delegate will institute appropriate diagnostic and therapeutic measures and keep the patient under observation for as long as is medically indicated. In this study any pre-arranged elective surgery will be excluded as an adverse event. 5.6 Data Quality Assurance Data Collection, Monitoring and Auditing The Principal Investigator and institution will provide direct access to source data/documents and will permit trial-related monitoring, auditing, review by the IEC, and regulatory agency inspections. The Sponsor or its designee will monitor the study in accordance with Good Clinical Practice (GCP). The Clinical Monitor is qualified by training and experience to oversee the conduct of the study. His/her responsibilities include study monitoring (review accuracy and completeness of records, source CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

31 Clinuvel Inc. Confidential Page 28 of 37 document checks), evaluation of study data (drug accountability, communication, and written records), monitoring of center facilities to ensure continued adequacy and adverse event monitoring. The Clinical Monitor maintains regular contact with the investigational center, through telephone contact, communication and on-center visits to ensure that the investigational plan and regulations governing the conduct of clinical trials are followed. These contacts are also to ensure that timely and accurate data will be submitted, that problems with inconsistent and incomplete data are addressed, and that the center facilities and management continue to be adequate for this study. Any questions regarding these matters are addressed with the Clinical Monitor. The Clinical Monitor will evaluate and summarize the findings of each visit in written reports, identify any repeat data problems with the Principal Investigator or delegate, and specify recommendations for the resolution of noted deficiencies. Standardized case report forms (CRF) will be provided for each eligible patient in this study only. Patients who provide written informed consent will be identified by their initials for the purpose of screening. All screening results will be recorded in patient source notes and the relevant patient s initials will be entered onto screening logs, which will be made available for monitoring by Clinuvel. If a patient fails screening tests (and is therefore declared ineligible to participate), the patient will end their involvement in the study, but may be reviewed at a later date for re-consent and re-screening if considered suitable by the Principal Investigator or delegate. This outcome would also be noted on screening logs against the patient s initials. If the patient successfully satisfies all screening tests and is therefore considered eligible to enter the study, a randomization number will be allocated to the eligible patient, which will used to track the patient throughout their involvement in the study. This outcome would also be noted on screening logs. The patient randomization number will be recorded on all pertinent study related documentation. The patient randomization number will consist of the assigned center number and a patient number in sequential order at that study site. All clinical information requested in the protocol will be recorded in the patient s notes and transferred to the CRF following the instructions provided below: All entries will be made using a black ball-point pen, to ensure the clarity of any reproduced copies of the CRF On the CRF and all other trial documentation, signatures or initials must be accompanied by the current date, with the date written by the person signing/initialing the document CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

32 Clinuvel Inc. Confidential Page 29 of 37 Corrections to CRF entries should be made by drawing a single line through the incorrect entry. The correct value(s) should be written in an adjacent space and the correction signed or initialed and dated Incorrect entries must not be obliterated or covered using masking/correction fluid or made illegible in any way A reasonable explanation must be given by the Principal Investigator or delegate for all missing data The Principal Investigator or delegate must sign and date a declaration on the CRF stating his/her responsibility for the quality of all data collected and that the data represent a complete and accurate record of the patient s participation in the trial If corrections are made after review and signature by the Principal Investigator or delegate, he/she will be made aware of the changes and this awareness documented by initialing and dating the changes. Before the study starts the local laboratory will provide a list of reference ranges for all laboratory tests to be undertaken, current laboratory accreditation/certification and details of the method used for quality control. These will be held by the Principal Investigator or delegate and a copy sent to the Clinical Monitor. The CRO performing the data management will be sent relevant details e.g. reference ranges. Any change in the laboratory, its procedures, reference ranges etc. during the study must be notified promptly to the Clinical Monitor. The Clinical Monitor will inform Data Management of these changes. The Clinical Monitor and Principal Investigator or delegate to insure accuracy, completeness, and compliance with the protocol will review all CRFs Database Management and Quality Control The study will be monitored by representatives of Clinuvel Inc, or its delegated representative, as frequently as is necessary to determine that data recording and protocol adherence are satisfactory. The CRFs and related source documents will be reviewed in detail by the representatives at each study visit, and identified discrepancies will be resolved. Data will be entered into a study-specific database. Any data entry discrepancies will be reviewed against the hard-copy CRF and corrected on-line. After completion of the entry process, computer logic CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

33 Clinuvel Inc. Confidential Page 30 of 37 checks will be run to check for such items as inconsistent study dates, outlying laboratory values, and any missing data; and any necessary corrections will be made to the database and documented. The detailed procedures for data entry, data coding, cleaning and electronic data transfer will be provided in a Data Management Plan. 5.7 Statistical Methods and Determination of Sample Size Statistical and Analytical Plans Formal statistical and analytical plans will be prepared prior to database lock and statistical analysis. The analysis will be performed after all data from Visit 4 (Day 180) or Early Termination are available. The analysis will be conducted ahead of the Safety Follow Up visit Efficacy Assessment Specification of Primary Efficacy Endpoint The primary efficacy endpoint is the duration of time (hours) spent in direct sunlight between 10:00 and 18:00 hours on days when no pain was experienced (pain score of 0) Specification of Secondary Efficacy Endpoint Combined sun exposure and phototoxic pain Duration of sun exposure (hours in direct sunlight) between 10:00 and 18:00 hours on days when no pain or mild pain was experienced (pain scores of 0-3). Sun exposure Duration of sun exposure (hours in direct sunlight) between 10:00 and 18:00 during the study. Quality of life Quality of life assessment score according to the DLQI and EPP-QoL questionnaires. Photoprovocation (in a subset of patients) The minimum symptom dose following photoprovocation on the lower back and dorsal surface of the hand, determined using the irradiation dose of the light source and the time to first development of symptoms at the site of photoprovocation. Phototoxicity phototoxic pain The maximum and total pain severity scores (Likert scale) for phototoxic episodes. The number of phototoxic episodes during the study. CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

34 Clinuvel Inc. Confidential Page 31 of Safety Assessment Specification of Primary Safety Endpoints The primary safety endpoint will be the type and incidence of treatment emergent adverse events Specification of Secondary Safety Endpoints The secondary safety endpoints will be: Physical examination changes from Screening. Changes in blood pressure and heart rate from Screening to all subsequent visits. Changes in clinical chemistry, hematology and urinalysis parameters from Screening to all subsequent visits Sample Size Analysis of data from the CUV029 and CUV030 studies demonstrated that a significant difference in the primary endpoint of the study could be detected with approximately 75 patients Analysis Plan Safety Population The Safety Population will include all enrolled participants. Participants screened but not enrolled will be shown in separate listings. ITT Population The ITT population will include all treated participants, who provide at least one post dose efficacy assessment. This will be the main population for all efficacy analyses Handling of Missing and Incomplete Data Analyses will be performed on the available data. There will be no imputation for missing efficacy data points with the following exceptions. Where a patient has completed a daily diary entry indicating that they have not had a reaction to light today but have not marked a pain severity score, a severity score of zero will be imputed. In the event that a patient has not marked the box indicating that they have spent time outdoors today but have shaded one or more of the time period spent outdoors boxes, the times CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

35 Clinuvel Inc. Confidential Page 32 of 37 indicate will be used in the analysis. Please refer to Appendix 3 for a copy of the patient diary page for recording reactions to light and time spent outdoors Demographic and Initial Characteristics Demographic and baseline characteristics will be summarized. Where measurements have been taken more than once prior to the scheduled baseline visit, baseline measurements will be taken as the last available data measured prior to this time point. If the baseline measurement is missing but there is a prior measurement recorded, this value will be carried forward and used as the baseline measurement Primary Efficacy Analysis Combined sun exposure and phototoxic pain The primary efficacy endpoint is the duration of time (hours) spent in direct sunlight between 10:00 and 18:00 hours on days when no pain was experienced (pain score of 0). The mean daily duration in direct sunlight exposure will be calculated for each patient and compared between the treatment arms using a Kruskal-Wallis test with a significance level of p<0.05. H 0 : there is no difference between the treatment arms in the time spent in direct sunlight on days when no phototoxic pain was reported Secondary Efficacy Analyses Combined sun exposure and phototoxic pain The mean daily duration of sun exposure (hours in direct sunlight) between 10:00 and 18:00 hours on days when no pain or mild pain was experienced (pain scores of 0-3) will be calculated for each patient and compared between the treatment arms using the Kruskal-Wallis test. Sun exposure The mean daily duration of sun exposure (hours in direct sunlight) between 10:00 and 18:00 during the study will be calculated for each patient and compared between the treatment arms using the Kruskal- Wallis test. Quality of life A between groups comparison of the change from baseline to each time point in the quality of life assessment scores (DLQI and EPP-QoL questionnaires) will be performed using the Kruskal-Wallis test. CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

36 Clinuvel Inc. Confidential Page 33 of 37 Photoprovocation (in a subset of patients) A between groups comparison of the change from baseline to each time point in the minimum symptom dose following photoprovocation on the lower back and dorsal surface of the hand will be performed using the Kruskal-Wallis test. Phototoxicity phototoxic pain The maximum and total pain severity scores (Likert scale) for phototoxic episodes. The number of phototoxic episodes per subject reported by the patient during the study. A between groups comparison of the scores for each of the above parameters will be performed using the Kruskal-Wallis test Safety Descriptive methods will be used to summarize the safety data. These will be based upon the safety population Adverse Events All adverse events, including non-treatment emergent events, will be listed. A treatment emergent adverse event will be: An event that was not present prior to or on the day of the first study medication administration but was present after study medication was administered. An event that was present prior to first administration of study medication and continued to occur after the administration of the first dose at an increased level of severity. An event that was present prior to administration of study medication and was documented as completely resolved and re-emerged after the administration of the first dose. The MedDRA adverse event dictionary will be used to map verbatim adverse event terms to preferred terms and body systems. The number of participants with treatment-emergent adverse events will be summarized by preferred term and body system for each treatment group. Treatment-emergent events will be further summarized by intensity, seriousness and relationship to study medication. The number of participants who early terminate treatment due to adverse events related to study medication will be tabulated. Summaries of the incidence of toxicities will be prepared, as appropriate. CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

37 Clinuvel Inc. Confidential Page 34 of 37 Serious adverse events and adverse events of special interest will be listed individually. If a serious adverse event occurs prior to the first dose of the study medication, this will be noted in the study report Clinical Laboratory Data Laboratory data will be summarized by descriptive statistics by treatment and assessment including changes from screening to each visit. Additionally shift tables with respect to the normal ranges will be generated from screening to each visit. Clinically significant laboratory results will be listed separately. All summaries of clinical laboratory data will include scheduled data collection points only Other Clinical Data Analyses The duration of study drug exposure and the number of participants exposed will be evaluated descriptively. Separate summaries with the detailed descriptive statistics will be generated and assessment for both the original values and for changes to baseline for vital signs, physical examination and body weight. Changes in physical examination and concomitant medications will be listed and summarized by frequency tables, if appropriate. 5.8 Early Termination of the Study The study may be terminated if the Sponsor, Investigator, or Study Monitor discovers conditions arising during the course of the study which indicate that the clinical investigation should be halted. The study may be terminated after appropriate consultation and discussion. Conditions that may warrant study termination include, but are not limited to, the discovery of a significant, unexpected and unacceptable risk to the participants, failure of the Investigator to enroll participants at an acceptable rate, insufficient adherence to the protocol requirements, completion of study objectives, or at the discretion of the Sponsor. 6.0 STUDY REPORT, PUBLICATION POLICY & STUDY DOCUMENTATION ARCHIVING CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

38 Clinuvel Inc. Confidential Page 35 of 37 Investigators are required to maintain all study documentation, including copies of CRFs, Informed Consents, and adequate records for the receipt and disposition of study medications, for a period of 15 years following study close-out. The Principal Investigator will permit study data to be accessible to the Monitor, Sponsor, or other authorized representatives of the Sponsor and Regulatory Agency. A file for each patient will be maintained that includes the signed Informed Consent form and copies of all source documentation related to that patient. The Principal Investigator will ensure the availability of the source documents from which the information on the CRF is derived. All information provided to the Principal Investigator (and study site staff) dealing with this study drug or the methodologies used in the protocol, as well as information obtained during the course of the study will be regarded as strictly confidential and proprietary to the Sponsor ("Proprietary Information"). The Investigator agrees not to disclose any information supplied by the Sponsor in any way without written permission as outlined in the Confidentiality section of this protocol. For the purposes of this section, "Investigator" includes, but is not limited to, the Principal Investigator and/or his/her agents, designees, sub-investigators, or other individuals involved in the running, administration, or collection/handling of participants/data for this study. Any formal presentation or publication of data from this trial will be considered as a joint publication by the Investigators and the appropriate personnel at Clinuvel Inc. Authorship will be determined by the Principal Investigator. It is mandatory that the first publication is based on data analyzed as stipulated in the protocol statistical section, and not by the Investigators themselves. Participating Investigators agree not to present data before the full, initial publication, unless formally agreed to by all other Investigators and Clinuvel Inc. Clinuvel Inc must receive copies of any intended communication in advance of publication, at least 30 working days for an abstract or oral presentation and 45 working days for a journal submission. Clinuvel Inc will review the communications for accuracy, thus avoiding potential discrepancies with submissions to the Health authorities, verify that confidential information is not inadvertently divulged, and provide any relevant supplementary information. 7.0 STUDY TIMETABLE Projected starting date (first-patient-in [FPI]): April/May 2012 CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

39 Clinuvel Inc. Confidential Page 36 of 37 Projected number of patients: Up to 75 Projected completion of patient accrual (last-patient-in [LPI]): June 2012 Patient study end date (last-patient-last-visit [LPLV]) December 2012 CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

40 Clinuvel Inc. Confidential Page 37 of REFERENCES 1. Lecha M. Erythropoietic porphyria. Photodermatol Photoimmunol Photomed 2003;19: Murphy GM. Diagnosis and management of the erythropoietic porphyrias. Dermatologic Therapy 2003; 16: Todd DJ. Clinical implications of the molecular biology of erythropoietic porphyria. J. Eur. Acad. Dermatol. Venerol 1998; 11: Schneider-Yin X, Gouya L, Meier-Weinand A et al. New insights into the pathogenesis of erythropoietic porphyria and their impact on patient care. Eur J Pediatr. 2000; 159: Mathews-Roth MM, Rosner B, Benfell K and Roberts JE. A double-blind study of cysteine photoprotection in erythropoietic porphyria. Photodermatol Photoimmunol Photomed 1994;10: Thunell S, Harper P, Brun A. Porphyrinism, porphyrin metabolism and porphyrias. IV. Pathophysiology of erythropoietic porphyria diagnosis, care and monitoring of the patient. Scand J Clin Lab Invest 2000; 60: Pathak MA. Melanin: Its Role In Human Protection., pp (Valdenmar Publishing Co.,1995) 8. Kaidbey KH, Agin PP, Sayre RM, Kligman AM. Photoprotection by melanin--a comparison of black and Caucasian skin. J Am Acad Dermatol 1979; 1: , Bustamante J, Bredeston L, Malanga G, Mordoh J. Role of melanin as a scavenger of active oxygen species. Pigment Cell Res. 1993; 6: Kollias N, Sayre RM, Zeise L, Chedekel MR. Photoprotection by melanin. J Photochem Photobiol 1991; B 9: De L. Castrucci AM., Hadley ME., Sawyer TK. and Hruby VJ. Synthesis and studies of superpotent melanotropins resistant to enzyme degradation. Comp. Biochem. Physiol. 78B: ; Sawyer TK, Sanfilippo PJ, Hruby VJ, Engel MH., Heward CB., Burnett JB and Hadley ME. 4- Norleucine, 7D-phenylalanine-α-melanocyte stimulating hormone: a highly potent -α-melanotropin with ultraprolonged biological activity. Proc. Nat. Acad. Sci. USA 77: ; Harms J, Lautenschlager S, Minder C and Minder E., An α-melanocyte-stimulating hormone analogue in erythropoietic protoporphyria. N Engl J Med 2009; Jan 15, Clinical Study Reports for CUV017, CUV029 and CUV030. (Data on file) CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

41 Clinuvel Inc. Confidential Page 38 of APPENDICES APPENDIX 1: STUDY FLOWCHART Study Procedure Informed consent taken Screening Visit 1 Visit 1b Visit 2 Visit 2b Visit 3 Visit 4 (Day Up to ) or Early Day 0 Day 30 Day 60 Day 90 Day 120 days Termination X Inclusion and exclusion criteria review X X Demographic information collected X Medical history taken Skin cancer risk factor questions completed General physical examination including ophthalmic examination Skin and oral mucosal examination by a dermatologist X X X X X X X Full body photography X X Vital signs X X X X X Weight / height measurement X 1 X Hematology and blood chemistry X X X X Urinalysis X X X X X Pregnancy test (serum β-hcg) Quality of life assessment (DLQI and EPP- QoL) Introduction to use of diary X X X X X X Issue patient with study diary X X X Pregnancy test (urine dipstick) X 2 X 2 X 2 X Photoprovocation X 3 X X 3 X X 3 Implant insertion X X X Adverse events review X X X X Concomitant medication review X X X X X Phototoxic reaction review X X X X 1 Height will be measured at Screening only to allow calculation of BMI X 2 Implant insertion only after confirmation that female patients are not pregnant X 3 Photoprovocation prior to implant administration (in a subset of patients only) CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

42 Clinuvel Inc. Confidential Page 39 of 37 APPENDIX 2: MEDICAL PHOTOGRAPHY Instructions: Hospital Medical photography units will not be used for this study. Principal Investigators or delegate will be required to take photographs using a standard 5 mega pixel (minimal) digital camera. At the protocol defined intervals the following photographs are to be taken: One full body photograph anterior and posterior views of the subject (clothing removed in line with standard medical practice) at Screening and Day 180 or Early Termination. Any suspicious lesions and/or hyperpigmented areas are to be photographed and monitored throughout the course of the study All photographs are required to be printed on standard A4 paper as well as stored on an electronic disc. In addition, they must all contain the subject s initials (if local regulations permit), study number and DOB. The date of photography and corresponding visit must also be documented on every photograph. CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

43 Clinuvel Inc. Confidential Page 40 of 37 APPENDIX 3: PATIENT DIARY (EXTRACT) The following is an extract from a patient diary. It shows the sections of the diary for recording daily phototoxicity and duration of sun exposure. DATE: (DD/MMM/YYYY) 1. EPP Monitoring 1.1 Have you experienced any reactions to light today? Yes No 1.2 If yes, please indicate on the scale below how bad your pain was from this reaction: No Pain Mild Moderate Severe Worst Imaginable 2. Time Spent Outdoors 2.1 Did you spend any time outdoors today? Yes No 2.2 If yes, please enter the time period that you were in direct sunlight. (Each box represents 15 minutes) 10:00 11:00 12:00 13:00 14:00 15:00 16:00 17:00 18: If yes, please enter the time period that you were in the shade. (Each box represents 15 minutes) 10:00 11:00 12:00 13:00 14:00 15:00 16:00 17:00 18:00 CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

44 Clinuvel Inc. Confidential Page 41 of 37 APPENDIX 4: EPP QUESTIONNAIRE BASELINE QUESTIONNAIRE (BEFORE DRUG ADMINISTERED) You are allowed to choose more than one answer: 1. Does EPP affect your life negatively A) Yes B) No C) Don t know 2. Which of the activities are inconceivable and impossible for you to engage in due to your disorder: A) Gardening B) Walking from parking lot to shopping mall C) Outdoor sports (tennis, running, baseball) D) Biking 3. Which of the measures do you take before going outside A) Checking the weather forecast B) Checking the time of day C) Checking the route to the destination D) Putting on for protective clothing 4. Which seasons do affect you most A) All seasons can affect me B) Spring C) Summer D) Winter CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

45 Clinuvel Inc. Confidential Page 42 of Which of the protective clothing do you wear if you are uncertain if the light is going to affect your skin A) Hat B) Balaclava C) Long sleeves D) Long pants E) Socks 6. Which of the activities do you avoid A) Beach walking B) Swimming C) Skiing D) Horse riding E) Mountaineering F) Other, please fill in.. 7. How does the disorder affect your life A) Affects my choice of work B) Affects my social contacts C) Affects my family life D) Affects my choice of partner E) Affects my quality of life F) Does not affect my life at all CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

46 Clinuvel Inc. Confidential Page 43 of How does the disorder affect your inner life A) Affects my confidence B) Makes me anxious C) Forces me to live a solitary life D) Makes me depressed E) Makes me angry F) Makes me disappointed about life G) Did not affect my inner life at all 9. How has the disease affected your past A) As a child I was restricted in my activities B) As a child I was isolated, few friends C) I was mostly indoors D) I had problems at school E) I couldn t play sports F) Had no effect at all 10. How has the disease affected your professional career A) Restricted my choices at college B) Restricted my choices at university C) Restricted my choices in my professional development D) Made me change my profession, occupation E) Could only do only certain jobs F) Did not affect my professional career at all CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

47 Clinuvel Inc. Confidential Page 44 of State which of the aspects impacts you most (one or more answers possible) A) Inability to explain the intensity of pain B) Inability to participate in normal life C) Inability to find a treatment D) Restricted in my choices 12. How has the disorder affected your immediate family in the past A) Not at all B) Some C) Much CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

48 Clinuvel Inc. Confidential Page 45 of 37 QUESTIONNAIRE (AFTER DRUG ADMINISTRATION) 1. Which differences have you noticed since you received the drug A) None B) Less sensitivity (phototoxicity) of the skin C) More sensitivity (phototoxicity) of the skin D) Less pain E) More pain F) Am able to tolerate light more 2. Which aspect characterizes best your attitude and outlook since receiving the drug A) Less anxious to experience skin symptoms B) More anxious to experience skin symptoms C) Less inclined to go outdoors D) More inclined to go outdoors 3. Since receiving the drug, how do you assess your ability and willingness to go outdoors A) No difference B) More confident to expose outdoors C) Sceptical about the ability to go outdoors D) Will gradually test myself to see whether symptoms occur 4. Which activities are you able to engage in, experience, participate A) Gardening B) Walking from parking lot to shopping mall C) Outdoor sports D) Biking CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

49 Clinuvel Inc. Confidential Page 46 of Which protective clothing are you using since receiving the drug A) Hat B) Balaclava COAT C) Long sleeves D) Long pants E) Socks 6. Which of the activities have you tried since receiving the drug A) Beach walking B) Swimming C) Skiing D) Horse riding E) Mountaineering F) Other, please fill in.. G) None 7. How do you best summarize your experience since receiving the drug A) I have less anxiety B) I have more anxiety C) I feel more confident D) I feel less confident E) None of the above CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

50 Clinuvel Inc. Confidential Page 47 of How has the treatment affected your life A) No improvement B) Much improvement C) Dramatic improvement 9. How do you best characterize your experience after receiving the drug A) I would request this drug all year B) I would request this drug during spring and summer C) I am unsure D) I would not request the drug 10. Since receiving the drug, I expose myself A) Less to outdoors conditions B) More to outdoors conditions C) Unchanged to my previous life Plus the following questionnaire CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

51 Clinuvel Inc. Confidential Page 48 of Over the last two months, how has your well-being been affected by EPP? Compared to the same period last year I have been Over the last two months, how much has your EPP symptoms influenced your capacity to go to work or school? Compared to the same period last year Over the last two months, how often did you feel the need to seek out shade? Compared to the same period last year Over the last two months, how much has EPP influenced the choice of the clothes you wear on a sunny day? Compared to the same period last year Over the last two months, how often did you feel you were at risk of developing EPP symptoms? Compared to the same period last year Over the last two months, how much has EPP affected any social or leisure activities on a sunny day? Compared to the same period last year Over the last two months, how much has EPP influenced your need to plan before leaving your house? Compared to the same period last year Over the last two months, has EPP limited your ability to undertake activities in a spontaneous manner? Compared to the same period last year Over the last two months, how often have you not worn protective clothing on a sunny day? Compared to the same period last year... Much better Better Same Worse Very much A lot A little Not at all More than usual Same as usual Less than usual Much less than usual Very much A lot A little Not at all Very often Often A little Not at all Very much A lot A little Not at all Very much A lot A little Not at all Very much A lot A little Not at all Very often Often Not often Not at all CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

52 Clinuvel Inc. Confidential Page 49 of Over the last two months, has EPP limited your ability to undertake activities in a spontaneous manner? Compared to the same period last year Over the last two months, how often have you not worn protective clothing on a sunny day? Compared to the same period last year Over the last two months, how much has EPP interfered with your going shopping or looking after your home (indoors and outdoors) or garden on a sunny day? Compared to the same period last year Over the last two months, how much has EPP prevented you from attending outdoor social activities with family and friends? Compared to the same period last year Over the last two months, how much has EPP limited your amount of outdoor activities? Compared to the same period last year Over the last two months, how often did you experience typical EPP skin complaints? Compared to the same period last year Over the last two months, how much has your quality of life improved? Compared to the same period last year Over the last two months, how much has EPP influenced your method of transportation or seating preference during transportation? Compared to the same period last year How much time (minutes) can you now spend in direct sunlight? 19. How much time (minutes) were you able to spend in direct sunlight during the same period last year? Very much A lot A little Not at all Very often Often Not often Not at all Very much A lot A little Not at all Very much A lot A little Not at all Very much A lot A little Not at all Very often Often Not often Not at all Very much A lot A little Not at all Very much A lot A little Not at all minutes minutes CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

53 Clinuvel Inc. Confidential Page 50 of 37 APPENDIX 5: PHOTOPROVOCATION METHODOLOGY 1. Purpose: Photoprovocation in Patients with EPP Erythropoietic protoporphyria (EPP) is a genetic disorder in which impaired ferrochelatase activity results in the accumulation of its substrate, protoporphyrin IX (PPIX). There are two main clinical manifestations of elevated PPIX: cutaneous phototoxicity and hepatobiliary disease. Phototoxicity is the more common of these and it usually presents in early childhood as intolerance to sun-exposure with patients experiencing severe burning pain in the skin most often on the face and hands. In order to assess the efficacy of afamelanotide in EPP, a subset of patients enrolled in the CUV039 study will undergo testing with a standardized light source. The procedure described here will be used to determine the minimal symptom dose (MSD). The efficacy analysis will compare the MSD in patients receiving afamelanotide treatment to those receiving placebo. Minimal symptom dose (MSD) To account for the variable description of the sensations described by EPP patients in response to phototesting or to light exposure, the outcome measure will be the minimal irradiation energy dose required to produce the earliest prodromal symptom (MSD), as described by the patient after photoprovocation with a broad spectrum light source (wavelength 400 to 650nm). 2. Equipment The apparatus used for photoprovocation has been constructed by Dr Chris Edwards. It consists of the following main components: 300 Watt xenon arc lamp light source Filter system: broad band (400 to 650nm) Figure A shows a diagrammatic representation of the apparatus. CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

54 Clinuvel Inc. Confidential Page 51 of 37 Shutter Collimator Water filter Filter holder Light tube Arc Lamp Beam turner Base Plate Support Adjustable light tube Figure A: Photoprovocation apparatus. The light is passed through a collimator and cooled by a water filter (wavelength cut off at 700nm). The use of a longpass filter that cuts off sharply the ultraviolet irradiation (< 400nm) allows only visible light to pass. A beam turner directs the light onto a selected area of approx. 33 mm in diameter of the patient s skin, which is then irradiated using an adjustable light tube. The areas typically chosen are the patient s lower back and dorsal surface of hand. The addition of a short pass filter (blocks wavelengths > 650nm) results in a sharp cut-on/cutoff broadband light spectrum from nm. The equipment is spectrally characterised and pre-calibrated using a spectroradiometer (measuring irradiation rates). For correct operation, and to account for variation in the lamp output, it is necessary to ensure that the output, measured as mw/cm 2, is within acceptance limits (within 10% of initial calibrated value established on installation visit) on each test day before photoprovocation procedures begin. Irradiation rate will be measured using the thermopile detector. 3. Methodology The minimal irradiation energy dose required to produce the earliest perceived symptom (MSD nm ) as determined by the EPP patient should be assessed on visit days 0, 30, 60, 90, 120 of the clinical study. Each test day an area of approximately 33mm in diameter (defined by the adjustable light tube touching patient s skin; see above) of the lower back and the dorsal surface of the hand should be exposed to the broadband light spectrum ( nm). CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

55 Clinuvel Inc. Confidential Page 52 of 37 The time of irradiation is limited by the time the patient feels the first symptom of discomfort. A maximum dose of 300J/cm 2 should be applied. Exposure time determines the doses of irradiation. The MSD nm is the lowest irradiation dose resulting in a symptom as described by the patient (pain, burning, etc). Figure B shows an overview of the procedure. For methodology compliance, at each test day, a different skin area must be exposed: On patient s lower back, irradiate from left to right according visit chronology. On the dorsal surface of hands, the right and left hand should alternately be exposed on each test day (start with left hand). Please write a note in the patient s medical source data which skin area of the lower back and which hand was exposed to the light source to ensure that each irradiation is to previously unexposed skin (naïve skin). Figure B: Methodology of Photoprovocation. 3.1 Risk factors to be considered During the photoprovocation procedure, the patient should not be exposed to an irradiation dose higher than 300 Joule/cm 2 to avoid potential burning. CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

56 Clinuvel Inc. Confidential Page 53 of Data recording Results are recorded at each test visit in the patient medical source data and transferred to the Case Report Form (CRF). All data must be recorded in the CRF and be available for Clinuvel monitoring by the assigned clinical research associate. On day 0, the first type of discomfort (e.g. burning), as determined by the patient, should be recorded by the operator (see chapter 6). In addition, the MSD nm has to be recorded. This irradiation dose will be measured as time of application of the calibrated intensity irradiation source and calculated with help of the supplied case record form. On the following test days, the MSD nm must be based on earliest symptom described by the patient on day Operating time frame For each patient, a maximum time of 40 minutes on each testing day should be taken into account for photoprovocation (2 measurements). 6. Operators Photoprovocation procedure should be performed by a qualified clinical study site staff member (investigator, study nurse) who was trained and instructed by Clinuvel. The source data should be recorded by the study investigator, in the patient s medical notes. CUV039: Multicentre Phase III EPP Study V 1: March 16, 2012

57 A Phase III, Multicentre, Double-Blind, Randomized, Placebo- Controlled Study to Confirm the Safety and Efficacy of Subcutaneous Bioresorbable Afamelanotide Implants in Patients with Erythropoietic Protoporphyria (EPP). [Short Title: Multicentre Phase III EPP Study 3] Protocol No: CUV039 Version 4: June 17, 2013 SPONSOR 40 Worth Street, Level 10 New York, NY USA (646) (Phone) (646) (Fax) Clinuvel Pharmaceuticals Limited Level 14, 190 Queen Street Melbourne, Victoria 3000 Australia (Phone) (Fax) This study will be conducted in compliance with Good Clinical Practices (GCP) and ICH guidelines, and all patient study documents will be archived by Clinuvel Pharmaceuticals Limited. CONFIDENTIAL Part or all of the information in this protocol may be unpublished material. Accordingly, this protocol is to be treated as confidential and restricted to its intended use. If any portion of this material is required for purposes of publication, authorization must be obtained from Clinuvel Pharmaceuticals Limited and must not be disclosed or used except as authorized in writing by Clinuvel Pharmaceuticals Limited. This material is the property of Clinuvel Pharmaceuticals Limited and must not be disclosed or used except as authorized in writing by Clinuvel Pharmaceuticals Limited. CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

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59 Clinuvel Inc. Confidential Page 2 of 56 PROTOCOL SYNOPSIS Name of company: Clinuvel Inc. Name of finished product: Afamelanotide Name of active ingredient: Nle 4 -D-Phe 7 - -MSH Title of study: A Phase III, Multicentre, Double-Blind, Randomized, Placebo-Controlled Study to Confirm the Safety and Efficacy of Subcutaneous Bioresorbable Afamelanotide Implants in Patients with Erythropoietic Protoporphyria (EPP) Study number: CUV039 Phase of development: III Study period: Approximately 8 months at each study center (including a 2 month recruitment period), plus 6 months follow-up period. Objectives: Primary objectives Determine whether afamelanotide can enable EPP patients to expose themselves to sunlight without incurring pain and phototoxic reactions. Secondary objectives Determine whether afamelanotide can: improve the quality of life of EPP patients reduce the susceptibility to provocation with a standardized light source (minimum symptom dose) in patients with EPP Evaluate the safety and tolerability of afamelanotide implants by measuring TEAEs in patients with EPP and investigate the reversibility of afamelanotide-induced increase in dermal pigmentation. Methodology: This is a randomized placebo-controlled study to be conducted in two parallel study arms for a six month period (three doses). Between 75 and 100 eligible patients will be enrolled. To determine eligibility for study inclusion, patients will undergo a screening evaluation up to 14 days prior to commencement. Patients will receive afamelanotide (16 mg implants) or placebo according to the following dosing regimen: - Group A will be administered afamelanotide implants on Days 0, 60 and 120, or - Group B will be administered placebo implants on Days 0, 60 and 120. The number and severity of phototoxic reactions, the type and duration of sun exposure, treatment-emergent adverse events and the use of concomitant medication will be recorded by patients in study diaries between Days 0 and 180. Quality of life will be measured using the DLQI and EPP-QoL questionnaires at Days 0, 60, 120 and 180. Participants will visit the clinic on Days 60, 120 and 180 for assessments of adverse events. All patients will have an electrocardiogram (EKG) performed at each study visit (from Day 60 onwards). A subset of patients will be photoprovoked on the lower back and dorsal surface of the hand and the minimal symptom dose (MSD) will be determined on Days 0, 30, 60, 90 and 120. CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

60 Clinuvel Inc. Confidential Page 3 of 56 Six months after completion of the efficacy assessment (Day 360), patients will return to the study site for a full safety assessment, including an evaluation of the reversibility of pigmentation. At this time an additional quality of life questionnaire will be administered, an inventory of activities taken and an EKG will be performed. No. of participants planned: participants in total. Treatment: Afamelanotide (16 mg implants). Diagnosis and main criteria for entry: To be eligible to enter the study, patients must meet the following inclusion criteria: - Male or female subjects with characteristic symptoms of EPP phototoxicity and a biochemically-confirmed diagnosis of EPP. - Aged 18 years old and above (inclusive). - Able to understand and sign the written Informed Consent Form. - Willing to take precautions to prevent pregnancy until completion of the study (Day 180). To be eligible to enter the study, patients must not meet any of the following exclusion criteria: - Any allergy to afamelanotide or the polymer contained in the implant or to lidocaine or other local anesthetic to be used during the administration of the study medication - EPP patients with significant hepatic involvement - Current Bowen s disease, basal cell carcinoma, squamous cell carcinoma, or other malignant or premalignant skin lesions. - Personal history of melanoma or dysplastic nevus syndrome. - Any other photodermatosis such as PLE, AP, DLE, CAD or SU. - Any evidence of clinically significant organ dysfunction or any clinically significant deviation from normal in the clinical or laboratory determinations. - Acute history of drug or alcohol abuse (in the last 6 months). - Patient assessed as not suitable for the study in the opinion of the Principal Investigator or delegate (e.g. noncompliance history, allergic to local anesthetics, faints when given injections or giving blood). - Participation in a clinical trial for an investigational agent within 30 days prior to the screening visit. - Prior and concomitant therapy with medications which may interfere with the objectives of the study, including drugs that cause photosensitivity or skin pigmentation. - Female who is pregnant (confirmed by positive serum β-hcg pregnancy test prior to baseline) or lactating. - Females of child-bearing potential (pre-menopausal, not surgically sterile) not using adequate contraceptive measures (i.e. oral contraceptives, diaphragm plus spermicide, intrauterine device). Test product: Afamelanotide (16 mg/implant) contained in a poly(d,l-lactide-co-glycolide) implant core. CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

61 Clinuvel Inc. Confidential Page 4 of 56 Dose: Release of 16 mg of afamelanotide over 7 to 10 days Mode of administration: Subcutaneous implantation Reference therapy: Poly(D,L-lactide-co-glycolide) implants. Criteria for evaluation: Efficacy Endpoints: Primary: Duration of direct sunlight exposure between 10:00 and 18:00 hours on days when no pain was experienced (Likert score of 0). Secondary: Combined sun exposure and phototoxic pain Duration of direct sunlight exposure between 10:00 and 18:00 hours on days when no or mild pain was experienced (Likert scores of 0 to 3). Duration of direct sunlight exposure between 10:00 and 15:00 hours on days when no pain was experienced (Likert score of 0). Sun exposure Duration of direct sunlight exposure between 10:00 and 18:00 hours during the study. Quality of life Assessed by the DLQI and EPP-QoL measured at baseline and on Days 60, 120 and 180. Photoprovocation A subset of patients will be photoprovoked on the lower back and dorsal surface of the hand to determine the minimum symptom dose on Days 0, 30, 60, 90 and 120. Phototoxicity phototoxic pain The maximum and total pain severity scores (Likert scale) for phototoxic episodes. The number of phototoxic episodes reported from Day 0 to Day 180. Safety and Tolerability Endpoints: Treatment-emergent adverse events (coded as MedDRA Preferred Terms). Changes in hematology, serum chemistry, urinalysis, physical examination and vital sign measurements from Screening to Study Days 60, 120, 180, and at Early Termination Visit, if applicable and significant abnormalities identified in EKG. Statistical Methods: Efficacy analyses: The primary efficacy endpoint of this study is: - The sunlight exposure for days without pain is calculated for each patient as the mean duration of daily direct sunlight exposure between 10:00 and 18:00 hours on study days when patients report not experiencing phototoxicity-associated pain (Likert score of 0). H 0 : there is no difference in the duration of sunlight exposure on days without pain between active and placebo groups. The difference between the groups will be assessed using the Kruskal-Wallis test. Secondary efficacy endpoints: Combined sun exposure and phototoxic pain CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

62 Clinuvel Inc. Confidential Page 5 of 56 The difference in the patient s average daily duration of direct sunlight exposure between 10:00 and 18:00 hours on days when no or mild pain was experienced (Likert scores of 0 to 3) between the treatment groups will be assessed using the Kruskal-Wallis test. The difference in the patient s average daily duration of direct sunlight exposure between 10:00 and 15:00 hours on days when no pain was experienced (Likert score of 0) between the treatment groups will be assessed using the Kruskal-Wallis test. Sun exposure The difference in average daily duration of direct sunlight exposure between 10:00 and 18:00 hours during the study between the groups will be assessed using the Kruskal-Wallis test. Quality of life The difference in quality of life as assessed by the DLQI and EPP-QoL measured at baseline and on Days 60, 120 and 180 between the groups will be assessed using the Kruskal-Wallis test. Photoprovocation A subset of patients will be photoprovoked on the lower back and dorsal surface of the hand to determine the minimum symptom dose on Days 0, 30, 60, 90 and 120. The difference between the groups in changes from baseline will be assessed using the Kruskal-Wallis test. Phototoxicity phototoxic pain - The maximum and total pain severity scores (Likert scale) for phototoxic episodes. - The number of phototoxic episodes reported from Day 0 to Day 180. The differences between the median results for the treatment groups will be assessed using the Kuuskal-Wallis test. Safety Analyses: The number of participants with treatment-emergent adverse events (TEAEs, including and clinically significant changes in laboratory parameters) will be summarized by MedDRA preferred term and body system for each treatment group. TEAEs will be further summarized by intensity, seriousness, outcome and relationship to study drug. CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

63 Clinuvel Inc. Confidential Page 6 of 56 TABLE OF CONTENTS Page No. SIGNATURES OF AGREEMENT FOR PROTOCOL AND AMENDMENTS... 1 PROTOCOL SYNOPSIS... 2 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ETHICS Institutional Review Board (IRB) Ethical Conduct of the Study Participant Information and Informed Consent Protocol Amendments Confidentiality STUDY PERSONNEL AND STUDY ADMINISTRATION INTRODUCTION AND STUDY RATIONALE STUDY OBJECTIVES Primary Objective Secondary Objectives INVESTIGATIONAL PLAN Overall Design and Plan of the Study Selection of Study Population Inclusion Criteria Exclusion Criteria Withdrawals and Replacement of Participants Study Medication Description of Study Medication Method of Assigning Participants to Treatment Group Dosage and Administration of Study Medication Packaging and Labeling of Study Medication Storage and Accountability Compliance CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

64 Clinuvel Inc. Confidential Page 7 of Prior and Concomitant Therapy Prior Therapy Concomitant Therapy Study Procedures Description of Study Days Study Procedures Flowchart Methods of Assessment Data Quality Assurance Data Collection, Monitoring and Auditing Database Management and Quality Control Statistical Methods and Determination of Sample Size Statistical and Analytical Plans Efficacy Assessment Safety Assessment Sample Size Analysis Plan Early Termination of the Study STUDY REPORT, PUBLICATION POLICY & STUDY DOCUMENTATION ARCHIVING STUDY TIMETABLE REFERENCES APPENDICES APPENDIX 1: STUDY FLOWCHART APPENDIX 2: MEDICAL PHOTOGRAPHY APPENDIX 3: PATIENT DIARY APPENDIX 4: EPP QUESTIONNAIRES APPENDIX 5: SCORING THE DLQI AND EPP-QoL APPENDIX 6: PHOTOPROVOCATION METHODOLOGY CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

65 Clinuvel Inc. Confidential Page 8 of 56 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS α-msh Alpha - Melanocyte stimulating hormone AE Adverse event BMI Body Mass Index BUN Blood urea nitrogen CAD Chronic Actinic Dermatitis CFR Code of Federal Regulations CK Creatine kinase (creatine phosphokinase) CRF Case report form CRO Contract research organization cm Centimeter DLE Discoid lupus erythematosus DLQI Dermatology Life Quality Index EKG Electrocardiogram EPP Erythropoietic protoporphyria EPP-QoL EPP-Specific Quality of Life Questionnaire FDA Food and Drug Administration GCP Good clinical practice -HCG -Human chorionic gonadotrophin ICH International Committee on Harmonization IRB Institutional Review Board ITT Intention-to-treat kg Kilogram MedDRA Medical Dictionary for Regulatory Activities MC1-R Melanocortin 1 receptor mg Milligram ml Milliliter nm Nanometer PLE Polymorphic Light Eruption PUVA Phototherapy with psoralen and ultraviolet A radiation SAE Serious adverse event SU Solar Urticaria TEAE Treatment-emergent adverse event TIBC Total Iron Binding Capacity UV Ultraviolet UVB Ultraviolet light B radiation WMA World Medical Association CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

66 Clinuvel Inc. Confidential Page 9 of ETHICS 1.1 Institutional Review Board (IRB) An appropriate Institutional Review Board will approve the protocol and the Participant Information and Informed Consent Form before the study is initiated at each center. Documentation of this approval will be provided to the Sponsor and/or the Sponsor s designee. The Principal Investigator(s) will have the following responsibilities: Obtain IRB approval of the protocol, informed consent documentation and any advertising material to recruit subjects; Obtain IRB approval for any protocol amendments and informed consent documentation revisions before implementing the changes; Provide the IRB with any information requested before or during the study; Submit progress reports to the IRB, as required, during the conduct of the study; Request review and approval of the study as needed; provide copies of all IRB re-approvals and relevant communication to the Sponsor; and, Notify the IRB as required of all serious and unexpected adverse events related to the study medications that occur or are reported by the Sponsor. 1.2 Ethical Conduct of the Study This study will be conducted in accordance with the Declaration of Helsinki, its revisions (Scotland, October 2000 and incorporating Notes of Clarification - Washington, 2002, Tokyo, 2004 and Seoul 2008) and ICH guidelines for Good Clinical Practice (GCP) governing the conduct of studies, and all applicable local regulations. The Principal Investigator will ensure that the study is conducted in accordance with prevailing local laws and regulations. The Principal Investigator is responsible for reporting to the Sponsor, the authorities and the IRB any modifications, safety updates, amendments, and violations of the protocol that impact on subject safety. 1.3 Participant Information and Informed Consent Prior to any study specific screening procedures, the Principal Investigator or nominee will explain to each participant and/or to his/her legal representative, if necessary, the nature of the study, its purpose, procedures to be performed, the necessity for withdrawal of prohibited medication, expected duration, CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

67 Clinuvel Inc. Confidential Page 10 of 56 and the benefits and risks of study participation. After this explanation and before any study specific procedures are performed, the subject must voluntarily sign an informed consent statement in the presence of a witness. The inclusion and exclusion criteria will be reviewed at Screening prior to study medication administration. 1.4 Protocol Amendments Changes in any portion of this protocol that affect subject safety and welfare or that alters the efficacy parameters will be documented in the form of a revision, signed by the appropriate Clinuvel Inc. personnel and the Principal Investigator, and approved by the study center's IRB and relevant Competent Authority (where applicable) before the revision is implemented. The IRB Chairperson may approve minor changes or may designate one or more members of the IRB to approve changes. Clarification or interpretation of the study protocol or changes in the methods of statistical analysis may be documented in the form of an administrative change. Administrative changes do not require the Principal Investigator s signature or IRB approval. Administrative changes will be transmitted to the Principal Investigator and a copy provided to the IRB for completeness. 1.5 Confidentiality All information provided to the Principal Investigator (and delegated study site staff) by the Sponsor, including clinical observations at the investigative center, are held strictly confidential and confined to the clinical personnel involved in conducting the study, under the supervision of the Principal Investigator. This includes, but is not limited to preclinical data, protocols, CRFs and verbal or written communications. This information is related in confidence to the IRB or other committees functioning in a similar capacity. A coded number will identify all reports, subject samples, and data published or submitted to third parties in order to maintain subject confidentiality. CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

68 Clinuvel Inc. Confidential Page 11 of STUDY PERSONNEL AND STUDY ADMINISTRATION Each Principal Investigator participating in this study will meet the following criteria: Accessible, interested, and well-organized support staff; Availability of diagnostic facilities to support study data requirements; Availability of physician emergency response at all times; The Principal Investigator will sign the Investigator agreement form and protocol which incorporates the Declaration of Helsinki. By signing the protocol, the Principal Investigator agrees to: 1. Conduct the study in accordance with the protocol and only make changes after notifying the Sponsor, except when required to protect the safety, rights, or welfare of subjects; 2. Personally conduct or supervise the study (or investigation); 3. Inform any subjects that the drug is being used for investigational purposes; 4. Ensure that the requirements relating to obtaining informed consent and IRB review and approval meet ICH-GCP guidelines and the Code of Federal Regulations (21 CFR Parts 50 and 56); 5. Report to the Sponsor any AEs that occur in the course of the study, in accordance with the protocol; 6. Read and understand the Investigator Brochure, including potential risks and side effects of the drug; 7. Ensure that all associates, colleagues and employees assisting in the conduct of the study are informed about their obligations in meeting the above commitments; 8. Maintain adequate and accurate records and make those records available for inspection by the Sponsor, the Sponsor s designated representative, or any agency authorized by law; 9. Ensure that the IRB that complies with the requirements of the ICH-GCP and the Code of Federal Regulations (21 CFR Part 56) will be responsible for initial and continuing review and approval of the clinical study; 10. Promptly report to the IRB and the Sponsor all changes in the research activity and all unanticipated problems involving risks to subjects or others (to include amendments); 11. Make no changes in the research study without approval, except when necessary to eliminate hazards to the subjects; and, 12. Comply with all other requirements regarding the obligations of the clinical investigators and all other pertinent requirements listed in the ICH-GCP guidelines. 13. Ensure any sub-investigator(s) or other delegates are accountable for adherence to GCP guidelines, the study protocol and other study-related documentation. CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

69 Clinuvel Inc. Confidential Page 12 of INTRODUCTION AND STUDY RATIONALE Erythropoietic protoporphyria (EPP) is a genetic disorder in which impaired ferrochelatase activity results in the accumulation of its substrate, protoporphyrin IX. There are two main clinical manifestations of raised protoporphyrin IX levels: cutaneous phototoxicity and hepatobiliary disease. Phototoxicity is the more common of these and it usually presents in early childhood as intolerance to sun-exposure with patients experiencing severe burning pain most often on the face and hands. It may last for several days and may be accompanied by swelling and redness on sun exposed areas 1-3. Accumulation of protoporphyrin IX is responsible for cutaneous phototoxicity leading to (i) pain, (ii) swelling, (iii) formation of ulcers 1 and (iv) discrete scarring. In the presence of light at 410 nm, protoporphyrin IX generates reactive oxygen species resulting in the typical phototoxic reactions. Protoporphyrin IX is eliminated exclusively via the liver. When the capacity of the biliary excretion pathway is exceeded, excess protoporphyrin IX may result in the formation of gallstones or cholestatic liver damage 4. Available treatment modalities for patients with EPP are limited. Avoidance of strong sunlight, either from direct exposure or through windows glass and the use of protective clothing is essential to prevent phototoxic reactions 1-3. Systemic β-carotene has been shown to be of benefit in the treatment of EPP although good efficacy data are lacking 2. The clinical benefits of other treatments such as PUVA, UVB, oral cysteine 5, cholestyramine and combinations thereof remain to be proven. The most effective measures are reflecting sunscreens containing titanium dioxide 6. Afamelanotide is a potent analogue of -MSH which stimulates the production of eumelanin in the skin (epidermis) without the specific cell damage that usually occurs when melanin production is stimulated by UV radiation 11,12. Melanin, in the form of eumelanin, is a photoprotective agent. The mechanisms proposed for photoprotection include, but are not limited to, the absorption and scattering of UV light, free radical scavenging and quenching of UV light 7,8. There is also increasing evidence that melanogenesis represents a major antioxidant defense mechanism in melanocytes, neutralizing the deleterious effects of free radicals and active oxygen species 9. Eumelanin acts as a neutral density filter and, unlike most sunscreens, reduces all wavelengths of light equally so that the photoprotection provided by epidermal melanin pigmentation is essentially independent of wavelength 10. CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

70 Clinuvel Inc. Confidential Page 13 of 56 Following a pilot study conducted in Switzerland 13, three placebo controlled studies have been completed in patients with EPP, two in Europe and one in the United States. Overall these studies demonstrated that afamelanotide: enabled patients to experience more direct sunlight exposure without suffering the consequences of the deep burning pain they would normally experience following such exposure was safe and well tolerated, with no noteworthy changes or trends in adverse events, vital signs, physical exam results or laboratory test parameters 14. This study aims to extend knowledge of the photoprotective effects of afamelanotide in EPP patients. 4.0 STUDY OBJECTIVES 4.1 Primary Objective The primary objective of this study is to determine whether afamelanotide can enable EPP patients to expose themselves to sunlight without incurring pain and phototoxic reactions. 4.2 Secondary Objectives Determine whether afamelanotide implants can: improve the quality of life of EPP patients reduce the susceptibility to provocation with a standardized light source (minimum symptom dose) in patients with EPP Evaluate the safety and tolerability of afamelanotide by measuring treatment-emergent adverse events (TEAEs) and investigate the reversibility of afamelanotide-induced increase in dermal pigmentation. 5.0 INVESTIGATIONAL PLAN 5.1 Overall Design and Plan of the Study This is a randomized placebo-controlled study to be conducted in two parallel study arms for a six month period (three doses). Between 75 and 100 eligible patients will be enrolled. To determine eligibility for study inclusion, patients will undergo a screening evaluation up to 14 days prior to commencement. Patients will be randomized to receive afamelanotide (16 mg implants) or placebo according to the following dosing regimen: - Group A will be administered afamelanotide implants on Days 0, 60 and 120, or CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

71 Clinuvel Inc. Confidential Page 14 of 56 - Group B will be administered placebo implants on Days 0, 60 and 120. The number and severity of phototoxic reactions, the type and duration of sun exposure, treatmentemergent adverse events and the use of concomitant medication will be recorded by patients in study diaries between Days 0 and 180. Quality of life will be measured using the EPP-QoL and DLQI questionnaires at Days 0, 60, 120 and 180. Participants will visit the clinic on Days 60, 120 and 180 for assessments of adverse events. All patients will have an EKG performed at each study visit (from Day 60 onwards). A subset of patients will be photoprovoked on the lower back and dorsal surface of the hand and the minimal symptom dose (MSD) will be determined on Days 0, 30, 60, 90 and 120. The target number of patients for photoprovocation is 20. Six months after completion of the efficacy assessment (Day 360), patients will return to the study site for a full safety assessment, including an evaluation of the reversibility of pigmentation of the epidermis. At this time an additional quality of life questionnaire will be administered, an inventory of activities taken and EKG procedure will be performed. 5.2 Selection of Study Population The target population consists of male and female patients with EPP who experience phototoxic reactions. Patients at each center will have a biochemically-confirmed diagnosis of EPP. The following inclusion and exclusion criteria must be met by each patient before enrollment in the study Inclusion Criteria The participants have to fulfill all of the following criteria for study participation: Male or female subjects with characteristic symptoms of EPP phototoxicity and a biochemicallyconfirmed diagnosis of EPP. Aged 18 years old and above (inclusive). Able to understand and sign the written Informed Consent Form. Willing to take precautions to prevent pregnancy until completion of the study (Day 180) Exclusion Criteria Any of the following criteria will exclude the patient from the study: CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

72 Clinuvel Inc. Confidential Page 15 of 56 Any allergy to afamelanotide or the polymer contained in the implant or to lidocaine or other local anesthetic to be used during the administration of study medication EPP patients with significant hepatic involvement Current Bowen s disease, basal cell carcinoma, squamous cell carcinoma, or other malignant or premalignant skin lesions. Personal history of melanoma or dysplastic nevus syndrome. Any other photodermatosis such as PLE, AP, DLE, CAD or SU. Any evidence of clinically significant organ dysfunction or any clinically significant deviation from normal in the clinical or laboratory determinations. Acute history of drug or alcohol abuse (in the last 6 months). Patient assessed as not suitable for the study in the opinion of the Principal Investigator or delegate (e.g. noncompliance history, allergic to local anesthetics, faints when given injections or giving blood). Participation in a clinical trial of an investigational agent within 30 days prior to the screening visit. Prior and concomitant therapy with medications which may interfere with the objectives of the study, including drugs that cause photosensitivity or skin pigmentation. Female who is pregnant (confirmed by positive serum β-hcg pregnancy test prior to baseline) or lactating. Females of child-bearing potential (pre-menopausal, not surgically sterile) not using adequate contraceptive measures (i.e. oral contraceptives, diaphragm plus spermicide, intrauterine device) Withdrawals and Replacement of Participants A discontinuation occurs when a patient does not complete the study as required by the study protocol. Participants will be free to discontinue their participation in this trial at any time for any reason. In addition, participants may be withdrawn from the trial at the discretion of the Principal Investigator or medically qualified nominee. A patient may withdraw for any reason, for example: Informed consent withdrawn by the patient Unacceptable level of patient non-compliance with protocol requirements Patient experienced an adverse event requiring study discontinuation When the Investigator s or nominee s best professional judgment would indicate that it would be in the patient s best interest to be withdrawn Violation of inclusion/exclusion requirements. The reasons for withdrawal or discontinuation of a patient will be recorded in the patient s medical notes and the CRF. If an AE is the reason for discontinuation, the event must be followed up and CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

73 Clinuvel Inc. Confidential Page 16 of 56 documented as described in the present protocol. If the patient discontinued for any reason after the enrolment into the study, a study termination visit as described in the present protocol should be performed at the time of study discontinuation, or as soon as possible after discontinuation. These will be documented in the patient s medical notes and the CRF. Any patient(s) withdrawn from the trial prior to their completion for any reason may be replaced, provided the replacement is able to complete the study before the start of winter. Data compiled to the point of discontinuation will be used. Participants violating any of the inclusion and exclusion criteria will be described as protocol violators. The way in which protocol violators will be handled in the statistical analysis is described in Section 5.7 of the protocol. 5.3 Study Medication Description of Study Medication The active implant is a sterile biodegradable and biocompatible poly(dl-lactide-co-glycolide) polymer excipient containing 16 mg of afamelanotide. The implants contain no other excipients and are sterile. The placebo implants are identical in size and contain only poly(dl-lactide-co-glycolide) polymer. Both sets of implants are manufactured by SurModics Pharmaceuticals, Birmingham, Alabama, USA Method of Assigning Participants to Treatment Group The study will be conducted at 7 study sites. To account for the differences in climatic conditions between the study sites and the potential impact that this will have on phototoxicity experienced, a computer generated randomization list for each study site will be used to assign each patient to a treatment arm. To ensure that treatment is balanced within study sites, the randomization method will employ a small block size will be used. Five individually sealed sets of computer-generated randomization codes (each set containing 48 randomized numbers) will be provided to the pharmacy. The study pharmacist will choose one of the five sealed envelopes and the selected randomization list will be used to randomize the subjects in this study. For each study site, patients who satisfy the inclusion/exclusion criteria will be allocated patient randomization numbers sequentially and chronologically, based on the timing of their attendance at the clinic for the first study implant. CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

74 Clinuvel Inc. Confidential Page 17 of Dosage and Administration of Study Medication Implants (afamelanotide or placebo) will be administered following application of a local anaesthetic on the designated study days. The implant will be administered subcutaneously via a 14G catheter needle into the fat above the anterior portion of the iliac crest. Any patient who experiences any severe adverse event(s) will be closely monitored. If the adverse event(s) is/are considered related to the drug and persists for more than 24 hours, the patient will be offered the opportunity to have the implant removed Packaging and Labeling of Study Medication Each implant is individually packed in a sealed borosilicate glass vial with a Teflon-faced rubber closure with full labeling details affixed. The label will include information in compliance with the local regulatory requirements for clinical trial / investigational medicinal products Storage and Accountability Study medications will be maintained in a safe and secure (restricted access) drug storage refrigerator and maintained at 2-8 C. The Principal Investigator and delegate will agree not to supply study drug to any persons other than those enrolled in the study. Current and accurate inventory and dispensing records will be kept for all study drugs and, upon study completion, a final inventory of all clinical supplies will be compiled. A copy of the drug receipt, inventory and drug accountability documentation will be retained in the Investigator s files. Records will be kept on a drug inventory and dispensing record form provided by Clinuvel Inc or on equivalent forms used by the pharmacy at the study site. After completion of the study, all unused study drugs will be returned to Clinuvel Inc or designee. Empty vials (following implant use) are to be retained. The Clinical Monitor will provide instructions to the center for drug shipment after checking the details of the shipment with the authorities and the Sponsor Compliance Data related to the administration of the study drug will be recorded in the patient s medical notes and the CRF. Case report forms will be completed and available for review and retrieval by Clinuvel Inc personnel or their representative. The Principal Investigator or delegate will review the CRFs for completeness and accuracy and sign and date the set of CRFs where indicated. Clinuvel Inc personnel CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

75 Clinuvel Inc. Confidential Page 18 of 56 or their representatives will review case report forms periodically for completeness, legibility and acceptability. The Principal Investigator or delegate will retain the completed Treating Physician s copy of the CRF for their files and forward the other copies to Clinuvel Inc or its representative according to instructions. 5.4 Prior and Concomitant Therapy Prior Therapy All subjects will be instructed to advise the Principal Investigator or delegate of any prescribed medicines, over-the-counter medications, dietary supplements or nutraceuticals that are being used. Medications should not be used for the seven days preceding treatment administration on Day 0 until study completion, except those which have been pre-approved by the Principal Investigator or delegate. Medications, which in the opinion of the Principal Investigator or delegate may interfere with the objectives of the study, whether prescribed or not, should not be taken from seven days prior to dosing until the end of the study Concomitant Therapy The Principal Investigator or delegate must be informed as soon as possible about any medication taken from the time of screening until the end of the study and these will be fully documented in the patient s medical notes and the CRF. In the event that a subject has taken a medication which has not been preapproved, the Principal Investigator or delegate will make a decision to continue or discontinue the subject, based whether the medication may interfere with the objectives of the study. These include drugs that cause photosensitivity or skin pigmentation. Reflecting sunscreens (e.g. containing titanium dioxide or zinc oxide) are permissible during this study and their continued use is advised if recommended by the physician. During the study, contraceptive therapy must not be changed. 5.5 Study Procedures This will be an outpatient study (see flowchart in Appendix 1). Participants will attend the clinic for a total of 5 visits, including the screening visit plus a follow up visit six months after completion of Visit 4. CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

76 Clinuvel Inc. Confidential Page 19 of 56 In a subset of participants undergoing photoprovocation (target number is 20 patients), a maximum of 7 clinic visits will be required, including the screening visit Description of Study Days Screening Period Screening (up to 14 days prior to study commencement) The Principal Investigator or delegate will assess eligibility for the study after the following procedures are performed: Signed, informed consent obtained prior to the performance of any study-specific procedures Review of inclusion and exclusion criteria Demographic information, including sex, date of birth, race and Fitzpatrick skin type Complete medical history Complete the standard questions to obtain details of skin cancer risk factors General physical examination Ophthalmic examination including retinal screening by an ophthalmologist Examination of the skin and oral mucosa by a dermatologist Full body anterior and posterior high resolution photography to provide a baseline, including suspicious, pre-existing skin lesions and sun-damaged fields (see Appendix 2). Vital signs Weight measurement Height measurement Blood sample for clinical laboratory evaluations (chemistry and hematology) Urinalysis specimen taken Serum -HCG pregnancy test for females Introduction to the use of the diary to record the number and severity of phototoxic reactions Review of concomitant medication use. CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

77 Clinuvel Inc. Confidential Page 20 of Study period Visit 1 (Day 0) After confirming all inclusion and exclusion criteria have been fully met, the following evaluations will be performed: Vital signs Measurement of quality of life assessment with EPP-QoL and DLQI questionnaires Completion of the baseline EPP questionnaire (see Appendix 4) Pregnancy test (urine dipstick) Issue patient with study diary In a subset of patients, susceptibility to phototoxic reactions - assessment of minimum symptom dose on the lower back and dorsal surface of hands Review of adverse events and concomitant medication use Implant administered (after all other evaluations have been completed). Visits 2 and 3 (Days 60 ± 5 and 120 ± 5) The following will be undertaken at these visits unless otherwise specified: Examination of the skin and oral mucosa by a dermatologist Vital signs Measurement of quality of life assessment with EPP-QoL and DLQI questionnaires Blood sample for clinical laboratory evaluations (chemistry and hematology) Urinalysis specimen taken 12 Lead EKG recorded Review of diary for adverse events and concomitant medication use Review of diary for phototoxic reactions Issue patient with new study diary Pregnancy test by urine dipstick prior to administration of the implant In a subset of patients, susceptibility to phototoxic reactions - assessment of minimum symptom dose on the lower back and dorsal surface of hands Study drug implant administered after all other evaluations have been completed. CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

78 Clinuvel Inc. Confidential Page 21 of 56 Visits 1b and 2b (Days 30 ± 5 and 90 ± 5) (Only applicable for subset of patients undergoing photoprovocation) Susceptibility to phototoxic reactions - assessment of minimum symptom dose on the lower back and dorsal surface of hands. Visit 4 (Day 180 ± 5 days) The following will be undertaken at these visits unless otherwise specified (please refer to flow chart): Ophthalmic examination including retinal screening by an ophthalmologist Examination of the skin and oral mucosa by a dermatologist General physical examination Full body anterior and posterior high resolution photography, including suspicious pre-existing skin lesions and sun-damaged fields (see Appendix 2). Vital signs Weight measurement Blood sample for clinical laboratory evaluations (chemistry and hematology) Urinalysis specimen taken 12 Lead EKG recorded Review of diary for adverse events and concomitant medication use Review of diary for phototoxic reactions Measurement of quality of life assessment with EPP-QoL and DLQI questionnaires Pregnancy test by urine dipstick Early termination When a patient s participation in the study is early terminated by either the patient or the Principal Investigator or delegate, the following evaluations should be performed: Ophthalmic examination including retinal screening by an ophthalmologist Examination of the skin and oral mucosa by a dermatologist General physical examination Full body anterior and posterior high resolution photography, including suspicious pre-existing skin lesions and sun-damaged fields (see Appendix 2) Vital signs CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

79 Clinuvel Inc. Confidential Page 22 of 56 Weight measurement Blood sample for clinical laboratory evaluations (chemistry and hematology) Urinalysis specimen taken 12 Lead EKG recorded Review of diary for adverse events and concomitant medication use Review of diary for phototoxic reactions Measurement of quality of life assessment with EPP-QoL and DLQI questionnaires Pregnancy test by urine dipstick Safety Follow Up Approximately six months after completion of the study (Day 360), patients will return to the study site for examination of the skin and oral mucosa by a dermatologist. A 12 lead EKG will also be recorded. At this follow up visit, patients will complete an end of study EPP questionnaire (see Appendix 4) Study Procedures Flowchart Please refer to Appendix 1 for the full study flowchart Methods of Assessment Assessment of Efficacy Variables Direct sunlight exposure Patients will record exposure times in a study-specific diary. Please refer to Appendix 3 for a copy of the patient diary page for recording reactions to light and time spent outdoors Phototoxic reactions EPP sufferers regularly tolerate pain with Likert scale severity scores of 3 and below without an adverse effect on their lifestyle. Moderate to severe pain (Likert scale scores 4 to 6 and 7 and above, respectively) do interfere with the life of an EPP sufferer and these scores will be used to determine the presence and severity of a phototoxic reaction. A phototoxic reaction will be deemed to have occurred CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

80 Clinuvel Inc. Confidential Page 23 of 56 if a reaction results in a patient reporting a Likert scale severity score of 4 and above for one or more consecutive days. The days on which the patient experiences pain as a result of phototoxic reactions (caused by exposure to natural light) will be recorded in a study diary. On each day such a reaction occurs, the patient will score their level of pain using an 11 point Likert Pain Intensity Scale. The total severity of an individual phototoxic reaction will be determined by adding the Likert scale severity scores for all days in an individual phototoxic reaction. The maximum severity of a phototoxic reaction will be determined by the highest daily Likert scale score that occurs during that phototoxic reaction. The number of phototoxic reactions will be determined by counting the number of episodes on which patients report a Likert scale score of 4 or more for one or more consecutive days Quality of life measurement The quality of life will be determined using the EPP-QoL and DLQI questionnaires. Both questionnaires will be completed at the site on Days 0, 60, 120 and180. In addition, a baseline and end of study EPP questionnaires will also be completed at the site respectively on Days 0 and 360 (see Appendix 4) Photoprovocation (subset of patients) An area of approximately 33 mm in diameter will be irradiated with light filtered to transmit radiation between 400 nm and 650 nm up to a maximum irradiation dose of 300 J/cm 2 using a standardized and calibrated light source. Irradiation from the light source can vary over time so it is calibrated before the test is performed. The time it takes for the patient to first experience symptoms together with the radiation output from the light source is used to calculate the Minimum Symptom Dose. See Appendix 5 for methodology Safety Variables Clinical Laboratory Evaluations A blood sample of approximately 15 ml will be taken for monitoring of safety at Screening, Days 60, 120 and 180, and at Early Termination Visit, if applicable. CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

81 Clinuvel Inc. Confidential Page 24 of 56 In addition to blood sampling, a urine sample will be collected for analysis at Screening, Days 60, 120 and 180, and at Early Termination Visit, if applicable. For women of childbearing potential, a pregnancy test will be performed on the serum sample collected at Screening and with dipstick at Days 0, 60, 120 and 180, and at Early Termination Visit, if applicable. The following laboratory tests will be performed using a local laboratory. Hematology Hemoglobin Red Blood Cell Count (RBC) Packed Cell Volume (PCV) Platelets White Blood Cell Count (WBC) Neutrophils Lymphocytes Monocytes Eosinophils Basophils Biochemistry Sodium Potassium Chloride Glucose Urea (BUN) Creatinine Alkaline Phosphatase (ALP) Phosphate Total Calcium Albumin Protein Total Bilirubin Gamma Glutamyl Transferase (GGT) Serum Iron Ferritin Transferrin or TIBC Alanine Aminotransferase (ALT) Aspartate Aminotransferase (AST) Lactate Dehydrogenase (LDH) Creatine Kinase (CK) Glomerular Filtration Rate Total Cholesterol Urinalysis Protein Blood Bilirubin Specific Gravity Glucose Ketones ph Nitrites (Microscopic examination to be undertaken if Dipstick results show any abnormality) All laboratory test results will be reviewed by the Principal Investigator or delegate. The Principal Investigator or delegate will sign and date all laboratory reports and evaluate clinical significance of all values outside the reference range and will document this within the laboratory report. If a laboratory value is outside the reference range and felt to represent a clinically significant change from the CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

82 Clinuvel Inc. Confidential Page 25 of 56 baseline value this will be reported as an adverse event on the Adverse Event CRF page. An assessment will be made regarding the relationship of the event to the study drug Physical Examination A general physical examination will be performed at Screening and Day 180, or at Early Termination Visit, if applicable. An ophthalmology examination is part of the general physical examination. Any changes from baseline examination will be evaluated and noted on the Case Report Form. The results of the physical examination at Screening will be classified for each site as normal, abnormal or not done. Changes will be indicated at Day 180, or at Early Termination Visit, if applicable. In addition, at Screening, any suspicious pre-existing skin lesions and sun damaged fields will be photographed. These will be re-photographed at Day 180, or at Early Termination Visit, if applicable and at the safety follow up visit (see Appendix 2) Weight/Height Weight (in kg) will be recorded at Screening, Day 180, or at Early Termination Visit, if applicable. Height (in cm) will also be measured at Screening to allow calculation of BMI Vital Signs Measurements Vital signs (blood pressure, temperature and pulse rate) will be recorded at all visits in a standardized manner, i.e. after the patient has rested in a sitting position for 5 minutes. These will be measured at Screening, Days 60, 120 and 180, or at Early Termination Visit, if applicable Adverse Events An adverse event is defined as any untoward medical event (clinical or laboratory) experienced by a patient during the course of a clinical trial, whether or not it is related to the investigational product. An adverse event may be a symptom, sign, or abnormal finding or test result. Whenever possible, the Principal Investigator or delegate will group together into a single term, signs and symptoms that constitute a single diagnosis. For example, cough, rhinitis and sneezing might be grouped together as "upper respiratory tract infection. Expected phototoxic symptoms due to environmental sun exposure will not be documented as Adverse Events. CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

83 Clinuvel Inc. Confidential Page 26 of 56 The Principal Investigator or delegate will monitor each patient closely for the development of adverse events, and any adverse experience spontaneously reported by or elicited from the patient or observed by the Investigators (physician or study staff) from Day 0 onwards will be recorded on the appropriate Adverse Events page of the Case Report Form. Reporting of adverse events by participants will be elicited by nonspecific questions such as Have you noticed any problems? or Do you feel different in any way? Participants will be encouraged to report adverse events at their onset. The Principal Investigator or delegate will record the adverse event(s) on the Case Report Form and provide the date and time of onset, severity, seriousness, relationship to study medication, date of resolution (or the fact that the event is still continuing), action taken, and outcome. A causality assessment will be made for every adverse event. If a laboratory value is outside the normal range, the Principal Investigator or delegate must comment on the findings in the laboratory report. For any clinical laboratory abnormality, the Principal Investigator or delegate will make a judgment as to clinical significance. All clinically significant laboratory abnormalities will be recorded on the Adverse Events page of the CRF. All adverse events will be followed up in accordance with good clinical practice. Adverse events will be graded for severity as defined below: Mild - The adverse event is transient and easily tolerated by the patient. Specific action is optional. Moderate - The adverse event causes the patient discomfort and interrupts the patient s usual activities. Severe - The adverse event causes considerable interference with the patient s usual activities and may be incapacitating or life-threatening. Outcome of the event must be described as one of the following: Resolved without sequelae Resolved with sequelae Continuing The Principal Investigator or delegate will be asked to document his/her opinion of the relationship of the event to the study drug as follows: None - The event can be readily explained by the patient's underlying medical condition or concomitant therapy and no temporal relationship exists between the study drug and the event. CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

84 Clinuvel Inc. Confidential Page 27 of 56 Unlikely - The temporal relationship between the event and the administration of the study drug is uncertain and it is likely that the event can be explained by the patient's medical condition or other therapies. Possible - There is some temporal relationship between the event and the administration of the study drug and the event is unlikely to be explained by the patient's medical condition or other therapies. Probable - The temporal relationship between the administration of the study drug is compelling, and the event cannot be explained by the patient's medical condition or other therapies. Definite The event follows a reasonable temporal sequence from administration of the medication, follows a known or suspected response pattern to the medication, is confirmed by improvement upon stopping or reducing the dosage of the medicine (dechallenge) and reappears upon repeated exposure (rechallenge). Serious Adverse Events A Serious Adverse Event (SAE) is any adverse event occurring at any dose that results in any of the following outcomes: Death Is life-threatening Requires inpatient hospitalization or a prolongation of an existing hospitalization Results in a persistent or significant disability/incapacity Is a congenital anomaly/birth defect. Important medical events that may not be immediately life threatening, result in death or require hospitalization but may be considered a serious adverse event when, based upon appropriate medical judgment, they may jeopardize the patient or may require medical or surgical intervention to prevent one of the outcomes listed in the definition above. Reporting: Any serious adverse event, including death due to any cause, which occurs during this study will be reported immediately by telephone (by the end of the next business day) to the appropriate Safety Department (telephone number of Clinuvel is (646) or ). In addition to the initial telephone report, all SAEs will be recorded on the Adverse Events page of the CRF, and a Serious Adverse Event form will be completed and sent via facsimile immediately to the CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

85 Clinuvel Inc. Confidential Page 28 of 56 appropriate Safety Department (fax number of Clinuvel: (646) or ). All SAEs require telephone notification and a written SAE report within 24 hours. The responsible Principal Investigator or delegate will determine whether the seriousness of the event warrants removal of any patient from the study. The Principal Investigator or delegate will institute appropriate diagnostic and therapeutic measures and keep the patient under observation for as long as is medically indicated. In this study any pre-arranged elective surgery will be excluded as an adverse event. 5.6 Data Quality Assurance Data Collection, Monitoring and Auditing The Principal Investigator and institution will provide direct access to source data/documents and will permit trial-related monitoring, auditing, review by the IEC, and regulatory agency inspections. The Sponsor or its designee will monitor the study in accordance with Good Clinical Practice (GCP). The Clinical Monitor is qualified by training and experience to oversee the conduct of the study. His/her responsibilities include study monitoring (review accuracy and completeness of records, source document checks), evaluation of study data (drug accountability, communication, and written records), monitoring of center facilities to ensure continued adequacy and adverse event monitoring. The Clinical Monitor maintains regular contact with the investigational center, through telephone contact, communication and on-center visits to ensure that the investigational plan and regulations governing the conduct of clinical trials are followed. These contacts are also to ensure that timely and accurate data will be submitted, that problems with inconsistent and incomplete data are addressed, and that the center facilities and management continue to be adequate for this study. Any questions regarding these matters are addressed with the Clinical Monitor. The Clinical Monitor will evaluate and summarize the findings of each visit in written reports, identify any repeat data problems with the Principal Investigator or delegate, and specify recommendations for the resolution of noted deficiencies. Standardized case report forms (CRF) will be provided for each eligible patient in this study only. Patients who provide written informed consent will be identified by their initials for the purpose of screening. All screening results will be recorded in patient source notes and the relevant patient s initials will be entered onto screening logs, which will be made available for monitoring by Clinuvel. If CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

86 Clinuvel Inc. Confidential Page 29 of 56 a patient fails screening tests (and is therefore declared ineligible to participate), the patient will end their involvement in the study, but may be reviewed at a later date for re-consent and re-screening if considered suitable by the Principal Investigator or delegate. This outcome would also be noted on screening logs against the patient s initials. If the patient successfully satisfies all screening tests and is therefore considered eligible to enter the study, a randomization number will be allocated to the eligible patient, which will used to track the patient throughout their involvement in the study. This outcome would also be noted on screening logs. The patient randomization number will be recorded on all pertinent study related documentation. The patient randomization number will consist of the assigned center number and a patient number in sequential order at that study site. All clinical information requested in the protocol will be recorded in the patient s notes and transferred to the CRF following the instructions provided below: All entries will be made using a black ball-point pen, to ensure the clarity of any reproduced copies of the CRF On the CRF and all other trial documentation, signatures or initials must be accompanied by the current date, with the date written by the person signing/initialing the document Corrections to CRF entries should be made by drawing a single line through the incorrect entry. The correct value(s) should be written in an adjacent space and the correction signed or initialed and dated Incorrect entries must not be obliterated or covered using masking/correction fluid or made illegible in any way A reasonable explanation must be given by the Principal Investigator or delegate for all missing data The Principal Investigator or delegate must sign and date a declaration on the CRF stating his/her responsibility for the quality of all data collected and that the data represent a complete and accurate record of the patient s participation in the trial If corrections are made after review and signature by the Principal Investigator or delegate, he/she will be made aware of the changes and this awareness documented by initialing and dating the changes. Before the study starts the local laboratory will provide a list of reference ranges for all laboratory tests to be undertaken, current laboratory accreditation/certification and details of the method used for CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

87 Clinuvel Inc. Confidential Page 30 of 56 quality control. These will be held by the Principal Investigator or delegate and a copy sent to the Clinical Monitor. The CRO performing the data management will be sent relevant details e.g. reference ranges. Any change in the laboratory, its procedures, reference ranges etc. during the study must be notified promptly to the Clinical Monitor. The Clinical Monitor will inform Data Management of these changes. The Clinical Monitor and Principal Investigator or delegate to ensure accuracy, completeness, and compliance with the protocol will review all CRFs Database Management and Quality Control The study will be monitored by representatives of Clinuvel Inc, or its delegated representative, as frequently as is necessary to determine that data recording and protocol adherence are satisfactory. The CRFs and related source documents will be reviewed in detail by the representatives at each study visit, and identified discrepancies will be resolved. Data will be entered into a study-specific database. Any data entry discrepancies will be reviewed against the hard-copy CRF and corrected on-line. After completion of the entry process, computer logic checks will be run to check for such items as inconsistent study dates, outlying laboratory values, and any missing data; and any necessary corrections will be made to the database and documented. The detailed procedures for data entry, data coding, cleaning and electronic data transfer will be provided in a Data Management Plan. 5.7 Statistical Methods and Determination of Sample Size Statistical and Analytical Plans Formal statistical and analytical plans will be prepared prior to database lock and statistical analysis. The analysis will be performed after all data from Visit 4 (Day 180) or Early Termination are available. The analysis will be conducted ahead of the Safety Follow Up visit Efficacy Assessment Specification of Primary Efficacy Endpoint The primary efficacy endpoint is the duration of time (hours) spent in direct sunlight between 10:00 and 18:00 hours on days when no pain was experienced (Likert score of 0). CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

88 Clinuvel Inc. Confidential Page 31 of Specification of Secondary Efficacy Endpoint Combined sun exposure and phototoxic pain Duration of sun exposure (hours in direct sunlight) between 10:00 and 18:00 hours on days when no pain or mild pain was experienced (Likert scores of 0-3). Duration of sun exposure (hours in direct sunlight) between 10:00 and 15:00 hours on days when no pain was experienced (Likert score of 0). Sun exposure Duration of sun exposure (hours in direct sunlight) between 10:00 and 18:00 during the study. Quality of life Quality of life assessment score according to the DLQI and EPP-QoL questionnaires. Photoprovocation (in a subset of patients (target n=20)) The minimum symptom dose following photoprovocation on the lower back and dorsal surface of the hand, determined using the irradiation dose of the light source and the time to first development of symptoms at the site of photoprovocation. Phototoxicity phototoxic pain The maximum and total pain severity scores (Likert scale) for phototoxic episodes. The number of phototoxic episodes during the study Safety Assessment Specification of Primary Safety Endpoints The primary safety endpoint will be the type and incidence of treatment emergent adverse events Specification of Secondary Safety Endpoints The secondary safety endpoints will be: Any significant abnormalities detected in EKG. Physical examination changes from Screening. Changes in blood pressure and heart rate from Screening to all subsequent visits. Changes in clinical chemistry, hematology and urinalysis parameters from Screening to all subsequent visits. CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

89 Clinuvel Inc. Confidential Page 32 of Sample Size Analysis of data from the CUV029 and CUV030 studies demonstrated that a significant difference in the primary endpoint of the study could be detected with approximately patients Analysis Plan Safety Population The Safety Population will include all enrolled participants. Participants screened but not enrolled will be shown in separate listings. ITT Population The ITT population will include all treated participants, who provide at least one post dose efficacy assessment. This will be the main population for all efficacy analyses Handling of Missing and Incomplete Data Analyses will be performed on the available data. There will be no imputation for missing efficacy data points with the following exceptions. Where a patient has completed a daily diary entry indicating that they have not had a reaction to light today but have not marked a pain severity score, a severity score of zero will be imputed. In the event that a patient has not marked the box indicating that they have spent time outdoors today but have shaded one or more of the time period spent outdoors boxes, the times indicate will be used in the analysis. Please refer to Appendix 3 for a copy of the patient diary page for recording reactions to light and time spent outdoors. Alternate imputation methods will also be used for sensitivity analyses purposes. Where limited numbers of phototoxic pain scores are missing, the last reported value will be entered for the missing value(s). For assessment of the number of phototoxic reactions, days with missing phototoxic pain scores will have two forms of imputation. These will be that the patient either did not or did have a phototoxic reaction, providing a best and worst case assessment. Imputations for the amount of sun exposure are not possible Demographic and Initial Characteristics Demographic and baseline characteristics will be summarized. CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

90 Clinuvel Inc. Confidential Page 33 of 56 Where measurements have been taken more than once prior to the scheduled baseline visit, baseline measurements will be taken as the last available data measured prior to this time point. If the baseline measurement is missing but there is a prior measurement recorded, this value will be carried forward and used as the baseline measurement Primary Efficacy Analysis Combined sun exposure and phototoxic pain The primary efficacy endpoint is the duration of time (hours) spent in direct sunlight between 10:00 and 18:00 hours on days when no pain was experienced (Likert score of 0). The mean daily duration in direct sunlight exposure will be calculated for each patient and compared between the treatment arms using a Kruskal-Wallis test with a significance level of p<0.05. H 0 : there is no difference between the treatment arms in the time spent in direct sunlight on days when no phototoxic pain was reported Secondary Efficacy Analyses Combined sun exposure and phototoxic pain The mean daily duration of sun exposure (hours in direct sunlight) between 10:00 and 18:00 hours on days when no pain or mild pain was experienced (Likert scores of 0-3) will be calculated for each patient and compared between the treatment arms using the Kruskal-Wallis test. The mean daily duration of sun exposure (hours in direct sunlight) between 10:00 and 15:00 hours on days when no pain was experienced (Likert score of 0) will be calculated for each patient and compared between the treatment arms using the Kruskal-Wallis test. Sun exposure The mean daily duration of sun exposure (hours in direct sunlight) between 10:00 and 18:00 during the study will be calculated for each patient and compared between the treatment arms using the Kruskal- Wallis test. Quality of life A between groups comparison of the change from baseline to each time point in the quality of life assessment scores (DLQI and EPP-QoL questionnaires) will be performed using the Kruskal-Wallis test. Photoprovocation (in a subset of patients (target n=20)) CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

91 Clinuvel Inc. Confidential Page 34 of 56 A between groups comparison of the change from baseline to each time point in the minimum symptom dose following photoprovocation on the lower back and dorsal surface of the hand will be performed using the Kruskal-Wallis test. Phototoxicity phototoxic pain The maximum and total pain severity scores (Likert scale) for phototoxic episodes. The number of phototoxic episodes per subject reported by the patient during the study. A between groups comparison of the scores for each of the above parameters will be performed using the Kruskal-Wallis test Safety Descriptive methods will be used to summarize the safety data. These will be based upon the safety population Adverse Events All adverse events, including non-treatment emergent events, will be listed. A treatment emergent adverse event will be: An event that was not present prior to or on the day of the first study medication administration but was present after study medication was administered. An event that was present prior to first administration of study medication and continued to occur after the administration of the first dose at an increased level of severity. An event that was present prior to administration of study medication and was documented as completely resolved and re-emerged after the administration of the first dose. The MedDRA adverse event dictionary will be used to map verbatim adverse event terms to preferred terms and body systems. The number of participants with treatment-emergent adverse events will be summarized by preferred term and body system for each treatment group. Treatment-emergent events will be further summarized by intensity, seriousness and relationship to study medication. The number of participants who early terminate treatment due to adverse events related to study medication will be tabulated. Summaries of the incidence of toxicities will be prepared, as appropriate. Serious adverse events and adverse events of special interest will be listed individually. If a serious adverse event occurs prior to the first dose of the study medication, this will be noted in the study report. CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

92 Clinuvel Inc. Confidential Page 35 of Clinical Laboratory Data Laboratory data will be summarized by descriptive statistics by treatment and assessment including changes from screening to each visit. Additionally shift tables with respect to the normal ranges will be generated from screening to each visit. Clinically significant laboratory results will be listed separately. All summaries of clinical laboratory data will include scheduled data collection points only Other Clinical Data Analyses The duration of study drug exposure and the number of participants exposed will be evaluated descriptively. Separate summaries with the detailed descriptive statistics will be generated and assessment for the EKG data and both the original values and for changes from baseline for vital signs, physical examination and body weight. Changes in physical examination and concomitant medications will be listed and summarized by frequency tables, if appropriate. 5.8 Early Termination of the Study The study may be terminated if the Sponsor, Investigator, or Study Monitor discovers conditions arising during the course of the study which indicate that the clinical investigation should be halted. The study may be terminated after appropriate consultation and discussion. Conditions that may warrant study termination include, but are not limited to, the discovery of a significant, unexpected and unacceptable risk to the participants, failure of the Investigator to enroll participants at an acceptable rate, insufficient adherence to the protocol requirements, completion of study objectives, or at the discretion of the Sponsor. 6.0 STUDY REPORT, PUBLICATION POLICY & STUDY DOCUMENTATION ARCHIVING CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

93 Clinuvel Inc. Confidential Page 36 of 56 Investigators are required to maintain all study documentation, including copies of CRFs, Informed Consents, and adequate records for the receipt and disposition of study medications, for a period of 15 years following study close-out. The Principal Investigator will permit study data to be accessible to the Monitor, Sponsor, or other authorized representatives of the Sponsor and Regulatory Agency. A file for each patient will be maintained that includes the signed Informed Consent form and copies of all source documentation related to that patient. The Principal Investigator will ensure the availability of the source documents from which the information on the CRF is derived. All information provided to the Principal Investigator (and study site staff) dealing with this study drug or the methodologies used in the protocol, as well as information obtained during the course of the study will be regarded as strictly confidential and proprietary to the Sponsor ("Proprietary Information"). The Investigator agrees not to disclose any information supplied by the Sponsor in any way without written permission as outlined in the Confidentiality section of this protocol. For the purposes of this section, "Investigator" includes, but is not limited to, the Principal Investigator and/or his/her agents, designees, sub-investigators, or other individuals involved in the running, administration, or collection/handling of participants/data for this study. Any formal presentation or publication of data from this trial will be considered as a joint publication by the Investigators and the appropriate personnel at Clinuvel Inc. Authorship will be determined by the Principal Investigator. It is mandatory that the first publication is based on data analyzed as stipulated in the protocol statistical section, and not by the Investigators themselves. Participating Investigators agree not to present data before the full, initial publication, unless formally agreed to by all other Investigators and Clinuvel Inc. Clinuvel Inc must receive copies of any intended communication in advance of publication, at least 30 working days for an abstract or oral presentation and 45 working days for a journal submission. Clinuvel Inc will review the communications for accuracy, thus avoiding potential discrepancies with submissions to the Health authorities, verify that confidential information is not inadvertently divulged, and provide any relevant supplementary information. CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

94 Clinuvel Inc. Confidential Page 37 of STUDY TIMETABLE Projected starting date (first-patient-in [FPI]): May 2012 Projected number of patients: Projected completion of patient accrual (last-patient-in [LPI]): July 2012 Patient study end date (last-patient-last-visit [LPLV]) July 2013 CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

95 Clinuvel Inc. Confidential Page 38 of REFERENCES 1. Lecha M. Erythropoietic porphyria. Photodermatol Photoimmunol Photomed 2003;19: Murphy GM. Diagnosis and management of the erythropoietic porphyrias. Dermatologic Therapy 2003; 16: Todd DJ. Clinical implications of the molecular biology of erythropoietic porphyria. J. Eur. Acad. Dermatol. Venerol 1998; 11: Schneider-Yin X, Gouya L, Meier-Weinand A et al. New insights into the pathogenesis of erythropoietic porphyria and their impact on patient care. Eur J Pediatr. 2000; 159: Mathews-Roth MM, Rosner B, Benfell K and Roberts JE. A double-blind study of cysteine photoprotection in erythropoietic porphyria. Photodermatol Photoimmunol Photomed 1994;10: Thunell S, Harper P, Brun A. Porphyrinism, porphyrin metabolism and porphyrias. IV. Pathophysiology of erythropoietic porphyria diagnosis, care and monitoring of the patient. Scand J Clin Lab Invest 2000; 60: Pathak MA. Melanin: Its Role In Human Protection., pp (Valdenmar Publishing Co.,1995) 8. Kaidbey KH, Agin PP, Sayre RM, Kligman AM. Photoprotection by melanin--a comparison of black and Caucasian skin. J Am Acad Dermatol 1979; 1: , Bustamante J, Bredeston L, Malanga G, Mordoh J. Role of melanin as a scavenger of active oxygen species. Pigment Cell Res. 1993; 6: Kollias N, Sayre RM, Zeise L, Chedekel MR. Photoprotection by melanin. J Photochem Photobiol 1991; B 9: De L. Castrucci AM., Hadley ME., Sawyer TK. and Hruby VJ. Synthesis and studies of superpotent melanotropins resistant to enzyme degradation. Comp. Biochem. Physiol. 78B: ; Sawyer TK, Sanfilippo PJ, Hruby VJ, Engel MH., Heward CB., Burnett JB and Hadley ME. 4- Norleucine, 7D-phenylalanine- -melanocyte stimulating hormone: a highly potent - -melanotropin with ultraprolonged biological activity. Proc. Nat. Acad. Sci. USA 77: ; Harms J, Lautenschlager S, Minder C and Minder E., An α-melanocyte-stimulating hormone analogue in erythropoietic protoporphyria. N Engl J Med 2009; Jan 15, Clinical Study Reports for CUV017, CUV029 and CUV030. (Data on file) CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

96 Clinuvel Inc. Confidential Page 39 of APPENDICES APPENDIX 1: STUDY FLOWCHART Study Procedure Informed consent taken Inclusion and exclusion criteria review X X Screening Visit 1 Visit 1b Visit 2 Visit 2b Visit 3 Visit 4 (Day Up to ) or Early Day 0 Day 30 Day 60 Day 90 Day 120 days Termination X Demographic information collected X Medical history taken Skin cancer risk factor questions completed General physical examination including ophthalmic examination Skin and oral mucosal examination by a dermatologist X X X X X X X Full body photography X X Vital signs X X X X X Weight / height measurement X 1 X Hematology and blood chemistry X X X X Urinalysis X X X X 12 Lead EKG X X X X Pregnancy test (serum β-hcg) Quality of life assessment (DLQI and EPP- QoL) Introduction to use of diary X X X X X X Issue patient with study diary X X X Pregnancy test (urine dipstick) X 2 X 2 X 2 X Photoprovocation X 3 X X 3 X X 3 Implant insertion X X X Adverse events review X X X X Concomitant medication review X X X X X Phototoxic reaction review X X X X 1 Height will be measured at Screening only to allow calculation of BMI X 2 Implant insertion only after confirmation that female patients are not pregnant X 3 Photoprovocation prior to implant administration (in a subset of patients only) Safety Follow Up Visit (Day 360 ±10) Skin and oral mucosal examination by a dermatologist End of Study EPP Questionnaire 12 Lead EKG CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

97 Clinuvel Inc. Confidential Page 40 of 56 APPENDIX 2: MEDICAL PHOTOGRAPHY Instructions: Hospital Medical photography units will not be used for this study. Principal Investigators or delegate will be required to take photographs using a standard 5 mega pixel (minimal) digital camera. At the protocol defined intervals the following photographs are to be taken: One full body photograph anterior and posterior views of the subject (clothing removed in line with standard medical practice) at Screening and Day 180 or Early Termination. Any suspicious lesions and/or hyperpigmented areas are to be photographed and monitored throughout the course of the study All photographs are required to be printed on standard A4 paper as well as stored on an electronic disc. In addition, they must all contain the subject s initials (if local regulations permit), study number and DOB. The date of photography and corresponding visit must also be documented on every photograph. CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

98 Clinuvel Inc. Confidential Page 41 of 56 APPENDIX 3: PATIENT DIARY The following is an extract from a patient diary. It shows the sections of the diary for recording daily phototoxicity and duration of sun exposure. DATE: (DD/MMM/YYYY) 1. EPP Monitoring 1.1 Have you experienced any reactions to light today? Yes No 1.2 If yes, please indicate on the scale below how bad your pain was from this reaction: No Pain Mild Moderate Severe Worst Imaginable 2. Time Spent Outdoors 2.1 Did you spend any time outdoors today? Yes No 2.2 If yes, please enter the time period that you were in direct sunlight. (Each box represents 15 minutes) 10:00 11:00 12:00 13:00 14:00 15:00 16:00 17:00 18: If yes, please enter the time period that you were in the shade. (Each box represents 15 minutes) 10:00 11:00 12:00 13:00 14:00 15:00 16:00 17:00 18:00 CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

99 Clinuvel Inc. Confidential Page 42 of 56 APPENDIX 4: EPP QUESTIONNAIRES BASELINE QUESTIONNAIRE (BEFORE DRUG ADMINISTERED) You are allowed to choose more than one answer: 1. Does EPP affect your life negatively A) Yes B) No C) Don t know 2. Which of the activities are inconceivable and impossible for you to engage in due to your disorder: A) Gardening B) Walking from parking lot to shopping mall C) Outdoor sports (tennis, running, baseball) D) Biking 3. Which of the measures do you take before going outside A) Checking the weather forecast B) Checking the time of day C) Checking the route to the destination D) Putting on for protective clothing 4. Which seasons do affect you most A) All seasons can affect me B) Spring C) Summer D) Winter CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

100 Clinuvel Inc. Confidential Page 43 of Which of the protective clothing do you wear if you are uncertain if the light is going to affect your skin A) Hat B) Balaclava C) Long sleeves D) Long pants E) Socks 6. Which of the activities do you avoid A) Beach walking B) Swimming C) Skiing D) Horse riding E) Mountaineering F) Other, please fill in.. 7. How does the disorder affect your life A) Affects my choice of work B) Affects my social contacts C) Affects my family life D) Affects my choice of partner E) Affects my quality of life F) Does not affect my life at all CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

101 Clinuvel Inc. Confidential Page 44 of How does the disorder affect your inner life A) Affects my confidence B) Makes me anxious C) Forces me to live a solitary life D) Makes me depressed E) Makes me angry F) Makes me disappointed about life G) Did not affect my inner life at all 9. How has the disease affected your past A) As a child I was restricted in my activities B) As a child I was isolated, few friends C) I was mostly indoors D) I had problems at school E) I couldn t play sports F) Had no effect at all 10. How has the disease affected your professional career A) Restricted my choices at college B) Restricted my choices at university C) Restricted my choices in my professional development D) Made me change my profession, occupation E) Could only do only certain jobs F) Did not affect my professional career at all CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

102 Clinuvel Inc. Confidential Page 45 of State which of the aspects impacts you most (one or more answers possible) A) Inability to explain the intensity of pain B) Inability to participate in normal life C) Inability to find a treatment D) Restricted in my choices 12. How has the disorder affected your immediate family in the past A) Not at all B) Some C) Much CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

103 Clinuvel Inc. Confidential Page 46 of 56 QUESTIONNAIRE (AFTER DRUG ADMINISTRATION) 1. Which differences have you noticed since you received the drug A) None B) Less sensitivity (phototoxicity) of the skin C) More sensitivity (phototoxicity) of the skin D) Less pain E) More pain F) Am able to tolerate light more 2. Which aspect characterizes best your attitude and outlook since receiving the drug A) Less anxious to experience skin symptoms B) More anxious to experience skin symptoms C) Less inclined to go outdoors D) More inclined to go outdoors 3. Since receiving the drug, how do you assess your ability and willingness to go outdoors A) No difference B) More confident to expose outdoors C) Sceptical about the ability to go outdoors D) Will gradually test myself to see whether symptoms occur 4. Which activities are you able to engage in, experience, participate A) Gardening B) Walking from parking lot to shopping mall C) Outdoor sports D) Biking CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

104 Clinuvel Inc. Confidential Page 47 of Which protective clothing are you using since receiving the drug A) Hat B) Balaclava COAT C) Long sleeves D) Long pants E) Socks 6. Which of the activities have you tried since receiving the drug A) Beach walking B) Swimming C) Skiing D) Horse riding E) Mountaineering F) Other, please fill in.. G) None 7. How do you best summarize your experience since receiving the drug A) I have less anxiety B) I have more anxiety C) I feel more confident D) I feel less confident E) None of the above CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

105 Clinuvel Inc. Confidential Page 48 of How has the treatment affected your life A) No improvement B) Much improvement C) Dramatic improvement 9. How do you best characterize your experience after receiving the drug A) I would request this drug all year B) I would request this drug during spring and summer C) I am unsure D) I would not request the drug 10. Since receiving the drug, I expose myself A) Less to outdoors conditions B) More to outdoors conditions C) Unchanged to my previous life Plus the following questionnaire: CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

106 Clinuvel Inc. Confidential Page 49 of Over the last two months, how has your well-being been affected by EPP? Compared to the same period last year I have been Over the last two months, how much has your EPP symptoms influenced your capacity to go to work or school? Compared to the same period last year Over the last two months, how often did you feel the need to seek out shade? Compared to the same period last year Over the last two months, how much has EPP influenced the choice of the clothes you wear on a sunny day? Compared to the same period last year Over the last two months, how often did you feel you were at risk of developing EPP symptoms? Compared to the same period last year Over the last two months, how much has EPP affected any social or leisure activities on a sunny day? Compared to the same period last year Over the last two months, how much has EPP influenced your need to plan before leaving your house? Compared to the same period last year Over the last two months, has EPP limited your ability to undertake activities in a spontaneous manner? Compared to the same period last year Over the last two months, how often have you not worn protective clothing on a sunny day? Compared to the same period last year... Much better Better Same Worse Very much A lot A little Not at all More than usual Same as usual Less than usual Much less than usual Very much A lot A little Not at all Very often Often A little Not at all Very much A lot A little Not at all Very much A lot A little Not at all Very much A lot A little Not at all Very often Often Not often Not at all CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

107 Clinuvel Inc. Confidential Page 50 of Over the last two months, has EPP limited your ability to undertake activities in a spontaneous manner? Compared to the same period last year Over the last two months, how often have you not worn protective clothing on a sunny day? Compared to the same period last year Over the last two months, how much has EPP interfered with your going shopping or looking after your home (indoors and outdoors) or garden on a sunny day? Compared to the same period last year Over the last two months, how much has EPP prevented you from attending outdoor social activities with family and friends? Compared to the same period last year Over the last two months, how much has EPP limited your amount of outdoor activities? Compared to the same period last year Over the last two months, how often did you experience typical EPP skin complaints? Compared to the same period last year Over the last two months, how much has your quality of life improved? Compared to the same period last year Over the last two months, how much has EPP influenced your method of transportation or seating preference during transportation? Compared to the same period last year How much time (minutes) can you now spend in direct sunlight? 19. How much time (minutes) were you able to spend in direct sunlight during the same period last year? Very much A lot A little Not at all Very often Often Not often Not at all Very much A lot A little Not at all Very much A lot A little Not at all Very much A lot A little Not at all Very often Often Not often Not at all Very much A lot A little Not at all Very much A lot A little Not at all minutes minutes CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

108 Clinuvel Inc. Confidential Page 51 of 56 APPENDIX 5: SCORING THE DLQI AND EPP-QoL The DLQI will be scored according to the scoring method published on the following website: The scoring method for the EPP-QoL is as follows: 1. Over the last two months, how has your well-being been affected by EPP? I have been: 2. Over the last two months, how much has your EPP symptoms influenced your capacity to go to work or school? 3. Over the last two months, how often did you feel the need to seek out shade? 4. Over the last two months, how much has EPP influenced the choice of the clothes you wear on a sunny day? 5. Over the last two months, how often did you feel you were at risk of developing EPP symptoms? 6. Over the last two months, how much has EPP affected any social or leisure activities on a sunny day? 7. Over the last two months, how much has EPP influenced your need to plan before leaving your house? Much better Better Same Worse Very much A lot A little Not at all More than usual Same as usual Less than usual Much less than usual Very much A lot A little Not at all Very often Often A little Not at all Very much A lot A little Not at all Very much A lot A little Not at all CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

109 Clinuvel Inc. Confidential Page 52 of Over the last two months, has EPP limited your ability to undertake activities in a spontaneous manner? 9. Over the last two months, how often have you not worn protective clothing on a sunny day? 10. Over the last two months, how much has EPP interfered with your going shopping or looking after your home (indoors and outdoors) or garden on a sunny day? 11. Over the last two months, how much has EPP prevented you from attending outdoor social activities with family and friends? Very much A lot A little Not at all Very often Often Not often Not at all Very much A lot A little Not at all Very much A lot A little Not at all Over the last two months, how much has EPP limited your amount of outdoor activities? 13. Over the last two months, how often did you experience typical EPP skin complaints? 14. Over the last two months, how much has your quality of life improved? Very much A lot A little Not at all Very often Often Not often Not at all Very much A lot A little Not at all 15. Over the last two months, how much has EPP influenced your method of transportation or seating preference during transportatio Very much A lot A little Not at all CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

110 Clinuvel Inc. Confidential Page 53 of 56 APPENDIX 6: PHOTOPROVOCATION METHODOLOGY 1. Purpose: Photoprovocation in Patients with EPP Erythropoietic protoporphyria (EPP) is a genetic disorder in which impaired ferrochelatase activity results in the accumulation of its substrate, protoporphyrin IX (PPIX). There are two main clinical manifestations of elevated PPIX: cutaneous phototoxicity and hepatobiliary disease. Phototoxicity is the more common of these and it usually presents in early childhood as intolerance to sun-exposure with patients experiencing severe burning pain in the skin most often on the face and hands. In order to assess the efficacy of afamelanotide in EPP, a subset of patients enrolled in the CUV039 study will undergo testing with a standardized light source. The procedure described here will be used to determine the minimal symptom dose (MSD). The efficacy analysis will compare the MSD in patients receiving afamelanotide treatment to those receiving placebo. Minimal symptom dose (MSD) To account for the variable description of the sensations described by EPP patients in response to phototesting or to light exposure, the outcome measure will be the minimal irradiation energy dose required to produce the earliest prodromal symptom (MSD), as described by the patient after photoprovocation with a broad spectrum light source (wavelength 400 to 650nm). 2. Equipment The apparatus used for photoprovocation has been constructed by Dr Chris Edwards. It consists of the following main components: 300 Watt xenon arc lamp light source Filter system: broad band (400 to 650nm) Figure A shows a diagrammatic representation of the apparatus. CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

111 Clinuvel Inc. Confidential Page 54 of 56 Shutter Collimator Water filter Filter holder Light tube Arc Lamp Beam turner Base Plate Support Adjustable light tube Figure A: Photoprovocation apparatus. The light is passed through a collimator and cooled by a water filter (wavelength cut off at 700nm). The use of a longpass filter that cuts off sharply the ultraviolet irradiation (< 400nm) allows only visible light to pass. A beam turner directs the light onto a selected area of approx. 33 mm in diameter of the patient s skin, which is then irradiated using an adjustable light tube. The areas typically chosen are the patient s lower back and dorsal surface of hand. The addition of a short pass filter (blocks wavelengths > 650nm) results in a sharp cut-on/cutoff broadband light spectrum from nm. The equipment is spectrally characterised and pre-calibrated using a spectroradiometer (measuring irradiation rates). For correct operation, and to account for variation in the lamp output, it is necessary to ensure that the output, measured as mw/cm 2, is within acceptance limits (within 10% of initial calibrated value established on installation visit) on each test day before photoprovocation procedures begin. Irradiation rate will be measured using the thermopile detector. 3. Methodology The minimal irradiation energy dose required to produce the earliest perceived symptom (MSD nm ) as determined by the EPP patient should be assessed on visit days 0, 30, 60, 90, 120 of the clinical study. Each test day an area of approximately 33mm in diameter (defined by the adjustable light tube touching patient s skin; see above) of the lower back and the dorsal surface of the hand should be exposed to the broadband light spectrum ( nm). CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

112 Clinuvel Inc. Confidential Page 55 of 56 The time of irradiation is limited by the time the patient feels the first symptom of discomfort. A maximum dose of 300J/cm 2 should be applied. Exposure time determines the doses of irradiation. The MSD nm is the lowest irradiation dose resulting in a symptom as described by the patient (pain, burning, etc). Figure B shows an overview of the procedure. For methodology compliance, at each test day, a different skin area must be exposed: On patient s lower back, irradiate from left to right according visit chronology. On the dorsal surface of hands, the right and left hand should alternately be exposed on each test day (start with left hand). Please write a note in the patient s medical source data which skin area of the lower back and which hand was exposed to the light source to ensure that each irradiation is to previously unexposed skin (naïve skin). Figure B: Methodology of Photoprovocation. 3.1 Risk factors to be considered During the photoprovocation procedure, the patient should not be exposed to an irradiation dose higher than 300 Joule/cm 2 to avoid potential burning. CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

113 Clinuvel Inc. Confidential Page 56 of Data recording Results are recorded at each test visit in the patient medical source data and transferred to the Case Report Form (CRF). All data must be recorded in the CRF and be available for Clinuvel monitoring by the assigned clinical research associate. On day 0, the first type of discomfort (e.g. burning), as determined by the patient, should be recorded by the operator (see chapter 6). In addition, the MSD nm has to be recorded. This irradiation dose will be measured as time of application of the calibrated intensity irradiation source and calculated with help of the supplied case record form. On the following test days, the MSD nm must be based on earliest symptom described by the patient on day Operating time frame For each patient, a maximum time of 40 minutes on each testing day should be taken into account for photoprovocation (2 measurements). 6. Operators Photoprovocation procedure should be performed by a qualified clinical study site staff member (investigator, study nurse) who was trained and instructed by Clinuvel. The source data should be recorded by the study investigator, in the patient s medical notes. CUV039: Multicentre Phase III EPP Study V4: June 17, 2013

114 Clinuvel Inc. Confidential A Phase III, Multicentre, Double-Blind, Randomized, Placebo-Controlled Study to Confirm the Safety and Efficacy of Subcutaneous Bioresorbable Afamelanotide Implants in Patients with Erythropoietic Protoporphyria (EPP) CUV039 Study Protocol Summary of Changes from Ver. 1.0 (16Mar12) to Ver. 2.0 (17Jul12) Section and page number Signature of Agreement Pg.1 Synopsis Pg. 2 Synopsis Pg. 2-3 Synopsis Pg. 3 Synopsis Pg. 4 Abbreviations Pg. 8 Sec. 5.1 Pg. 14 Sec. 5.1 Pg. 14 Sec Pg July 2012 Description of Change Version 2 Protocol Date: July 17, 2012 Study period - plus 6 months follow-up period. Methodology - All patients will have an electrocardiogram (EKG) performed at each study visit (from Day 60 onwards) - Six months after completion (Day360) an EKG will be performed No. of participants planned: participants in total Safety and Tolerability Endpoints: and significant abnormalities identified in EKG CAD: Chronic Actinic Dermatitis EKG: Electrocardiogram SU: Solar Urticaria TIBC: Total Iron Binding Capacity Overall Design and Plan of the Study - All patients will have an EKG performed at each study visit (from Day 60 onwards). - Six months after completion (Day360) an EKG will be performed Overall Design and Plan of the Study The target number of patients for photoprovocation is 20 Method of Assigning Participants to Treatment Group The study will be conducted at 7 study sites. To account for the Administrative change Rationale Extension of follow up period from 3 to 6 months Addition of EKG for safety monitoring Correction of inconsistency in previous version of protocol Addition of EKG for safety monitoring Administrative changes plus addition of EKG Addition of EKG for safety monitoring Inclusion of the target number of participant for photoprovocation Expansion of the details of the method of randomization being used in the study Page 1

115 Clinuvel Inc. Confidential Section and page number Sec Pg. 17 Sec Pgs Sec Pg. 17 Sec Pg. 24 Sec Pg. 25 Sec Pg. 31 Sec Pg. 32 Sec Pg July 2012 Description of Change differences in climatic conditions between the study sites and the potential impact that this will have on phototoxicity experienced To ensure that treatment is balanced within study sites, the randomization method will employ a small block size. Five individually sealed sets of computer-generated randomization codes (each set containing 48 randomized numbers) will be provided to the pharmacy. The study pharmacist will choose one of the five sealed envelopes and the selected randomization list will be used to randomize the subjects in this study. Packaging and Labeling of Study Medication Each implant is individually packed in a sealed borosilicate glass vial with a Teflon-faced rubber closure with full labeling details affixed. Study Period - 12 Lead EKG recorded. - Six months after completion of the study (Day360) A 12 lead EKG will also be recorded. Quality of life measurement In addition, a baseline and end of study EPP questionnaires will also be completed at the site respectively on Days 0 and 360 (see Appendix 4). Clinical Laboratory Evaluations BUN Transferrin Physical Examination Suspicious pre-existing lesions will be photographed at the safety follow up visit. Photoprovocation (target n=20) Secondary Safety Endpoints Any significant abnormalities detected in EKG. Sample Size patients Rationale Expansion and update of the information provided for the container and closure Addition of EKG for safety monitoring Extension of follow up period from 3 to 6 months Administrative changes Extension of follow up period from 3 to 6 months Inclusion of the target number of participant for photoprovocation Addition of EKG for safety monitoring Correction of inconsistency in previous version of protocol Page 2

116 Clinuvel Inc. Confidential Section and page number Sec Pg. 32 Sec Pg. 35 Sec. 7.0 Pg. 36 Sec. 9.0 Appendix 1 Pg. 38 Sec. 9.0 Appendix 5 Pgs Description of Change Handling of Missing and Incomplete Data Alternate imputation methods will also be used for sensitivity analyses purposes. Where limited numbers of phototoxic pain scores are missing, the last reported value will be entered for the missing value(s). For assessment of the number of phototoxic reactions, days with missing phototoxic pain scores will have two forms of imputation. These will be that the patient either did not or did have a phototoxic reaction, providing a best and worst case assessment. Imputations for the amount of sun exposure are not possible." Other Clinical Data Analyses Summaries with the detailed descriptive statistics will be generated for the EKG data. Study Timetable Projected number of patients: Projected completion of patient accrual (last-patient-in [LPI]):July 2012 Patient study end date (last-patient-last-visit [LPLV]):July 2013 Study Flowchart - 12 Lead EKG for Visit 2, Visit 3, Visit 4/ET - Safety Follow Up Visit (Day 360 ±10) Skin and oral mucosal examination by a dermatologist End of Study EPP Questionnaire 12 Lead EKG Scoring the DLQI and EPP-QoL The DLQI will be scored according to the scoring method published on the following website: Rationale Expansion and clarification of the method for handling missing data in the analysis of results Addition of EKG for safety monitoring Correction of inconsistency in previous version of protocol Amendment of timeline to be consistent with the extension of the follow up period from 3 to 6 months Addition of EKG for safety monitoring Amendment of timeline to be consistent with the extension of the follow up period from 3 to 6 months Inclusion of details of the scoring method for the DLQI quality of life assessment tool 26 July 2012 Page 3

117 Clinuvel Inc. A Phase III, Multicentre, Double-Blind, Randomized, Placebo-Controlled Study to Confirm the Safety and Efficacy of Subcutaneous Bioresorbable Afamelanotide Implants in Patients with Erythropoietic Protoporphyria (EPP) Confidential CUV039 Study Protocol Summary of Changes from Ver. 2 (17Jul12) to Ver. 3 (18Mar13) Section and Description of Change Rationale page number Cover page Version 3: March 18, 2013 Administrative change. Cover page 40 Worth Street, Level 10 New York, NY USA (646) (Phone) (646) (Fax) Signature of Version 3: March 18, 2013 Agreement Pg.1 Signature of Agreement Pg.1 Serious Adverse Events Pg. 27 Serious Adverse Events Pg. 28 QOL Questionnaire Pg. 49 Footer of all pages Sponsor representative Dr Dennis Wright Acting Chief Scientific Officer Reporting telephone number of Clinuvel is (646) Reporting fax number of Clinuvel: (646) Question 10: Over the last two months, has EPP limited your ability to undertake activities in a spontaneous manner? Compared to the same period last year... Question 11: Over the last two months, how often have you not worn protective clothing on a sunny day? Compared to the same period last year... Version 3: March 18, 2013 Administrative change: update of Clinuvel US office address and telephone/ fax numbers. Administrative change. Administrative change. Administrative change: update of Clinuvel US office telephone number. Administrative change: update of Clinuvel US office fax number. Administrative change/ typographic error: questions 10 and 11 are a repeat of questions 8 and 9. Administrative change.

118 Clinuvel Inc. Confidential A Phase III, Multicentre, Double-Blind, Randomized, Placebo-Controlled Study to Confirm the Safety and Efficacy of Subcutaneous Bioresorbable Afamelanotide Implants in Patients with Erythropoietic Protoporphyria (EPP) CUV039 Study Protocol Summary of Changes from Ver. 3.0 (18MAR13) to Ver. 4.0 (17JUN13) Section and page number Description of Change Rationale Cover Page Version 4: June 17, 2013 Administrative change. Signature of Agreement Pg. 1 Synopsis Criteria for Evaluation Pg.4 Synopsis Criteria for Evaluation Pg.4 Synopsis Statistical Methods Pg. 5 Specification of Primary Efficacy Endpoint Pg. 30 Specification of Secondary Efficacy Endpoint Pg. 31 Specification of Secondary Efficacy Endpoint Pg. 31 Primary Efficacy Analysis Pg. 33 FINAL - 17JUN13 Version 4: June 17, 2013 Changed from pain score of 0 to Likert score of 0 Duration of direct sunlight exposure between 10:00 and 15:00 hours on days when no pain was experienced (Likert score of 0) The difference in the patient s average daily duration of direct sunlight exposure between 10:00 and 15:00 hours on days when no pain was experienced (Likert score of 0) between the treatment groups will be assessed using the Kruskal-Wallis test. Changed from pain score of 0 to Likert score of 0 Changed from pain scores of 0-3 to Likert scores of 0-3 Duration of sun exposure (hours in direct sunlight) between 10:00 and 15:00 hours on days when no pain was experienced (Likert score of 0). Changed from pain score of 0 to Likert score of 0 Administrative change. Wording change to maintain consistency. Additional secondary endpoint analysis of a subset of data from the primary endpoint i.e. an assessment of 10:00 to 15:00 hours. The primary endpoint is for 10:00 to 18:00 hours. Additional secondary endpoint analysis of a subset of data from the primary endpoint i.e. an assessment of 10:00 to 15:00 hours. The primary endpoint is for 10:00 to 18:00 hours. Wording change to maintain consistency. Wording change to maintain consistency. Additional secondary endpoint analysis of a subset of data from the primary endpoint i.e. an assessment of 10:00 to 15:00 hours. The primary endpoint is for 10:00 to 18:00 hours. Wording change to maintain consistency. Page 1

119 Clinuvel Inc. Confidential Section and page number Description of Change Rationale Secondary Efficacy Analyses Pg. 33 Secondary Efficacy Analyses Pg. 33 Changed from pain scores of 0-3 to Likert scores of 0-3 The mean daily duration of sun exposure (hours in direct sunlight) between 10:00 and 15:00 hours on days when no pain was experienced (Likert score of 0) will be calculated for each patient and compared between the treatment arms using the Kruskal-Wallis test. Wording change to maintain consistency. Footer for all pages V 4: June 17, 2013 Administrative change. Additional secondary endpoint analysis of a subset of data from the primary endpoint i.e. an assessment of 10:00 to 15:00 hours. The primary endpoint is for 10:00 to 18:00 hours. FINAL - 17JUN13 Page 2

120 D Statistical Analysis Plan Protocol No.: CUV039 Statistical Analysis Plan CUV039 TITLE: A PHASE III, MULTICENTRE, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED STUDY TO CONFIRM THE SAFETY AND EFFICACY OF SUBCUTANEOUS BIORESORBABLE AFAMELANOTIDE IMPLANTS IN PATIENTS WITH ERYTHROPOIETIC PROTOPORPHYRIA (EPP). STUDY SPONSOR: Clinuvel Pharmaceuticals Limited Level Queen Street Melbourne VIC 3000 SPONSOR CONTACT: Dennis Wright PhD Vice President, Scientific Affairs Clinuvel AG Neuhofstrasse 3D 6340 Baar Switzerland Tel: Tel: Fax: Fax: Document History: Document Version Version Date Statistical Analysis Plan CUV039 Final 09 May 2013 CONFIDENTIALITY STATEMENT: All information concerning the study drug supplied by the Sponsor in connection with this study, and not previously published, is considered confidential and proprietary information. This information includes the Investigator s Brochure, clinical protocol, subject information and informed consent, and case report forms. This confidential information shall remain the sole property of the Sponsor, shall not be disclosed to others without prior written consent from the Sponsor and shall not be used except in the performance of this study. The information developed during the conduct of this clinical study is also considered confidential and will be used by the Sponsor in connection with the development of the study drug. This information may be disclosed as deemed necessary by the Sponsor. CONFIDENTIAL Page 1 of 18 Final, 09 May 2013

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122 D Statistical Analysis Plan Protocol No.: CUV039 TABLE OF CONTENTS 1. Scope of the Statistical Analysis Plan Relevant CPR Standard Operating Procedures and Guidances Introduction General Design Study Objectives Study Treatment Sample Size Study Endpoints Data Listings and Summary tables Sources of Data Patient Randomisation Number Maintaining the Study Blind Assessment Time Point Identifiers Data Derived by Calculation Analysis Packages Descriptive Statistics in Summary Tables Handling of Missing Data Adjustment for Multiplicity Coding Abbreviations Safety and Subject Disposition Data Safety Population Safety Assessments Subject Disposition Analysis Safety Data Presentation and Analysis Efficacy Data Efficacy Analysis Set Efficacy Assessments Efficacy Presentation and Analysis Data Listings and Summary Tables Preliminary Data Analysis Listings and Tables for Clinical Study Report Data Transfer to the Study Sponsor General Considerations for Data Management and Analysis Electronic Data Management Electronic Data Security and Back-up Archiving APPENDICES Appendix 1: Planned Data Listings Appendix 2: Planned Summary Tables Appendix 3: Study Data Overview CONFIDENTIAL Page 3 of 18 Final, 09 May 2013

123 D Statistical Analysis Plan Protocol No.: CUV SCOPE OF THE STATISTICAL ANALYSIS PLAN This Statistical Analysis Plan is an adjunct to Clinuvel Pharmaceuticals Ltd Study CUV039, Protocol Version 2: 17 July The Statistical Analysis Plan details the procedures for the statistical methods used in the analysis of the data. 2. RELEVANT CPR STANDARD OPERATING PROCEDURES AND GUIDANCES The following CPR SOPs are relevant to this Statistical Analysis Plan: SOP S-DM-002 Clinical Data Analysis and Presentation SOP S-DM-010 Statistical Analysis Plans 3. INTRODUCTION 3.1. General Design This was a randomized placebo-controlled study conducted in two parallel study arms for a six month period (three doses). It was planned that between 75 and 100 eligible patients would be enrolled. A screening evaluation was conducted up to 14 days prior to commencement to determine patient eligibility. Patients were randomized to receive afamelanotide (16 mg implants) or placebo according to the following dosing regimen: - Group A, administered afamelanotide implants on Days 0, 60 and 120, or - Group B, administered placebo implants on Days 0, 60 and 120. The number and severity of phototoxic reactions, the type and duration of sun exposure, treatmentemergent adverse events and the use of concomitant medication were recorded by patients in study diaries between Days 0 and 180. Quality of life was measured using the EPP-QoL and DLQI questionnaires at Days 0, 60, 120 and 180. Participants visited the clinic on Days 60, 120 and 180 for assessments of adverse events. All patients had an EKG performed at each study visit (from Day 60 onwards). A subset of patients were photoprovoked on the lower back and dorsal surface of the hand and the minimal symptom dose (MSD) was determined on Days 0, 30, 60, 90 and 120. The target number of patients for photoprovocation was 20. Six months after completion of the efficacy assessment (Day 360), it is planned that patients will return to the study site for a full safety assessment, including an evaluation of the reversibility of pigmentation of the epidermis. At this time an additional quality of life questionnaire will be administered, an inventory of activities taken and EKG procedure will be performed Study Objectives Primary: To determine whether afamelanotide can enable EPP patients to expose themselves to sunlight without incurring pain and phototoxic reactions. Secondary: Determine whether afamelanotide implants can: o improve the quality of life of EPP patients o reduce the susceptibility to provocation with a standardized light source (minimum symptom dose) in patients with EPP Evaluate the safety and tolerability of afamelanotide by measuring treatment-emergent adverse events (TEAEs) and investigate the reversibility of afamelanotide-induced increase in dermal pigmentation. CONFIDENTIAL Page 4 of 18 Final, 09 May 2013

124 D Statistical Analysis Plan Protocol No.: CUV Study Treatment Subjects will be administered three doses of afamelanotide (16 mg) or placebo as subcutaneous implants on Days 0, 60 and Sample Size Analysis of data from the CUV029 and CUV030 studies demonstrated that a significant difference in the primary endpoint of the study could be detected with approximately patients Study Endpoints Primary efficacy endpoint: Duration of time (hours) spent in direct sunlight between 10:00 and 18:00 hours on days when no pain was experienced (pain score of 0 on a 0-10 Likert scale). Secondary efficacy endpoints: Combined sun exposure and phototoxic pain Duration of direct sunlight exposure (hours in direct sunlight) between 10:00 and 18:00 hours on days when no pain or mild pain was experienced (pain scores of 0-3 on a 0-10 Likert scale). Sun exposure Duration of direct sunlight exposure (hours in direct sunlight) between 10:00 and 18:00 during the study. Quality of life Quality of life assessment score according to the DLQI and EPP-QoL questionnaires. Photoprovocation (in a subset of patients (target n=20)) The minimum symptom dose following photoprovocation on the lower back and dorsal surface of the hand, determined using the irradiation dose of the light source and the time to first development of symptoms at the site of photoprovocation. Phototoxicity phototoxic pain o The maximum and total pain severity scores (0-10 Likert scale) for phototoxic episodes. o The number of phototoxic episodes during the study. The primary safety endpoint will be the type and incidence of treatment emergent adverse events. The secondary safety endpoints will be: Any significant abnormalities detected in EKG. Physical examination changes from Screening. Changes in blood pressure and heart rate from Screening to all subsequent visits. Changes in clinical chemistry, hematology and urinalysis parameters from Screening to all subsequent visits. 4. DATA LISTINGS AND SUMMARY TABLES 4.1. Sources of Data CPR will establish a study specific electronic database from which data listings and summary tables will be generated for the Final Report. The database will record the data from Screening through to the Follow-up Safety Visit of the study. Analysis datasets will be generated from the data extracted from the study database, along with the following data entered separately or received from other sources: Randomisation, provided by the unblinded monitors 4.2. Patient Randomisation Number The study was conducted at 7 study sites. The patient randomization number is a four digit number of the format snnn, s is a site indicator, and nnn is a sequence number within each site. CONFIDENTIAL Page 5 of 18 Final, 09 May 2013

125 D Statistical Analysis Plan Protocol No.: CUV039 To account for the differences in climatic conditions between the study sites and the potential impact that this would have on phototoxicity experienced, a computer generated randomization list for each study site was used to assign each patient to a treatment arm. To ensure that treatment was balanced within study sites, the randomization method used a small block size. Five individually sealed sets of computer-generated randomization codes (each set containing 48 randomized numbers) were provided to the pharmacy. The study pharmacist chose one of the five sealed envelopes and the selected randomization list was used to randomize the subjects in this study. For each study site, patients who satisfied the inclusion/exclusion criteria were allocated patient randomization numbers sequentially and chronologically, based on the timing of their attendance at the clinic for the first study implant. The listings for inclusion in an appendix to the report will be prepared after the study has been unblinded following database lock. In the listings, subjects will be identified by randomisation number Maintaining the Study Blind In this double blind study, all personnel involved, i.e. physicians, site staff, and participants were to remain blinded at all times, except in an emergency where knowledge of the codebreak was required to provide appropriate treatment. A partial unblinding will occur following data management entry of efficacy assessments and diary entries at 6 months (including data entry, validation, and query resolution), to allow for an interim efficacy analysis to be performed, The only personnel to be unblinded for the interim efficacy analysis are the CPR analysis team (including the biostatisticians performing the unblinded efficacy analysis), and Dennis Wright PhD (Vice President, Scientific Affairs, Clinuvel). The study blind will be maintained for physicians, site staff, participants, CPR data management group, monitors, and all other Clinuvel personnel, until after database lock following the12-month follow-up safety visits Assessment Time Point Identifiers In the data listings for the report, scheduled assessment time points will be identified as follows: Screening Study Day for on-study assessments scheduled to be performed only once on any day Visit Number for on-study assessments scheduled to be performed only once at any visit 4.5. Data Derived by Calculation The following data fields for inclusion in the data listings will be derived by calculation: Age (in integer years), calculated as (Screening Date Date of Birth) Treatment-emergent Indicator for adverse event, assigned as Treatment-Emergent if (Onset Date + Onset Time) >= (Date of First Dose + Time of First Dose) Non Treatment-Emergent if (Onset Date + Onset Time) < (Date of First Dose + Time of First Dose) Adverse event time since first dose (in hours, to one decimal place), calculated as (Onset Date + Onset Time) (Date of First Dose + Time of First Dose) Adverse event duration (in hours, to one decimal place), calculated as (Resolution Date + Resolution Time Onset Date - Onset Time) 4.6. Analysis Packages SAS 9.2 or higher (SAS Institute Inc., Cary, NC, USA) will be used for statistical analysis, including generating data listings and summary tables. CONFIDENTIAL Page 6 of 18 Final, 09 May 2013

126 D Statistical Analysis Plan Protocol No.: CUV039 Microsoft Excel 2003 or higher (Microsoft Corporation) may be used for the preparation of summary tables and graphical presentations for inclusion in the body of the Clinical Study Report Descriptive Statistics in Summary Tables Summaries will be provided by treatment and overall, as appropriate. For safety and subject disposition data, quantitative data will be summarised by descriptive statistics, including number of subjects, mean, standard deviation, minimum, maximum, and median where appropriate. Qualitative data will be summarised by count per category, and number and percentage of subjects within group or overall, where appropriate Handling of Missing Data The initial analysis will be performed on the available data, with no imputation for missing efficacy data points. A response of No to the question Have you experienced any reaction to light today? will be treated as a pain severity score of zero. A response of No to the question Did you spend any time outdoors today? will be treated as zero time spent in direct sunlight. Database entry of diaries with some dates will be addressed by data management procedures, as described in Appendix 4, which also includes data management procedures for other inconsistencies, such as invalid and duplicate entries. Missing data will be imputed for sensitivity analyses. The following imputation rules supersede those proposed in section of the protocol. For assessment of the number of phototoxic reactions, days with missing phototoxic pain scores will have two forms of imputation. These will be that the patient either did not or did have a phototoxic reaction, providing a best and worst case assessment, as follows: Missing pain scores best case assessment: all missing pain scores will be imputed as zero. Missing pain scores worst case assessment: missing pain scores will be imputed as a score indicative of a phototoxic reaction (i.e. a score of at least 4 on the 0-10 Likert scale). o o o Missing pain scores will be set to a score of 4 on the 0-10 Likert scale. This score, which is the lowest pain score indicative of a phototoxic reaction, was the upper quartile value of non-zero pain scores as reported in previous studies in EPP patients. However, if the last reported known pain score immediately preceding a missing value is greater than 4, than the missing value will be imputed by the last reported known pain score. This is consistent with the imputation rule in section , which states Where limited numbers of phototoxic pain scores are missing, the last reported value will be entered for the missing value(s). In the event that the upper quartile value of non-zero pain scores reported in this study is greater than 4 on the 0-10 Likert scale, this higher value will be used as the default value for imputation of missing pain scores. For assessment of the exposure to direct sunlight, days with time in direct sunlight will have two forms of imputation. These will be that the patient either did not or did spend some time in direct sunlight, providing a best and worst case assessment, as follows: Missing time in direct sunlight best case: all missing time in direct sunlight will be imputed as 2 hours, which was the upper quartile value of non-zero time outdoors, regardless of direct sunlight/shade exposure type as reported in previous studies in EPP patients. In the event that the upper quartile value of time in direct sunlight reported in this study is greater than 2 hours, this higher value will be used as the default value for imputation of missing pain scores. Missing time in direct sunlight worst case: all missing time in direct sunlight will be imputed as zero hours Adjustment for Multiplicity There will be no adjustments of p-values / confidence intervals due to multiple testing. CONFIDENTIAL Page 7 of 18 Final, 09 May 2013

127 D Statistical Analysis Plan Protocol No.: CUV Coding Abbreviations The following coding abbreviations will be used in data listings, as appropriate, and included in the key in a footnote: CS LOQ NA NCS ND NR NRQ NS UK or UNK Clinically significant Limit of Quantification Not applicable Not clinically significant Test is not done Not recorded Not required No sample obtained Unknown 5. SAFETY AND SUBJECT DISPOSITION DATA 5.1. Safety Population The Safety Population will include all enrolled participants. In the protocol (section 5.7.5), it was stated that participants screened but not enrolled would be shown in separate listings. However, no data for inclusion in the study database have been collected for these patients, thus there will be no listings pertaining to patients screened but not enrolled Safety Assessments Adverse events and concomitant medications used: Continuous monitoring throughout the study period Vital signs (blood pressure, temperature and pulse rate): Screening Day 60 Day 120 Day 180 (or at Early Termination Visit, if applicable). Clinical laboratory tests (Biochemistry, Haematology, and Urinalysis): Screening Day 60 Day 120 Day 180 (or at Early Termination Visit, if applicable). EKG: Day 60 Day 120 Day 180 (or at Early Termination Visit, if applicable). Physical examination including all major organ systems: Screening CONFIDENTIAL Page 8 of 18 Final, 09 May 2013

128 D Statistical Analysis Plan Protocol No.: CUV039 Day 180 (or at Early Termination Visit, if applicable). Weight: Screening (and height, for determination of Body Mass Index (BMI)) Day 180 (or at Early Termination Visit, if applicable) Subject Disposition Analysis Details of participation will be tabulated by subject. Completion status will be summarised by treatment group. Demographics will be tabulated by subject and summarised by treatment group and overall. Details of administration of investigational product will be tabulated by subject. Exposure to investigational product will be summarised by treatment group. Medical history data and physical examination data at baseline will be listed by subject. Any untoward findings identified on physical examinations after the administration of the first dose of study medication will be captured as an adverse event if those findings meet the definition of an adverse event as defined in the protocol. Protocol deviations will be tabulated by subject. A summary of protocol deviations will be prepared for inclusion in the clinical study report Safety Data Presentation and Analysis All clinical safety and tolerability data will be listed for each subject. Adverse events, concomitant medications, clinical laboratory parameters, vital signs and EKG parameters for each subject will be tabulated in data listings. Descriptive methods will be used to summarize the safety data. These will be based upon the safety population. Safety data will be summarized descriptively in tabular form. Summaries of key safety data assessed over time may also be presented in graphical form, as appropriate. Where summaries include changes from baseline, the baseline value will be the most recent assessment prior to administrations of study treatment. Where measurements have been taken more than once prior to the scheduled baseline visit, baseline measurements will be taken as the last available data measured prior to this time point. If the baseline measurement is missing but there is a prior measurement recorded, this value will be carried forward and used as the baseline measurement. All adverse events, including non-treatment emergent events, will be listed. A treatment emergent adverse event will be: An event that was not present prior to or on the day of the first study medication administration but was present after study medication was administered. An event that was present prior to first administration of study medication and continued to occur after the administration of the first dose at an increased level of severity. An event that was present prior to administration of study medication and was documented as completely resolved and re-emerged after the administration of the first dose. The MedDRA adverse event dictionary will be used to map verbatim adverse event terms to preferred terms and body systems. The number of participants with treatment-emergent adverse events will be summarized by preferred term and body system for each treatment group. Treatmentemergent events will be further summarized by intensity, seriousness and relationship to study medication. The number of participants who early terminate treatment due to adverse events related to study medication will be tabulated. Summaries of the incidence of toxicities will be prepared, as appropriate. Serious adverse events and adverse events of special interest will be listed individually. If a serious adverse event occurs prior to the first dose of the study medication, this will be noted in the study report. CONFIDENTIAL Page 9 of 18 Final, 09 May 2013

129 D Statistical Analysis Plan Protocol No.: CUV039 AEs will be summarised by treatment, grouped according to system organ class and preferred term, and tabulated with descriptive statistics, where appropriate. Laboratory data for biochemistry, hematology and urinalysis will be summarized by descriptive statistics by treatment and assessment including changes from screening to each visit. Additionally shift tables with respect to the normal ranges will be generated from screening to each visit. Clinically significant laboratory results will be listed separately. All summaries of clinical laboratory data will include scheduled data collection points only. The duration of study drug exposure and the number of participants exposed will be evaluated descriptively. Separate summaries with the detailed descriptive statistics will be generated and assessment for the EKG data Vital signs (systolic/diastolic blood pressure, temperature and pulse rate) will be tabulated and summarised by treatment and study timepoint. A summary of changes from pre-dose baseline will also be presented. Changes in physical examination and body weight and concomitant medications will be listed and summarized by frequency tables, if appropriate. 6. EFFICACY DATA 6.1. Efficacy Analysis Set The intent-to-treat (ITT) population will include all treated participants, who provide at least one post dose efficacy assessment. This will be the main population for all efficacy analyses. The efficacy evaluable population of study completers will include all ITT population members who did not prematurely terminate the study and provided data to Day 180 (Visit 4). This population may be used for supplementary efficacy analyses. Summaries of efficacy assessments will be presented for the ITT analysis set, by treatment group, with supplementary summaries of key endpoints for the study completers Efficacy Assessments Pain and phototoxicity: Daily recordings throughout the study period in study diary Phototoxicity defined as a pain score of at least 4 on a 0-10 Likert scale Phototoxic episode defined as consecutive days with a pain score of at least 4 on each day Direct sunlight exposure: Daily recordings throughout the study period in study diary Quality of Life (DLQI and EPP-QoL): Day 0 Day 60 Day 120 Day 180 (or Early Termination Visit, if applicable) Photoprovocation (a subset of patients only): Day 0 prior to implant Day 30 Day 60 prior to implant Day 90 CONFIDENTIAL Page 10 of 18 Final, 09 May 2013

130 D Statistical Analysis Plan Protocol No.: CUV039 Day 120 prior to implant 6.3. Efficacy Presentation and Analysis Efficacy assessment will be tabulated for each subject, and summarized with descriptive statistics by treatment group. Combined sun exposure (phototoxic pain = none) The primary efficacy endpoint is the duration of time (hours) spent in direct sunlight between 10:00 and 18:00 hours on days when no pain was experienced (pain score of 0). The mean daily duration in direct sunlight exposure will be calculated for each patient and compared between the treatment arms using a Kruskal-Wallis test with a significance level of p<0.05. H 0 : there is no difference between the treatment arms in the time spent in direct sunlight on days when no phototoxic pain was reported. Combined sun exposure (phototoxic pain = none or mild) The mean daily duration of sun exposure (hours in direct sunlight) between 10:00 and 18:00 hours on days when no pain or mild pain was experienced (pain scores of 0-3) will be calculated for each patient and compared between the treatment arms using the Kruskal-Wallis test. Sun exposure The mean daily duration of sun exposure (hours in direct sunlight) between 10:00 and 18:00 during the study will be calculated for each patient and compared between the treatment arms using the Kruskal-Wallis test. Quality of life A between groups comparison of the change from baseline to each time point in the quality of life assessment scores (DLQI and EPP-QoL questionnaires) will be performed using the Kruskal-Wallis test. The DLQI will be scored according to the scoring method published on the following website: The EPP-QoL will be scored in accordance with Appendix 5 of the protocol. Photoprovocation (in a subset of patients (target n=20)) A between groups comparison of the change from baseline to each time point in the minimum symptom dose following photoprovocation on the lower back and dorsal surface of the hand will be performed using the Kruskal-Wallis test. Phototoxicity phototoxic pain The maximum and total pain severity scores (Likert scale) for phototoxic episodes. The number of phototoxic episodes per subject reported by the patient during the study. A between groups comparison of the scores for each of the above parameters will be performed using the Kruskal-Wallis test. 7. DATA LISTINGS AND SUMMARY TABLES 7.1. Preliminary Data Analysis An analysis will be performed on unblinded efficacy data after all subjects have reached Day 180, with restrictions on the unblinding as noted above in Section 4.3. The results of this analysis will only be made available in summary form, in such a way that the treatment allocation is not revealed for any individual subject. A clinical study report will be prepared following the Safety Follow Up Visit (Day 360). This will include the analysis of all safety results and a final analysis of the efficacy results, updated from the Day 180 results to include data for the additional quality of life assessments performed at the Safety Follow Up Visit (Day 360) CONFIDENTIAL Page 11 of 18 Final, 09 May 2013

131 D Statistical Analysis Plan Protocol No.: CUV Listings and Tables for Clinical Study Report Tabulated data and summary tables will be provided to the Sponsor in a form suitable for inclusion as appendices to the Clinical Study Report, in RTF or PDF format. The data listings and summary tables planned to be generated from the study data are listed in Appendix 1 and Appendix 2, respectively. The numbering and titles may vary in the final presentation, depending on the amount of data to be presented. Draft tables will be provided to the Sponsor for review prior to final analysis. Results of the statistical analyses will be retained in the CPR study file for reference Data Transfer to the Study Sponsor Results of statistical analysis will be tabulated and provided to the Sponsor as appendices to the Clinical Study Report or retained in the Study File for reference as appropriate. At the conclusion of the study, CPR will provide the Sponsor with an electronic copy of the listings, tables and graphs. This may be provided by , by FTP upload, or on transportable electronic media such as CD/DVD, as determined by the Sponsor. 8. GENERAL CONSIDERATIONS FOR DATA MANAGEMENT AND ANALYSIS 8.1. Electronic Data Management All listings, tables and figures for inclusion in the appendices of the clinical study report will be generated using SAS programs. A copy of final listings, tables and figures will be printed and retained in the CPR Study File. Each paper version of the listings, tables and figures will bear the date and initials of the staff member responsible for generating the listing, table or figure, and the staff member conducting the quality control review. Any erroneous results identified during the checking process will be corrected by update of the SAS program, and the document recreated. A new hard copy of the document will be printed and then re-checked. To ensure an accurate data trail is maintained, corrections to electronic documents will be supported by paper records marked as superseded and detailing the corrective action and the date and initials of the verifying CPR staff member. If statistical analysis is repeated with a modified data set, the new data produced will be saved as a new file Electronic Data Security and Back-up Electronic documents containing study data will be password protected at all times and access will only be available to authorised CPR staff. A backup of all computer records will be performed daily Archiving At the conclusion of the study, the database will be archived. Copies will be retained in the CPR study file for a minimum of 15 years, and in the CPR secure archives in accordance with CPR standard operating procedures. CONFIDENTIAL Page 12 of 18 Final, 09 May 2013

132 D Statistical Analysis Plan Protocol No.: CUV039 Appendix 1: Planned Data Listings The following listings are planned to be generated for this study: Subject Information Listing Subject Enrollment Listing Conclusion of Study Participation Listing Protocol Deviations and Violations Listing Inclusion Criteria Listing Exclusion Criteria Listing Analysis Populations Listing EPP Medical History Listing Demographics and Baseline Characteristics Listing Vital Signs at Screening and Baseline Visits Listing Medical History Listing Physical Examination Listing Skin Appearance Listing Ophthalmological Examination Listing Dermatological Examination (Cutaneous) Listing Dermatological Examination (Oral Cavity) Listing Skin Cancer Risk Factors Listing Previous Prophylactic Medications Listing Full Body Photography Listing Study Drug Administration and Compliance Listing Adverse Events Listing Serious Adverse Events Listing Hematology Results Listing Biochemistry Results Listing Urinalysis Results Listing EKG Assessments Listing Pregnancy Testing Listing Concomitant Medications Listing Photoprovocation Listing Patient Diary Data Listing Dermatology Quality of Life Index Listing EPP On-Study Questionnaire Listing EPP Baseline Questionnaire Listing EPP Status at Baseline Listing EPP Followup Questionnaire CONFIDENTIAL Page 13 of 18 Final, 09 May 2013

133 D Statistical Analysis Plan Protocol No.: CUV039 Appendix 2: Planned Summary Tables The following summary tables are planned to be produced, however the table numbers and titles may vary, depending on the amount of data to be presented. If figures are prepared for inclusion in the body of the clinical study report, then corresponding figures will be added in Section Baseline and Demographic Data Table Enrollment Summary: Safety Population Table Patient Disposition Summary: Safety Population Table Fitzpatrick Skin Type and Skin Cancer Risk Factor: Safety Population Table a Demographics and Baseline Characteristics: Safety Population Table b Demographics and Baseline Characteristics: ITT Population Table c Demographics and Baseline Characteristics: Study Completers Table a Baseline Disease Characteristics: Safety Population Table b Baseline Disease Characteristics: ITT Population Table c Baseline Disease Characteristics: Study Completers Note: if the safety population and ITT population are the same, then only one set of summaries will be produced for this population, and the tables will be renumbered accordingly Efficacy Data Table Summary by Subject of Reported Sunlight Exposure and Pain: ITT Population Table Summary by Subject of Reported Sunlight Exposure and Pain: Study Completers Table Summary by Subject of Reported Sunlight Exposure and Pain: ITT Population, Best Case Imputation Table Summary by Subject of Reported Sunlight Exposure and Pain: ITT Population, Worst Case Imputation Table Reported Sunlight Exposure, When Patients Experienced No Pain: Study Completers Table Reported Sunlight Exposure, When Patients Experienced No Pain: ITT Population Table Reported Sunlight Exposure, When Patients Experienced No Pain: ITT Population, Best Case Imputation Table Reported Sunlight Exposure, When Patients Experienced No Pain: ITT Population, Worst Case Imputation Table Reported Sunlight Exposure, When Patients Experienced No Pain or Mild Pain: ITT Population Table Reported Sunlight Exposure, When Patients Experienced No Pain or Mild Pain: Study Completers Table Reported Sunlight Exposure, When Patients Experienced No Pain or Mild Pain: ITT Population, Best Case Imputation CONFIDENTIAL Page 14 of 18 Final, 09 May 2013

134 D Statistical Analysis Plan Protocol No.: CUV039 Table Reported Sunlight Exposure, When Patients Experienced No Pain or Mild Pain: ITT Population, Worst Case Imputation Table Reported Sunlight Exposure Throughout the Whole Study: ITT Population Table Reported Sunlight Exposure Throughout the Whole Study: Study Completers Table Reported Sunlight Exposure Throughout the Whole Study: ITT Population, Best Case Imputation Table Reported Sunlight Exposure Throughout the Whole Study: ITT Population, Worst Case Imputation Table Quality of Life - DLQI Questionnaire by Item: ITT Population Table Quality of Life - DLQI Questionnaire by Item: Study Completers Table Quality of Life - Supplementary EPP Specific Questionnaire by Item: ITT Population Table Quality of Life - Supplementary EPP Specific Questionnaire by Item: Study Completers Table Changes in Quality of Life DLQI Questionnaire: ITT Population Table Changes in Quality of Life DLQI Questionnaire: Study Completers Table Changes in Quality of Life Supplementary EPP Specific Questionnaire: ITT Population Table Changes in Quality of Life Supplementary EPP Specific Questionnaire: Study Completers Table Minimum Symptom Dose Following Photoprovocation on the Dorsal Surface of Hand: Subset of ITT Population Table Minimum Symptom Dose Following Photoprovocation on the Dorsal Surface of Hand: Subset of Study Completers Table Minimum Symptom Dose Following Photoprovocation on the Lower Back: Subset of ITT Population Table Minimum Symptom Dose Following Photoprovocation on the Lower Back: Subset of Study Completers Table Number of Phototoxic Episodes per Subject Over the Entire Study: ITT Population Table Number of Phototoxic Episodes per Subject Over the Entire Study: ITT Population Table Number of Phototoxic Episodes per Subject Over the Entire Study: ITT Population, Best Case Imputation Table Number of Phototoxic Episodes per Subject Over the Entire Study: ITT Population, Worst Case Imputation Table Maximum and Total Severity Score Per Phototoxic Episode: ITT Population Table Maximum and Total Severity Score Per Phototoxic Episode: ITT Population Table Maximum and Total Severity Score Per Phototoxic Episode: ITT Population, Best Case Imputation Table Maximum and Total Severity Score Per Phototoxic Episode: ITT Population, Worst Case Imputation CONFIDENTIAL Page 15 of 18 Final, 09 May 2013

135 D Statistical Analysis Plan Protocol No.: CUV039 Figure Distribution Over a Day of Number of Subjects Spending Time in Direct Sunlight: ITT Population Figure Distribution Over a Day of Number of Subjects Spending Time in Direct Sunlight: Study Completers Figure Distribution of Total Time Spent in Direct Sunlight per Subject: ITT Population Figure Distribution of Total Time Spent in Direct Sunlight per Subject: Study Completers 14,3 Safety Data / Adverse Events Table Extent of Exposure to Study Drug: Safety Population Table Overall Summary of Treatment-Emergent Adverse Events: Safety Population Table Treatment-Emergent Adverse Events by System Organ Class and Preferred Term: Safety Population Table Serious Adverse Events: Safety Population Table Treatment Emergent Adverse Events by Relationship: Safety Population Table Treatment Emergent Adverse Events by Severity: Safety Population Table Summary of Haematology Results: Safety Population Table Summary of Biochemistry Results: Safety Population Table Summary of Urinalysis Results: Safety Population Table Shift Table for Haematology Results: Safety Population Table Shift Table for Biochemistry Results: Safety Population Table Shift Table for Urinalysis Results: Safety Population Table Summary of Vital Signs Data: Safety Population Table Summary of Body Weight: Safety Population Table Summary of EKG Assessments: Safety population Table Summary of Physical Examination Data: Safety Population CONFIDENTIAL Page 16 of 18 Final, 09 May 2013

136 D Statistical Analysis Plan Protocol No.: CUV039 Appendix 3: Study Data Overview Study Procedure Informed consent taken Inclusion and exclusion criteria review Demographic information collected Medical history taken Skin cancer risk factor questions completed General physical examination including ophthalmic examination Skin and oral mucosal examination by a dermatologist Screening Visit 1 Visit 1b Visit 2 Visit 2b Visit 3 Visit 4 Up to -14 days X X X X X X Day 0 Day 30 Day 60 Day 90 Day 120 X (Day 180) or Early Termination X X X X Full body photography X X Vital signs X X X X X Weight / height measurement X 1 X Hematology and blood chemistry X X X X Urinalysis X X X X 12 Lead EKG X X X Pregnancy test (serum β-hcg) Quality of life assessment (DLQI and EPP-QoL) Introduction to use of diary X X X X X X Issue study diary X X X Pregnancy test (urine dipstick) X 2 X 2 X 2 X Photoprovocation X 3 X X 3 X X 3 Implant insertion X X X Adverse events review X X X X Concomitant medication review X X X X X Phototoxic reaction review X X X X 1 Height will be measured at Screening only to allow calculation of body mass index (BMI). X 2 Implant insertion only after confirmation that female patients are not pregnant. X 3 Photoprovocation prior to implant administration (in a subset of subjects only). Safety Follow Up Visit (Day 360 ± 10) Skin and oral mucosal examination by a dermatologist End of Study EPP Questionnaire 12 Lead EKG X CONFIDENTIAL Page 17 of 18 Final, 09 May 2013

137 D Statistical Analysis Plan Protocol No.: CUV039 Appendix 4: Data Management of Missing, Duplicate or Invalid Diary Entries The following rules will be applied in data management of diaries with missing, duplicate or invalid dates. Where the same dates are duplicated on two different diaries: o diary entries later than the date of the next visit will not be entered into the database when there is an entry with the same date in the next diary issued at that visit o diary entries prior to the visit when the diary was issued will not be entered into the database when there is an entry with the same date in the previous diary Where the same dates are duplicated within a diary: o If there is another date missing and the order of the entries is clear, then the date of the inconsistency entry will be changed to fit the logical ordering o If there are no missing dates and the data for the two entries are not identical, then a worst case approach will be used If pain scores are not the same, then data will be entered from the diary entry with the highest pain score If pain scores are the same, but total time in direct sunlight is not the same, then data will be entered from the diary entry with the longest time in direct sunlight If pain scores are the same and total time in direct sunlight are the same, but total time in shade in not the same, then data will be entered from the diary entry with the longest time in shade Where dates are not filled out: o If there is a date missing and the order of the entries is clear, then the date of the inconsistency entry will be changed to fit the logical ordering o If the number of blank dates is less than the number of dates missing, then assign the dates from the start of the interval with missing dates, and impute that data are not available for subsequent missing dates in the sequence Where invalid dates are entered in the diary: o If there is an invalid date (eg 31 Jun) and there is a missing date to provide logical ordering (e.g. 01Jul is missing), then the invalid date will be changed accordingly o If there is an invalid date (eg 31 Jun) and there is no missing date to provide logical ordering, then the data for the invalid date will not be entered The following rules will be applied in data management of diaries with missing, duplicate or inconsistent information within a daily entry. Where a non-zero pain score is given but the subject has responded No to the question Have you experienced any reaction to light today? or the response is blank, the response will be amended to Yes. Where some time in direct sunlight or shade is indicated but the subject has responded No to the question Did you spend any time outdoors today? or the response is blank, the response will be amended to Yes. Where the patient has responded Yes to the question Did you spend any time outdoors today? and no time blocks have been checked, but there is a comment in the margin of the diary about significant outdoor time outside of 10:00-18:00, the comment will be captured in the database. Where the margin note indicates that the patient spent some time in a car during the target time period, the relevant time blocks will be considered to be time spent in shade, if either the time blocks are blank for both sun and shade, or the time blocks are filled out for both sun and shade. CONFIDENTIAL Page 18 of 18 Final, 09 May 2013

138 D Statistical Analysis Plan Protocol No.: CUV039 Statistical Analysis Plan CUV039 TITLE: A PHASE III, MULTICENTRE, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED STUDY TO CONFIRM THE SAFETY AND EFFICACY OF SUBCUTANEOUS BIORESORBABLE AFAMELANOTIDE IMPLANTS IN PATIENTS WITH ERYTHROPOIETIC PROTOPORPHYRIA (EPP). STUDY SPONSOR: Clinuvel Pharmaceuticals Limited Level Queen Street Melbourne VIC 3000 SPONSOR CONTACT: Dennis Wright PhD Acting Chief Scientific Officer Clinuvel AG Neuhofstrasse 3D 6340 Baar Switzerland Tel: Tel: Fax: Fax: Document History: Document Version Version Date Statistical Analysis Plan CUV039 Final 09 May 2013 Rev 1 28 August 2013 CONFIDENTIALITY STATEMENT: All information concerning the study drug supplied by the Sponsor in connection with this study, and not previously published, is considered confidential and proprietary information. This information includes the Investigator s Brochure, clinical protocol, subject information and informed consent, and case report forms. This confidential information shall remain the sole property of the Sponsor, shall not be disclosed to others without prior written consent from the Sponsor and shall not be used except in the performance of this study. The information developed during the conduct of this clinical study is also considered confidential and will be used by the Sponsor in connection with the development of the study drug. This information may be disclosed as deemed necessary by the Sponsor. CONFIDENTIAL Page 1 of 18 Rev 1, 28 August 2013 [A of 651]

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140 D Statistical Analysis Plan Protocol No.: CUV039 TABLE OF CONTENTS 1. Scope of the Statistical Analysis Plan Relevant CPR Standard Operating Procedures and Guidances Introduction General Design Study Objectives Study Treatment Sample Size Study Endpoints Data Listings and Summary tables Sources of Data Patient Randomisation Number Maintaining the Study Blind Assessment Time Point Identifiers Data Derived by Calculation Analysis Packages Descriptive Statistics in Summary Tables Handling of Missing Data Adjustment for Multiplicity Coding Abbreviations Safety and Subject Disposition Data Safety Population Safety Assessments Subject Disposition Analysis Safety Data Presentation and Analysis Efficacy Data Efficacy Analysis Set Efficacy Assessments Efficacy Presentation and Analysis Data Listings and Summary Tables Preliminary Data Analysis Listings and Tables for Clinical Study Report Data Transfer to the Study Sponsor General Considerations for Data Management and Analysis Electronic Data Management Electronic Data Security and Back-up Archiving APPENDICES Appendix 1: Planned Data Listings Appendix 2: Planned Summary Tables Appendix 3: Study Data Overview Appendix 4: Data Management of Missing, Duplicate or Invalid Diary Entries CONFIDENTIAL Page 3 of 18 Rev 1, 28 August 2013 [A of 651]

141 D Statistical Analysis Plan Protocol No.: CUV SCOPE OF THE STATISTICAL ANALYSIS PLAN This Statistical Analysis Plan is an adjunct to Clinuvel Pharmaceuticals Ltd Study CUV039, Protocol Version 4: 17 June The Statistical Analysis Plan details the procedures for the statistical methods used in the analysis of the data. 2. RELEVANT CPR STANDARD OPERATING PROCEDURES AND GUIDANCES The following CPR SOPs are relevant to this Statistical Analysis Plan: SOP S-DM-002 Clinical Data Analysis and Presentation SOP S-DM-010 Statistical Analysis Plans 3. INTRODUCTION 3.1. General Design This was a randomized placebo-controlled study conducted in two parallel study arms for a six month period (three doses). It was planned that between 75 and 100 eligible patients would be enrolled. A screening evaluation was conducted up to 14 days prior to commencement to determine patient eligibility. Patients were randomized to receive afamelanotide (16 mg implants) or placebo according to the following dosing regimen: - Group A, administered afamelanotide implants on Days 0, 60 and 120, or - Group B, administered placebo implants on Days 0, 60 and 120. The number and severity of phototoxic reactions, the type and duration of sun exposure, treatmentemergent adverse events and the use of concomitant medication were recorded by patients in study diaries between Days 0 and 180. Quality of life was measured using the EPP-QoL and DLQI questionnaires at Days 0, 60, 120 and 180. Participants visited the clinic on Days 60, 120 and 180 for assessments of adverse events. All patients had an EKG performed at each study visit (from Day 60 onwards). A subset of patients were photoprovoked on the lower back and dorsal surface of the hand and the minimal symptom dose (MSD) was determined on Days 0, 30, 60, 90 and 120. The target number of patients for photoprovocation was 20. Six months after completion of the efficacy assessment (Day 360), it is planned that patients will return to the study site for a full safety assessment, including an evaluation of the reversibility of pigmentation of the epidermis. At this time an additional quality of life questionnaire will be administered, an inventory of activities taken and EKG procedure will be performed Study Objectives Primary: To determine whether afamelanotide can enable EPP patients to expose themselves to sunlight without incurring pain and phototoxic reactions. Secondary: Determine whether afamelanotide implants can: o o improve the quality of life of EPP patients reduce the susceptibility to provocation with a standardized light source (minimum symptom dose) in patients with EPP Evaluate the safety and tolerability of afamelanotide by measuring treatment-emergent adverse events (TEAEs) and investigate the reversibility of afamelanotide-induced increase in dermal pigmentation. CONFIDENTIAL Page 4 of 18 Rev 1, 28 August 2013 [A of 651]

142 D Statistical Analysis Plan Protocol No.: CUV Study Treatment Subjects will be administered three doses of afamelanotide (16 mg) or placebo as subcutaneous implants on Days 0, 60 and Sample Size Analysis of data from the CUV029 and CUV030 studies demonstrated that a significant difference in the primary endpoint of the study could be detected with approximately patients Study Endpoints Primary efficacy endpoint: Duration of time (hours) spent in direct sunlight between 10:00 and 18:00 hours on days when no pain was experienced (pain score of 0 on an 11-point Likert scale). Secondary efficacy endpoints: Combined sun exposure and phototoxic pain o Duration of time (hours) spent in direct sunlight between 10:00 and 15:00 hours on days when no pain was experienced (pain score of 0 on an 11-point Likert scale). o Duration of direct sunlight exposure (hours in direct sunlight) between 10:00 and 18:00 hours on days when no pain or mild pain was experienced (pain scores of 0-3 on an 11- point Likert scale). Sun exposure o Duration of direct sunlight exposure (hours in direct sunlight) between 10:00 and 18:00 during the study. Quality of life o Quality of life assessment score according to the DLQI and EPP-QoL questionnaires. Photoprovocation (in a subset of patients (target n=20)) o The minimum symptom dose following photoprovocation on the lower back and dorsal surface of the hand, determined using the irradiation dose of the light source and the time to first development of symptoms at the site of photoprovocation. Phototoxicity phototoxic pain o The maximum and total pain severity scores (11-point Likert scale) for phototoxic episodes. o The number of phototoxic episodes during the study. The primary safety endpoint will be the type and incidence of treatment emergent adverse events. The secondary safety endpoints will be: Any significant abnormalities detected in EKG. Physical examination changes from Screening. Changes in blood pressure and heart rate from Screening to all subsequent visits. Changes in clinical chemistry, hematology and urinalysis parameters from Screening to all subsequent visits. 4. DATA LISTINGS AND SUMMARY TABLES 4.1. Sources of Data CPR will establish a study specific electronic database from which data listings and summary tables will be generated for the Final Report. The database will record the data from Screening through to the Follow-up Safety Visit of the study. Analysis datasets will be generated from the data extracted from the study database, along with the following data entered separately or received from other sources: Randomisation, provided by the unblinded monitors CONFIDENTIAL Page 5 of 18 Rev 1, 28 August 2013 [A of 651]

143 D Statistical Analysis Plan Protocol No.: CUV Patient Randomisation Number The study was conducted at 7 study sites. The patient randomization number is a four digit number of the format snnn, s is a site indicator, and nnn is a sequence number within each site. To account for the differences in climatic conditions between the study sites and the potential impact that this would have on phototoxicity experienced, a computer generated randomization list for each study site was used to assign each patient to a treatment arm. To ensure that treatment was balanced within study sites, the randomization method used a small block size. Five individually sealed sets of computer-generated randomization codes (each set containing 48 randomized numbers) were provided to the pharmacy. The study pharmacist chose one of the five sealed envelopes and the selected randomization list was used to randomize the subjects in this study. For each study site, patients who satisfied the inclusion/exclusion criteria were allocated patient randomization numbers sequentially and chronologically, based on the timing of their attendance at the clinic for the first study implant. The listings for inclusion in an appendix to the report will be prepared after the study has been unblinded following database lock. In the listings, subjects will be identified by randomisation number Maintaining the Study Blind In this double blind study, all personnel involved, i.e. physicians, site staff, and participants were to remain blinded at all times, except in an emergency where knowledge of the codebreak was required to provide appropriate treatment. A partial unblinding will occur following data management entry of efficacy assessments and diary entries at 6 months (including data entry, validation, and query resolution), to allow for an interim efficacy analysis to be performed, The only personnel to be unblinded for the interim efficacy analysis are the CPR analysis team (including the biostatisticians performing the unblinded efficacy analysis), and Dennis Wright PhD (Acting Chief Scientific Officer, Clinuvel). The study blind will be maintained for physicians, site staff, participants, CPR data management group, monitors, and all other Clinuvel personnel, until after database lock following the12-month follow-up safety visits Assessment Time Point Identifiers In the data listings for the report, scheduled assessment time points will be identified as follows: Screening Study Day for on-study assessments scheduled to be performed only once on any day Visit Number for on-study assessments scheduled to be performed only once at any visit 4.5. Data Derived by Calculation The following data fields for inclusion in the data listings will be derived by calculation: Age (in integer years), calculated as (Screening Date Date of Birth) Treatment-emergent Indicator for adverse event, assigned as Treatment-Emergent if (Onset Date + Onset Time) >= (Date of First Dose + Time of First Dose) Non Treatment-Emergent if (Onset Date + Onset Time) < (Date of First Dose + Time of First Dose) Adverse event time since first dose (in hours, to one decimal place), calculated as (Onset Date + Onset Time) (Date of First Dose + Time of First Dose) Adverse event duration (in hours, to one decimal place), calculated as (Resolution Date + Resolution Time Onset Date - Onset Time) CONFIDENTIAL Page 6 of 18 Rev 1, 28 August 2013 [A of 651]

144 D Statistical Analysis Plan Protocol No.: CUV Analysis Packages SAS 9.2 or higher (SAS Institute Inc., Cary, NC, USA) will be used for statistical analysis, including generating data listings and summary tables. Microsoft Excel 2003 or higher (Microsoft Corporation) may be used for the preparation of summary tables and graphical presentations for inclusion in the body of the Clinical Study Report Descriptive Statistics in Summary Tables Summaries will be provided by treatment and overall, as appropriate. For safety and subject disposition data, quantitative data will be summarised by descriptive statistics, including number of subjects, mean, standard deviation, minimum, maximum, and median where appropriate. Qualitative data will be summarised by count per category, and number and percentage of subjects within group or overall, where appropriate Handling of Missing Data The initial analysis will be performed on the available data, with no imputation for missing efficacy data points. A response of No to the question Have you experienced any reaction to light today? will be treated as a pain severity score of zero. A response of No to the question Did you spend any time outdoors today? will be treated as zero time spent in direct sunlight. Database entry of diaries with some dates will be addressed by data management procedures, as described in Appendix 4, which also includes data management procedures for other inconsistencies, such as invalid and duplicate entries. Missing data will be imputed for sensitivity analyses. The following imputation rules supersede those proposed in section of the protocol. For assessment of the number of phototoxic reactions, days with missing phototoxic pain scores will have two forms of imputation. These will be that the patient either did not or did have a phototoxic reaction, providing a best and worst case assessment, as follows: Missing pain scores best case assessment: all missing pain scores will be imputed as zero. Missing pain scores worst case assessment: missing pain scores will be imputed as a score of 2 on the 11-point Likert scale. o o Missing pain scores will be set to a score of 2 on the 11-point Likert scale. It is noted that this is the 95-percentile of pain scores, i.e. that over 95% of pain scores reported by all patients enrolled in the CUV039 study were between 0 (no pain) and 2 on the 11-point Likert scale. However, if the last reported pain score on the day immediately preceding a missing value is greater than 2, then the missing value will be imputed by the last reported known pain score. This is consistent with the imputation rule in section , which states Where limited numbers of phototoxic pain scores are missing, the last reported value will be entered for the missing value(s). For assessment of the exposure to direct sunlight, days with time in direct sunlight will have two forms of imputation. These will be that the patient either did not or did spend some time in direct sunlight, providing a best and worst case assessment, as follows: Missing time in direct sunlight best case: all missing time in direct sunlight will be imputed as 1 hour. In the event that the upper quartile value of time in direct sunlight reported in this study is greater than 1 hour, this higher value will be used as the default value for imputation of missing pain scores. Missing time in direct sunlight worst case: all missing time in direct sunlight will be imputed as zero hours. CONFIDENTIAL Page 7 of 18 Rev 1, 28 August 2013 [A of 651]

145 D Statistical Analysis Plan Protocol No.: CUV Adjustment for Multiplicity Since there is one primary endpoint to be compared between two treatments, there will be no multiple testing, and hence no adjustments of p-values / confidence intervals due to multiple testing Coding Abbreviations The following coding abbreviations will be used in data listings, as appropriate, and included in the key in a footnote: CS LOQ NA NCS ND NR NRQ NS UK or UNK Clinically significant Limit of Quantification Not applicable Not clinically significant Test is not done Not recorded Not required No sample obtained Unknown 5. SAFETY AND SUBJECT DISPOSITION DATA 5.1. Safety Population The Safety Population will include all enrolled participants. In the protocol (section 5.7.5), it was stated that participants screened but not enrolled would be shown in separate listings. However, no data for inclusion in the study database have been collected for these patients, thus there will be no listings pertaining to patients screened but not enrolled Safety Assessments Adverse events and concomitant medications used: Continuous monitoring throughout the study period Vital signs (blood pressure, temperature and pulse rate): Screening Day 60 Day 120 Day 180 (or at Early Termination Visit, if applicable). Clinical laboratory tests (Biochemistry, Haematology, and Urinalysis): Screening Day 60 Day 120 Day 180 (or at Early Termination Visit, if applicable). EKG: Day 60 Day 120 CONFIDENTIAL Page 8 of 18 Rev 1, 28 August 2013 [A of 651]

146 D Statistical Analysis Plan Protocol No.: CUV039 Day 180 (or at Early Termination Visit, if applicable). Physical examination including all major organ systems: Screening Day 180 (or at Early Termination Visit, if applicable). Weight: Screening (and height, for determination of Body Mass Index (BMI)) Day 180 (or at Early Termination Visit, if applicable) Subject Disposition Analysis Details of participation will be tabulated by subject. Completion status will be summarised by treatment group. Demographics will be tabulated by subject and summarised by treatment group and overall. Details of administration of investigational product will be tabulated by subject. Exposure to investigational product will be summarised by treatment group. Medical history data and physical examination data at baseline will be listed by subject. Any untoward findings identified on physical examinations after the administration of the first dose of study medication will be captured as an adverse event if those findings meet the definition of an adverse event as defined in the protocol. Protocol deviations will be tabulated by subject. A summary of protocol deviations will be prepared for inclusion in the clinical study report Safety Data Presentation and Analysis All clinical safety and tolerability data will be listed for each subject. Adverse events, concomitant medications, clinical laboratory parameters, vital signs and EKG parameters for each subject will be tabulated in data listings. Descriptive methods will be used to summarize the safety data. These will be based upon the safety population. Safety data will be summarized descriptively in tabular form. Summaries of key safety data assessed over time may also be presented in graphical form, as appropriate. Where summaries include changes from baseline, the baseline value will be the most recent assessment prior to administrations of study treatment. Where measurements have been taken more than once prior to the scheduled baseline visit, baseline measurements will be taken as the last available data measured prior to this time point. If the baseline measurement is missing but there is a prior measurement recorded, this value will be carried forward and used as the baseline measurement. All adverse events, including non-treatment emergent events, will be listed. A treatment emergent adverse event will be: An event that was not present prior to or on the day of the first study medication administration but was present after study medication was administered. An event that was present prior to first administration of study medication and continued to occur after the administration of the first dose at an increased level of severity. An event that was present prior to administration of study medication and was documented as completely resolved and re-emerged after the administration of the first dose. The listing of adverse events will include MedDRA preferred term and system organ class along with the verbatim adverse event description, noting the version of MedDRA used for the mapping of terms. The number of participants with treatment-emergent adverse events will be summarized by preferred term and body system for each treatment group. Treatment-emergent events will be further summarized by intensity, seriousness and relationship to study medication. The number of participants who early terminate treatment due to adverse events related to study medication will be tabulated. Summaries of the incidence of toxicities will be prepared, as appropriate. CONFIDENTIAL Page 9 of 18 Rev 1, 28 August 2013 [A of 651]

147 D Statistical Analysis Plan Protocol No.: CUV039 Serious adverse events and adverse events of special interest will be listed individually. If a serious adverse event occurs prior to the first dose of the study medication, this will be noted in the study report. AEs will be summarised by treatment, grouped according to system organ class and preferred term, and tabulated with descriptive statistics, where appropriate. Laboratory data for biochemistry, hematology and urinalysis will be summarized by descriptive statistics by treatment and assessment including changes from screening to each visit. Additionally shift tables with respect to the normal ranges will be generated from screening to each visit. Clinically significant laboratory results will be listed separately. All summaries of clinical laboratory data will include scheduled data collection points only. The duration of study drug exposure and the number of participants exposed will be evaluated descriptively. Separate summaries with the detailed descriptive statistics will be generated and assessment for the EKG data Vital signs (systolic/diastolic blood pressure, temperature and pulse rate) will be tabulated and summarised by treatment and study timepoint. A summary of changes from pre-dose baseline will also be presented. Changes in physical examination and body weight and concomitant medications will be listed and summarized by frequency tables, if appropriate. 6. EFFICACY DATA 6.1. Efficacy Analysis Set The intent-to-treat (ITT) population will include all treated participants, who provide at least one post dose efficacy assessment. This will be the main population for all efficacy analyses. The efficacy evaluable population of study completers will include all ITT population members who did not prematurely terminate the study and provided data to Day 180 (Visit 4). This population may be used for supplementary efficacy analyses. Summaries of efficacy assessments will be presented for the ITT analysis set, by treatment group, with supplementary summaries of key endpoints for the study completers Efficacy Assessments Pain and phototoxicity: Daily recordings throughout the study period in study diary Phototoxicity defined as a pain score of at least 4 on a 0-10 Likert scale Phototoxic episode defined as consecutive days with a pain score of at least 4 on each day Direct sunlight exposure: Daily recordings throughout the study period in study diary Quality of Life (DLQI and EPP-QoL): Day 0 Day 60 Day 120 Day 180 (or Early Termination Visit, if applicable) Photoprovocation (a subset of patients only): Day 0 prior to implant CONFIDENTIAL Page 10 of 18 Rev 1, 28 August 2013 [A of 651]

148 D Statistical Analysis Plan Protocol No.: CUV039 Day 30 Day 60 prior to implant Day 90 Day 120 prior to implant 6.3. Efficacy Presentation and Analysis Efficacy assessment will be tabulated for each subject, and summarized with descriptive statistics by treatment group. Combined sun exposure (phototoxic pain = none) The primary efficacy endpoint is the duration of time (hours) spent in direct sunlight between 10:00 and 18:00 hours on days when no pain was experienced (pain score of 0). The mean daily duration in direct sunlight exposure will be calculated for each patient and compared between the treatment arms using a Kruskal-Wallis test with a significance level of p<0.05. H 0 : there is no difference between the treatment arms in the time spent in direct sunlight on days when no phototoxic pain was reported. Combined sun exposure (phototoxic pain = none or mild) The mean daily duration of sun exposure (hours in direct sunlight) between 10:00 and 15:00 hours on days when no pain was experienced (pain score of 0) will be calculated for each patient and compared between the treatment arms using the Kruskal-Wallis test. The mean daily duration of sun exposure (hours in direct sunlight) between 10:00 and 18:00 hours on days when no pain or mild pain was experienced (pain scores of 0-3) will be calculated for each patient and compared between the treatment arms using the Kruskal-Wallis test. Sun exposure The mean daily duration of sun exposure (hours in direct sunlight) between 10:00 and 18:00 during the study will be calculated for each patient and compared between the treatment arms using the Kruskal-Wallis test. Quality of life A between groups comparison of the change from baseline to each time point in the quality of life assessment scores (DLQI and EPP-QoL questionnaires) will be performed using the Kruskal-Wallis test. The DLQI will be scored according to the scoring method published on the following website: The EPP-QoL will be scored in accordance with the scoring method as described in Appendix 5 of the protocol, and also a parallel analysis using the revised scoring algorithm proposed by Oxford Outcomes following validation of the EPP-QoL assessment tool. Photoprovocation (in a subset of patients (target n=20)) A between groups comparison of the change from baseline to each time point in the minimum symptom dose following photoprovocation on the lower back and dorsal surface of the hand will be performed using the Kruskal-Wallis test. Phototoxicity phototoxic pain The maximum and total pain severity scores (Likert scale) for phototoxic episodes. The number of phototoxic episodes per subject reported by the patient during the study. A between groups comparison of the scores for each of the above parameters will be performed using the Kruskal-Wallis test. CONFIDENTIAL Page 11 of 18 Rev 1, 28 August 2013 [A of 651]

149 D Statistical Analysis Plan Protocol No.: CUV DATA LISTINGS AND SUMMARY TABLES 7.1. Preliminary Data Analysis An analysis will be performed on unblinded efficacy data after all subjects have reached Day 180, with restrictions on the unblinding as noted above in Section 4.3. The results of this analysis will only be made available in summary form, in such a way that the treatment allocation is not revealed for any individual subject. A clinical study report will be prepared following the Safety Follow Up Visit (Day 360). This will include the analysis of all safety results and a final analysis of the efficacy results, updated from the Day 180 results to include data for the additional quality of life assessments performed at the Safety Follow Up Visit (Day 360) 7.2. Listings and Tables for Clinical Study Report Tabulated data and summary tables will be provided to the Sponsor in a form suitable for inclusion as appendices to the Clinical Study Report, in RTF or PDF format. The data listings and summary tables planned to be generated from the study data are listed in Appendix 1 and Appendix 2, respectively. The numbering and titles may vary in the final presentation, depending on the amount of data to be presented. Draft tables will be provided to the Sponsor for review prior to final analysis. Results of the statistical analyses will be retained in the CPR study file for reference Data Transfer to the Study Sponsor Results of statistical analysis will be tabulated and provided to the Sponsor as appendices to the Clinical Study Report or retained in the Study File for reference as appropriate. At the conclusion of the study, CPR will provide the Sponsor with an electronic copy of the listings, tables and graphs. This may be provided by , by FTP upload, or on transportable electronic media such as CD/DVD, as determined by the Sponsor. 8. GENERAL CONSIDERATIONS FOR DATA MANAGEMENT AND ANALYSIS 8.1. Electronic Data Management All listings, tables and figures for inclusion in the appendices of the clinical study report will be generated using SAS programs. A copy of final listings, tables and figures will be printed and retained in the CPR Study File. Each paper version of the listings, tables and figures will bear the date and initials of the staff member responsible for generating the listing, table or figure, and the staff member conducting the quality control review. Any erroneous results identified during the checking process will be corrected by update of the SAS program, and the document recreated. A new hard copy of the document will be printed and then re-checked. To ensure an accurate data trail is maintained, corrections to electronic documents will be supported by paper records marked as superseded and detailing the corrective action and the date and initials of the verifying CPR staff member. If statistical analysis is repeated with a modified data set, the new data produced will be saved as a new file Electronic Data Security and Back-up Electronic documents containing study data will be password protected at all times and access will only be available to authorised CPR staff. A backup of all computer records will be performed daily Archiving At the conclusion of the study, the database will be archived. Copies will be retained in the CPR study file for a minimum of 15 years, and in the CPR secure archives in accordance with CPR standard operating procedures. CONFIDENTIAL Page 12 of 18 Rev 1, 28 August 2013 [A of 651]

150 D Statistical Analysis Plan Protocol No.: CUV039 Appendix 1: Planned Data Listings The following listings are planned to be generated for this study: Subject Information Listing Subject Enrollment Listing Conclusion of Study Participation Listing Protocol Deviations and Violations Listing Inclusion Criteria Listing Exclusion Criteria Listing Analysis Populations Listing EPP Medical History Listing Demographics and Baseline Characteristics Listing Vital Signs at Screening and Baseline Visits Listing Medical History Listing Physical Examination Listing Skin Appearance Listing Ophthalmological Examination Listing Dermatological Examination (Cutaneous) Listing Dermatological Examination (Oral Cavity) Listing Skin Cancer Risk Factors Listing Previous Prophylactic Medications Listing Full Body Photography Listing Study Drug Administration and Compliance Listing Adverse Events Listing Serious Adverse Events Listing Hematology Results Listing Biochemistry Results Listing Urinalysis Results Listing EKG Assessments Listing Pregnancy Testing Listing Concomitant Medications Listing Photoprovocation Listing Patient Diary Data Listing Dermatology Quality of Life Index Listing EPP Quality-of-Life On-Study Questionnaire, Original Scoring Listing EPP Quality-of-Life On-Study Questionnaire, Oxford Outcomes Scoring Listing EPP Baseline Questionnaire Listing EPP Status at Baseline Listing EPP Follow up Questionnaire CONFIDENTIAL Page 13 of 18 Rev 1, 28 August 2013 [A of 651]

151 D Statistical Analysis Plan Protocol No.: CUV039 Appendix 2: Planned Summary Tables The following summary tables are planned to be produced, however the table numbers and titles may vary, depending on the amount of data to be presented. If figures are prepared for inclusion in the body of the clinical study report, then corresponding figures will be added in Section Baseline and Demographic Data Table Enrollment Summary: Safety Population Table Patient Disposition Summary: Safety Population Table Fitzpatrick Skin Type and Skin Cancer Risk Factor: Safety Population Table a Demographics and Baseline Characteristics: Safety Population Table b Demographics and Baseline Characteristics: ITT Population Table c Demographics and Baseline Characteristics: Study Completers Table a Baseline Disease Characteristics: Safety Population Table b Baseline Disease Characteristics: ITT Population Table c Baseline Disease Characteristics: Study Completers Note: if the safety population and ITT population are the same, then only one set of summaries will be produced for this population, and the tables will be renumbered accordingly Efficacy Data Table Summary by Subject of Reported Sunlight Exposure and Pain: ITT Population Table Summary by Subject of Reported Sunlight Exposure and Pain: Study Completers Table Summary by Subject of Reported Sunlight Exposure and Pain: ITT Population, Best Case Imputation Table Summary by Subject of Reported Sunlight Exposure and Pain: ITT Population, Worst Case Imputation Table Reported Sunlight Exposure (10:00-15:00), When Patients Experienced No Pain: Study Completers Table Reported Sunlight Exposure (10:00-15:00), When Patients Experienced No Pain: ITT Population Table Reported Sunlight Exposure (10:00-15:00), When Patients Experienced No Pain: ITT Population, Best Case Imputation Table Reported Sunlight Exposure (10:00-15:00), When Patients Experienced No Pain: ITT Population, Worst Case Imputation Table Reported Sunlight Exposure (10:00-18:00), When Patients Experienced No Pain: Study Completers Table Reported Sunlight Exposure (10:00-18:00), When Patients Experienced No Pain: ITT Population Table Reported Sunlight Exposure (10:00-18:00), When Patients Experienced No Pain: ITT Population, Best Case Imputation CONFIDENTIAL Page 14 of 18 Rev 1, 28 August 2013 [A of 651]

152 D Statistical Analysis Plan Protocol No.: CUV039 Table Reported Sunlight Exposure (10:00-18:00), When Patients Experienced No Pain: ITT Population, Worst Case Imputation Table Reported Sunlight Exposure, When Patients Experienced No Pain or Mild Pain: ITT Population Table Reported Sunlight Exposure, When Patients Experienced No Pain or Mild Pain: Study Completers Table Reported Sunlight Exposure, When Patients Experienced No Pain or Mild Pain: ITT Population, Best Case Imputation Table Reported Sunlight Exposure, When Patients Experienced No Pain or Mild Pain: ITT Population, Worst Case Imputation Table Reported Sunlight Exposure Throughout the Whole Study: ITT Population Table Reported Sunlight Exposure Throughout the Whole Study: Study Completers Table Reported Sunlight Exposure Throughout the Whole Study: ITT Population, Best Case Imputation Table Reported Sunlight Exposure Throughout the Whole Study: ITT Population, Worst Case Imputation Table Quality of Life - DLQI Questionnaire by Item: ITT Population Table Quality of Life - DLQI Questionnaire by Item: Study Completers Table Changes in Quality of Life DLQI Questionnaire: ITT Population Table Changes in Quality of Life DLQI Questionnaire: Study Completers Table Quality of Life - Supplementary EPP Specific Questionnaire by Item (Original Scoring): ITT Population Table Quality of Life - Supplementary EPP Specific Questionnaire by Item (Original Scoring): Study Completers Table Changes in Quality of Life Supplementary EPP Specific Questionnaire (Original Scoring): ITT Population Table Changes in Quality of Life Supplementary EPP Specific Questionnaire (Original Scoring): Study Completers Table Quality of Life - Supplementary EPP Specific Questionnaire by Item (Original Scoring): ITT Population Table Quality of Life - Supplementary EPP Specific Questionnaire by Item (Original Scoring): Study Completers Table Changes in Quality of Life Supplementary EPP Specific Questionnaire (Original Scoring): ITT Population Table Changes in Quality of Life Supplementary EPP Specific Questionnaire (Original Scoring): Study Completers Table Minimum Symptom Dose Following Photoprovocation on the Dorsal Surface of Hand: Subset of ITT Population Table Minimum Symptom Dose Following Photoprovocation on the Dorsal Surface of Hand: Subset of Study Completers Table Minimum Symptom Dose Following Photoprovocation on the Lower Back: Subset of ITT Population Table Minimum Symptom Dose Following Photoprovocation on the Lower Back: Subset of Study Completers CONFIDENTIAL Page 15 of 18 Rev 1, 28 August 2013 [A of 651]

153 D Statistical Analysis Plan Protocol No.: CUV039 Table Number of Phototoxic Episodes per Subject Over the Entire Study: ITT Population Table Number of Phototoxic Episodes per Subject Over the Entire Study: ITT Population Table Number of Phototoxic Episodes per Subject Over the Entire Study: ITT Population, Best Case Imputation Table Number of Phototoxic Episodes per Subject Over the Entire Study: ITT Population, Worst Case Imputation Table Maximum and Total Severity Score Per Phototoxic Episode: ITT Population Table Maximum and Total Severity Score Per Phototoxic Episode: ITT Population Table Maximum and Total Severity Score Per Phototoxic Episode: ITT Population, Best Case Imputation Table Maximum and Total Severity Score Per Phototoxic Episode: ITT Population, Worst Case Imputation Figure Distribution Over a Day of Number of Subjects Spending Time in Direct Sunlight: ITT Population Figure Distribution Over a Day of Number of Subjects Spending Time in Direct Sunlight: Study Completers Figure Distribution of Total Time Spent in Direct Sunlight per Subject: ITT Population Figure Distribution of Total Time Spent in Direct Sunlight per Subject: Study Completers 14,3 Safety Data / Adverse Events Table Extent of Exposure to Study Drug: Safety Population Table Overall Summary of Treatment-Emergent Adverse Events: Safety Population Table Treatment-Emergent Adverse Events by System Organ Class and Preferred Term: Safety Population Table Serious Adverse Events: Safety Population Table Treatment Emergent Adverse Events by Relationship: Safety Population Table Treatment Emergent Adverse Events by Severity: Safety Population Table Summary of Haematology Results: Safety Population Table Summary of Biochemistry Results: Safety Population Table Summary of Urinalysis Results: Safety Population Table Shift Table for Haematology Results: Safety Population Table Shift Table for Biochemistry Results: Safety Population Table Shift Table for Urinalysis Results: Safety Population Table Summary of Vital Signs Data: Safety Population Table Summary of Body Weight: Safety Population Table Summary of EKG Assessments: Safety population Table Summary of Physical Examination Data: Safety Population CONFIDENTIAL Page 16 of 18 Rev 1, 28 August 2013 [A of 651]

154 D Statistical Analysis Plan Protocol No.: CUV039 Appendix 3: Study Data Overview Study Procedure Screening Visit 1 Visit 1b Visit 2 Visit 2b Visit 3 Visit 4 Up to -14 days Day 0 Day 30 Day 60 Day 90 Day 120 (Day 180) or Early Termination Informed consent taken Inclusion and exclusion criteria review Demographic information collected Medical history taken Skin cancer risk factor questions completed General physical examination including ophthalmic examination Skin and oral mucosal examination by a dermatologist X X X X X X X X X X X Full body photography X X Vital signs X X X X X Weight / height measurement X 1 X Hematology and blood chemistry X X X X Urinalysis X X X X 12 Lead EKG X X X Pregnancy test (serum β-hcg) Quality of life assessment (DLQI and EPP-QoL) Introduction to use of diary X X X X X X Issue study diary X X X Pregnancy test (urine dipstick) X 2 X 2 X 2 X Photoprovocation X 3 X X 3 X X 3 Implant insertion X X X Adverse events review X X X X Concomitant medication review X X X X X Phototoxic reaction review X X X X 1 Height will be measured at Screening only to allow calculation of body mass index (BMI). X 2 Implant insertion only after confirmation that female patients are not pregnant. X 3 Photoprovocation prior to implant administration (in a subset of subjects only). Safety Follow Up Visit (Day 360 ± 10) Skin and oral mucosal examination by a dermatologist End of Study EPP Questionnaire 12 Lead EKG X CONFIDENTIAL Page 17 of 18 Rev 1, 28 August 2013 [A of 651]

155 D Statistical Analysis Plan Protocol No.: CUV039 Appendix 4: Data Management of Missing, Duplicate or Invalid Diary Entries The following rules will be applied in data management of diaries with missing, duplicate or invalid dates. Where the same dates are duplicated on two different diaries: o diary entries later than the date of the next visit will not be entered into the database when there is an entry with the same date in the next diary issued at that visit o diary entries prior to the visit when the diary was issued will not be entered into the database when there is an entry with the same date in the previous diary Where the same dates are duplicated within a diary: o If there is another date missing and the order of the entries is clear, then the date of the inconsistency entry will be changed to fit the logical ordering o If there are no missing dates and the data for the two entries are not identical, then a worst case approach will be used If pain scores are not the same, then data will be entered from the diary entry with the highest pain score If pain scores are the same, but total time in direct sunlight is not the same, then data will be entered from the diary entry with the longest time in direct sunlight If pain scores are the same and total time in direct sunlight are the same, but total time in shade is not the same, then data will be entered from the diary entry with the longest time in shade Where dates are not filled out: o If there is a date missing and the order of the entries is clear, then the date of the inconsistency entry will be changed to fit the logical ordering o If the number of blank dates is less than the number of dates missing, then assign the dates from the start of the interval with missing dates, and impute that data are not available for subsequent missing dates in the sequence Where invalid dates are entered in the diary: o If there is an invalid date (eg 31 Jun) and there is a missing date to provide logical ordering (e.g. 01Jul is missing), then the invalid date will be changed accordingly o If there is an invalid date (eg 31 Jun) and there is no missing date to provide logical ordering, then the data for the invalid date will not be entered The following rules will be applied in data management of diaries with missing, duplicate or inconsistent information within a daily entry. Where a non-zero pain score is given but the subject has responded No to the question Have you experienced any reaction to light today? or the response is blank, the response will be amended to Yes. Where some time in direct sunlight or shade is indicated but the subject has responded No to the question Did you spend any time outdoors today? or the response is blank, the response will be amended to Yes. Where the patient has responded Yes to the question Did you spend any time outdoors today? and no time blocks have been checked, but there is a comment in the margin of the diary about significant outdoor time outside of 10:00-18:00, the comment will be captured in the database. Where the margin note indicates that the patient spent some time in a car during the target time period, the relevant time blocks will be considered to be time spent in shade, if either the time blocks are blank for both sun and shade, or the time blocks are filled out for both sun and shade. CONFIDENTIAL Page 18 of 18 Rev 1, 28 August 2013 [A of 651]