Clinical Trial Report

Transcription

1 Clinical Trial Report Explorative trial evaluating the efficacy, tolerability and safety of LEO applied in a split-face (left/right) topical design in adults with moderate to severe acne Design of trial: Phase 2a, single-centre, prospective, randomised, vehicle-controlled, double-blind, split-face (left/right) design trial. The clinical trial, including the archival of essential documents, was conducted in compliance with the clinical trial protocol, GCP, and the applicable regulatory requirement(s). LEO Pharma A/S Trial ID: EXP-1223 Date: 29-Aug-2017 Version: Final TMF Version 1.0

2 Trial ID: EXP Aug-2017 Page 2 of 166 Clinical Trial Report Statement Approval Statement LEO Pharma A/S The following persons have approved this clinical trial report using electronic signatures as presented on the last page of this document: PPD PPD M.Sc. Global Clinical Operations PPD PPD MD Medical Science and Safety Approval Statement, International Coordinating Investigator The coordinating investigator approves the clinical trial report by manually signing the International Coordinating Investigator Clinical Trial Report Approval Form, which is a separate document adjoined to this clinical trial report. The following person has approved this clinical trial report: Hala Koudsi, MD International Coordinating Investigator

3 Trial ID: EXP Aug-2017 Page 3 of 166 Guidance Documents This clinical trial report is designed to comply with the standards issued by the International Conference on Harmonisation (ICH) E3 Structure and Content of Clinical Trial Reports and clarified in the ICH E3 Q&A document, E6 Good Clinical Practice, E9 Statistical Principles for Clinical Trials, and M4 Common Technical Document (1, 2, 3, 4, 5). Registration of the Clinical Trial The trial was registered at ClinicalTrials.gov on 13-Oct-2015, trial registration number: NCT The results are disclosed in accordance with applicable national regulations and LEO Pharma A/S procedures. Clinical Trial Period Date of First Subject First Visit: 10-Jun-2016 Date of Last Subject Last Visit: 31-Mar-2017 Synopsis The synopsis of this clinical trial report exists as a separately approved document.

4 Trial ID: EXP Aug-2017 Page 4 of 166 Table of Contents Clinical Trial Report Statement... 2 Guidance Documents... 3 Registration of the Clinical Trial... 3 Clinical Trial Period... 3 Synopsis... 3 Table of Contents... 4 List of Tables (In-Text)... 8 List of Figures (In-Text)... 9 List of Appendices List of Abbreviations and Definition of Terms Ethics Institutional Review Board (IRB)/Independent Ethics Committee (IEC) and Regulatory Authorities Ethical Conduct of the Trial Subject Information and Informed Consent Investigators and Trial Administrative Structure Introduction Trial Objectives Primary Objective Secondary Objectives Exploratory Objectives Investigational Plan Overall Trial Design Overview of the trial SRC evaluation for progression between the cohorts Criteria for unacceptable LSRs, safety, and tolerability Criteria for trial termination Trial periods Screening phase (Day -28 to Day -1) Pre-treatment phase (Day 1) Treatment phase (Day 1 to Day 3)... 21

5 Trial ID: EXP Aug-2017 Page 5 of Post-treatment phase (Day 2 to Week 12) Discussion of Trial Design, Including the Choice of Control Groups Selection of Trial Population Inclusion criteria Exclusion criteria Withdrawal criteria Treatments Treatments administered Investigational medicinal products (IMPs) Method of assigning subjects to treatment groups Selection and timing of dose for each subject Blinding Prior and concomitant therapy Treatment compliance Trial Schedule and Assessments Frequency and timing of measurements Baseline characteristics and demographics assessed Efficacy measurements assessed Investigator assessments Subject-reported outcomes Safety measurements assessed Adverse events Other events to be reported Other safety measurements Vital signs and physical examination Clinical laboratory tests Appropriateness of measurements Trial Endpoints Primary endpoint Secondary endpoints Exploratory endpoints Data Quality and Assurance Changes to the Conduct of the Trial Statistical Methods Determination of Sample Size Statistical and Analytical Plan Summary... 40

6 Trial ID: EXP Aug-2017 Page 6 of General principles Definition of trial analysis sets Statistical analysis and data presentation Handling of missing values Interim analysis and data monitoring Multiplicity adjustments Changes to the Statistical Analysis Plan Software and Dictionaries Trial Population Disposition of Subjects Protocol Deviation Trial Analysis Sets Allocation to treatment Full analysis set (FAS) Safety analysis set (SAS) Per protocol analysis set (PPS) Demographic and Other Baseline Characteristics Exposure and Treatment Compliance Efficacy Evaluation Primary Endpoint Total lesion count in acne lesion areas for LEO and vehicle gel at Week Other analyses including sensitivity analyses The mean total lesion count change from baseline to Week Actual treatment analysis Additional sensitivity analyses Secondary Endpoints Inflammatory lesion count in acne lesion areas for LEO gel 0.018% and vehicle gel at Week Non-inflammatory lesion count in acne lesion areas for LEO gel 0.018% and vehicle gel at Week IGA of acne lesion areas for LEO gel 0.018% and vehicle gel at Week Composite and component LSR score at all visits Occurrence of unacceptable LSR scores or unacceptable safety and tolerability events at all visits Other Analysis of Efficacy Explorative Endpoints Total lesion count in acne lesion areas on Day 1 and at Weeks 2, 4, 8, and 12 (time course)... 63

7 Trial ID: EXP Aug-2017 Page 7 of Inflammatory lesion count in acne lesion areas on Day 1 and at Weeks 2, 4, 8, and 12 (time course) Non-inflammatory lesion count in acne lesion areas on Day 1 and at Weeks 2, 4, 8, and 12 (time course) IGA of acne lesion areas on Day 1 and at Weeks 2, 4, 8, and 12 (time course) Treatment success (IGA) Inflammatory cytokine expression at time points defined after evaluation of the clinical data Microbiome profile at time points defined after evaluation of the clinical data Subject evaluation of Acne QoL (the past week) on Day 1 and Week Subject evaluation of TSQM II at Week Subject global cosmetic score at Week Efficacy Conclusions Safety Evaluation Adverse Events Brief summary of adverse events Display of adverse events Analysis of adverse events Adverse events by severity Adverse events related to IMP Deaths, Other Serious Adverse Events, and Other Significant Adverse Events Other Events to be reported Local Skin Responses (LSRs) Composite LSR score Component LSR score Occurrence of unacceptable LSR scores or unacceptable safety and tolerability events at all visits Vital Signs Clinical Laboratory Evaluation Safety Conclusions Discussion and Overall Conclusions Discussion Overall Conclusions References... 82

8 Trial ID: EXP Aug-2017 Page 8 of 166 End-of-Text Tables and Figures, Baseline Characteristics and Investigational Medicinal Product Data End-of-Text Tables and Figures, Efficacy Data End-of-Text Tables and Figures, Safety Data List of Tables (In-Text) Table 1 Unacceptable local skin responses Table 2 Local skin response score criteria for not administering second or third treatment Table 3 Administration of investigational medicinal products (IMPs) Table 4 Identity of test product Table 5 Identity of reference product Table 6 Schedule of trial procedures Table 7 Fitzpatrick skin type Table 8 Specified medical history for acne vulgaris Table 9 IGA scale for acne vulgaris Table 10 Subject disposition: All subjects randomised Table 11 Age group, sex, race, ethnicity and skin type - SAS Table 12 Age, weight, height, BMI, and duration of Acne at baseline - SAS Table 13 Acne history - SAS Table 14 Previous treatment history - SAS Table 15 Concurrent diagnoses - SAS Table 16 Concomitant medication at baseline - SAS Table 17 Treatment compliance, number of days treated - SAS Table 18 Analysis of total lesion count Week 12 multiple imputation methods - planned treatment - FAS Table 19 Summary of total lesion change from baseline - planned treatment - FAS Table 20 Summary of total lesion percent change from baseline - planned treatment - FAS Table 21 Analysis of total lesion count Week 12 OC - actual treatment - FAS Table 22 Summary of total lesion change from baseline - actual treatment - FAS... 56

9 Trial ID: EXP Aug-2017 Page 9 of 166 Table 23 Summary of total lesion percent change from baseline - actual treatment - FAS Table 24 Analysis of total lesion count Week 12 OC - planned treatment - FAS Table 25 Analysis of total lesion count Week 12 - laterality OC - planned treatment - FAS Table 26 Analysis of total lesion count Week 12 - LOCF - planned treatment - FAS Table 27 Summary of Investigator s global assessment FAS Table 28 Analysis of IGA treatment success at Week 12- FAS Table 29 Summary of acne QoL - FAS Table 30 Summary of TSQM II at Week 12 - FAS Table 31 Summary of subject global cosmetic score at Week 12 - FAS Table 32 Overall summary of treatment emergent adverse events - SAS Table 33 Treatment emergent adverse events by SOC and PT - SAS Table 34 Treatment emergent adverse events by severity, SOC and PT - SAS Table 35 Treatment emergent related adverse events by SOC and PT - SAS List of Figures (In-Text) Figure 1 Trial design Figure 2 Mean total lesion counts versus time - planned treatment - FAS Figure 3 Percent change total lesion count versus time - planned treatment - FAS Figure 4 Mean total lesion count versus time - actual treatment - FAS Figure 5 Percent change total lesion count versus time - actual treatment - FAS Figure 6 Mean inflammatory lesion count versus time - FAS Figure 7 Mean non-inflammatory lesion count versus time - FAS Figure 8 Mean composite LSR versus time - planned treatment - SAS Figure 9 Mean composite LSR versus time - actual treatment - SAS Figure 10 LSR counts by type (1) Planned treatment SAS Figure 11 LSR counts by type (2) Planned treatment SAS Figure 12 LSR counts by type (3) Planned treatment SAS... 77

10 Trial ID: EXP Aug-2017 Page 10 of 166 List of Appendices Trial Information Appendix No. Appendix Title Status Appendix 1.1 Clinical Trial Protocol and Amendments Enclosed Appendix 1.2 Sample CRF Enclosed Appendix 1.3 List of IEC or IRBs and Representative Written Enclosed Information for the Subjects and Sample Consent Form Appendix 1.4 Trial Administrative Structure, List of Investigators, and Enclosed CV for Coordinating Investigator Appendix 1.5 Signature of Coordinating Investigator Enclosed Appendix 1.6 Listing of Subjects receiving Investigational Medicinal Product from Specific Batches Available upon request Appendix 1.7 Randomisation Scheme and Codes Enclosed Appendix 1.8 Audit Certificate NA Appendix 1.9 Documentation of Statistical Methods Enclosed Appendix 1.10 Documentation of Laboratory Standardisation Methods NA and Quality Assurance Procedures Appendix 1.11 Publications based on the Trial NA Appendix 1.12 Important Publications Referenced in the Clinical Trial Report Available upon request Listings Appendix No. Appendix Title Status Appendix 2.1 Discontinued Subjects Enclosed Appendix 2.2 Protocol Deviations Enclosed Appendix 2.3 Trial Analysis Sets Enclosed Appendix 2.4 Demographic Data Enclosed Appendix 2.5 Compliance and/or Investigational Medicinal Product Enclosed Concentration Data Appendix 2.6 Efficacy Data Enclosed Appendix 2.7 Safety Data Enclosed Appendix 2.8 Listing of Laboratory Values by Subject Enclosed

11 Trial ID: EXP Aug-2017 Page 11 of 166 List of Abbreviations and Definition of Terms List of Abbreviations AE Adverse event AK Actinic keratosis ANCOVA Analysis of covariance BPO Benzoyl peroxide CI Confidence interval CRF Case report form CTR Clinical trial report EoT End-of-text GCP Good Clinical Practice FAS Full analysis set ICH International Conference on Harmonisation IGA Investigator s Global Assessment IEC Independent ethics committee IMP/IP Investigational medicinal product/ Investigational product IRB Institutional review board KA Keratoacanthoma LOCF Last observation carried forward LSR Local skin response MedDRA Medical Dictionary for Regulatory Activities OC Observed case PD Protocol deviation PPS Per protocol analysis set QoL Quality of life SAE Serious adverse event SAPU Statistical analysis plan update SAS Safety analysis set SD Standard deviation SE Standard error SOC MedDRA system organ class SOP Standard Operating Procedure SCC Squamous cell carcinoma TA Treatment area TA left TA right Treated acne lesions area at the left side (of the face) Treated acne lesions area at the left side (of the face)

12 Trial ID: EXP Aug-2017 Page 12 of 166 TSQM II Tx WHO Treatment Satisfaction Questionnaire for Medication Treatment World Health Organisation Definition of terms Terms defined by ICH Guidelines are not mentioned here. Area of acne lesions or acne lesion area In some places referred to as treatment area (TA). Assessment A (cluster of) characteristic(s) measured and/or recorded for a subject. Concomitant medication Any medication used by a subject during the clinical trial apart from the trial medication. Enrolled subject A subject for who informed consent has been obtained and who has been registered in a clinical trial. Endpoint An assessment or a transformation of the assessment(s) described on a subject level, for which a statistical analysis is performed, that is, a p-value or a confidence interval (CI) is stated, or for which tabulation serves as important supportive evidence of efficacy/safety.

13 Trial ID: EXP Aug-2017 Page 13 of Ethics 1.1 Institutional Review Board (IRB)/Independent Ethics Committee (IEC) and Regulatory Authorities The clinical trial protocol and any relevant amendments to the clinical trial protocol were approved by/received favourable opinion from the relevant IRB/IEC before the enrolment of subjects. The appropriate regulatory authority was notified of and approved the clinical trial, as required. A list of all IECs/IRBs consulted is given in Appendix Ethical Conduct of the Trial This clinical trial was conducted in accordance with the revision current at the start of the trial of the World Medical Association s Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects. All subjects received written and verbal information concerning the clinical trial as specified in Section 1.3. Subjects were asked to consent that their personal data were recorded, collected, processed and could be transferred to EU and non-eu countries in accordance with any national legislation regulating privacy and data protection. 1.3 Subject Information and Informed Consent All subjects received written and verbal information concerning the clinical trial. This information emphasised that participation in the clinical trial was voluntary and that the subject could withdraw from the clinical trial at any time and for any reason. All subjects were given an opportunity to ask questions and were given sufficient time to consider before consenting. The subject s signed and dated informed consent to participate in the clinical trial was obtained prior to any trial related activities being carried out in accordance with ICH Good Clinical Practice (GCP) Section 4.8 and all applicable laws and regulations. A representative subject information sheet and informed consent form is provided in Appendix 1.3.

14 Trial ID: EXP Aug-2017 Page 14 of Investigators and Trial Administrative Structure LEO Pharma A/S was the sponsor of the clinical trial and participating LEO affiliates were authorised to act on behalf of the sponsor in the countries where the clinical trial was conducted. Appendix 1.4 contains detailed information about the trial administrative structure including authors of the clinical trial report as well as a list of trial site(s) and investigator(s) and other persons whose participation materially affected the conduct of the trial; it also includes members of the safety review committee. One trial site located in the US participated in the trial; is referred to as USA02.

15 Trial ID: EXP Aug-2017 Page 15 of Introduction Acne vulgaris, commonly referred to as acne, is a very common chronic inflammatory skin disease, particularly among adolescents and young adults (6). Moderate to severe acne can reduce the quality of life (QoL) and self-esteem and cause disfiguring, persistent scarring and dyspigmentation. Current topical and systemic treatment options for acne often require therapy for 3 6 months and are frequently associated with some degree of local side-effects during the treatment period (such as dryness, skin irritation, or scaling). This often reduces compliance and consequently leads to disease relapse and disappointing treatment outcomes. Thus, there is an unmet medical need for safe and effective acne treatments of short duration. Ingenol disoxate gel (LEO 43204) is a novel ingenol derivative currently in phase 3 clinical development for field treatment of actinic keratosis (AK) on treatment areas up to 250 cm 2.on the face, scalp, and chest (7). Another ingenol derivative, ingenol mebutate, is approved under the brand name Picato(r) for topical treatment of AK in a contiguous skin area up to 25 cm 2. Case reports also indicate a beneficial effect of ingenol mebutate on acne. After accidental exposure to ingenol mebutate-containing material on the face, 2 employees at a manufacturing plant and a research laboratory, respectively, reported clearance of pre-existing acne, following complete resolution of severe facial skin responses to the ingenol mebutate exposure (9). The observation that the strongest local skin response (LSR) to ingenol mebutate occurs around the hair follicles (10) suggests accentuated cell death and inflammation in the pilosebaceous unit. This could reduce the size and sebum production of the sebaceous gland, similar to the effect of photodynamic therapy combined with aminolaevulinic acid in the treatment of acne (11). Such therapy has been shown to reduce acne disease severity for up to 20 weeks (11, 12, 13). The therapy is associated with transient erythema, crusting oedema, temporary changes in pigmentation, and pustular eruptions (13); this is similar to the LSRs induced by ingenol mebutate. Thus, we hypothesised that the inflammation and LSR induced by ingenol disoxate gel would improve acne by reducing 1) the size of the sebaceous glands, 2) the sebum production, and 3) the colonisation of Propionibacterium acnes (P. acnes) in the sebaceous glands all of which are key factors in the development of acne. Historically, with topically applied acne products, the change from baseline in total lesion count after 12 weeks of treatment in phase 3 clinical trials are reported to range from 45-70% (14,15,16,17,18) while the vehicle effect typically is around 36-38% (14, 15, 16). For these studies, the change from baseline for adapalene 0.1% and 0.3% gel (14, 15) is approximately 48-56%. For benzoyl peroxide (BPO) 2.5% (15), azelaic acid 20% (17) and clindamycin 1.0

16 Trial ID: EXP Aug-2017 Page 16 of 166 % (18), the change from baseline is approximately 46-49%. For combination products of adapalene (0.1% or 0.3%) with BPO 2.5% the change from baseline is reported to be approximately 70% (15,16) and for combinations of BPO 2.5% with clindamycin (1.0% or 1.2%), it is approximately 60-65% (17,18). The objective of this 12-week exploratory phase 2a trial was to evaluate the efficacy, safety and tolerability of ingenol disoxate gel (LEO gel 0.018%) in the treatment of moderate to severe acne vulgaris. 40 young adult subjects were treated once daily for up to 3 consecutive days with ingenol disoxate gel and vehicle gel in acne lesion areas on opposite cheeks of the face.

17 Trial ID: EXP Aug-2017 Page 17 of Trial Objectives 4.1 Primary Objective To assess the efficacy of treatment with LEO gel 0.018% and vehicle gel on acne vulgaris disease severity 12 weeks after end of treatment. Treatment is defined as once-daily application of LEO gel 0.018% and vehicle gel for up to 3 days. 4.2 Secondary Objectives To assess the safety and tolerability of treatment with LEO gel 0.018% and vehicle gel 12 weeks after end of treatment. 4.3 Exploratory Objectives To evaluate the time course of clinical efficacy of LEO gel 0.018% and vehicle gel and, based on this, define a time point for evaluation of the effect on expression of inflammatory biomarkers and skin microbiome. To assess patient-reported outcomes using the acne-specific quality of life questionnaire (Acne-QoL, [20, 21]) and the Treatment Satisfaction Questionnaire for Medication (TSQM II, [22]). To assess the effect of LEO gel 0.018% and vehicle gel on subject-evaluated change in cosmetic skin appearance using a Subject Global Cosmetic Score questionnaire.

18 Trial ID: EXP Aug-2017 Page 18 of Investigational Plan 5.1 Overall Trial Design Overview of the trial This was a phase 2a, single-centre, prospective, randomised, vehicle-controlled, double-blind, 12-week trial in 40 subjects with moderate to severe acne vulgaris. Using a split-face (left/right) design, the trial enabled intra-individual comparison of LEO gel 0.018% and vehicle gel, each administered to an acne lesion area on opposite cheeks of the face. The trial consisted of 4 phases: a 4-week screening phase, a Day 1 pre-treatment phase, a Day 1-3 treatment phase, and a 12-week post-treatment phase (as illustrated in Figure 1 and further described in Section 5.1.3). The entire clinical trial protocol and any amendments are presented in Appendix 1.1 and the unique pages of the electronic case report form (ecrf) are presented in Appendix 1.2. Figure 1 Trial design The subjects were enrolled sequentially into 4 cohorts (total n=40). Progression from one cohort to the next was decided by the Safety Review Committee following a review of LSRs, safety, and tolerability after the last subject in each cohort had completed the Week 2 visit. Cohort 1 (n=3): Treatment escalation with once daily application of IMPs for 1, 2, and 3 days, respectively, for each of the 3 subjects. Subjects received treatment sequentially so that the second and third subjects were not dosed until a safety evaluation of the preceding subject had been done. The first subject was dosed for 1 day, the second subject for up to 2 days, and the third subject for up to 3 days. The safety evaluation that determined whether the next subject could be dosed consisted of the maximal LSR score from evaluations on Days 1, 2, 3, 4, 8, and at Week 2 or until considerable reduction of LSR score or any treatment-related AEs had been observed. For the second and third subject, treatment on Days 2 and 3 depended on the criteria defined in Section Subjects not receiving the optional treatment on Days 2 or 3 owing to

19 Trial ID: EXP Aug-2017 Page 19 of 166 severe LSRs or treatment-related adverse events (AEs) remained in the trial and attended the scheduled follow-up visits. Cohort 2 (n=6): once daily treatment for 3 days with Days 2 and 3 optional, depending on predefined criteria (see Section ). A maximum of 2 subjects per week were enrolled. The subjects followed the same scheduled visits as in Cohort 1. Cohort 3 (n=6): once daily treatment for 3 days with Days 2 and 3 optional, depending on predefined criteria (see Section ). Subjects were enrolled without restrictions to the number of subjects per week. The subjects followed the same scheduled visits as in Cohort 1. Cohort 4 (n=25): once daily treatment for 3 days with Days 2 and 3 optional, depending on predefined criteria (see Section ). Subjects were enrolled without restrictions to the number of subjects per week. The visit on Day 8 took place as a phone call SRC evaluation for progression between the cohorts Criteria for unacceptable LSRs, safety, and tolerability Unacceptable LSRs, safety and tolerability in an individual subject were defined as: 1. Clinically relevant signs or symptoms that in the opinion of the investigator were deemed unacceptable. 2. Occurrence of LSRs as specified in Table 1. Table 1 Occurrence One of the following Two of the following Unacceptable local skin responses Local skin response component(s) Grade 4 crusting Grade 4 erosion/ulceration Grade 4 vesiculation/pustulation extending significantly outside treatment areas Grade 4 erythema Grade 3 crusting Grade 4 swelling extending significantly outside treatment areas Grade 3 erosion/ulceration Grade 3 vesiculation/pustulation Criteria for trial termination The trial was to be terminated if the perception of the benefit/risk ratio (judged from the frequency of unacceptable clinical symptoms, signs, or [serious] AEs [(S)AEs]) became unfavourable (main criteria being the occurrence of unacceptable events) for the

20 Trial ID: EXP Aug-2017 Page 20 of 166 continuation of the trial. Owing to the design of the trial, there were no statistical criteria for trial termination. The following cumulative frequencies of subjects with unacceptable LSRs, safety, and tolerability events (as defined above) would strongly support trial termination: 2 out of 3 subjects with unacceptable LSRs, safety and tolerability events after Cohort 1. 3 out of 9 subjects with unacceptable LSRs, safety and tolerability events after Cohort 2 (cumulative). 5 out of 15 subjects with unacceptable LSRs, safety and tolerability events after Cohort 3 (cumulative) Trial periods Screening phase (Day -28 to Day -1) After receiving information about the protocol, LSRs and other risks, subjects willing to participate in this clinical trial signed the trial-specific informed consent. Screening and Day 1 could be combined. At the screening visit, the (sub)investigator confirmed the diagnosis of acne vulgaris and assessed the overall disease severity using the IGA of the full face (see Section ). The subject s eligibility for the trial was checked according to the inclusion and exclusion criteria. Subjects who were ineligible solely owing to current or recent use of prohibited therapies could be re-screened after a washout period. Any decision to stop an ongoing therapy was to be discussed and approved by the (sub)investigator. During the trial this did not become relevant for any subject. For eligible subjects, assessments listed in Table 6 were performed and recorded in the ecrf. Two symmetrically located acne lesion areas of approximately 36 cm 2 (6 6 cm) on the left (TA left ) and right (TA right ) cheeks of the face were identified and documented on individual transparent film(s) using a 3-point landmark technique. The (sub)investigator assessed the disease severity in TA left and TA right using the IGA scale and lesion count (see Section ) Pre-treatment phase (Day 1) If the screening and Day 1 visits were not combined, eligibility was confirmed by review of inclusion and exclusion criteria prior to randomisation.

21 Trial ID: EXP Aug-2017 Page 21 of 166 Following randomisation, subjects completed the Acne-QoL questionnaire before safety and any other assessments were undertaken. Women of childbearing potential had a urine pregnancy test performed. In Cohorts 2, 3 and 4, non-invasive samples (tape lifts and swabs) were taken from TA left and TA right for analyses of inflammatory biomarkers and skin microbiome profile. All subjects in Cohorts 3 and 4 were photographed at screening for documentation of eligibility. Subjects in Cohorts 1, 2, and 3 were photographed at all site visits from Day 1 and all subsequent visits for documentation of physical appearance. Each subject was randomised to active treatment on either TA left or TA right. The other side was treated with vehicle gel Treatment phase (Day 1 to Day 3) Treatment visits took place on Days 1, 2, and 3. The individual transparent film(s) were used to locate the acne lesion areas. LSR scores for the acne lesion areas, any new or ongoing AEs, and concomitant medication were recorded in the ecrf. Site staff applied IMPs to the acne lesion areas as per the randomisation schedule. Subjects were instructed in how long the IMP should remain on the skin and how it could be washed off. They were reminded about precautions regarding accidental transfer of the IMP to eyes and other areas. Treatment on Days 2 and 3 depended on the following criteria: The subject not evaluating their response to treatment as intolerable. The (sub)investigator not evaluating LSRs or treatment-related AEs as unacceptable. The LSR scores not exceeding predefined criteria (see Table 2).

22 Trial ID: EXP Aug-2017 Page 22 of 166 Table 2 Local skin response score criteria for not administering second or third treatment Local skin response component(s) Score on Day 2 or Day 3 Erosion/ulceration 2 Vesiculation/pustulation 3 Any LSR component =4 Flaking/scaling + crusting 5 (sum) Flaking/scaling + crusting + vesiculation/pustulation 6 (sum) If a subject was not treated on Day 2 or Day 3, the reason was recorded in the ecrf and the subject remained in the trial and attended the scheduled post-treatment (follow-up) visits Post-treatment phase (Day 2 to Week 12) Post-treatment assessment: Days 2, 3, 4, and 8. If a subject was not treated on Day 2 or Day 3, trial procedures followed the trial schedule (Table 6). The individual transparent film(s) were used to locate each acne lesion area for assessments. LSR scores for the acne lesion areas, any new or ongoing AEs, and concomitant medication were recorded. On Day 8, subjects in Cohorts 1, 2, and 3 attended a site visit, whereas subjects in Cohort 4 were contacted by phone and asked about tolerability (their subjective evaluation), AEs, and concomitant medication. If a subject in Cohort 4 expressed worsening of LSR or treatmentrelated AEs on Day 8, the (sub)investigator decided whether an unscheduled trial site visit was required. Post-treatment assessment: Weeks 2, 4, 8, and 12. LSR scores for the acne lesion areas, any new or ongoing AEs, and concomitant medication were recorded, along with clinical assessment of TA left and TA right (IGA and lesion count, Section ). Tape-lifts and swabs for biomarker and microbiome analyses were taken from TA left and TA right after all other assessments had been completed. At Week 12, subjects completed the Acne-QoL questionnaire, the TSQM II, and the Subject Global Cosmetic Score before any other assessments were undertaken. The questionnaires are included in the clinical trial protocol (Appendices 5, 11, and 12) in Appendix 1.1.

23 Trial ID: EXP Aug-2017 Page 23 of Discussion of Trial Design, Including the Choice of Control Groups To ensure unbiased evaluation of the efficacy and safety of LEO gel 0.018% in the treatment of acne, the trial was vehicle-controlled and double-blinded. To limit the number of exposed subjects, the trial used a split-face (left/right) design, enabling intra-individual comparison of LEO gel 0.018% and vehicle gel. This design requires fewer subjects to achieve the statistical power for detecting a treatment effect than a parallel trial design using between-subject comparison. To mitigate the risk of unexpected severe LSRs and AEs in this patient population where LEO has not previously been tested, the trial included a small treatment escalation cohort with close safety monitoring (Section 5.1.1) and an interim analysis of safety and tolerability data by a Safety Review Committee before Cohort 2 was initiated. In addition, the initiation of the subsequent 2 cohorts were separated by interim analysis of safety and tolerability data by a Safety Review Committee (Section 6.2.3) Only subjects with Fitzpatrick skin type I III (Table 7) were included in the trial owing to lack of safety data from subjects with darker skin types and a potential higher risk of post-inflammatory hyperpigmentation. The FDA guidance for developing drugs for acne vulgaris (19) recommends 12 weeks of treatment and 4 weeks of follow-up after end of treatment. These recommendations were not considered relevant for this trial, which included a treatment period of only up to 3 days and a subsequent post-treatment follow-up period of 12 weeks due to the expected mode of action of LEO In previous clinical trials of LEO in field treatment for AK in the face, LSRs have been transient and have typically resolved within 2-4 weeks of treatment (7). The final assessment of efficacy at Week 12 was selected based on the expectation of efficacy lasting several months. 5.3 Selection of Trial Population Inclusion criteria All of the following criteria needed to be met for a subject to be enrolled in the trial: 1. Informed consent form signed and dated after subject received verbal and written information about the clinical trial. 2. Diagnosis of acne vulgaris of the face. 3. Acne vulgaris disease severity in the full face and in the acne lesion areas scored as moderate to severe (grade 3-4) according to the IGA scale (see Section ).

24 Trial ID: EXP Aug-2017 Page 24 of Disease severity and total lesion count similar in both acne lesion areas (with a maximal 2-fold difference in total lesion count). 5. Fitzpatrick skin type I III. 6. Age 18 to 35 years (inclusive). 7. Overall good health including well-controlled diseases (for example, hypertension, diabetes, or thyroid disease), as determined by medical history, physical examination, and vital signs (blood pressure, heart rate). 8. If the subject was a woman of childbearing potential *, she had to have a confirmed negative pregnancy test prior to trial treatment AND had to be willing to use effective contraception at trial entry and until completion of the trial. Effective contraception was defined as follows: o Abstinence (when in line with the preferred and usual lifestyle of the subject). o Vasectomised partner (given that the subject was monogamous). o Intrauterine device. o Double barrier method defined as 2 distinct barrier methods. o Hormonal contraceptive (oral hormonal birth control, oestrogenic vaginal ring, percutaneous contraceptive patches, implants and injectables) for at least 1 menstrual cycle prior to enrolment. * Women were considered of childbearing potential unless they had a confirmed clinical history of sterility (for example, had undergone hysterectomy or tubal ligation). 9. Ability to communicate with the (sub)investigator and understand and comply with the requirements of the trial Exclusion criteria Any of the following criteria would disqualify a subject from participating in the trial: 1. Nodulocystic acne, acne conglobata, acne fulminans, secondary acne (for example, chloracne, drug-induced acne). 2. Previous history of keloid formation or post-inflammatory hyperpigmentation. 3. Fitzpatrick skin type IV VI. 4. A subject for whom the (sub)investigator would recommend systemic therapy for the subject, to prevent risk of scarring owing to current disease severity of acne vulgaris.

25 Trial ID: EXP Aug-2017 Page 25 of Excessive facial hair, facial skin disorders or skin reactions that could interfere with trial assessments (including but not limited to AK, eczema, psoriasis, seborrheic dermatitis, rosacea, and acute or recent sunburn). 6. Clinical diagnosis, history or evidence of any medical condition that would expose the subject to an undue risk of severe AEs or interfere with assessments of safety and efficacy during the course of the trial, as determined by the investigator's clinical judgement. 7. Supine blood pressure at screening >140/90 mmhg or <90/50 mmhg, or heart rate at screening >100 bpm or <50 bpm after up to 15 minutes of rest. 8. Herpes simplex (type 1 and/or type 2) with recurrent outbreaks (6 or more outbreaks per year), or a recent (within 2 months) or current outbreak. 9. Known infection with HIV. 10. Any haematological malignancies. 11. Use of cosmetic or therapeutic products and procedures that could interfere with the assessments of the acne lesion areas. 12. Known sensitivity or allergy to any of the ingredients in the vehicle gel or IMP. 13. Treatment with ingenol mebutate gel in the face within the last 12 months. 14. Change of use of hormonal oral contraceptives within 6 months of randomisation. 15. Subject was known to be or, in the opinion of the (sub)investigator, unlikely to comply with the clinical trial protocol (for example owing to alcoholism, drug abuse or psychotic state) or was impossible to contact in case of emergency. 16. Current participation in any other interventional clinical trial or previously enrolled in an interventional clinical trial, which in the opinion of the (sub)investigator could interfere with the interpretation of the trial results. 17. Close affiliation with the (sub)investigator (for example, a close relative) or a person working at the trial sites or as an employee of the sponsor. 18. Pregnancy, breastfeeding, or intention to become pregnant during the trial Withdrawal criteria Subjects could withdraw from the trial for any of the following reasons: 1. Unacceptable treatment efficacy: the (sub)investigator was free to withdraw the subject at any time based on a medical judgement. 2. Unacceptable AEs or LSRs: any AEs or LRS that the (sub)investigator or the subject considered unacceptable. 3. Exclusion criteria: any exclusion criteria that emerged/became apparent during the subject s participation in the clinical trial.

26 Trial ID: EXP Aug-2017 Page 26 of Voluntary withdrawal: subjects were free to withdraw from the clinical trial at any time and for any reason. Subjects who became pregnant during the trial had to withdraw. Subjects who had a positive pregnancy test at screening or Day 1 were to be excluded and complete an End of Trial Form. Subjects who had a positive pregnancy test at visits after treatment (Weeks 2, 4, 8, or 12) could remain in the trial for follow-up. Reason(s) for withdrawal was recorded in the ecrf and medical records. Subjects who were discovered, after enrolment/randomisation, not to have fulfilled all in-/ exclusion criteria at the time of enrolment were to discontinue treatment unless the (sub)investigator, based on clinical and ethical evaluation, found discontinuation inappropriate. Subjects who discontinued treatment after at least 1 treatment were to remain in the trial for follow-up assessments. AEs were to be followed up in all subjects as described in Section Subjects withdrawn were not to be substituted. 5.4 Treatments Treatments administered Subjects were treated with LEO gel 0.018% (test product) and vehicle gel (reference product) applied by trial site staff to the acne lesion areas as detailed in Table 3. Table 3 Administration of investigational medicinal products (IMPs) Route of administration Area of application Application frequency Daily maximum Time of day for application Relation of time of application to dietary intake Topical Left and right cheek acne lesion treatment areas (TA left and TA right ) of approximately 36 cm 2 each Once daily for up to 3 consecutive days Approximately 1/3 of a tube per acne lesion treatment area, applied by the trial staff as a thin wet layer No specific requirements No specific requirements

27 Trial ID: EXP Aug-2017 Page 27 of Investigational medicinal products (IMPs) Table 4 and Table 5 describe the identity of the 2 IMPs. Table 4 Identity of test product Name of finished test product Ingenol disoxate (LEO 43204) gel 0.018% Formulation Gel Active ingredient name/strength Ingenol disoxate/0.018% (w/w) Excipients CCI Manufacturer of bulk medication Manufacturer of subject treatment packages Batch number/expiry date LEO Pharma A/S or LEO Laboratories Ltd. CCI P14083/Feb-2017 Table 5 Identity of reference product Name of finished reference product Vehicle gel Formulation Gel Active ingredient name/strength None Excipients CCI Manufacturer of bulk product Manufacturer of subject treatment packages Batch numbers/expiry dates LEO Pharma A/S or LEO Laboratories Ltd. P14077/Dec P14075/Jun-2017 Listing of subjects receiving IMP from specific batches is available upon request.

28 Trial ID: EXP Aug-2017 Page 28 of Method of assigning subjects to treatment groups Subjects were randomised to treatment on the left and right cheek acne lesion treatment areas (TA left and TA right ) with LEO gel 0.018% and vehicle gel. The randomisation scheme/code list is found in Appendix Selection and timing of dose for each subject LEO gel 0.018% has not previously been administered to subjects between 18 and 35 years of age with acne vulgaris. Previous clinical trials with field treatment for AK in the face included only subjects over 40 years of age and Fitzpatrick skin type I-III. These trials have shown good tolerability and safety of LEO gel 0.018% when used in a 3-day, once-daily dosing regimen (7). In this exploratory trial, it was therefore considered safe to test the same strength of LEO gel 0.018% for once daily treatment for up to 3 consecutive days in combination with a trial design with close safety monitoring and the Safety Review Committee (see Section 5.1.1) Blinding All staff involved in the conduct of the trial and all subjects remained blinded to treatment allocation for the entire duration of the trial. The packaging and labelling of the IMPs contained no evidence of the allocated treatment. It was not considered possible to differentiate between the IMPs solely by sensory evaluation. Consequently, it was expected that the subjects and the site staff remained unaware of the individual treatment assignments during the conduct of the clinical trial Prior and concomitant therapy Prohibited medication and procedures prior to trial entry are detailed in the exclusion criteria (Section 5.3.2). Any medication and procedures during the trial were recorded along with the indication. Make-up and sunscreens were not allowed in the acne lesion areas from 3 days prior to Day 1 and until 15 days after last IMP application. Moreover, make-up and sunscreens were not allowed from the evening before follow-up visits at Weeks 4, 8, and 12 until after the assessments. Non-medicated and non-irritant emollients, lotions, creams, gels or foams were not allowed in the acne lesion areas from 3 days prior to Day 1 and during treatment days, and 3 days before trial visits. Eye make-up within the periorbital area and lipstick were allowed from 1 day after the last treatment day.

29 Trial ID: EXP Aug-2017 Page 29 of 166 Icepacks, cooling fans, weak analgesics with or without antihistamine, and mild sedatives were permitted to attenuate burning sensation, oedema, pain, and sleep loss arising from the trial treatment. Icepacks and cooling fans were not considered medical intervention, but were to be recorded in the ecrf as concomitant medication. Subjects were not to undergo any elective medical procedure without prior consultation with the (sub)investigator. Elective procedures (such as minor day surgery or dental surgery) that might require hospitalisation or anaesthesia were to be deferred during the first 15 days after first IMP administration Treatment compliance Treatment was administered by trial site staff at the clinic according to the protocol. The investigator kept an inventory of the IMP given to each subject, and this inventory was checked by the monitor during monitoring visits to ensure correct dispensing of the IMP. Any unused IMP was returned and fully accounted for using drug accountability forms. 5.5 Trial Schedule and Assessments Frequency and timing of measurements The schedule of all trial procedures for all trial visits is presented in Table 6.

30 Trial ID: EXP Aug-2017 Page 30 of 166 Table 6 Schedule of trial procedures Screening Visit Day 0 Day 1 Day 2 Day 3 Day 4 Day 8 Week 2 Week 4 Week 8 Visit number 1 2 * Visit window Informed consent Day -28 to Day 1 Inclusion/exclusion criteria X X Demographics Height and weight X X X Identification of acne lesion areas X X X X X X X X X X Medical history and concurrent diagnosis Acne treatment history X X Concomitant medication X X X X X X X X X X Abbreviated physical examination X X Vital signs X X Urine pregnancy test X X X X X X ±3 days ±3 days ±5 days Week 12 ±1 week Clinical assessments of full face IGA Clinical assessments of TA left and TA right for IGA and lesion count X X X X X X X Photos 3,4 1,2,3 1,2,3 1,2,3 1,2,3 1,2,3 1,2,3 1,2,3 1,2,3 1,2,3 Subject questionnaire Acne QoL X X Subject questionnaire TSQM II Subject Global Cosmetic Score Tape lift + swab for inflammatory biomarker analysis (not Cohort 1) Randomisation Administration of IMP X X 1 X 1 X X X X X X LSR evaluation X X X X 1,2,3 X X X X Adverse events X X X X X X X X X Phone call 4 X X End of Trial Form 1,2,3,4 = Cohorts 1-4; IGA = Investigator s Global Assessment; TSQM II = Treatment Satisfaction Questionnaire for Medication. * Could be performed the same day as screening. 1 Treatment on Days 2 and 3 depended on the criteria in Section X

31 Trial ID: EXP Aug-2017 Page 31 of Baseline characteristics and demographics assessed Data recorded at screening included date of birth, sex, race, ethnic origin, Fitzpatrick skin type (Table 7), height, weight, and relevant medical and surgical history including medical history pertaining to acne vulgaris (Table 8). Table 7 Type I II III IV V VI Reference [8] Table 8 Fitzpatrick skin type Description Always burns easily, never tans Always burns easily, tans minimally Burns moderately, tans gradually (light brown) Burns minimally, always tans well (moderate brown) Rarely burns, tans very well (moderate brown) Never burns, deeply pigmented Specified medical history for acne vulgaris Detailed history Debut Characteristics at debut (yes/no) Current disease characteristics (yes/no) Family history (yes/no) Previous acne vulgaris therapy (yes/no) *used 1 month ecrf recording Age at onset Early and more severe sebum production Early onset relative to menarche Mild facial comedones Persistent refractory disease Responding to standard therapies but relapsing Acne scarring Acne on trunk Hyperseborrhea Moderate to severe acne in one parent Moderate to severe acne in one sibling Systemic retinoids* Systemic antibiotics* Systemic hormone therapy for acne control* Topical retinoid monotherapy* Topical retinoid combination therapy* Other topical combination therapies* Topical benzoyl peroxide* Azealic acid* Photodynamic therapy Chemical peels Other light based therapies (specify) Other topical therapies (specify)

32 Trial ID: EXP Aug-2017 Page 32 of Efficacy measurements assessed Investigator assessments The investigator assessments were conducted by an experienced and qualified dermatologist. All assessments of each subject were performed by the same dermatologist. At screening, acne lesion treatment areas (TA left and TA right ) were identified and documented on an individual transparent film using a 3-point landmark technique. At all subsequent visits, the transparent film was used to locate the acne lesion areas for further treatment or assessments of the treated skin. The following clinical assessments were made at visits as specified in Table 6: 1. IGA (Table 9) of the full face at screening to determine the severity of acne vulgaris. 2. IGA (Table 9), non-inflammatory lesion count (open and closed comedones), and inflammatory lesion count (erythematous papules and pustules) in TA left and TA right at screening, baseline (Day 1), and Weeks 2, 4, 8, and end of trial (Week 12). 3. LSR assessments (see Section ) in TA left and TA right on Day 1 prior to application of IMP, and on all subsequent site visits. 4. Standardised photographs of the face (left side, frontal, and right side) at baseline, prior to treatment, and on all subsequent site visits (only for cohorts 1, 2, and 3). 5. All skin findings other than LSRs and acne were reported as medical history at screening or as AEs at subsequent visits. 6. Biomarker and microbiome sampling (tape lifts and swabs) from TA left and TA right for subjects in Cohorts 2, 3, and 4 at baseline and Weeks 2, 4, 8, and end of trial. Samples were stored for later analysis (reported separately). Table 9 IGA scale for acne vulgaris Grade Description 0 Clear skin with no inflammatory and non-inflammatory lesions 1 Almost clear; rare non-inflammatory lesions with no more than 1 small inflammatory lesion 2 Mild severity; greater than Grade 1; some non-inflammatory lesions with no more than a few inflammatory lesions (papules/pustules only, no nodular lesions) 3 Moderate severity; greater than Grade 2; up to many non-inflammatory lesions and some inflammatory lesions, but no more than 1 small nodular lesion 4 Severe; greater than Grade 3; up to many non-inflammatory and inflammatory lesions, but no more than a few nodular lesions Reference [18]

33 Trial ID: EXP Aug-2017 Page 33 of Subject-reported outcomes At baseline (Day 1) and end of trial (Week 12), subjects completed the Acne-QoL questionnaire, designed to assess the following 4 domains: self-perception, role-social, roleemotional, and acne symptoms (20, 21). At end of trial, subjects completed the TSQM II designed to assess the following 4 domains: effectiveness, side effects, convenience, and global satisfaction (22) as well as the Subject Global Cosmetic Score. Subject-reported outcome measures were completed prior to any other assessments at the respective trial visits in the following order: Acne-QoL, TSMQ II, and Subject Global Cosmetic Score Safety measurements assessed Adverse events The definition of AEs and SAEs as well as the means of obtaining and reporting events and the rating of these, are described in the clinical trial protocol (Section 9 and Appendix 7 and 8) in Appendix 1.1. LSRs matching the criteria in the LSR grading scale were reported in the LSR sections in the ecrf and not as AEs in the ecrf, even if they required treatment. Skin responses other than those identified in the LSR scale were recorded as AEs. Any LSR classified as an SAE was to be added to the AE form in the ecrf as well as reported to LEO Global Pharmacovigilance on the SAE form within 24 hours. Any treatments for an LSR were to be recorded on the concomitant medication page of the ecrf with the most significant LSR serving as the reason for treatment (for example swelling-lsr, if swelling was the most significant LSR). During the trial, the investigator followed up for a final outcome on all AEs. Once a subject had completed the trial, LSRs as well as AEs classified as possibly or probably related to the IMP and deemed clinically relevant were to be followed up for 2 months or until a final outcome was determined, whichever came first. SAEs were to be followed up until a final outcome had been established, that is, the follow-up could continue beyond the end of the clinical trial. No SAEs were reported during trial.

34 Trial ID: EXP Aug-2017 Page 34 of 166 SAEs occurring after the completion of the clinical trial were not to be routinely sought or recorded. However, such events were to be reported to LEO Global Pharmacovigilance if the (sub)investigator became aware of them Other events to be reported Other events to be reported included pregnancy, overdose, medication error, misuse, abuse, aggravation of condition, and AEs of special interest. AEs considered to be of special interest were development of keratoacanthoma (KA) or squamous cell carcinoma (SCC), which have been reported in previous clinical trials investigating LEO gel for treatment of AK in subjects with sun-damaged skin. The subjects in the current trial were not expected to have sun-damaged skin (23), owing to their young age (up to 35 years), and were thus considered to have a very low risk of developing KA or SCC. However, to ensure collection of all information relevant for surveillance, SCCs and KAs in the acne lesion areas were to be recorded as AEs of special interest in the ecrf, and a histology report was to be sent to Global Pharmacovigilance Other safety measurements LSRs in the acne lesion areas were assessed on Day 1 prior to first IMP application and at all subsequent visits as indicated in Table 6. LSRs were defined as erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration. The presence/absence and grade of each LSR were recorded using the LSR grading scale, included in the clinical trial protocol (Appendix 6) in Appendix 1.1. Any LSR identified within the acne lesion area that did not match the criteria in the LSR grading scale was reported as an AE Vital signs and physical examination Blood pressure and heart rate were assessed after approximately 5 15 minutes of rest in a supine position at the visits indicated in Table 6. An abbreviated physical examination including general appearance, regional lymph nodes, and dermatologic examination of the skin was performed at the visits indicated in Table Clinical laboratory tests For women of childbearing potential, a qualitative urine pregnancy test (dip-stick) of human chorionic gonadotropin was performed as scheduled in Table 6. The test was performed at the trial site.

35 Trial ID: EXP Aug-2017 Page 35 of Appropriateness of measurements Investigator assessments of efficacy included lesion counts and IGA of acne lesion areas, in accordance with the FDA guidance for developing drugs for acne vulgaris (19). Incorporating both quantitative and qualitative elements, these assessments were conducted by an experienced and qualified dermatologist and were considered reliable, reproducible, and accurate. Subject assessments of efficacy included: Acne-QoL, an acne-specific questionnaire documented to be reliable, valid, and useful in assessing therapeutic effects on acne in clinical trials (20, 21). TSQM II, a validated, general measure of treatment satisfaction for medication accounting for effectiveness, side effects, convenience, and global satisfaction that is comparable across medication types and patient conditions (22). Subject Global Cosmetic Score, a tool to capture the subject s own evaluation of appearance and feel of the skin following treatment with the IMP. LSRs were assessed using a defined LSR rating scale that has been employed in previous trials with LEO gel for treatment of AK (7). Safety was assessed using standard clinical methods of subject evaluations, such as AE monitoring and vital sign measurements. In addition, safety and tolerability data were reviewed by a Safety Review Committee during the trial. Standardised serial photographs were taken of subjects in Cohorts 1, 2, and 3 to document the skin appearance and aid the safety review. There were no photographs taken after Visit 2 of the subjects in Cohort 4 (Section 5.8). The degree of inflammatory response in the skin was assessed using an established panel of biomarkers, and the skin microbiome profile was assessed using sequencing technology (described in a separate biomarker report). 5.6 Trial Endpoints Primary endpoint Total lesion count (inflammatory and non-inflammatory) in acne lesion areas for LEO gel 0.018% and vehicle gel at Week 12.

36 Trial ID: EXP Aug-2017 Page 36 of Secondary endpoints Inflammatory lesion count in acne lesion areas for LEO gel 0.018% and vehicle gel at Week 12. Non-inflammatory lesion count in acne lesion areas for LEO gel 0.018% and vehicle gel at Week 12. IGA of acne lesion areas for LEO gel 0.018% and vehicle gel at Week 12. Composite and component LSR score at all visits. Occurrence of unacceptable LSR scores or unacceptable safety and tolerability events at all visits (as described in Section 5.1.1) Exploratory endpoints Total lesion count in acne lesion areas on Day 1 and at Weeks 2, 4, 8, and 12 (time course). Inflammatory lesion count in acne lesion areas on Day 1 and at Weeks 2, 4, 8, and 12 (time course). Non-inflammatory lesion count in acne lesion areas on Day 1 and at Weeks 2, 4, 8, and 12 (time course). IGA of acne lesion areas on Day 1 and at Weeks 2, 4, 8, and 12 (time course). Treatment success, that is, at least a 2-grade improvement of IGA at Week 12 compared with baseline. Inflammatory cytokine expression at time points defined after evaluation of the clinical data. Microbiome profile at time points defined after evaluation of the clinical data. Subject evaluation of Acne-QoL on Day 1 and Week 12. Subject evaluation of TSQM II at Week 12. Subject Global Cosmetic Score at Week 12.

37 Trial ID: EXP Aug-2017 Page 37 of Data Quality and Assurance LEO has implemented a system of quality assurance including all the elements described in this clinical trial report. Within this system, company standard operating procedures (SOPs) are implemented to ensure that clinical trials are conducted in compliance with regulatory requirements and GCP. Quality control is applied to each stage of data handling to ensure that data are accurate, reliable and processed correctly. Trial site, facilities, laboratories, and all data (including sources) and documentation were available for GCP audit by LEO Pharma A/S or inspection by competent authorities. Trial Monitoring LEO Pharma A/S, as sponsor of this clinical trial, is responsible to the authorities for assuring the proper conduct of the trial with regard to clinical trial protocol adherence and validity of the data recorded on the ecrfs. The company, therefore, assigned persons to monitor this clinical trial. It was their duty to serve as the principal link between (sub)investigators and LEO Pharma A/S and advise the investigators on the collection and maintenance of complete, legible, well organised, and easily retrievable data for the clinical trial. In addition, they were to explain to the investigators any aspect of the conduct of the trial, including interpretation of the clinical trial protocol, and purpose of collection of the specified data and reporting responsibilities. Case Report Forms Data were collected by means of electronic data capture. The investigator or staff authorised by the investigator entered subject data into ecrfs. Data recorded in the ecrfs was accessible to site staff through a secure internet connection immediately after entry. The ecrfs was maintained in an up-to-date condition at all times. The investigator electronically signed all ecrfs used. This signature information (including date of signature) was kept in the audit trail and could not be altered. Data Handling Subject data were entered into the ecrf by authorised site staff in a timely manner. Queries for discrepant data were generated automatically by the system upon entry or generated manually by the monitor or the trial data manager. All queries, whether generated by the system or by a user, were in an electronic format. This systematic validation ensured that a clean and consistent database was provided prior to the statistical analysis being performed.

38 Trial ID: EXP Aug-2017 Page 38 of Changes to the Conduct of the Trial The following 4 protocol amendments were issued, for the reasons stated: Version 2.0, 21-Apr The clinical part of the trial was moved to a new site to improve the rate of recruitment. As the new investigator had previous experience with ingenol disoxate (LEO 43204) from trials in subjects with AK, the change was not expected to have a negative impact on the evaluation of safety, LSR and endpoints. The visit on Day 8 for Cohorts 1, 2, and 3 was changed to a site visit instead of a phone call to allow for assessment of LSR score (and any AEs) and thereby provide further details of the overall LSR time course and tolerability for evaluation by the Safety Review Committee. The cumulative number of unacceptable events for trial termination was reduced for Cohorts 2 and 3 (Section 5.1.1) to further improve subject safety and to align with previous trials of LEO in patients with AK. The extent of photo documentation from Day 1 and all subsequent visits was reduced to include only Cohorts 1, 2 and 3, and the physical examination and assessment of vital signs were limited to the screening and end of trial visits. As a means of simplifying the trial, the changes were considered safe, since no clinically relevant safety findings from these assessments have been reported in previous trials of LEO in patients with AK. The exploratory endpoints for evaluating physical skin parameters were removed to further simplify the protocol.

39 Trial ID: EXP Aug-2017 Page 39 of 166 Version 3.0, 26-May The planned sampling for inflammatory biomarker and microbiome analyses was removed for the 3 subjects randomised in Cohort 1 (but remained for subjects in Cohorts 2, 3, and 4). This was done so as not to delay recruitment while deciding which laboratory would analyse the samples and which sampling method should be used. As these analyses were exploratory, the change did not affect the safety and efficacy evaluations of the trial. Version 4.0, 28-Jun The exploratory analysis of inflammatory biomarkers was outsourced to a different laboratory than planned for faster results, and the method was updated. The method for the microbiome analysis was also updated (but the laboratory for this analysis remained unchanged). Version 5.0, 15-Sep All subjects in Cohort 3 and 4 had to have photographs taken at screening for documentation of eligibility. The first 2 amendments were issued before the first subject was enrolled; the last amendments were issued after the first subject was enrolled. However, neither the safety of the subjects enrolled prior to this amendment nor the integrity of the data was compromised. Changes to the analysis described in the clinical trial protocol are detailed in the statistical analysis plan update (SAPU) and changes to the SAPU are found in Section 6.3.

40 Trial ID: EXP Aug-2017 Page 40 of Statistical Methods 6.1 Determination of Sample Size With a sample size of 38 subjects, a difference between LEO and vehicle could be detected with a statistical power of 84% in an intra-individual comparison trial, using a paired 2-sided t-test at a significance level of 5% and assuming an approximate total lesion count of 36 at baseline, approximate reductions from baseline to end of trial of 12.4 (34%) for LEO and 7.3 (20%) for vehicle, and a standard deviation (SD) of the difference between treatments at end of treatment up to The assumption on sample size was that all but the first 2 of 40 subjects randomised would be included in the efficacy analyses (see Section ). The assumptions on efficacy relied on experiences from a previous trial conducted by LEO in subjects with acne (24), along with an expected reduction in SD for the primary endpoint of at least 20% owing to the intraindividual comparisons. 6.2 Statistical and Analytical Plan Summary The statistical analysis was planned in the clinical trial protocol, Appendix 1.1 and further detailed in the SAPU, Appendix 1.9. Overall, the statistical analyses were performed as outlined in these documents. The SAPU was finalised after blind review of the data but before unblinding of the trial General principles All significance tests were 2-sided with a significance level of 5%. All confidence intervals (CIs) are presented with 95% degree of confidence. An observed cases approach was used for tabulations of data by visit and for graphical presentation by visit (that is, involving only those subjects who attended each specific visit). Categorical data were summarised using the number and percentage of subjects in each category. Continuous data were summarised using the mean, median, SD, minimum and maximum values (range) Definition of trial analysis sets All subjects enrolled in the trial are accounted for in the clinical trial report.

41 Trial ID: EXP Aug-2017 Page 41 of 166 All subjects randomised except the first 2 subjects, for whom exposure of IMP was reduced, were included in the full analysis set (FAS) and analysed for efficacy. Hence, the FAS included 38 subjects. Exclusions from the FAS could be considered in special cases as described in ICH E9, section 5.2.1, and were to be justified accordingly. A per protocol analysis set (PPS) was defined by excluding subjects from the FAS based on a review of protocol deviations before unblinding of the trial. Any decision to exclude a subject from the PPS was to be justified. A safety analysis set (SAS) was defined by all randomised and exposed subjects. The SAS therefore includes 40 subjects. The decisions regarding inclusion/exclusion of subjects and/or subject data from the trial analysis sets were documented in the SAPU before breaking the randomisation code Statistical analysis and data presentation Demographics and other baseline characteristics, AEs and other safety measurements are summarised for the safety analysis set using descriptive statistics (data summaries, listings, and figures). The primary endpoint was analysed for the FAS, which was regarded as primary. The treatment effect on total lesion count (inflammatory and non-inflammatory) at Week 12 (primary endpoint) was evaluated within the framework of an analysis of covariance (ANCOVA) model with treatment as fixed effect, baseline total lesion count as a covariate, and subject as a random effect. LEO and vehicle were compared by means of a t-test on the estimated treatment contrast in the model. The estimated difference, 95% CI, and test probability are presented, along with the least square means and corresponding 95% CI. A sensitivity analysis investigating the potential effect of laterality was performed by adding this effect to the above model. Secondary endpoints were analysed for the FAS and SAS (LSRs). Inflammatory and non-inflammatory lesion counts and their sum are summarised by treatment and visit, along with mean curves over time, using descriptive statistics. IGA of disease severity is summarised by treatment and visit using descriptive statistics.

42 Trial ID: EXP Aug-2017 Page 42 of 166 For LSRs, the incidence and grade are summarised by treatment and visit time point using descriptive statistics for each of the 6 individual LSRs (see Section ). LSRs leading to withdrawal from trial or withdrawal of IMP are listed. A composite LSR score is obtained by summing the 6 individual LSR scores (range 0 24) at each visit (Visit 2/Day 1 to Visit 10/Week 12). The composite score and change from baseline are summarised by treatment at visit time point using descriptive statistics. The maximum composite LSR score across visits and the visits of occurrence of the maximum composite LSR score are tabulated by treatment. The first visit after maximum LSR was reached, where the composite LSR score was less than or equal to the composite score at baseline, is tabulated by treatment group. Exploratory endpoints were analysed for the FAS. Treatment success derived from IGA, that is, at least a 2-grade improvement of IGA at Week 12 compared with baseline, was tabulated and tested by a McNemar s test; Acne-QoL is summarised by each of the 4 domains contained within the questionnaire. TSQM II is summarised by overall outcome and by each of the 4 domains contained within the questionnaire. The Subject Global Cosmetic Score is summarised by treatment. The analysis of inflammatory cytokine expression and microbiome data is specified in a separate analysis plan and the results are reported separately Handling of missing values Subjects with missing counts of inflammatory and non-inflammatory lesions at Weeks 2, 4, and 8 were excluded from the analyses based on the FAS and the PPS set for these time points, and missing lesion counts were therefore not imputed for these subjects. For subjects with missing lesion counts at Week 12, the missing lesion counts were imputed and the endpoints subsequently derived from the imputed values. A multiple imputation method was used to handle missing data. The method relied on the assumption that missing data were missing at random, that is, the probability that an observation was missing could depend on observed data but was unrelated to the data not observed. All imputations were performed by lesion type and treatment group. Imputation of missing values for subjects with a monotone missing data pattern (that is, a time point for the subject existed where all observations before the time point were present and all later observations were missing) was based on the full observed dataset excluding subjects

43 Trial ID: EXP Aug-2017 Page 43 of 166 with a non-monotone missing data pattern. Missing values for lesion counts at Week 12 were imputed sequentially from a linear regression model with lesion counts at previous visits as covariates and treatment compliance (as identified by means of protocol deviations) as factor. For subjects with a non-monotone missing data pattern, lesion counts at Week 12 were imputed using data from subjects without a non-monotone missing data pattern based on the Markov Chain Monte Carlo method, including compliance effect and lesion counts at Weeks 2, 4, and 8 as continuous variables. In case of non-convergence, the compliance effect was excluded from the imputation model. The imputed values at Week 12 were rounded to the nearest non-negative integer. Sensitivity analyses of the methods for handling missing data were performed for the analyses of the imputed endpoints using last observation carried forward (LOCF) imputation and an observed cases (OC) approach Interim analysis and data monitoring Appendix 1.4 includes the composition of the Safety Review Committee; the dose escalation procedure is found in LEO Safety Review Committee Charter (edoc no ). For all subjects in Cohort 1, 2 and 3, blinded data were analysed after Week 2 to evaluate LSRs, safety, and tolerability and determine progression to the next cohort (see Section 5.1.1). The analyses included: Evaluation of AEs, using the investigator s term. Number of subjects at any time with occurrence of unacceptable LSRs (Table 1). Descriptive statistics of composite and component LSR scores summarised by visit and sideness (TA left /TA right ). Plots of mean and individual profiles of composite LSR scores by visit and sideness (TA left /TA right ). Descriptive statistics of maximum composite and component LSR scores in TA left and TA right summarised by visit. Plots of mean and individual profiles of maximum composite LSR scores in TA left and TA right summarised by visit. List of individual component LSR scores. In summary, review conclusions supported progression from one cohort to the next.

44 Trial ID: EXP Aug-2017 Page 44 of Multiplicity adjustments No adjustments for multiplicity were made. 6.3 Changes to the Statistical Analysis Plan An actual treatment analysis was introduced with 3 subjects having treatment reallocated; see Section Added to the primary endpoint analysis were change and percent change from baseline of total lesion counts. 6.4 Software and Dictionaries SAS version 9.4 was used to create tables, figures, and listings as well as for power calculation and statistical analysis. MedDRA version 19.0 was used for coding of AEs and medical history. WHO-DD version MAR 1, 2016 was used for coding concomitant medication.

45 Trial ID: EXP Aug-2017 Page 45 of Trial Population 7.1 Disposition of Subjects 59 subjects were enrolled in the trial by signing informed consent (Appendix 2.3-EoT Listing 1.1 and Appendix 2.1-EoT Listing 1.3) and 40 subjects were randomised with the first 3 subjects in Cohort 1, followed by 6 subjects in each of Cohorts 2 and 3, and the last 25 subjects in Cohort 4 (Table 10). The 19 subjects who were not randomised were all screen failures, with 18 subjects not fulfilling inclusion criterion No. 3 (acne vulgaris disease severity in the full face and in the acne lesion areas scored as moderate to severe [Grade 3-4] according to the IGA scale) and one subject not fulfilling inclusion criterion No. 6 (age 18 to 35 years) (Section 5.3.1). 34 subjects completed the trial (Table 10). The 6 non-completers are presented in Appendix 2.1-EoT Listing 1.2; 4 subjects were lost to follow-up and 2 subjects withdrew voluntarily; these subjects are also described in Section 3 of the SAPU (Appendix 1.9). 7 subjects had one or more missing visits as shown in Appendix 2.2-EoT Listing 2.2, and 16 subjects had one or more visits the outside visit window as shown in Appendix 2.2-EoT Listing 2.1. The visits outside the visit window were discussed at the blind data review meeting and the SAPU Section 3 describes the background for the decisions made (Appendix 1.9); no visit reallocation or deletion of data points was performed. Table 10 Subject disposition: All subjects randomised Cohort 1 (N=3) n (%) Cohort 2 (N=6) n (%) Cohort 3 (N=6) n (%) Cohort 4 (N=25) n (%) Total (N=40) n (%) Randomised set 3 (100) 6 (100) 6 (100) 25 (100) 40 (100) Full Analysis Set 1 (33) 6 (100) 6 (100) 25 (100) 38 (95) Per-Protocol Analysis set 1 (33) 5 (83) 6 (100) 20 (80) 32 (80) Safety Analysis Set 3 (100) 6 (100) 6 (100) 25 (100) 40 (100) Completed the trial 3 (100) 5 (83) 6 (100) 20 (80) 34 (85) Discontinued from the trial 0 (0) 1 (17) 0 (0) 5 (20) 6 (15) Unacceptable treatment efficacy 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Unacceptable adverse events 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Exclusion criteria 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Voluntary withdrawal 0 (0) 0 (0) 0 (0) 2 (8) 2 (5) Other reasons 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Lost to follow-up 0 (0) 1 (17) 0 (0) 3 (12) 4 (10) Death 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) N = Number of subjects. n = number of subjects with data. %=percentage of subjects with data. Leo_Pharma/EXP/EXP-1223/F01 - tab_subdisp.sas/tab_subdisp.rtf/11aug2017 Cross-reference: EoT Table 1.1

46 Trial ID: EXP Aug-2017 Page 46 of Protocol Deviation A list of trial issues and protocol deviations (PDs) is available in Appendix 2.2 (Appendix 2.2-EoT Listing 3.1). A total of 3 PDs concerning 3 subjects were evaluated as being major. The 3 subjects violated the protocol as they were treated after their LSR evaluation exceeded the predefined criteria for continued treatment on Day 2 and Day 3 (see Section ); Appendix 2.7-EoT Listing 7.5 shows that the 3 subjects had LSRs above the defined criteria, but were treated with IMP. When the deviations were discovered, it was assessed that the PDs had not led to safety issues and efficacy evaluations were performed as planned. None of the PDs led to exclusion from any analysis set. Appendix 2.2-EoT Listing 3.2 contains the Investigator s comments relating to issues observed during the trial. 7.3 Trial Analysis Sets The analysis sets were determined based on the criteria defined in Section 6.2.1, according to the consolidated clinical trial protocol, Appendix 1.1 and the SAPU, Appendix 1.9. All decisions on the inclusion and exclusion of subjects from analyses were made while the data were still blinded. Appendix 2.3-EoT Listing 1.1 shows the individual allocation to analysis sets and the number of subjects in each analysis set is summarised in Table Allocation to treatment During a review of individual LSRs (Section 11.4), it was assessed that the randomised treatment ( planned treatment ) for 3 subjects were probably not the actual treatment given at all applications as high LSRs in the vehicle treated area and no reactions on the LEO treated area were observed. It was therefore decided to include a definition of actual treatment, which differed from the randomised (planned) treatment for these 3 subjects, i.e. the 3 subject s actual treatment was reallocated to the opposite sites than planned (Appendix 2.3-EoT Listing 1.1) Full analysis set (FAS) All except the first 2 subjects included in Cohort 1 (according to protocol) were included in the FAS, thus the FAS comprised 38 subjects. At Week 12, FAS comprised 32 subjects as 6 subjects discontinued before Week 12.

47 Trial ID: EXP Aug-2017 Page 47 of Safety analysis set (SAS) The SAS comprised all 40 randomised subjects. Presence or confirmed absence of AEs was available for all randomised subjects Per protocol analysis set (PPS) The PPS was defined as all subjects from the FAS (n=38) who: completed the trial. had no other major protocol deviations deemed to influence the evaluation of efficacy. 6 subjects were excluded from the PPS, all for the reason of not completing the trial. The PPS hence comprised 32 subjects. A list of subject excluded from the PPS is provided in Appendix 2.3 (Appendix 2.3-EoT Listing 1.1). 7.4 Demographic and Other Baseline Characteristics Demographic and other baseline characteristics of the trial population are summarised in Table 11 and Table 12. Individual demographic data are shown in Appendix 2.4-EoT Listing 4.1. The trial population of 60% males was aged 18 to 34 years (mean 21.9 years) with most subjects being in the age group < 25 years (85%). The subjects were mainly White (82.5%) of Hispanic or Latino ethnicity (67.5%) and their skin type was classified as Fitzpatrick skin Type II (35%) or Type III (65%). They had had acne for a mean of 6.8 years ranging from 3 to 20 years. The mean BMI of the trial population was in the overweight category (26.5 kg/m 2 ), but ranged from underweight to severely obese.

48 Trial ID: EXP Aug-2017 Page 48 of 166 Table 11 Age group, sex, race, ethnicity and skin type - SAS Total (N=40) n (%) Age group (45.0) (40.0) (15.0) Total 40 (100) Sex Female 16 (40.0) Male 24 (60.0) Total 40 (100) Race Asian 4 (10.0) Native hawaiian or other pacific islander 3 (7.5) White 33 (82.5) Total 40 (100) Ethnicity Hispanic or latino 27 (67.5) Not hispanic or latino 13 (32.5) Total 40 (100) Skin classification Type II 14 (35.0) Type III 26 (65.0) Total 40 (100) N = Number of subjects. n = number of subjects with data. %=percentage of subjects with data. Leo_Pharma/EXP/EXP-1223/F01 - tab_demo.sas/tab_demo2.rtf/11aug2017 Cross-reference: EoT Table 1.3 Table 12 Age, weight, height, BMI, and duration of Acne at baseline - SAS Total (N=40) Age (years) n 40 Mean (SD) 21.9 (3.8) Median 21.0 Min 18 Max 34 Weight (kg) n 40 Mean (SD) 77.1 (23.9) Median 72.2 Min 48.5 Max Height (m) n 40 Mean (SD) 1.71 (0.09) Median 1.70 Min 1.50 Max 1.98 BMI (kg/m/m) n 40 Mean (SD) 26.5 (8.2) Median 24.9 Min 17.1 Max 59.3 Duration of Acne (years) n 40 Mean (SD) 6.8 (3.5) Median 6.0 Min 3 Max 20 N = Number of subjects. n = Number of subjects with data. SD = Standard Deviation. Leo_Pharma/EXP/EXP-1223/F01 - tab_demo.sas/tab_demo1.rtf/11aug2017 Cross-reference: EoT Table 1.2

49 Trial ID: EXP Aug-2017 Page 49 of 166 The specified medical history for poor prognostic factors for acne is summarised in Table 13 and individual acne medical histories are shown in Appendix 2.4-EoT Listings 4.3 and 4.4. Acne history characteristics were to a high degree related to sebum production/seborrheia and comedones (85% to 95% of subjects); persistent refractory disease and acne scarring were present in 92.5% and 77.5% of subjects, respectively. Table 13 Acne history - SAS Total (N=40) Acne History n (%) Characteristics at onset Early and more severe sebum production 38 (95.0) Early onset relative to menarche 13 (81 3) Mild facial comedones 38 (95.0) Current disease characteristics Acne on trunk 17 (42 5) Acne scarring 31 (77 5) Hyperseborrheia 34 (85.0) Persistent refractory disease 37 (92 5) Responding to standard therapies but relapsing 22 (55.0) Family history Moderate to severe acne in at least one parent 6 (15.0) Moderate to severe acne in at least one sibiling 15 (37 5) N = Number of subjects. n = number of subjects with data. %=percentage of subjects with data. For "Early onset relative to menarche" the denominator is number of females. Leo_Pharma/EXP/EXP-1223/F01 - tab_ak.sas/tab_ak1.rtf/11aug2017 Cross-reference: EoT Table 1.4 Acne treatment history is summarised in Table 14; 60% of the 25 previously treated subjects had used topical benzoyl peroxide, while other topical therapies had only been used in up to 16% of subjects. Previous systemic acne treatment was not reported for any subject. Individual acne treatment history is shown in Appendix 2.4-EoT Listing 4.6. Table 14 Previous treatment history - SAS Total (N=40) Acne Treatment History n (%) Other topical combination therapies 3 (12) Topical Azealic acid 1 (4) Topical benzoyl peroxide 15 (60) Topical retinoid combination therapy 2 (8) Topical retinoid monotherapy 4 (16) N = Number of subjects. n = number of subjects with data. %=percentage of subjects with data. Leo_Pharma/EXP/EXP-1223/F01 - tab_cm_prev.sas/tab_cm_prev.rtf/11aug2017 Cross-reference: EoT Table 1.5 Appendix 2.4-EoT Listing 4.2 shows individual medical histories other than acne and Table 15 summarises concurrent diagnoses, which 7 subjects had, asthma being most frequent (3 subjects).

50 Trial ID: EXP Aug-2017 Page 50 of 166 Table 15 Concurrent diagnoses - SAS MedDRA Body System Organ Class Preferred Term Total (N=40) n (%) Any medical/surgical history 7 (17 5) Respiratory, thoracic and mediastinal disorders 3 ( 7 5) Asthma 3 ( 7 5) Skin and subcutaneous tissue disorders 2 ( 5.0) Hyperhidrosis 1 ( 2 5) Dermatitis atopic 1 ( 2 5) Musculoskeletal and connective tissue disorders 1 ( 2 5) Arthralgia 1 ( 2 5) Immune system disorders 1 ( 2 5) Seasonal allergy 1 ( 2 5) Nervous system disorders 1 ( 2 5) Migraine 1 ( 2 5) Metabolism and nutrition disorders 1 ( 2 5) Hypovitaminosis 1 ( 2 5) Renal and urinary disorders 1 ( 2 5) Nephrolithiasis 1 ( 2 5) Blood and lymphatic system disorders 1 ( 2 5) Anaemia 1 ( 2 5) General disorders and administration site conditions 1 ( 2 5) Fatigue 1 ( 2 5) Infections and infestations 1 ( 2 5) Bronchitis 1 ( 2 5) Psychiatric disorders 1 ( 2 5) Depression 1 ( 2 5) N = Number of subjects. n = Number of subjects with data. % = Percentage of subjects with data. Leo_Pharma/EXP/EXP-1223/F01 - tab_mh sas/tab_mh2.rtf/11aug2017 Cross-reference: EoT Table 1.7 Concomitant medication at baseline concerned 2 subjects as summarised in Table 16; the individual concomitant medication(s) are shown in Appendix 2.4-EoT Listing 4.5.

51 Trial ID: EXP Aug-2017 Page 51 of 166 Table 16 Concomitant medication at baseline - SAS MedDRA Body System Organ Class Preferred Term Total (N=40) n (%) Any concomitant medication 2 ( 5.0) Various 2 ( 5.0) Other Therapeutic Products 2 ( 5.0) Musculo-Skeletal System 1 ( 2.5) Propionic Acid Derivatives 1 ( 2.5) N = Number of subjects. n = Number of subjects with data. % = Percentage of subjects with data. Leo_Pharma/EXP/EXP-1223/F01 - tab_conmed.sas/tab_conmed1.rtf/11aug2017 Cross-reference: EoT Table Exposure and Treatment Compliance Treatment was applied as described in Section The number of days treated are summarised in Table 17. IMP administration per subject is presented in Appendix 2.5-EoT Listing 5.1; the 3 subjects in Cohort 1 were treated 1, 2 and 3 days, respectively, which was according to protocol. One subject in Cohort 2 was treated for 2 days and the rest of the subjects in Cohort 2 to 4 were treated for 3 days, which was the intended number of dosing days if no dose limiting LSRs occurred (Section 5.1.2). The subject treated for only 2 days had IMP withdrawn after 2 days of treatment on own request due to burning on the right cheek (see Appendix 2.2-EoT Listing 3.2 and Appendix 2.7-EoT Listing 7.5); the event was reported as an AE (Appendix 2.7-EoT Listing 7.1). The duration of treatment in the cohorts and for the total population is summarised in EoT Table 1.10; all cohorts except Cohort 2 were on average treated for the planned number of days. However, 3 subjects violated the protocol and were treated on Day 2 and 3 although they shouldn't have been according to the protocol criteria (see Section 7.2). Table 17 Treatment compliance, number of days treated - SAS Cohort 1 (N=3) n (%) Cohort 2 (N=6) n (%) Cohort 3 (N=6) n (%) Cohort 4 (N=25) n (%) Total (N=40) n (%) Number of days 3 1 (33.3) 5 (83.3) 6 ( 100) 25 ( 100) 37 (92.5) 2 1 (33.3) 1 (16.7) ( 5.0) 1 1 (33.3) ( 2.5) N = Number of subjects. n = number of subjects with data. %=percentage of subjects with data. Leo_Pharma/EXP/EXP-1223/F01 - tab_ex.sas/tab_ex.rtf/11aug2017 Cross-reference: EoT Table 1.9

52 Trial ID: EXP Aug-2017 Page 52 of Efficacy Evaluation In the following sections LEO gel 0.018% is referred to as LEO and vehicle gel is referred to as vehicle. Acne lesion area is referred to as just area. 9.1 Primary Endpoint Total lesion count in acne lesion areas for LEO and vehicle gel at Week 12 The mean (±SE) total lesion counts in acne lesion areas on Day 1 and at Weeks 2, 4, 8, and 12 is shown in Figure 2 (time course). Total lesion count by visit is summarised in EoT Table 2.1. Individual time course curves are presented in EoT Figures 2.7 to 2.11 and individual facial lesion counts are presented in Appendix 2.6-EoT Listing 6.1. Of notice, for a large part of the subjects, one of the treatment areas showed the exact same lesion counts at all visit. This mainly affected the vehicle treated area and could affect the reliability of the results. As seen in Figure 2, a decrease in mean total lesion counts was seen after end of treatment and it continued steadily to Week 12, most pronounced in the LEO treated area. Figure 2 Mean total lesion counts versus time - planned treatment - FAS Cross-reference: EoT Figure 2.1

53 Trial ID: EXP Aug-2017 Page 53 of 166 At Week 12, the mean number of acne lesions in the LEO treated area was statistically significantly lower compared to the vehicle treated area (Table 18). Table 18 Analysis of total lesion count Week 12 multiple imputation methods - planned treatment - FAS Leo Gel 0.018% Vehicle n Mean SD Minimum 2 1 Maximum LSMeans % CI ( 19.85, 27 29) ( 29.18, 36.62) Difference % CI (-14.71, -3.96) P-value <.001 n = number of subjects with data. SD=Standard deviation. LSMean values and difference is from ANCOVA model with treatment as fixed effect and baseline total lesion count as covariate and subject as random effect. 100 simulations of monotone multiple imputation is performed. Summary statistics are found across these 100 simulations. Comparisons are by Proc Mianalyze. Leo_Pharma/EXP/EXP-1223/F01 - tab_ana_les_mi.sas/tab_ana_les_mi_fas.rtf/11aug2017 Cross-reference: EoT Table Other analyses including sensitivity analyses The mean total lesion count change from baseline to Week 12 The mean total lesion count change from baseline to Week 12 in the LEO treated area was (95% CI [-19.3, -10.4]) (Table 19) corresponding to a -38.6% change from baseline (95% CI [-50.3, -26.8]) (Table 20); the vehicle result was -5.9 (95% CI [-10.3, -1.6]) mean total lesion count change, corresponding to a -18.2% change from baseline (95% CI [-32.3, -4.2]). Table 19 Summary of total lesion change from baseline - planned treatment - FAS Treatment Visit n Mean SD Median Min Max 95% CI LEO gel 0.018% Week ( -4.40, -2.17) Week ( -7.99, -4.58) Week (-13.99, -7.95) Week (-19.28,-10.40) Vehicle gel Week ( -1.12, 0.49) Week ( -3.20, 0.57) Week ( -5.60, -0.09) Week (-10.27, -1.60) n = number of subjects with data. SD=Standard deviation. Leo_Pharma/EXP/EXP-1223/F01 - tab_les_chg.sas/tab_les_chg_pln.rtf/11aug2017 Cross-reference: EoT Table 2.9

54 Trial ID: EXP Aug-2017 Page 54 of 166 Table 20 Summary of total lesion percent change from baseline - planned treatment - FAS Treatment Visit n Mean SD Median Min Max 95% CI LEO gel 0.018% Week (-14.81, -5.90) Week (-23.90,-12.05) Week (-37.82,-20.72) Week (-50.30,-26.83) Vehicle gel Week ( -3.94, 2.74) Week (-10.91, 4.69) Week (-22.24, 1.45) Week (-32.26, -4.19) n = number of subjects with data. SD=Standard deviation. Leo_Pharma/EXP/EXP-1223/F01 - tab_les_chg.sas/tab_les_pchg_pln.rtf/11aug2017 Cross-reference: EoT Table 2.11 Figure 3 shows the mean (±SE) percent change in total lesion count versus time. The largest percent change from baseline was seen in the LEO treated area where the change started shortly after end of treatment and continued steadily to Week 12. Figure 3 Percent change total lesion count versus time - planned treatment - FAS Cross-reference: EoT Figure 2.3

55 Trial ID: EXP Aug-2017 Page 55 of Actual treatment analysis The definition of actual treatment is found in Section The mean (±SE) total lesion count in acne lesion areas on Day 1 and at Weeks 2, 4, 8, and 12 is shown in Figure 4 (time course). Figure 4 Mean total lesion count versus time - actual treatment - FAS Cross-reference: EoT Figure 2.2 At Week 12, the mean number of acne lesions in the LEO treated area was statistically significantly lower compared to the vehicle treated area (Table 21).

56 Trial ID: EXP Aug-2017 Page 56 of 166 Table 21 Analysis of total lesion count Week 12 OC - actual treatment - FAS Leo Gel 0.018% (N=38) Vehicle (N=38) n Mean SD Minimum 1 2 Maximum LSMeans % CI [ 17.52, 25.15] [ 29.92, 37.54] Difference % CI [-17.79, -7.00] P-value <.001 n = number of subjects with data. SD=Standard deviation. LSMean values and difference is from ANCOVA model with treatment as fixed effect and baseline total lesion count as covariate and subject as random effect. Actual treatment is determined post database lock by inspecting the LSR. For subjects PPD PPD and PPD treatments were interchanged. Leo_Pharma/EXP/EXP-1223/F01 - tab_ana_les.sas/tab_ana_les_acttrt_fas.rtf/11aug2017 Cross-reference: EoT Table 2.8 The mean total lesion count change from baseline at Week 12 in the LEO treated area was (95% CI [-21.0, -12.5]) (Table 22) corresponding to a -44.2% (95% CI [-55.9, -32.6]) change from baseline (Table 23). The vehicle lesion count change was -4.0 (95% CI [-7.8, -0.2]) corresponding to a -12.6% (95% CI [-25.2, 0.1]) change from baseline. Table 22 Summary of total lesion change from baseline - actual treatment - FAS Treatment Visit n Mean SD Median Min Max 95% CI LEO gel 0.018% Week ( -4.48, -2.32) Week ( -8.46, -5.25) Week (-14.98, -9.32) Week (-21.04,-12.52) Vehicle gel Week ( -0.99, 0.59) Week ( -2.51, 1.03) Week ( -4.08, 0.75) Week ( -7.83, -0.17) n = number of subjects with data. SD=Standard deviation. Actual treatment is determined post database lock by inspecting the LSR. For subjects PPD PPD and PPD treatments were interchanged. Leo_Pharma/EXP/EXP-1223/F01 - tab_les_chg.sas/tab_les_chg_act.rtf/11aug2017 Cross-reference: EoT Table 2.10

57 Trial ID: EXP Aug-2017 Page 57 of 166 Table 23 Summary of total lesion percent change from baseline - actual treatment - FAS Treatment Visit n Mean SD Median Min Max 95% CI LEO gel 0.018% Week (-15.06, -6.28) Week (-25.24,-13.87) Week (-40.84,-24.49) Week (-55.87,-32.59) Vehicle gel Week ( -3.59, 3.03) Week ( -9.10, 6.03) Week (-18.27, 4.27) Week (-25.19, 0.08) n = number of subjects with data. SD=Standard deviation. Actual treatment is determined post database lock by inspecting the LSR. For subjects PPD PPD and PPD treatments were interchanged. Leo_Pharma/EXP/EXP-1223/F01 - tab_les_chg.sas/tab_les_pchg_act.rtf/11aug2017 Cross-reference: EoT Table 2.12 Figure 5 shows mean (±SE) percent change in total lesion count versus time. The largest percent change from baseline was seen in the LEO treated area where the change started shortly after end of treatment and continued steadily to Week 12.

58 Trial ID: EXP Aug-2017 Page 58 of 166 Figure 5 Percent change total lesion count versus time - actual treatment - FAS Additional sensitivity analyses Cross-reference: EoT Figure 2.4 At Week 12, the PPS consisted of the same subjects as the FAS, so no additional sensitivity analysis was performed using the PPS. An observed cases (OC) analysis (Table 24) supported the primary endpoint analysis.

59 Trial ID: EXP Aug-2017 Page 59 of 166 Table 24 Analysis of total lesion count Week 12 OC - planned treatment - FAS Leo Gel 0.018% (N=38) Vehicle (N=38) n Mean SD Minimum 2 1 Maximum LSMeans % CI [ 19.08, 27 39] [ 27.67, 35.98] Difference % CI [-14.47, -2.71] P-value n = number of subjects with data. SD=Standard deviation. LSMean values and difference is from ANCOVA model with treatment as fixed effect and baseline total lesion count as covariate and subject as random effect. Leo_Pharma/EXP/EXP-1223/F01 - tab_ana_les.sas/tab_ana_les_fas.rtf/11aug2017 Cross-reference: EoT Table 2.5 A sensitivity analysis including laterality ( sideness left vs. right) as a covariate was performed. The result is summarised in Table 25; the result was comparable to the primary endpoint result. Table 25 Analysis of total lesion count Week 12 - laterality OC - planned treatment - FAS Leo Gel 0.018% (N=38) Vehicle (N=38) n Mean SD Minimum 2 1 Maximum LSMeans % CI [ 19.11, 27.48] [ 27.58, 35.96] Difference % CI [-14.41, -2.55] P-value n = number of subjects with data. SD=Standard deviation. LSMean values and difference is from ANCOVA model with treatment as fixed effect and baseline total lesion count and laterality as covariates and subject as random effect. Leo_Pharma/EXP/EXP-1223/F01 - tab_ana_les.sas/tab_ana_les_sens_fas.rtf/11aug2017 Cross-reference: EoT Table 2.7 Furthermore, a LOCF analysis was performed. The results are shown in Table 26; the analysis supported the main analysis.

60 Trial ID: EXP Aug-2017 Page 60 of 166 Table 26 Analysis of total lesion count Week 12 - LOCF - planned treatment - FAS Leo Gel 0.018% (N=38) Vehicle (N=38) n Mean SD Minimum 2 1 Maximum LSMeans % CI [ 21.93, 29.29] [ 29.74, 37.10] Difference % CI [-13.02, -2.60] P-value n = number of subjects with data. SD=Standard deviation. LSMean values and difference is from ANCOVA model with treatment as fixed effect and baseline total lesion count as covariate and subject as random effect. Leo_Pharma/EXP/EXP-1223/F01 - tab_ana_les.sas/tab_ana_les_locf_fas.rtf/11aug2017 Cross-reference: EoT Table Secondary Endpoints All secondary endpoints are randomised treatment ( planned treatment ); see Section Inflammatory lesion count in acne lesion areas for LEO gel 0.018% and vehicle gel at Week 12 The mean inflammatory lesion count in acne lesion areas on Day 1 and at Weeks 2, 4, 8, and 12 is shown in Figure 6 (time course) and inflammatory lesion count by visit is summarised in EoT Table 2.2. Individual time course curves are presented in EoT Figures 2.12 to At Week 12, the mean (±SE) number of inflammatory acne lesions in the LEO treated area was numerically lower (3.8±5.3) compared to the vehicle treated area (5.9±4.6); the mean baseline (Day 1) count was in the range of 7.7 (vehicle) to 8.4 (LEO 43204).

61 Trial ID: EXP Aug-2017 Page 61 of 166 Figure 6 Mean inflammatory lesion count versus time - FAS Cross-reference: EoT Figure Non-inflammatory lesion count in acne lesion areas for LEO gel 0.018% and vehicle gel at Week 12 The mean non-inflammatory lesion count in acne lesion areas on Day 1 and at Weeks 2, 4, 8, and 12 is shown in Figure 7 (time course) and non-inflammatory lesion count by visit is summarised in EoT Table 2.3. Individual time course curves are presented in EoT Figures 2.17 to At Week 12, the mean (±SE) number of non-inflammatory acne lesions in the LEO treated area was numerically lower (20.0±14.3) compared to the vehicle treated area (25.3±19.7); the mean baseline (Day 1) count was in the range 29.8 (vehicle) to 31.5 (LEO 43204).

62 Trial ID: EXP Aug-2017 Page 62 of 166 Figure 7 Mean non-inflammatory lesion count versus time - FAS Cross-reference: EoT Figure IGA of acne lesion areas for LEO gel 0.018% and vehicle gel at Week 12 IGA of disease severity is summarised by treatment and visit using descriptive statistics (Table 27) and individual IGA is presented in Appendix 2.6-EoT Listing 6.2. At Week 12, the majority of subjects had an IGA score of 2 (mild) in the LEO treated area (59% of subjects) and an IGA score of 3 (moderate) in the vehicle treated area (75% of subjects); at baseline, 95% of subjects had a score 3 (both areas). Percent subjects with an IGA score 2 (clear to mild acne) at Week 12 was 69% in the LEO treated area compared to 22% in the vehicle treated area.

63 Trial ID: EXP Aug-2017 Page 63 of 166 Table 27 Summary of Investigator s global assessment FAS Visit IGA score LEO Gel 0.018% (N=38) n (%) Vehicle (N=38) n (%) Full face (N=38) n (%) Screening 3 36 (94.7) 37 (97.4) 33 (86.8) 4 2 ( 5.3) 1 ( 2.6) 5 (13.2) Day (94.7) 37 (97.4) 4 2 ( 5.3) 1 ( 2.6) Week (31.4) 2 ( 5.7) 3 23 (65.7) 32 (91.4) 4 1 ( 2.9) 1 ( 2.9) Week (57.1) 6 (17.1) 3 14 (40.0) 28 (80.0) 4 1 ( 2.9) 1 ( 2.9) Week ( 3.0) 2 21 (63.6) 6 (18.2) 3 10 (30.3) 26 (78.8) 4 1 ( 3.0) 1 ( 3.0) Week ( 9.4) 2 ( 6.3) 2 19 (59.4) 5 (15.6) 3 9 (28.1) 24 (75.0) 4 1 ( 3.1) 1 ( 3.1) N = Number of subjects. n = Number of subjects with data. % = percent within visit. Leo_Pharma/EXP/EXP-1223/F01 - tab_sum_iga.sas/tab_sum_iga.rtf/11aug2017 Cross-reference: EoT Table Composite and component LSR score at all visits The endpoint result is described in Safety Section Occurrence of unacceptable LSR scores or unacceptable safety and tolerability events at all visits Occurrence of unacceptable LSR scores or unacceptable safety and tolerability events at all visits (as described in Section 5.1.1) is described in Safety Section Other Analysis of Efficacy Explorative Endpoints Exploratory endpoints were analysed for the FAS Total lesion count in acne lesion areas on Day 1 and at Weeks 2, 4, 8, and 12 (time course) See primary endpoint Section Inflammatory lesion count in acne lesion areas on Day 1 and at Weeks 2, 4, 8, and 12 (time course) See secondary endpoint Section

64 Trial ID: EXP Aug-2017 Page 64 of Non-inflammatory lesion count in acne lesion areas on Day 1 and at Weeks 2, 4, 8, and 12 (time course) See secondary endpoint Section IGA of acne lesion areas on Day 1 and at Weeks 2, 4, 8, and 12 (time course) See secondary endpoint Section Treatment success (IGA) There was no statistically significant difference between LEO and vehicle in treatment success defined as at least a two grade improvement in IGA at Week 12 compared to baseline (Table 28). Table 28 Analysis of IGA treatment success at Week 12- FAS SOC LEO Gel 0.018% (N=38) n (%) Vehicle (N=38) n (%) Treatment failure Treatment succes P-value Treatment success is defined as at least a two grade improvement from baseline to week 12. Testing is by McNemars test. N = Number of subjects. n = Number of subjects with data. % = percent of subjects with data. Leo_Pharma/EXP/EXP-1223/F01 - tab_ana_iga.sas/tab_ana_iga.rtf/11aug2017 Cross-reference: EoT Table Inflammatory cytokine expression at time points defined after evaluation of the clinical data The inflammatory cytokine expression is reported separately from the CTR Microbiome profile at time points defined after evaluation of the clinical data The analysis of data relating to the microbiome is reported separately from the CTR Subject evaluation of Acne QoL (the past week) on Day 1 and Week 12 Acne QoL, summarised by each of the 4 domains contained within the questionnaire, is presented in Table 29. The mean values in each of the domains were numerically higher at Week 12 compared to Day 1, indicating an improved QoL. The mean acne QoL total score,

65 Trial ID: EXP Aug-2017 Page 65 of 166 reflecting the combined effect of LEO and vehicle, changed from ~49 to ~70 from baseline to Week 12. Table 29 Summary of acne QoL - FAS Total (N=38) Self perception Day 1 n 38 Mean SD 8.05 Median 11.5 Min 0 Max 29 Week 12 n 32 Mean SD 9.74 Median 20 Min 0 Max 30 Role-social Day 1 n 38 Mean SD 7.05 Median 12 Min 0 Max 24 Week 12 n 32 Mean SD 7.8 Median 18 Min 0 Max 24 Role-emotional Day 1 n 38 Mean SD 8.49 Median 11.5 Min 0 Max 29 Week 12 n 32 Mean SD Median 20.5 Min 0 Max 30 Acne symptoms Day 1 n 38 Mean 12.5 SD 6.49 Median 12.5 Min 0 Max 26 Week 12 n 32 Mean SD 8 2 Median 17.5 Min 2 Max 30 Acne total Day 1 n 38 Mean 49.11

66 Trial ID: EXP Aug-2017 Page 66 of 166 Total (N=38) SD Median 46 Min 1 Max 101 Week 12 n 32 Mean SD Median 75 Min 3 Max 114 N = Number of subjects. n = number of subjects with data. SD=Standard deviation. Range for Role-social is 0-24 for other domains 0-30 and for total Leo_Pharma/EXP/EXP-1223/F01 - tab_sum.sas/tab_sum_qol.rtf/11aug2017 Cross-reference: EoT Table Subject evaluation of TSQM II at Week 12 TSQM II by overall outcome (total) and by each of the 4 domains contained within the questionnaire is reflecting the combined effect of LEO and vehicle. The derived TSQM II dimension scores (0 [worst score] to 100 [best score]) are summarised in Table 30. The domain evaluating side-effects had the relatively highest (best) mean score (~95); convenience and global satisfaction had mean scores of ~70 and effectiveness had the lowest mean score (~60). The TSQM total mean score was ~74.

67 Trial ID: EXP Aug-2017 Page 67 of 166 Table 30 Summary of TSQM II at Week 12 - FAS Total (N=38) Effectiveness Week 12 n 32 Mean SD Median Min 0 Max 100 Side effects Week 12 n 25 Mean SD 9.84 Median 100 Min 66.7 Max 100 Convenience Week 12 n 32 Mean SD Median Min 38.9 Max 100 Global satisfaction Week 12 n 32 Mean SD Median 75 Min 25 Max 100 TSQM total Week 12 n 32 Mean SD Median Min 46.3 Max 97.2 N = Number of subjects. n = number of subjects with data. SD=Standard deviation. Range is for all domains and for total Leo_Pharma/EXP/EXP-1223/F01 - tab_sum.sas/tab_sum_tsqm.rtf/11aug2017 Cross-reference: EoT Table Subject global cosmetic score at Week 12 The subject global cosmetic score (rating from 0 [much worsened] to 4 [much improved]) at Week 12 is summarised by treatment in Table 31. More subjects had a score 3 in the LEO treated area compared to the vehicle treated area; only one subject had a score below 2 and that was in the vehicle treated area.

68 Trial ID: EXP Aug-2017 Page 68 of 166 Table 31 Summary of subject global cosmetic score at Week 12 - FAS Question Cosmetic score LEO Gel 0.018% (N=38) n (%) Vehicle (N=38) n (%) Overall appearance of the treatment area 0 - Much worsened 1 ( 3.1) 2 - No change 7 (21.9) 10 (31.3) 3 - Somewhat improved 20 (62.5) 16 (50.0) 4 - Much improved 5 (15.6) 5 (15.6) Overall feel of the treatment area 0 - Much worsened 1 ( 3.1) 2 - No change 8 (25.0) 10 (31.3) 3 - Somewhat improved 19 (59.4) 16 (50.0) 4 - Much improved 5 (15.6) 5 (15.6) N = Number of subjects. n = Number of subjects with data. % = percent within visit. Leo_Pharma/EXP/EXP-1223/F01 - tab_sum_cosm.sas/tab_sum_cosm.rtf/11aug2017 Cross-reference: EoT Table Efficacy Conclusions At Week 12, the mean number of total acne lesions was statistically significantly lower in the LEO treated area compared to the vehicle treated area (P<0.001). o The percentage change from baseline in the LEO treated area was -39% compared to -18% in the vehicle treated area. o Performing a sensitivity analysis with 3 subjects treatment reallocated to what was believed to be the actual treatment based on the LSRs reported, the percentage change from baseline was -44% (LEO treated area) and -13% (vehicle treated area). At Week 12, the mean (±SD) inflammatory lesions count was numerically lower in the LEO treated area (3.8±5.3) compared to the vehicle treated area (5.9±4.6) and the mean (±SD) non-inflammatory lesions count was numerically lower in the LEO treated area (20.0±14.3) compared to the vehicle treated area (25.3±19.7). At Week 12, percent subjects with an IGA score 2 (clear to mild acne) was 69% in the LEO treated area compared to 22% in the vehicle treated area.

69 Trial ID: EXP Aug-2017 Page 69 of Safety Evaluation 10.1 Adverse Events Brief summary of adverse events AE tables summarise treatment emergent AEs (TEAEs). No deaths, SAEs or AEs leading to discontinuation from the trial were reported (Table 32). A total of 23 AEs in 19 subjects were reported with 20 AEs in 18 subjects being in the LEO treated area. Of notice is that the one AE in the vehicle treated area probably was related to LEO treatment (see Section 7.3.1). This should be taken into account when reading the following safety results (it is in-text marked with # ). All except 2 AEs in 1 subject were cutaneous with 4 events in 4 subjects being moderate (3 in the LEO area and 1 in the vehicle area # ) (Section ) and the rest being mild. In all, 21 AEs in 19 subjects were judged by the investigator to be related to IMP, all but 1 # in the LEO area (Section ). All AEs by cohort, subject, System Organ Class (SOC), and Preferred Term (PT) are shown in Appendix 2.7-EoT Listing 7 1. Table 32 Overall summary of treatment emergent adverse events - SAS Non-cutaneous (N=40) n (%) E LEO Gel 0.018% (N=40) n (%) E Vehicle (N=40) n (%) E Total (N=40) n (%) Any TEAEs 1 (2.5) 2 18 (45.0) 20 1 (2.5) 1 19 (47.5) 23 Deaths 0 (0.0) 0 0 (0.0) 0 0 (0.0) 0 0 (0.0 ) 0 Serious TEAEs 0 (0.0) 0 0 (0.0) 0 0 (0.0) 0 0 (0.0 ) 0 TEAEs leading to discontinuation from the trial 0 (0.0) 0 0 (0.0) 0 0 (0.0) 0 0 (0.0 ) 0 Related AEs 0 (0.0) 0 18 (45.0) 20 1 (2.5) 1 19 (47.5) 21 Severe TEAEs 0 (0.0) 0 0 (0.0) 0 0 (0.0) 0 0 (0.0 ) 0 Moderate TEAEs 0 (0.0) 0 3 (7 5) 3 1 (2.5) 1 4 (10.0) 4 Mild TEAEs 1 (2.5) 2 15 (37 5) 17 0 (0.0) 0 15 (37.5) 19 N=Number of subjects in Safety Analysis Set. E=Number of events. n=number of subjects with adverse event. % = Percentage of subjects with adverse event. Related AEs=AE assessed by investigator as possibly/probably related to investigational product TEAE=Treatment Emergent Adverse Event. Leo_Pharma/EXP/EXP-1223/F01 - tab_ae_sum.sas/tab_ae_sum.rtf/11aug2017 Cross-reference: EoT Table 3.1 E

70 Trial ID: EXP Aug-2017 Page 70 of Display of adverse events The AEs by SOC and PT are summarised in Table 33. Table 33 Treatment emergent adverse events by SOC and PT - SAS SOC PT Non-cutaneous (N = 40) n (%) E LEO Gel 0.018% (N = 40) n (%) E Vehicle (N = 40) n (%) E Gastrointestinal disorders Nausea 1 (2.5) 1 Total 1 (2.5) 1 General disorders and administration site conditions Application site pruritus 2 (5.0) 2 Application site pain 18 (45.0) 18 1 (2.5) 1 Total 18 (45.0) 20 1 (2.5) 1 Nervous system disorders Headache 1 (2.5) 1 Total 1 (2.5) 1 N = Number of subjects. n = Number of subjects with data. % = Percentage of subjects with event. E = number of events. Leo_Pharma/EXP/EXP-1223/F01 - tab_ae.sas/tab_ae_soc.rtf/11aug2017 Cross-reference: EoT Table Analysis of adverse events The majority of subjects experiencing any AE (Table 32) experienced AEs belonging to the SOC General disorders and administration site conditions as shown in Table 33; all but 2 of these were application site reactions with the PTs application site pain and application site pruritus; all of these but 1 # applications site pain were in the LEO area. Gastrointestinal disorders (PT nausea) and Nervous system disorders (PT headache) were both experienced by 2.5% corresponding to 1 subject Adverse events by severity AEs by severity, SOC and PT are summarised in Table 34. The majority of subjects with AEs had mild AEs mainly in the LEO area; 4 subjects had moderate AEs (3 in LEO area and 1 in vehicle area # ), all with PT application site pain.

71 Trial ID: EXP Aug-2017 Page 71 of 166 Table 34 Treatment emergent adverse events by severity, SOC and PT - SAS Severity SOC PT Non-cutaneous (N = 40) n (%) E LEO Gel 0.018% (N = 40) n (%) E Vehicle (N = 40) n (%) E Mild Gastrointestinal disorders Nausea 1 (2.5) 1 Total 1 (2.5) 1 General disorders and administration site conditions Application site pain 15 (37.5) 15 Application site pruritus 2 (5.0) 2 Total 15 (37.5) 17 Nervous system disorders Headache 1 (2.5) 1 Total 1 (2.5) 1 Moderate General disorders and administration site Application site pain 3 (7.5) 3 1 (2.5) 1 conditions Total 3 (7.5) 3 1 (2.5) 1 N = Number of subjects. n = Number of subjects with data. % = Percentage of subjects with event. E = number of events. Leo_Pharma/EXP/EXP-1223/F01 - tab_ae.sas/tab_ae_soc_sev.rtf/11aug2017 Cross-reference: EoT Table Adverse events related to IMP 21 AEs were judged probably/possible related to IMP by the investigator as summarised in Table 32. All of these, but 1 # (applications site pain) were in the LEO area as shown in Table 35. Table 35 Treatment emergent related adverse events by SOC and PT - SAS SOC PT Non-cutaneous (N = 40) n (%) E LEO Gel 0.018% (N = 40) n (%) E Vehicle (N = 40) n (%) E General disorders and administration site conditions Application site pain 18 (45.0) 18 1 (2.5) 1 Application site pruritus 2 (5.0) 2 Total 18 (45.0) 20 1 (2.5) 1 N = Number of subjects. n = Number of subjects with data. % = Percentage of subjects with event. E = number of events. Leo_Pharma/EXP/EXP-1223/F01 - tab_ae.sas/tab_ae_soc_rel.rtf/11aug2017 Cross-reference: EoT Table Deaths, Other Serious Adverse Events, and Other Significant Adverse Events No deaths or SAEs were reported and no subjects were withdrawn due to AEs Other Events to be reported There were no other events reported such as pregnancy, overdose, medication error, misuse, aggravation of condition, or AEs of special interest (see Section ).

72 Trial ID: EXP Aug-2017 Page 72 of Local Skin Responses (LSRs) Composite LSR score At Day 1 (baseline), the mean LSR composite score was approximately 0.1 (LEO treated area) and 0 (vehicle treated area) (EoT Table 3.7). Figure 8 shows that for the LEO treated area, the mean LSR composite score started to increase immediately after start of treatment (Day2) and peaked at Day 4 (mean score 4.3; range 0 to 13; EoT Table 3.7); it was almost back to Day 1 level at Week 4. The mean LSR composite score for the vehicle treated area showed an increase between Day 2 and Day 8 (Figure 8), similarly to the LEO treated area; individual subject profiles were therefore evaluated (EoT Figures 3.3 to 3.7). 3 subjects were identified having composite LSR scores larger than 4 in the vehicle treated area and not in the LEO treated area (EoT Figures 3.6 and 3.7). These 3 subjects had treatment allocation changed to additionally generate efficacy result (primary endpoint) and composite LSR results for what was assumed to be the actual treatment (Section 7.3.1). The actual treatment result is shown in Figure 9; in this figure the vehicle treated area is close to Day 1 level at all time points and the LEO treated area has a similar profile as planned treatment, but with a higher peak at Day 4 (mean score ~5). EoT Tables 3.8 to 3.11 summarise composite LSR score change from baseline, the maximum post baseline score, visits of first occurrence of maximum post baseline score, and first visit of return to or below baseline score.

73 Trial ID: EXP Aug-2017 Page 73 of 166 Figure 8 Mean composite LSR versus time - planned treatment - SAS Cross-reference: EoT Figure 3.1 Figure 9 Mean composite LSR versus time - actual treatment - SAS Cross-reference: EoT Figure 3.2

74 Trial ID: EXP Aug-2017 Page 74 of Component LSR score Component LSR score results are presented for planned treatment. At Day 1, a few subjects had crusting and/or flaking/scaling present (Figure 10 to Figure 12) consistent with the presence of inflammatory acne lesions. The day after the first treatment (Day 2), some subjects developed erythema and/or swelling and to a lesser extent the other components of LSRs (excluding erosion/ulceration, which was not present at any time point) with more subjects having the LEO treated area affected compared to vehicle treated area. EoT Table 3.5 summarises LSR components score by visit time and EoT Table 3.6 summarises the maximum post baseline LSR components score. Appendix 2.7-EoT Listings 7.6 to 7.11 show presence/no presence of individual LSR component scores.

75 Trial ID: EXP Aug-2017 Page 75 of 166 Figure 10 LSR counts by type (1) Planned treatment SAS Day 8: Assessed were subjects from Cohorts 1-3 and 3 subjects from Cohort 4 Cross-reference: EoT Figure 3.8

76 Trial ID: EXP Aug-2017 Page 76 of 166 Figure 11 LSR counts by type (2) Planned treatment SAS Day 8: Assessed were subjects from Cohorts 1-3 and 3 subjects from Cohort 4 Cross-reference: EoT Figure 3.9

77 Trial ID: EXP Aug-2017 Page 77 of 166 Figure 12 LSR counts by type (3) Planned treatment SAS Day 8: Assessed were subjects from Cohorts 1-3 and 3 subjects from Cohort 4 Cross-reference: EoT Figure Occurrence of unacceptable LSR scores or unacceptable safety and tolerability events at all visits There was no occurrence of unacceptable LSR scores or unacceptable safety and tolerability events at any visits as assessed by investigator.

78 Trial ID: EXP Aug-2017 Page 78 of Vital Signs A summary of vital sign values at screening and Week 12 is presented in EoT Table 3.12; the average vital sign observations were within normal range. Change from baseline in vital signs is presented in EoT Table Overall, the values were regarded normal. Individual vital signs are presented in Appendix 2.7-EoT Listing Clinical Laboratory Evaluation Laboratory values over time A urine pregnancy test was taken during trial at the time points shown in Table 6. Appendix 2.8-EoT Listing 8.1 shows the individual test results; no subject tested had a positive test result Safety Conclusions No significant safety issues were reported; 47.5% of the subjects experienced AEs, most of them being mild IMP related administration site conditions (pruritus and pain). 4 subjects had an IMP related moderate application site AE (3 in the LEO treated area and 1 in the vehicle treated area); all 4 AEs recovered and the subjects completed the trial. It should be noted that the one related moderate AE in the vehicle treated area could have been LEO related, because the area probably was treated with LEO The time course profile of the LSRs was as expected based on previous trials with the LEO in AK; the peak mean composite LSR score occurred at Day 4 and was back to baseline level by week 4. The peak level of the mean composite LSR score seen in this patient population was low. There were no clinically significant abnormal findings for vital signs.

79 Trial ID: EXP Aug-2017 Page 79 of Discussion and Overall Conclusions 11.1 Discussion Patient population The target population in this trial was adult patients with moderate to severe acne vulgaris in the face. The enrolled subjects were predominantly (95%) rated as moderate disease severity on the IGA scale at baseline. The total facial lesion counts were not assessed, but within the two treatment areas (i.e. left + right cheek) the sum of acne lesions was approximately 75 to 80 and dominated by non-inflammatory lesions. The disease severity level in terms of IGA and total lesion counts is considered similar to what has been evaluated in phase 3 clinical trials evaluation topical therapies for facial acne vulgaris. It should be noted that the phase 3 trials included subjects from 12 years of age (13, 14, 15, 16, 17). Consistent with a patient population over 18 years of age, there was a high proportion of subjects with poor prognostic factors for severe and protracted acne as assessed by the specified acne medical history (25). A large proportion of subjects had early and more severe sebum production/hyper seborrheia (95% and 85% of subjects), persistent disease and acne scarring (92.5 % and 77.5 % of subjects). In addition, the patient population was characterized by having tried only a limited number of topical therapies except from BPO and none of the subjects had previously been treated with systemic medications for acne. In summary, the enrolled patient population consisted of adults with persistent and relatively untreated moderate acne vulgaris. Treatment allocation During review of the LSR results it was noted the planned treatments for 3 subjects were probably not the actual treatments given at all applications. High LSRs in the vehicle treated area and no LSRs in the LEO treated area were observed. It was therefore decided to include a definition of actual treatment, which differed from the randomised treatment for these 3 subjects, i.e. the 3 subject s actual treatments were reallocated to the opposite sites than planned. The consequence of switching these 3 subjects was reduced application site reactions in the vehicle treated area and a marginally better efficacy result in the LEO treated area. Efficacy The analysis for the primary endpoint showed a significant reduction in the mean total lesion count at Week 12 for LEO % gel compared to vehicle. Consistent with the change in total lesion count, a numerical improvement (LEO % gel vs. vehicle) was observed for both the inflammatory lesion counts and non-inflammatory lesion counts. For the vehicle treated areas, it was noted that the mean change from baseline was relatively small and that for many subjects the variation in lesion counts between visits was very small.

80 Trial ID: EXP Aug-2017 Page 80 of 166 The low level of fluctuation in acne lesion counts between visits was unexpected. For most subjects this observation may question the unbiasedness of the vehicle lesion counts towards a higher lesion count and thereby suggest the possibility that the observed efficacy is overestimated when comparing active vs. vehicle. To evaluate the treatment efficacy in the possible absence of an unbiased vehicle control the mean total lesion count was also assessed by a change from baseline to Week 12 analysis as in a trial without any control group. The analysis outcome for LEO % gel was -39% in the pre-specified analysis for planned treatment and -44% in the sensitivity analysis for actual treatment. This result, after only 3 days of treatment and 12 weeks of follow-up, may be compared indirectly to -45 to -56% change in total lesion count after 12 weeks of daily treatment with other topical treatments, which also showed similar shape of time vs. effect curves (13, 14, 16, 17). This indicates that the treatment with LEO has a prolonged effect on the skin and acne pathogenesis. Consistent with residual lesion counts in most subjects, the IGA did not show a significant treatment success. However, considering subjects achieving clear, almost clear or mild at Week 12, there was a large difference compared to vehicle: 69% versus 22%. These numbers may be compared to 75% and 62.5% achieving the same scores after 12 weeks of treatment with adapalen 0.1% combined with BPO 2.5% or adapalene 0.1% alone, respectively (14). Lastly, the objective findings of improvement in acne were supported by observed changes in the Acne QoL indicating some beneficial effect of the combined treatment with LEO and vehicle, although the subject evaluated Cosmetic Scores only indicated a small difference in favour of LEO compared to vehicle. Treatment satisfaction and AEs The TSQM II assessment results except for effectiveness were overall on par with what has been observed for AK trials. The mainly mild and short lasting AEs (e.g. pruritus and pain) seen in the LEO % gel treated area was as expected. The LSRs observed, both at baseline and post-treatment, were milder than anticipated and previously observed in patients with AK for whom the scale was developed. This indicates that LEO is well tolerated in this acne patient population and that the pre-existing inflammation associated with acne does not appear to exacerbate the LSRs.

81 Trial ID: EXP Aug-2017 Page 81 of Overall Conclusions LEO gel 0.018% statistically significantly reduced mean total acne lesion count compared to vehicle 12 weeks after end of once daily treatment for up to 3 days (P<0.001). The estimated magnitude of effect, evaluated as percent change from baseline, was -39%. Based on AEs and LSRs it was found that LEO gel 0.018% was well tolerated.

82 Trial ID: EXP Aug-2017 Page 82 of References 1. ICH E3. Structure and Content of Clinical Study Reports. November ICH E3 (R1). ICH E3 Guideline: Structure and Content of Clinical Study Reports Questions and Answers. July ICH E6 (R1). Guideline for Good Clinical Practice. June ICH E9. Statistical Principles for Clinical Trials. February ICH M4E (R1). The Common Technical Document for the Registration of Pharmaceuticals for Human Use Efficacy. September Williams HC, Dellavalle RP, Garner S. Acne vulgaris. Lancet. 2012;379: LEO Investigator's Brochure Actinic Keratosis, Field Therapy, Edition no. 5, LEO Pharma A/S, 16 September Fitzpatrick TB. The validity and practicality of sun-reactive skin types I through VI. Arch Dermatol. 1988;124: LEO Addendum to Investigator's Brochure Acne Vulgaris (Exploratory), Edition no. 1, LEO Pharma A/S, 16 September Ulrich M, Lange-Asschenfeldt S, Röwert-Huber J, Völker-CM, Oesterdal M., Skak K, Zibert JR, Stockfleth E. Assessment of the in-vivo effects of ingenol mebutate 0.05 gel for the treatment of actinic field cancerization by reflectance confocal microscopy. 2014; 15th World Congress on Cancers of the Skin, Abstract Hongcharu W, Taylor CR, Chang Y, Aghassi D, Suthamjariya K, Anderson RR. Topical ALA-Photodynamic therapy for the treatment of acne vulgaris. J Invest Dermatol. 2000;115: Yeung CK, Shek SY, Bjerring P, Yu CS, Kono T, Chan HH. A comparative study of intense pulsed light alone and its combination with photodynamic therapy for the treatment of facial acne in Asian skin. Lasers Surg Med. 2007;39: Sakamoto FH, Torezan L, Anderson RR. Photodynamic therapy for acne vulgaris: a critical review from basics to clinical practice: part II. Understanding parameters for acne treatment with photodynamic therapy. J Am Acad Dermatol. 2010;63: Thiboutot D, Pariser DM, Egan N, Flores J, Herndon JH Jr, Kanof NB, Kempers SE, Maddin S, Poulin YP, Wilson DC, Hwa J, Liu Y, Graeber M; Adapalene Study Group. Adapalene gel 0.3% for the treatment of acne vulgaris: a multicenter, randomized, double-blind, controlled, phase III trial. J Am Acad Dermatol. 2006;54:

83 Trial ID: EXP Aug-2017 Page 83 of Gollnick HP, Draelos Z, Glenn MJ, Rosoph LA, Kaszuba A, Cornelison R, Gore B, Liu Y, Graeber M; Adapalene-BPO Study Group. Adapalene-benzoyl peroxide, a unique fixed-dose combination topical gel for the treatment of acne vulgaris: a transatlantic, randomized, double-blind, controlled study in 1670 patients. Br J Dermatol. 2009;161: Stein Gold L, Weiss J, Rueda MJ, Liu H, Tanghetti E. Moderate and Severe Inflammatory Acne Vulgaris Effectively Treated with Single-Agent Therapy by a New Fixed-Dose Combination Adapalene 0.3 %/Benzoyl Peroxide 2.5 % Gel: A Randomized, Double-Blind, Parallel-Group, Controlled Study. Am J Clin Dermatol. 2016;17: Schaller M, Sebastian M, Ress C, Seidel D, Hennig M. A multicentre, randomized, single-blind, parallel-group study comparing the efficacy and tolerability of benzoyl peroxide 3%/clindamycin 1% with azelaic acid 20% in the topical treatment of mild-tomoderate acne vulgaris. J Eur Acad Dermatol Venereol. 2016;30: Kawashima M, Hashimoto H, Alió Sáenz AB, Ono M, Yamada M. Clindamycin phosphate 1 2%-benzoyl peroxide 3 0% fixed-dose combination gel has an effective and acceptable safety and tolerability profile for the treatment of acne vulgaris in Japanese patients: a phase III, multicentre, randomised, single-blinded, activecontrolled, parallel-group study. Br J Dermatol. 2015;172: Guidance of Industry. Acne Vulgaris: Developing Drugs for Treatment. Draft Guidance. U.S. Department of Health and Human Services, Food and Drug Administration. Center for Drug Evaluation and Research. September Girman CJ, Hartmaier S, Thiboutot D, Johnson J, Barber B, DeMuro-Mercon C, et al. Evaluating health-related quality of life in patients with facial acne: development of a self-administered questionnaire for clinical trials. Qual Life Res. 1996;5: Martin AR, Lookingbill DP, Botek A, Light J, Thiboutot D, Girman CJ. Health-related quality of life among patients with facial acne: Assessment of a new acne-specific QoL questionnaire. Clin Exp Dermatol. 2001;26: Atkinson MJ, Kumar R, Cappelleri JC, Hass SL. Hierarchical construct validity of the Treatment Satisfaction Questionnaire for Medication (TSQM version II) among outpatient pharmacy consumers. Value Health. 2005;8(Suppl 1):S9-S Memon AA, Tomenson JA, Bothwell J, Friedmann PS. Prevalence of solar damage and actinic keratosis in a Merseyside population. Br J Dermatol. 2000;142:

84 Trial ID: EXP Aug-2017 Page 84 of LP Clinical Study Report. Exploratory study evaluating the efficacy and the tolerability of the sequential application of two marketed products in patients with acne vulgaris, using a Split-Face model. LEO Pharma A/S, 04 October 2012, EudraCT Number: Dréno B, Bettoli V, Ochsendorf F, Perez-Lopez M, Mobacken H, Degreef H, Layton. A. An expert view on the treatment of acne with systemic antibiotics and/or oral isotretinoin in the light of the new European recommendations. Eur J Dermatol. 2006;16:

85 Trial ID: EXP Aug-2017 Page 85 of Tables and Figures, Baseline Characteristics and Investigational Product Data List of Tables Table 1 1 Subject disposition: All subjects randomised Table 1 2 Age, weight, height, BMI, and duration of Acne at baseline SAS Table 1 3 Age group, sex, race, ethnicity and skin type SAS Table 1 4 Acne history SAS Table 1 5 Previous treatment history - SAS Table 1 6 Concomitant medication at baseline - SAS Table 1 7 Concurrent diagnoses SAS Table 1 8 Concurrent procedures SAS Table 1 9 Treatment compliance, number of days treated SAS Table 1 10 Treatment duration - SAS... 95

86 Trial ID: EXP Aug-2017 Page 86 of 166 Table 1 1 Subject disposition: All subjects randomised Cohort 1 (N=3) n (%) Cohort 2 (N=6) n (%) Cohort 3 (N=6) n (%) Cohort 4 (N=25) n (%) Total (N=40) n (%) Randomised set 3 (100) 6 (100) 6 (100) 25 (100) 40 (100) Full Analysis Set 1 (33) 6 (100) 6 (100) 25 (100) 38 (95) Per-Protocol Analysis set 1 (33) 5 (83) 6 (100) 20 (80) 32 (80) Safety Analysis Set 3 (100) 6 (100) 6 (100) 25 (100) 40 (100) Completed the trial 3 (100) 5 (83) 6 (100) 20 (80) 34 (85) Discontinued from the trial 0 (0) 1 (17) 0 (0) 5 (20) 6 (15) Unacceptable treatment efficacy 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Unacceptable adverse events 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Exclusion criteria 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Voluntary withdrawal 0 (0) 0 (0) 0 (0) 2 (8) 2 (5) Other reasons 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Lost to follow-up 0 (0) 1 (17) 0 (0) 3 (12) 4 (10) Death 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) N = Number of subjects. n = number of subjects with data. %=percentage of subjects with data. Leo_Pharma/EXP/EXP-1223/F01 - tab_subdisp.sas/tab_subdisp.rtf/11aug2017

87 Trial ID: EXP Aug-2017 Page 87 of 166 Table 1 2 Age, weight, height, BMI, and duration of Acne at baseline SAS Total (N=40) Age (years) n 40 Mean (SD) 21.9 (3.8) Median 21.0 Min 18 Max 34 Weight (kg) n 40 Mean (SD) 77.1 (23.9) Median 72.2 Min 48.5 Max Height (m) n 40 Mean (SD) 1.71 (0.09) Median 1.70 Min 1.50 Max 1.98 BMI (kg/m/m) n 40 Mean (SD) 26.5 (8.2) Median 24.9 Min 17.1 Max 59.3 Duration of Acne (years) n 40 Mean (SD) 6.8 (3.5) Median 6.0 Min 3 Max 20 N = Number of subjects. n = Number of subjects with data. SD = Standard Deviation. Leo_Pharma/EXP/EXP-1223/F01 - tab_demo.sas/tab_demo1.rtf/11aug2017

88 Trial ID: EXP Aug-2017 Page 88 of 166 Table 1 3 Age group, sex, race, ethnicity and skin type SAS Total (N=40) n (%) Age group (45.0) (40.0) (15.0) Total 40 (100) Sex Female 16 (40.0) Male 24 (60.0) Total 40 (100) Race Asian 4 (10.0) Native hawaiian or other pacific islander 3 (7.5) White 33 (82.5) Total 40 (100) Ethnicity Hispanic or latino 27 (67.5) Not hispanic or latino 13 (32.5) Total 40 (100) Skin classification Type II 14 (35.0) Type III 26 (65.0) Total 40 (100) N = Number of subjects. n = number of subjects with data. %=percentage of subjects with data. Leo_Pharma/EXP/EXP-1223/F01 - tab_demo.sas/tab_demo2.rtf/11aug2017

89 Trial ID: EXP Aug-2017 Page 89 of 166 Table 1 4 Acne history SAS Acne History Total (N=40) n (%) Characteristics at onset Early and more severe sebum production 38 (95.0) Early onset relative to menarche 13 (81 3) Mild facial comedones 38 (95.0) Current disease characteristics Acne on trunk 17 (42 5) Acne scarring 31 (77 5) Hyperseborrheia 34 (85.0) Persistent refractory disease 37 (92 5) Responding to standard therapies but relapsing 22 (55.0) Family history Moderate to severe acne in at least one parent 6 (15.0) Moderate to severe acne in at least one sibiling 15 (37 5) N = Number of subjects. n = number of subjects with data. %=percentage of subjects with data. For "Early onset relative to menarche" the denominator is number of females. Leo_Pharma/EXP/EXP-1223/F01 - tab_ak.sas/tab_ak1.rtf/11aug2017

90 Trial ID: EXP Aug-2017 Page 90 of 166 Table 1 5 Previous treatment history - SAS Acne Treatment History Total (N=40) n (%) Other topical combination therapies 3 (12) Topical Azealic acid 1 (4) Topical benzoyl peroxide 15 (60) Topical retinoid combination therapy 2 (8) Topical retinoid monotherapy 4 (16) N = Number of subjects. n = number of subjects with data. %=percentage of subjects with data. Leo_Pharma/EXP/EXP-1223/F01 - tab_cm_prev.sas/tab_cm_prev.rtf/11aug2017

91 Trial ID: EXP Aug-2017 Page 91 of 166 Table 1 6 Concomitant medication at baseline - SAS MedDRA Body System Organ Class Preferred Term Total (N=40) n (%) Any concomitant medication 2 ( 5.0) Various 2 ( 5.0) Other Therapeutic Products 2 ( 5.0) Musculo-Skeletal System 1 ( 2.5) Propionic Acid Derivatives 1 ( 2.5) N = Number of subjects. n = Number of subjects with data. % = Percentage of subjects with data. Leo_Pharma/EXP/EXP-1223/F01 - tab_conmed.sas/tab_conmed1.rtf/11aug2017

92 Trial ID: EXP Aug-2017 Page 92 of 166 Table 1 7 Concurrent diagnoses SAS MedDRA Body System Organ Class Preferred Term Total (N=40) n (%) Any medical/surgical history 7 (17.5) Respiratory, thoracic and mediastinal disorders 3 ( 7.5) Asthma 3 ( 7.5) Skin and subcutaneous tissue disorders 2 ( 5.0) Hyperhidrosis 1 ( 2.5) Dermatitis atopic 1 ( 2.5) Musculoskeletal and connective tissue disorders 1 ( 2.5) Arthralgia 1 ( 2.5) Immune system disorders 1 ( 2.5) Seasonal allergy 1 ( 2.5) Nervous system disorders 1 ( 2.5) Migraine 1 ( 2.5) Metabolism and nutrition disorders 1 ( 2.5) Hypovitaminosis 1 ( 2.5) Renal and urinary disorders 1 ( 2.5) Nephrolithiasis 1 ( 2.5) Blood and lymphatic system disorders 1 ( 2.5) Anaemia 1 ( 2.5) General disorders and administration site conditions 1 ( 2.5) Fatigue 1 ( 2.5) Infections and infestations 1 ( 2.5) Bronchitis 1 ( 2.5) Psychiatric disorders 1 ( 2.5) Depression 1 ( 2.5) N = Number of subjects. n = Number of subjects with data. % = Percentage of subjects with data. Leo_Pharma/EXP/EXP-1223/F01 - tab_mh.sas/tab_mh2.rtf/11aug2017

93 Trial ID: EXP Aug-2017 Page 93 of 166 Table 1 8 Concurrent procedures SAS N = Number of subjects. n = Number of subjects with data. % = Percentage of subjects with data. NO DATA FOUND FOR THIS TABLE Leo_Pharma/EXP/EXP-1223/F01 - tab_cm.sas/tab_cm1.rtf/11aug2017

94 Trial ID: EXP Aug-2017 Page 94 of 166 Table 1 9 Treatment compliance, number of days treated SAS Cohort 1 (N=3) n (%) Cohort 2 (N=6) n (%) Cohort 3 (N=6) n (%) Cohort 4 (N=25) n (%) Total (N=40) n (%) Number of days 3 1 (33.3) 5 (83.3) 6 ( 100) 25 ( 100) 37 (92.5) 2 1 (33.3) 1 (16.7) ( 5.0) 1 1 (33.3) ( 2.5) N = Number of subjects. n = number of subjects with data. %=percentage of subjects with data. Leo_Pharma/EXP/EXP-1223/F01 - tab_ex.sas/tab_ex.rtf/11aug2017

95 Trial ID: EXP Aug-2017 Page 95 of 166 Table 1 10 Treatment duration - SAS Duration from first to last dosing (days) Cohort 1 (N=3) Cohort 2 (N=6) Cohort 3 (N=6) Cohort 4 (N=25) n Mean SD Median Min Max N = Number of subjects. n = number of subjects with data. SD=Standard deviation. Total (N=40) Leo_Pharma/EXP/EXP-1223/F01 - tab_dur.sas/tab_dur.rtf/11aug2017

96 Trial ID: EXP Aug-2017 Page 96 of Tables and Figures, Efficacy Data List of Tables Table 2 1 Summary of total lesion count by visit - FAS Table 2 2 Summary of inflammatory lesion count by visit - FAS Table 2 3 Summary of non-inflammatory lesion count by visit FAS Table 2 4 Analysis of total lesion count Week 12 MI - planned treatment - FAS Table 2 5 Analysis of total lesion count Week 12 - OC - planned treatment - FAS Table 2 6 Analysis of total lesion count Week 12 LOCF - planned treatment - FAS Table 2 7 Analysis of total lesion count Week 12 OC - laterality - planned treatment - FAS Table 2 8 Analysis of total lesion count Week 12 - OC - actual treatment - FAS Table 2 9 Summary of total lesion change from baseline - planned treatment FAS Table 2 10 Summary of total lesion change from baseline - actual treatment - FAS Table 2 11 Summary of total lesion percent change from baseline - planned treatment FAS Table 2 12 Summary of total lesion percent change from baseline - actual treatment - FAS 109 Table 2 13 Summary of Investigator s global assessment - FAS Table 2 14 Analysis of Investigator s global assessment treatment success at Week 12 FAS Table 2 15 Summary of acne QoL FAS Table 2 16 Summary of TSQM II at Week 12 FAS Table 2 17 Summary of subject global cosmetic score at Week 12 FAS List of Figures Figure 2-1 Mean total lesion count versus time - planned treatment - FAS Figure 2-2 Mean total lesion count versus time - actual treatment - FAS Figure 2-3 Percent change total lesion count versus time - planned treatment FAS

97 Trial ID: EXP Aug-2017 Page 97 of 166 Figure 2-4 Percent change total lesion count versus time - actual treatment FAS Figure 2-5 Mean inflammatory lesion count versus time FAS Figure 2-6 Mean non-inflammatory lesion count versus time FAS Figure 2-7 Total lesion count by subject (1) FAS Figure 2-8 Total lesion count by subject (2) FAS Figure 2-9 Total lesion count by subject (3) FAS Figure 2-10 Total lesion count by subject (4) FAS Figure 2-11 Total lesion count by subject (5) FAS Figure 2-12 Inflammatory lesion count by subject (1) - FAS Figure 2-13 Inflammatory lesion count by subject (2) FAS Figure 2-14 Inflammatory lesion count by subject (3) FAS Figure 2-15 Inflammatory lesion count by subject (4) FAS Figure 2-16 Inflammatory lesion count by subject (5) FAS Figure 2-17 Non-inflammatory lesion count by subject (1) FAS Figure 2-18 Non-inflammatory lesion count by subject (2) FAS Figure 2-19 Non-inflammatory lesion count by subject (3) FAS Figure 2-20 Non-inflammatory lesion count by subject (4) FAS Figure 2-21 Non-inflammatory lesion count by subject (5) FAS

98 Trial ID: EXP Aug-2017 Page 98 of 166 Table 2 1 Summary of total lesion count by visit - FAS Leo Gel 0.018% (N=38) Vehicle (N=38) Screening n Mean SD Median Min 6 6 Max Day 1 n Mean SD Median Min 6 6 Max Week 2 n Mean SD Median Min 4 6 Max Week 4 n Mean SD Median Min 3 6 Max Week 8 n Mean SD Median Min 1 0 Max Week 12 n Mean SD Median Min 2 1 Max N = Number of subjects. n = number of subjects with data. SD=Standard deviation. Leo_Pharma/EXP/EXP-1223/F01 - tab_lesions_sum.sas/tab_lesion_sum.rtf/11aug2017

99 Trial ID: EXP Aug-2017 Page 99 of 166 Table 2 2 Summary of inflammatory lesion count by visit - FAS Leo Gel 0.018% (N=38) Vehicle (N=38) Screening n Mean SD Median Min 1 2 Max Day 1 n Mean SD Median Min 1 3 Max Week 2 n Mean SD Median Min 1 3 Max Week 4 n Mean SD Median Min 0 2 Max Week 8 n Mean SD Median Min 0 0 Max Week 12 n Mean SD Median Min 0 0 Max N = Number of subjects. n = number of subjects with data. SD=Standard deviation. Leo_Pharma/EXP/EXP-1223/F01 - tab_lesions_sum.sas/tab_lesion_infl.rtf/11aug2017

100 Trial ID: EXP Aug-2017 Page 100 of 166 Table 2 3 Summary of non-inflammatory lesion count by visit FAS Leo Gel 0.018% (N=38) Vehicle (N=38) Screening n Mean SD Median Min 3 1 Max Day 1 n Mean SD Median Min 3 1 Max Week 2 n Mean SD Median Min 3 1 Max Week 4 n Mean SD Median Min 2 1 Max Week 8 n Mean SD Median Min 1 0 Max Week 12 n Mean SD Median Min 0 0 Max N = Number of subjects. n = number of subjects with data. SD=Standard deviation. Leo_Pharma/EXP/EXP-1223/F01 - tab_lesions_sum.sas/tab_lesion_non_infl.rtf/11aug2017

101 Trial ID: EXP Aug-2017 Page 101 of 166 Table 2 4 Analysis of total lesion count Week 12 MI - planned treatment - FAS Leo Gel 0.018% Vehicle n Mean SD Minimum 2 1 Maximum LSMeans % CI ( 19.85, 27.29) ( 29.18, 36.62) Difference % CI (-14.71, -3.96) P-value <.001 n = number of subjects with data. SD=Standard deviation. LSMean values and difference is from ANCOVA model with treatment as fixed effect and baseline total lesion count as covariate and subject as random effect. 100 simulations of monotone multiple imputation is performed. Summary statistics are found across these 100 simulations. Comparisons are by Proc Mianalyze. Leo_Pharma/EXP/EXP-1223/F01 - tab_ana_les_mi.sas/tab_ana_les_mi_fas.rtf/11aug2017

102 Trial ID: EXP Aug-2017 Page 102 of 166 Table 2 5 Analysis of total lesion count Week 12 - OC - planned treatment - FAS Leo Gel 0.018% (N=38) Vehicle (N=38) n Mean SD Minimum 2 1 Maximum LSMeans % CI [ 19.08, 27.39] [ 27.67, 35.98] Difference % CI [-14.47, -2.71] P-value n = number of subjects with data. SD=Standard deviation. LSMean values and difference is from ANCOVA model with treatment as fixed effect and baseline total lesion count as covariate and subject as random effect. Leo_Pharma/EXP/EXP-1223/F01 - tab_ana_les.sas/tab_ana_les_fas.rtf/11aug2017

103 Trial ID: EXP Aug-2017 Page 103 of 166 Table 2 6 Analysis of total lesion count Week 12 LOCF - planned treatment - FAS Leo Gel 0.018% (N=38) Vehicle (N=38) n Mean SD Minimum 2 1 Maximum LSMeans % CI [ 21.93, 29.29] [ 29.74, 37.10] Difference % CI [-13.02, -2.60] P-value n = number of subjects with data. SD=Standard deviation. LSMean values and difference is from ANCOVA model with treatment as fixed effect and baseline total lesion count as covariate and subject as random effect. Leo_Pharma/EXP/EXP-1223/F01 - tab_ana_les.sas/tab_ana_les_locf_fas.rtf/11aug2017

104 Trial ID: EXP Aug-2017 Page 104 of 166 Table 2 7 Analysis of total lesion count Week 12 OC - laterality - planned treatment - FAS Leo Gel 0.018% (N=38) Vehicle (N=38) n Mean SD Minimum 2 1 Maximum LSMeans % CI [ 19.11, 27.48] [ 27.58, 35.96] Difference % CI [-14.41, -2.55] P-value n = number of subjects with data. SD=Standard deviation. LSMean values and difference is from ANCOVA model with treatment as fixed effect and baseline total lesion count and laterality as covariates and subject as random effect. Leo_Pharma/EXP/EXP-1223/F01 - tab_ana_les.sas/tab_ana_les_sens_fas.rtf/11aug2017

105 Trial ID: EXP Aug-2017 Page 105 of 166 Table 2 8 Analysis of total lesion count Week 12 - OC - actual treatment - FAS Leo Gel 0.018% (N=38) Vehicle (N=38) n Mean SD Minimum 1 2 Maximum LSMeans % CI [ 17.52, 25.15] [ 29.92, 37.54] Difference % CI [-17.79, -7.00] P-value <.001 n = number of subjects with data. SD=Standard deviation. LSMean values and difference is from ANCOVA model with treatment as fixed effect and baseline total lesion count as covariate and subject as random effect. Actual treatment is determined post database lock by inspecting the LSR. For subjects PPD PPD and PPD treatments were interchanged. Leo_Pharma/EXP/EXP-1223/F01 - tab_ana_les.sas/tab_ana_les_acttrt_fas.rtf/11aug2017

106 Trial ID: EXP Aug-2017 Page 106 of 166 Table 2 9 Summary of total lesion change from baseline - planned treatment FAS Treatment Visit n Mean SD Median Min Max 95% CI LEO gel 0.018% Week ( -4.40, -2.17) Week ( -7.99, -4.58) Week (-13.99, -7.95) Week (-19.28,-10.40) Vehicle gel Week ( -1.12, 0.49) Week ( -3.20, 0.57) Week ( -5.60, -0.09) Week (-10.27, -1.60) n = number of subjects with data. SD=Standard deviation. Leo_Pharma/EXP/EXP-1223/F01 - tab_les_chg.sas/tab_les_chg_pln.rtf/11aug2017

107 Trial ID: EXP Aug-2017 Page 107 of 166 Table 2 10 Summary of total lesion change from baseline - actual treatment - FAS Treatment Visit n Mean SD Median Min Max 95% CI LEO gel 0.018% Week ( -4.48, -2.32) Week ( -8.46, -5.25) Week (-14.98, -9.32) Week (-21.04,-12.52) Vehicle gel Week ( -0.99, 0.59) Week ( -2.51, 1.03) Week ( -4.08, 0.75) Week ( -7.83, -0.17) n = number of subjects with data. SD=Standard deviation. Actual treatment is determined post database lock by inspecting the LSR. For subjects PPD PPD and PPD treatments were interchanged. Leo_Pharma/EXP/EXP-1223/F01 - tab_les_chg.sas/tab_les_chg_act.rtf/11aug2017

108 Trial ID: EXP Aug-2017 Page 108 of 166 Table 2 11 Summary of total lesion percent change from baseline - planned treatment FAS Treatment Visit n Mean SD Median Min Max 95% CI LEO gel 0.018% Week (-14.81, -5.90) Week (-23.90,-12.05) Week (-37.82,-20.72) Week (-50.30,-26.83) Vehicle gel Week ( -3.94, 2.74) Week (-10.91, 4.69) Week (-22.24, 1.45) Week (-32.26, -4.19) n = number of subjects with data. SD=Standard deviation. Leo_Pharma/EXP/EXP-1223/F01 - tab_les_chg.sas/tab_les_pchg_pln.rtf/11aug2017

109 Trial ID: EXP Aug-2017 Page 109 of 166 Table 2 12 Summary of total lesion percent change from baseline - actual treatment - FAS Treatment Visit n Mean SD Median Min Max 95% CI LEO gel 0.018% Week (-15.06, -6.28) Week (-25.24,-13.87) Week (-40.84,-24.49) Week (-55.87,-32.59) Vehicle gel Week ( -3.59, 3.03) Week ( -9.10, 6.03) Week (-18.27, 4.27) Week (-25.19, 0.08) n = number of subjects with data. SD=Standard deviation. Actual treatment is determined post database lock by inspecting the LSR. For subjects PPD PPD and PPD treatments were interchanged. Leo_Pharma/EXP/EXP-1223/F01 - tab_les_chg.sas/tab_les_pchg_act.rtf/11aug2017

110 Trial ID: EXP Aug-2017 Page 110 of 166 Table 2 13 Summary of Investigator s global assessment - FAS Visit IGA score LEO Gel 0.018% (N=38) n (%) Vehicle (N=38) n (%) Full face (N=38) n (%) Screening 3 36 (94.7) 37 (97.4) 33 (86.8) 4 2 ( 5.3) 1 ( 2.6) 5 (13.2) Day (94.7) 37 (97.4) 4 2 ( 5.3) 1 ( 2.6) Week (31.4) 2 ( 5.7) 3 23 (65.7) 32 (91.4) 4 1 ( 2.9) 1 ( 2.9) Week (57.1) 6 (17.1) 3 14 (40.0) 28 (80.0) 4 1 ( 2.9) 1 ( 2.9) Week ( 3.0) 2 21 (63.6) 6 (18.2) 3 10 (30.3) 26 (78.8) 4 1 ( 3.0) 1 ( 3.0) Week ( 9.4) 2 ( 6.3) 2 19 (59.4) 5 (15.6) 3 9 (28.1) 24 (75.0) 4 1 ( 3.1) 1 ( 3.1) N = Number of subjects. n = Number of subjects with data. % = percent within visit. Leo_Pharma/EXP/EXP-1223/F01 - tab_sum_iga.sas/tab_sum_iga.rtf/11aug2017

111 Trial ID: EXP Aug-2017 Page 111 of 166 Table 2 14 Analysis of Investigator s global assessment treatment success at Week 12 FAS SOC LEO Gel 0.018% (N=38) n (%) Vehicle (N=38) n (%) Treatment failure Treatment succes P-value Treatment success is defined as at least a two grade improvement from baseline to week 12. Testing is by McNemars test. N = Number of subjects. n = Number of subjects with data. % = percent of subjects with data. Leo_Pharma/EXP/EXP-1223/F01 - tab_ana_iga.sas/tab_ana_iga.rtf/11aug2017

112 Trial ID: EXP Aug-2017 Page 112 of 166 Table 2 15 Summary of acne QoL FAS Total (N=38) Self perception Day 1 n 38 Mean SD 8.05 Median 11.5 Min 0 Max 29 Week 12 n 32 Mean SD 9.74 Median 20 Min 0 Max 30 Role-social Day 1 n 38 Mean SD 7.05 Median 12 Min 0 Max 24 Week 12 n 32 Mean SD 7.8 Median 18 Min 0 Max 24 Role-emotional Day 1 n 38 Mean SD 8.49 Median 11.5 Min 0 Max 29 Week 12 n 32 Mean SD Median 20.5 Min 0 Max 30 Acne symptoms Day 1 n 38 Mean 12.5 SD 6.49 Median 12.5 Min 0 Max 26 Week 12 n 32 Mean SD 8.2 Median 17.5 Min 2 Max 30 Acne total Day 1 n 38 Mean SD Median 46 Min 1

113 Trial ID: EXP Aug-2017 Page 113 of 166 Table 2 15 Summary of acne QoL FAS, cont. Total (N=38) Max 101 Week 12 n 32 Mean SD Median 75 Min 3 Max 114 N = Number of subjects. n = number of subjects with data. SD=Standard deviation. Range for Role-social is 0-24 for other domains 0-30 and for total Leo_Pharma/EXP/EXP-1223/F01 - tab_sum.sas/tab_sum_qol.rtf/11aug2017

114 Trial ID: EXP Aug-2017 Page 114 of 166 Table 2 16 Summary of TSQM II at Week 12 FAS Total (N=38) Effectiveness Week 12 n 32 Mean SD Median Min 0 Max 100 Side effects Week 12 n 25 Mean SD 9.84 Median 100 Min 66.7 Max 100 Convenience Week 12 n 32 Mean SD Median Min 38.9 Max 100 Global satisfaction Week 12 n 32 Mean SD Median 75 Min 25 Max 100 TSQM total Week 12 n 32 Mean SD Median Min 46.3 Max 97.2 N = Number of subjects. n = number of subjects with data. SD=Standard deviation. Range is for all domains and for total Leo_Pharma/EXP/EXP-1223/F01 - tab_sum.sas/tab_sum_tsqm.rtf/11aug2017

115 Trial ID: EXP Aug-2017 Page 115 of 166 Table 2 17 Summary of subject global cosmetic score at Week 12 FAS Question Cosmetic score LEO Gel 0.018% (N=38) n (%) Vehicle (N=38) n (%) Overall appearance of the treatment area 0 - Much worsened 1 ( 3.1) 2 - No change 7 (21.9) 10 (31.3) 3 - Somewhat improved 20 (62 5) 16 (50.0) 4 - Much improved 5 (15.6) 5 (15.6) Overall feel of the treatment area 0 - Much worsened 1 ( 3.1) 2 - No change 8 (25.0) 10 (31.3) 3 - Somewhat improved 19 (59.4) 16 (50.0) 4 - Much improved 5 (15.6) 5 (15.6) N = Number of subjects. n = Number of subjects with data. % = percent within visit. Leo_Pharma/EXP/EXP-1223/F01 - tab_sum_cosm.sas/tab_sum_cosm.rtf/11aug2017

116 Trial ID: EXP Aug-2017 Page 116 of 166 Figure 2-1 Mean total lesion count versus time - planned treatment - FAS

117 Trial ID: EXP Aug-2017 Page 117 of 166 Figure 2-2 Mean total lesion count versus time - actual treatment - FAS

118 Trial ID: EXP Aug-2017 Page 118 of 166 Figure 2-3 Percent change total lesion count versus time - planned treatment FAS

119 Trial ID: EXP Aug-2017 Page 119 of 166 Figure 2-4 Percent change total lesion count versus time - actual treatment FAS

120 Trial ID: EXP Aug-2017 Page 120 of 166 Figure 2-5 Mean inflammatory lesion count versus time FAS

121 Trial ID: EXP Aug-2017 Page 121 of 166 Figure 2-6 Mean non-inflammatory lesion count versus time FAS

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137 Trial ID: EXP Aug-2017 Page 137 of Tables and Figures, Safety Data List of Tables Table 3 1 Overall summary of treatment emergent adverse events - SAS Table 3 2 Treatment emergent adverse events by SOC and PT- SAS Table 3 3 Treatment emergent adverse events by severity, SOC and PT SAS Table 3 4 Treatment emergent related adverse events by SOC and PT (by treatment) SAS Table 3 5 LSR components by visit SAS Table 3 6 LSR components, maximum post baseline score SAS Table 3 7 Composite LSR score by visit SAS Table 3 8 Composite LSR score change from baseline by visit SAS Table 3 9 Composite LSR, maximum post baseline score - SAS Table 3 10 Composite LSR, visit of first occurrence of maximum post baseline score SAS Table 3 11 Composite LSR, first visit of return to or below Composite LSR baseline score SAS Table 3 12 Vital signs - SAS Table 3 13 Change from baseline in vital signs - SAS List of Figures Figure 3-1 Mean composite LSR versus time - planned treatment - SAS Figure 3-2 Mean composite LSR versus time - actual treatment - SAS Figure 3-3 Composite LSR by subject (1) - SAS Figure 3-4 Composite LSR by subject (2) - SAS Figure 3-5 Composite LSR by subject (3) - SAS Figure 3-6 Composite LSR by subject (4) SAS Figure 3-7 Composite LSR by subject (5) - SAS

138 Trial ID: EXP Aug-2017 Page 138 of 166 Figure 3-8 LSR count by type (1) SAS Figure 3-9 LSR count by type (2) - SAS Figure 3-10 LSR count by type (3) SAS

139 Trial ID: EXP Aug-2017 Page 139 of 166 Table 3 1 Overall summary of treatment emergent adverse events - SAS Non-cutaneous (N=40) n (%) E LEO Gel 0.018% (N=40) n (%) E Vehicle (N=40) n (%) E Total (N=40) n (%) Any TEAEs 1 (2.5) 2 18 (45.0) 20 1 (2.5) 1 19 (47.5) 23 Deaths 0 (0.0) 0 0 (0.0) 0 0 (0.0) 0 0 (0.0 ) 0 Serious TEAEs 0 (0.0) 0 0 (0.0) 0 0 (0.0) 0 0 (0.0 ) 0 TEAEs leading to discontinuation from the trial 0 (0.0) 0 0 (0.0) 0 0 (0.0) 0 0 (0.0 ) 0 Related AEs 0 (0.0) 0 18 (45.0) 20 1 (2.5) 1 19 (47.5) 21 Severe TEAEs 0 (0.0) 0 0 (0.0) 0 0 (0.0) 0 0 (0.0 ) 0 Moderate TEAEs 0 (0.0) 0 3 (7 5) 3 1 (2.5) 1 4 (10.0) 4 Mild TEAEs 1 (2.5) 2 15 (37 5) 17 0 (0.0) 0 15 (37.5) 19 N=Number of subjects in Safety Analysis Set. E=Number of events. n=number of subjects with adverse event. % = Percentage of subjects with adverse event. Related AEs=AE assessed by investigator as possibly/probably related to investigational product TEAE=Treatment Emergent Adverse Event. Leo_Pharma/EXP/EXP-1223/F01 - tab_ae_sum.sas/tab_ae_sum.rtf/11aug2017 E

140 Trial ID: EXP Aug-2017 Page 140 of 166 Table 3 2 Treatment emergent adverse events by SOC and PT- SAS SOC PT Noncutaneous (N = 40) n (%) E LEO Gel 0.018% (N = 40) n (%) E Vehicle (N = 40) n (%) E Gastrointestinal disorders Nausea 1 (2.5) 1 Total 1 (2.5) 1 General disorders and administration site Application site 2 (5.0) 2 conditions pruritus Application site pain 18 (45.0) 18 1 (2.5) 1 Total 18 (45.0) 20 1 (2.5) 1 Nervous system disorders Headache 1 (2.5) 1 Total 1 (2.5) 1 N = Number of subjects. n = Number of subjects with data. % = Percentage of subjects with event. E = number of events. Leo_Pharma/EXP/EXP-1223/F01 - tab_ae.sas/tab_ae_soc rtf/11aug2017

141 Trial ID: EXP Aug-2017 Page 141 of 166 Table 3 3 Treatment emergent adverse events by severity, SOC and PT SAS Severity SOC PT Non-cutaneous (N = 40) n (%) E LEO Gel 0.018% (N = 40) n (%) E Vehicle (N = 40) n (%) E Mild Gastrointestinal disorders Nausea 1 (2.5) 1 Total 1 (2.5) 1 General disorders and administration site conditions Application site pain 15 (37.5) 15 Application site pruritus 2 (5.0) 2 Total 15 (37.5) 17 Nervous system disorders Headache 1 (2.5) 1 Total 1 (2.5) 1 Moderate General disorders and administration site Application site pain 3 (7.5) 3 1 (2.5) 1 conditions Total 3 (7.5) 3 1 (2.5) 1 N = Number of subjects. n = Number of subjects with data. % = Percentage of subjects with event. E = number of events. Leo_Pharma/EXP/EXP-1223/F01 - tab_ae.sas/tab_ae_soc_sev.rtf/11aug2017

142 Trial ID: EXP Aug-2017 Page 142 of 166 Table 3 4 Treatment emergent related adverse events by SOC and PT (by treatment) SAS SOC PT Non-cutaneous (N = 40) n (%) E LEO Gel 0.018% (N = 40) n (%) E Vehicle (N = 40) n (%) E General disorders and administration site conditions Application site pain 18 (45.0) 18 1 (2.5) 1 Application site pruritus 2 (5.0) 2 Total 18 (45.0) 20 1 (2.5) 1 N = Number of subjects. n = Number of subjects with data. % = Percentage of subjects with event. E = number of events. Leo_Pharma/EXP/EXP-1223/F01 - tab_ae.sas/tab_ae_soc_rel.rtf/11aug2017

143 Trial ID: EXP Aug-2017 Page 143 of 166 Table 3 5 LSR components by visit SAS Visit Score LEO Gel 0.018% (N=40) n (%) Vehicle (N=40) n (%) Crusting Day (97) 39 (100) 2 1 (2.6) Day (97) 39 (100) 3 1 (2.6) Day (74) 36 (92) 1 5 (13) 1 (2.6) 2 5 (13) 1 (2.6) 3 1 (2.6) Day (54) 33 (87) 1 8 (22) 2 (5.3) 2 6 (16) 2 (5.3) 3 3 (8.1) 1 (2.6) Day (33) 15 (94) 1 5 (33) 1 (6.3) 2 5 (33) Week (69) 32 (89) 1 8 (23) 1 (2.8) 2 3 (8.6) 2 (5.6) 3 1 (2.8) Week (94) 36 (97) 1 2 (5.7) 1 (2.7) Week (97) 35 (100) 2 1 (2.9) Week (97) 34 (100) 1 1 (2.9) Erosion/Ulceration Day (100) 39 (100) Day (100) 39 (100) Day (100) 39 (100) Day (100) 38 (100) Day (100) 16 (100) Week (100) 36 (100) Week (100) 37 (100) Week (100) 35 (100) Week (100) 34 (100) Erythema Day (100) 39 (100) Day (53) 33 (85) 1 8 (21) 3 (7.7) 2 6 (16) 2 (5.1) 3 4 (11) 1 (2.6) Day (24) 31 (79) 1 11 (29) 2 (5.1) 2 13 (34) 3 (7.7) 3 5 (13) 3 (7.7) Day (27) 33 (87) 1 8 (22) 1 (2.6) 2 9 (24) 1 (2.6) 3 10 (27) 3 (7.9) Day (60) 16 (100) 1 4 (27) 2 1 (6.7) 3 1 (6.7) Week (89) 35 (97) 1 3 (8.6) 1 (2.8)

144 Trial ID: EXP Aug-2017 Page 144 of 166 Visit Score LEO Gel 0.018% (N=40) n (%) Vehicle (N=40) n (%) N = Number of subjects. n = number of subjects with data. (%)=percentage of subjects with data within visit. Leo_Pharma/EXP/EXP-1223/F01 - tab_lsr_comp.sas/tab_lsr_comp1.rtf/11aug2017

145 Trial ID: EXP Aug-2017 Page 145 of 166 Table 3.5 LSR components by visit - SAS Visit Score LEO Gel 0.018% (N=40) n (%) Vehicle (N=40) n (%) 2 1 (2.9) Week (97) 37 (100) 1 1 (2.9) Week (100) 35 (100) Week (100) 34 (100) Flaking/Scaling Day (97) 39 (100) 3 1 (2.6) Day (97) 39 (100) 1 1 (2.6) Day (66) 36 (92) 1 10 (26) 2 (5.1) 2 3 (7.9) 1 (2.6) Day (41) 32 (84) 1 11 (30) 3 (7.9) 2 7 (19) 2 (5.3) 3 4 (11) 1 (2.6) Day (20) 14 (88) 1 8 (53) 2 (13) 2 4 (27) Week (54) 35 (97) 1 11 (31) 2 5 (14) 3 1 (2.8) Week (86) 36 (97) 1 5 (14) 1 (2.7) Week (97) 35 (100) 2 1 (2.9) Week (97) 34 (100) 1 1 (2.9) Swelling Day (100) 39 (100) Day (84) 38 (97) 1 2 (5.3) 2 3 (7.9) 1 (2.6) 3 1 (2.6) Day (66) 37 (95) 1 7 (18) 1 (2.6) 2 6 (16) 1 (2.6) Day (73) 37 (97) 1 8 (22) 1 (2.6) 2 2 (5.4) Day (93) 16 (100) 1 1 (6.7) Week (100) 36 (100) Week (100) 37 (100) Week (100) 35 (100) Week (100) 34 (100) Vesiculation/Pustulation Day (100) 39 (100) Day (95) 38 (97) 1 1 (2.6) 3 1 (2.6) 4 1 (2.6) Day (79) 37 (95) 1 4 (11)

146 Trial ID: EXP Aug-2017 Page 146 of 166 Table 3.5 LSR components by visit - SAS Visit Score LEO Gel 0.018% (N=40) n (%) Vehicle (N=40) n (%) N = Number of subjects. n = number of subjects with data. (%)=percentage of subjects with data within visit. Leo_Pharma/EXP/EXP-1223/F01 - tab_lsr_comp.sas/tab_lsr_comp1.rtf/11aug2017

147 Trial ID: EXP Aug-2017 Page 147 of 166 Table 3.5 LSR components by visit - SAS Visit Score LEO Gel 0.018% (N=40) n (%) Vehicle (N=40) n (%) 2 3 (7.9) 1 (2.6) 3 1 (2.6) 1 (2.6) Day (65) 36 (95) 1 4 (11) 2 5 (14) 1 (2.6) 3 4 (11) 1 (2.6) Day (87) 16 (100) 1 1 (6.7) 3 1 (6.7) Week (97) 36 (100) 1 1 (2.9) Week (100) 37 (100) Week (100) 35 (100) Week (97) 34 (100) 1 1 (2.9) N = Number of subjects. n = number of subjects with data. (%)=percentage of subjects with data within visit. Leo_Pharma/EXP/EXP-1223/F01 - tab_lsr_comp.sas/tab_lsr_comp1.rtf/11aug2017

148 Trial ID: EXP Aug-2017 Page 148 of 166 Table 3 6 LSR components, maximum post baseline score SAS Score LEO Gel 0.018% (N=40) n (%) Vehicle (N=40) n (%) Crusting 0 15 (38) 33 (83) 1 9 (23) 2 (5.0) 2 12 (30) 4 (10) 3 4 (10) 1 (2.5) Erosion/Ulceration 0 40 (100) 40 (100) Erythema 0 10 (25) 32 (80) 1 5 (13) 2 (5.0) 2 11 (28) 2 (5.0) 3 14 (35) 4 (10) Flaking/Scaling 0 9 (23) 33 (83) 1 15 (38) 4 (10) 2 12 (30) 2 (5.0) 3 4 (10) 1 (2.5) Swelling 0 22 (55) 38 (95) 1 11 (28) 1 (2.5) 2 6 (15) 1 (2.5) 3 1 (2.5) Vesiculation/Pustulation 0 25 (63) 38 (95) 1 5 (13) 2 5 (13) 3 5 (13) 1 (2.5) 4 1 (2.5) N = Number of subjects. n = number of subjects with data. (%)=percentage of subjects with data. Leo_Pharma/EXP/EXP-1223/F01 - tab_lsr_comp.sas/tab_lsr_comp2.rtf/11aug2017

149 Trial ID: EXP Aug-2017 Page 149 of 166 Table 3 7 Composite LSR score by visit SAS Visit LEO Gel 0.018% (N=40) Vehicle (N=40) Day 1 n Mean SD Median Min 0 0 Max 5 0 Day 2 n Mean SD Median Min 0 0 Max 9 9 Day 3 n Mean SD Median Min 0 0 Max Day 4 n Mean SD Median Min 0 0 Max Day 8 n Mean SD Median Min 0 0 Max 10 2 Week 2 n Mean SD Median Min 0 0 Max 5 7 Week 4 n Mean SD Median Min 0 0 Max 3 1 Week 8 n Mean SD Median Min 0 0 Max 4 0 Week 12 n Mean SD Median Min 0 0

150 Trial ID: EXP Aug-2017 Page 150 of 166 Visit LEO Gel 0.018% (N=40) Vehicle (N=40) Max 2 0 N = Number of subjects. n = number of subjects with data. SD=Standard deviation. Leo_Pharma/EXP/EXP-1223/F01 - tab_lsr.sas/tab_lsr1.rtf/11aug2017

151 Trial ID: EXP Aug-2017 Page 151 of 166 Table 3 8 Composite LSR score change from baseline by visit SAS Visit LEO Gel 0.018% (N=40) Vehicle (N=40) Day 2 n Mean SD Median Min -5 0 Max 9 9 Day 3 n Mean SD Median Min 0 0 Max Day 4 n Mean SD Median Min 0 0 Max Day 8 n Mean SD Median Min 0 0 Max 10 2 Week 2 n Mean SD Median Min -3 0 Max 5 7 Week 4 n Mean SD Median Min -5 0 Max 3 1 Week 8 n Mean SD Median Min -5 0 Max 4 0 Week 12 n Mean SD Median Min -5 0 Max 2 0 N = Number of subjects. n = number of subjects with data. SD=Standard deviation. Leo_Pharma/EXP/EXP-1223/F01 - tab_lsr.sas/tab_lsr2.rtf/11aug2017

152 Trial ID: EXP Aug-2017 Page 152 of 166 Table 3 9 Composite LSR, maximum post baseline score SAS LEO Gel 0.018% (N=40) Vehicle (N=40) n 31 8 Mean SD Median Min 2 2 Max N = Number of subjects. n = number of subjects with at least one post baseline score above 0. SD=Standard deviation. Leo_Pharma/EXP/EXP-1223/F01 - tab_lsr.sas/tab_lsr3.rtf/11aug2017

153 Trial ID: EXP Aug-2017 Page 153 of 166 Table 3 10 Composite LSR, visit of first occurrence of maximum post baseline score SAS Visit LEO Gel 0.018% (N=40) n (%) Vehicle (N=40) n (%) Day 2 5 (16.1) 1 (12.5) Day 3 6 (19.4) 2 (25.0) Day 4 18 (58.1) 5 (62.5) Day 8 2 (6.5) N = Number of subjects. n = number of subjects with data. (%)=percentage of subjects with data. Only subjects with at least one post baseline score above zero included. Leo_Pharma/EXP/EXP-1223/F01 - tab_lsr_visit.sas/tab_lsr_visit1.rtf/11aug2017

154 Trial ID: EXP Aug-2017 Page 154 of 166 Table 3 11 Composite LSR, first visit of return to or below Composite LSR baseline score SAS Visit LEO Gel 0.018% (N=40) n (%) Vehicle (N=40) n (%) Day 8 1 (3.3) 1 (16.7) Week 2 10 (33.3) 1 (16.7) Week 4 15 (50.0) 2 (33.3) Week 8 4 (13.3) 2 (33.3) N = Number of subjects. n = number of subjects with data. (%)=percentage of subjects with data. Only subjects with a max LSR larger than 0 and return to or below baseline included. Leo_Pharma/EXP/EXP-1223/F01 - tab_lsr_visit.sas/tab_lsr_visit2.rtf/11aug2017

155 Trial ID: EXP Aug-2017 Page 155 of 166 Table 3 12 Vital signs - SAS n Mean SD Median Minimum Maximum Systolic Blood Pressure (mmhg) Screening Week Diastolic Blood Pressure (mmhg) Screening Week Heart Rate (beats/min) Screening Week N = Number of subjects. n = Number of subjects with data. SD = Standard Deviation. Leo_Pharma/EXP/EXP-1223/F01 - tab_vs.sas/tab_vs.rtf/11aug2017

156 Trial ID: EXP Aug-2017 Page 156 of 166 Table 3 13 Change from baseline in vital signs - SAS n Mean SD Median Minimum Maximum Systolic Blood Pressure (mmhg) Week Diastolic Blood Pressure (mmhg) Week Heart Rate (beats/min) Week N = Number of subjects. n = Number of subjects with data. SD = Standard Deviation. Leo_Pharma/EXP/EXP-1223/F01 - tab_vs.sas/tab_vs_chg.rtf/11aug2017

157 Trial ID: EXP Aug-2017 Page 157 of 166 Figure 3-1 Mean composite LSR versus time - planned treatment - SAS

158 Trial ID: EXP Aug-2017 Page 158 of 166 Figure 3-2 Mean composite LSR versus time - actual treatment - SAS

159 PPD PPD PPD PPD PPD PPD PPD PPD PPD

160 PPD PPD PPD PPD PPD PPD PPD PPD PPD

161 PPD PPD PPD PPD PPD PPD PPD PPD PPD

162 PPD PPD PPD PPD PPD PPD PPD PPD PPD

163 PPD PPD PPD PPD

164 Trial ID: EXP Aug-2017 Page 164 of 166 Figure 3-8 LSR count by type (1) SAS