Rose Living with Acute Intermittent Porphyria

Transcription

1 1 Rose Living with ute Intermittent Porphyria

2 CLIICAL OVERVIEW OF TE ACUTE EPATIC PORPYRIAS (APs) Inborn Errors of eme Biosynthesis Robert J. Desnick, Ph.D., M.D. Dean for Genetic & Genomic Medicine ofessor & Chair Emeritus Department of Genetics & Genomic Sciences Icahn School of Medicine at Mount Sinai, ew York, Y

3 ACUTE EPATIC PORPYRIAS (APs) OUTLIE Brief Review: eme Biosynthesis & Regulation The ute epatic Porphyrias (APs): evalence ute and Chronic Manifestations Pathogenesis of ute Attacks Current Therapies: eme Replacement Orthotopic Liver Transplantation

4 Mitochondria EME BIOSYTETIC PATWAY SUCCIYL COA GLYCIE COŌ C C 2 CoAS C O C 2 COO ALA-SYTASE (ALAS) B 6 CoAS CO 2 COO C 2 C 2 C=O C AMIOLEVULIIC ACID (ALA) ALA - DEYDRATASE 2 O 2 C 2 MB-SYTASE COŌ COO C 2 C 2 C 2 PORPOBILIOGE (PBG) 4 3 Cytoplasm Vi C3 C3 C3 Fe Vi C3 O 2 + Fe ++ EME FERROCELATASE URO-SYTASE YDROXYMETYLBILAE 2 O Vi C3 C3 Vi C3 C PROTOPORPYRI IX 6 URO - PROTO-OXIDASE DECARBOXYLASE Vi C UROPORPYRIOGE III 4 4 CO 2 C3 C3 C3 Vi C PROTOPORPYRIOGE IX 2CO 2 2 COPRO-OXIDASE C3 C3 C3 COPROPORPYRIOGE III

5 EME BIOSYTETIC PATWAY - LIVER Mitochondria SUCCIYL COA GLYCIE COŌ C C 2 CoAS C O FEEDBACK C 2 COO ALA-SYTASE 1 (ALAS1) B 6 CoAS CO 2 COO C 2 C 2 C=O C ALA REPRESSIO ALA - DEYDRATASE 2 O 2 C 2 MB-SYTASE COŌ COO C 2 C 2 C 2 PBG 4 3 Cytoplasm Vi C3 C3 C3 Fe Vi C3 O 2 + Fe ++ EME FERROCELATASE URO-SYTASE YDROXYMETYLBILAE 2 O Vi C3 C3 Vi C3 C PROTOPORPYRI IX 6 URO - PROTO-OXIDASE DECARBOXYLASE Vi C UROPORPYRIOGE III 4 4 CO 2 C3 C3 C3 Vi C PROTOPORPYRIOGE IX 2CO 2 2 COPRO-OXIDASE C3 C3 C3 COPROPORPYRIOGE III

6 EME BIOSYTETIC PATWAY - LIVER Mitochondria SUCCIYL COA GLYCIE COŌ C C 2 CoAS C O C 2 COO ALA-SYTASE 1 (ALAS1) B 6 CoAS CO 2 COO C 2 C 2 C=O C AMIOLEVULIIC ACID (ALA) ALA - DEYDRATASE 2 O 2 C 2 MB-SYTASE COŌ COO C 2 C 2 C Cytoplasm PORPOBILIOGE (PBG) Vi C3 C3 C3 Fe Vi C3 O 2 + Fe ++ EME FERROCELATASE URO-SYTASE YDROXYMETYLBILAE 2 O Vi C3 C3 Vi C3 C PROTOPORPYRI IX 6 URO - PROTO-OXIDASE DECARBOXYLASE Vi C UROPORPYRIOGE III 4 4 CO 2 C3 C3 C3 Vi C PROTOPORPYRIOGE IX 2CO 2 2 COPRO-OXIDASE C3 C3 C3 COPROPORPYRIOGE III

7 ACUTE EPATIC PORPYRIAS (APs) Porphyria Autosomal Dominant: ute Intermittent Porphyria (AIP) MB-Synthase ereditary Coproporphyria (CP) COPRO-Synthase Variegate Porphyria (VP) PROTO-Synthase Autosomal Recessive: ALA-Dehydratase Deficient Porphyria (ADP) ALA-Dehydratase Major Clinical Manifestations: Life-Threatening ute eurovisceral Attacks Chronic europathic Pain & ogressive europathy Deficient Enzyme tivity (% of ormal) 50% 50% 50% <5% Biochemical & Molecular Diagnoses: Most Patients Identified During/After an ute Attack: Markedly Elevated Urinary/Plasma ALA/ PBG (>5-15, >20-120, resp.) Increased Liver ALAS1 mra and Enzyme tivity (10-15) Mutation Analysis Identifies All Patients

8 ESTIMATED PREVALECE OF APs Country Patients/100,000 Sweden 4-5* Finland 2-3* UK & Western Europe 2-5* United States 2-5** American Porphyria Foundation Patient Registry 6200 Registered Members, ~3,700 ute epatic Patients, Most Are Biochemically/Mutation Confirmed: AIP: 2,798 CP: 592 VP: 312 Total = 3,702 *Andersson C.,AIP in orthern Sweden, PhD Thesis, 1997; Elder et al.,j.inherit Metab Dis Epub ov 1, 2012, **Estimated

9 MOUT SIAI PORPYRIA DIAGOSTIC & TREATMET CETER ute epatic Porphyria Patients Annual umber Diagnosed and Mutations Confirmed; 1/1/2010 to 11/30/2016 Year AIP VP CP Total (11 Months) Total Initial Misdiagnosis is Common in Many Patients Mean Time from First Symptoms to Diagnosis is ~10 Years evalence likely Underestimated

10 APs: MAIFESTATIOS ute eurovisceral Attacks: odrome: Confusion: Brain Fog, Insomnia, Fatigue - Warning Signal ute Attack: Excruciating Abdominal Pain, Vomiting, BP and R Can ogress to: Muscle Weakness, Paralysis, Seizures, if Untreated ecipitating Factors that Increase ALAS1: Drugs (P450 Inducers), Alcohol Dieting, Low Caloric Intake ormonal Changes (Menstruation), Etc. Chronic Manifestations: Between Attacks: Many Patients ave ogressive europathy & Severe europathic Pain Requiring Pain Medication Fatigue, Chronic ausea, Weakness and Insomnia Difficulty Maintaining Work tivities, Live in Fear of Attack

11 PATOGEESIS OF TE ACUTE ATTACKS I AIP ormal epatic eme-mediated Feedback Repression Glycine + Succinyl CoA ALAS1 ALAD MB-Synthase ALA PBG MB EME 50% MB-Synthase ALAS1 ALAD ALA PBG MB EME Decreased epatic eme-mediated Feedback Repression Clinically Manifest AIP

12 ACUTE ITERMITTET PORPYRIA (AIP) Most Common ute epatic Porphyria Clinical Groups Based on Frequency of ute Attacks: Recurrent Attacks: 4 or more attacks/yr; Men & Women As Frequent as Weekly or Monthly Women with Monthly Attacks during Luteal Phase of Menstrual Cycle About 50% ave Daily Symptoms Between Attacks Sporadic Attacks: < 3 Attacks/yr; Men & Women Asymptomatic igh ALA/PBG Excreters (ASE): evious Attack in Most Cases, with Persistently Elevated ALA and PBG At igh Risk of Recurrent Attacks and May ave Disease Complications

13 ACUTE EUROVISCERAL ATTACKS: ICIDECE OF SYMPTOMS Symptom % of Patients Abdominal Pain 95 Vomiting 72 Constipation 70 Muscle Weakness 68 Tachycardia 62 Mental Symptoms 48 ypertension 45 Convulsions 15 Paralysis 10

14 MAAGEMET OF ACUTE PORPYRIC ATTACKS Admit to ospital or Outpatient Clinic ASAP Treatment Delay Can Result in Worsening of Symptoms, olonged Recovery and Life-threatening Complications Withdraw All Common ecipitants (Drugs, Alcohol, Fasting, Infection...) Use Opiates as eeded for Pain Order ematin (Panhematin ) (Inhibits ALAS1) 3-4 mg/kg IV Daily for 4 Days or Until Symptoms Improve

15 SAFETY OF EMI ematin (Panhematin ) 1 ST Orphan Drug, 1982 Approved Based on Small Open Label Studies, but in Clinical Use for >30 Years Adverse Reactions or Side Effects 1-4 : Phlebitis, Coagulopathy 1, Fever, hing, Malaise, Migraine, emolysis, One Case of Circulatory Collapse 2, One Case of Transient Renal Failure After Excessive Dose 3 Tachyphylaxis Reported in Patients with Long Term Use 5 Chronic Use Requires a Port with Infection and Thrombosis Risk Chronic Use as Been Associated with Iron Overload FDA as ot Approved ophylactic Use 1 Morris DL, et al. Ann Intern Med 1981;95:700-1.; 2 Khanderia U. Clin Pharm 1986;5: Dhar GJ, et al. ta Med Scand 1978;203: ; 4 Anderson KE, et al. Am J Med. 2006; 119:801.e19-24, 5 Besur et al. Metabolites 2014; 4,

16 CASE STUDY- RECURRET ATTACKS I A 30 Y/O FEMALE WIT AIP 20 Attacks in a Year 32 Days of IV ematin ospitalization for Some Attacks, Others On Demand Breakthrough Attacks Despite Bi-weekly eme ophylaxis Extremely Poor Quality of Life, Multiple Days Lost from Work

17 mmol/mmol Creatinine LIVER TRASPLATATIO I ACUTE EPATIC PORPYRIA Soonawalla et al., Lancet 363: , 2004 A 19 y/o Woman with Multiple Recurrent ute Attacks Unresponsive to ematin ad an Orthotopic Liver Transplant Transplant Demonstrated Importance of Liver in Disease Pathogenesis ~10 Additional Patients Transplanted in Europe Domino Transplant Patients ad Increased ALA & PBG and Attacks Challenges: igh Frequency of epatic Artery Thromboses Limited Availability of Organs igh Morbidity & Mortality e-tx: 37 Attacks over 29 Months Post-Tx: one for > 10 Years Urinary Excretion of ALA & PBG after Liver Transplant ALA/Creatinine PBG/Creatinine r after Liver Transplant

18 IDEAL EXT GEERATIO TERAPY Excellent Safety ofile Effective for ophylaxis in Recurrent Attack Patients Decrease umber of Attacks Minimize Symptoms in Between Attacks o Evidence of Tachyphylaxis Convenient Administration: Ideally Subcutaneous or Oral Route to Avoid Portacath Potential for at ome Use Faster/Longer Lasting Effects for ute Treatment: Minimize Multi-Day ospitalizations

19 RATIOALE FOR TARGETIG EPATIC ALAS1 ALAS1 mra Strongly Upregulated During Attacks ematin Down Modulates ALAS1 Addition of eme to Liver Cells in Culture Leads to Reduced ALAS1 mra Liver Transplant Is Curative Domino Transplant Recipients ave Increased ALA/PBG & ave AIP Symptoms Liver Derived ALA & PBG Drive Attacks

20 COCLUSIOS ute epatic Porphyrias Are Panethnic and a Worldwide oblem Attacks Can Be Either Recurrent or Sporadic: Life-Threatening Signs and Symptoms Poor Quality of Life, Long ospital Stays Chronic & ogressive europathic Pain & europathy ALAS1 Targeting in Liver as Been Validated: Liver Transplant and eme Infusion Therapy Unmet eed for ew Therapeutic Options: Effective for ophylaxis Better Safety ofile and Faster Onset Easier Drug Delivery Strategy

21 Givosiran (AL-AS1) Pushkal Garg, M.D. Senior Vice esident, Clinical Development 21

22 Givosiran: Investigational RAi Therapeutic Therapeutic ypothesis Knockdown of Liver ALAS1 otein to Reduce ALA/PBG ALA/PBG induce porphyria symptoms ALAS1 protein Givosiran (AL-AS1) knockdown of ALAS1 reduces ALA/PBG production and prevents attacks Givosiran (AL-AS1) 22

23 Givosiran Phase 1 Study: Parts A and B Study Design and Objectives Part A: Single-Ascending Dose (SAD) Randomized 3:1, Single-blind, Placebo-controlled, in Asymptomatic igh Excreter Patients (ASE) 0.035* mg/kg x 1 SC, = mg/kg x 1 SC, = mg/kg x 1 SC, =4 1.0 mg/kg x 1 SC, =4 Part A and B Study Objectives: imary: safety Secondary: PK and PD (ALA, PBG) Exploratory: ALAS1 mra by cerd 2.5 mg/kg x 1 SC, =4 Part B: Multiple-Ascending Dose (MAD) Randomized 3:1, Single-blind, Placebo-controlled, in ASE Patients 0.35 mg/kg, qmx2 SC, =4 1.0mg/kg, qmx2 SC, =4 23 Clinicaltrials.gov: CT *0.035 mg/kg cohort dosed after 0.10 and 0.35 mg/kg cohorts

24 Mean [+/- SEM] ALAS1 mra Lowering Relative to Baseline (%) Givosiran Phase 1 Study Interim Results Part A Pharmacodynamic Data: Serum ALAS1 mra by cerd ALAS1 mra induced approximately 3-fold in ASE compared to normal healthy volunteers Rapid, dose-dependent, and durable ALAS1 mra lowering after single dose 64 ± 1% mean (SEM) maximal reduction in 2.5 mg/kg dose group Remaining ALAS1 mra levels after highest dose similar to levels in normal healthy individuals P< SAD Placebo (=5) mg/kg Givosiran (=3) 0.10 mg/kg Givosiran (=3) 0.35 mg/kg Givosiran (=3) 1.0 mg/kg Givosiran (=3) 2.5 mg/kg Givosiran (=3) Days since first dose ormal healthy individual 24 Data in database as of 28 Jun 2016 Sardh et al., SSIEM, September 2016

25 Mean [± SEM] Creatinine ormalized PBG Relative to Baseline Mean [± SEM] Creatinine ormalized ALA Relative to Baseline Givosiran Phase 1 Study Interim Results Part A Pharmacodynamic Data: Urinary PBG and ALA Part A (SAD): PBG Part A (SAD): ALA Month Month Parts A and B Safety Summary Givosiran was generally well tolerated o discontinuations or serious adverse events related to study drug o clinically significant changes in physical examination or laboratory tests 2 mild and transient injection site reactions SAD Placebo (=5) mg/kg Givosiran (=3) 0.1 mg/kg Givosiran (=3) mg/kg Givosiran (=3) 1.0 mg/kg Givosiran (=3) 2.5 mg/kg Givosiran (=3) SAD, Single-Ascending Dose; 5 subjects had >1 treatment assignment: 2 subjects repeated Part A; 3 subjects enrolled in Parts A and B; Reference ranges: ALA UL: < 3.9 or 3.8 mmol/mol Cr at sites 101 or 201; PBG UL: < 1.6 or 1.5 mmol/mol Cr at sites 101 or *Data transfer date: 07 ov 2016; Sardh et al., AS, December 2016

26 Givosiran Phase 1 Study: Part C Overview* Run-in Phase (3 months) Run-in Observation Run-in Observation D0 Givosiran Treatment Phase (6 months) D84 Cohort 1, 2.5 mg/kg q3m x 2, =4 Cohort 2, 2.5 mg/kg qm x 4, =4 D168 Run-in Observation Cohort 3, 5 mg/kg qm x 4, =4 Run-in Observation Cohort 4, 5 mg/kg q3m x 2, =4 Study Design Placebo-controlled, double-blind, randomized 3:1, multiple dose study in AIP patients with recurrent attacks Key Inclusion Criteria: o Genetic confirmation of AIP o 2 attacks in past 6 months if on-demand treatment or willing to stop hemin prophylaxis during study. One attack in run-in required for randomization. Objectives Safety and tolerability of givosiran Characterize givosiran PK and PD Exploratory Objectives Clinical activity of givosiran on attack characteristics and treatment Characterize circulating ALAS1 mra from the liver in urine and serum 26 *Data cut-off is D168 for Cohort 1 (unblinded) and D84 for Cohort 2 (blinded) Clinicaltrials.gov: CT

27 Interim Givosiran Phase 1 (Part C) Study Results* Demographics and Baseline Disease tivity: Cohorts 1 and 2 Demographics (=8) Age, years; mean (range) 39.4 (21-60) Sex: Female, n (%) 7 (88) Race: White/Caucasian, n (%) 8 (100) Patient Reported Attack umber in last 12 mos; mean (range) 17.9 (0-50) emin prophylaxis use prior to study, n (%) 5 (62) Baseline Disease tivity (=8) Baseline PBG, mmol/mol Cr; mean (min, max) 48.6 (12.3, 88.2) Baseline ALA, mmol/mol Cr; mean (min, max) 23 (2.6, 36.7) 27 *Data transfer date: 07 ov 2016; Sardh et al., AS, December 2016 UL: ALA <3.9 or 3.8 mmol/mol Cr; PBG < 1.6 or 1.5 mmol/mol Cr depending on site

28 Interim Givosiran Phase 1 (Part C) Study Results* Safety and Tolerability in AIP Patients with Recurrent Attacks o drug-related SAEs in Cohorts 1-4 Cohorts 1 and 2 o discontinuations due to AEs During treatment period, all randomized patients (8/8) reported at least 1 nonporphyria attack AE o o o o Majority of AEs mild or moderate in severity AEs reported in 3 patients were abdominal pain, nausea, vomiting, nasopharyngitis, and headache (3 patients each) Possibly or definitely related AEs reported in 2 cases were injection site reaction and myalgia; all mild o clinically significant changes in vital signs, EKG, clinical laboratory parameters or physical examination Cohort 3 After data transfer date, one patient experienced an SAE of acute pancreatitis complicated by pulmonary embolism resulting in death o o Event assessed as unlikely related to givosiran or placebo by investigator due to presence of gallbladder sludge Safety Review Committee in agreement with assessment 28 *Data transfer date: 07 ov 2016; Sardh et al., AS, December 2016

29 Interim Givosiran Phase 1 (Part C) Study Results* Clinical tivity Data: Cohort 1, Placebo Patient Run-in 120 Treatment Study Day PBG ALA eme Porphyria Attack ospitalization mmol/mol/cr Period Weeks Attacks Attacks Annualized Max Attack-Free Interval (Days) emin Doses emin Doses Annualized Run-In Treatment *Data transfer date: 07 ov 2016; Sardh et al., AS, December 2016

30 Interim Givosiran Phase 1 (Part C) Study Results* Clinical tivity Data: Cohort 1, Givosiran Patient 1 Run-in Study Day Treatment PBG ALA eme Porphyria Attack ospitalization mmol/mol/cr Period Weeks Attacks Attacks Annualized Max Attack-Free Interval (Days) emin Doses emin Doses Annualized Run-In Treatment *Data transfer date: 07 ov 2016; Sardh et al., AS, December 2016

31 Interim Givosiran Phase 1 (Part C) Study Results* Clinical tivity Data: Cohort 1, Givosiran Patient 2 Run-in Study Day Treatment PBG ALA eme Porphyria Attack ospitalization mmol/mol/cr Period Weeks Attacks Attacks Annualized Max Attack-Free Interval (Days) emin Doses emin Doses Annualized Run-In Treatment *Data transfer date: 07 ov 2016; Sardh et al., AS, December 2016

32 Interim Givosiran Phase 1 (Part C) Study Results* Clinical tivity Data: Cohort 1, Givosiran Patient 3 Run-in Treatment PBG ALA Study Day eme Porphyria Attack ospitalization mmol/mol/cr Period Weeks Attacks Attacks Annualized Max Attack-Free Interval (Days) emin Doses emin Doses Annualized Run-In Treatment *Data transfer date: 07 ov 2016; Sardh et al., AS, December 2016

33 % Decrease in Annualized Attack Rate % Decrease in Annualized emin Doses Maximum Attack Free Interval (Ratio Relative to Run-In) Interim Givosiran Phase 1 (Part C) Study Results* Summary of Clinical tivity Data Cohorts 1 and 2 in AIP Patients Givosiran Treated Period Relative to Run-in 100 Cohort 1: Mean 74% Decrease in Annualized Attack Rate Cohort 1: Mean 75% Decrease in Annualized emin Doses Cohort 1: Maximum Attack Free Interval 10.5x Relative to Run-In PBO Givo- 1 Givo- 2 Givo- 3 Mean C1- Givo Mean C2 0 PBO Givo- 1 Givo- 2 Givo- 3 Mean C1- Givo Mean C2 0 PBO Givo- 1 Givo- 2 Givo- 3 Mean C1- Givo Mean C2 Cohort 1 Cohort 2 Cohort 1 Cohort 2 Cohort 1 Cohort 2 Cohort 1 is through D168, Cohort 2 through D84 of the treatment phase Cohort 2 data is aggregated (including placebo) to protect blind 33 *Data transfer date: 07 ov 2016; Sardh et al., AS, December 2016

34 Interim Givosiran Phase 1 (Part C) Study Results* Summary and Study ext Steps Givosiran safety and tolerability o drug-related SAEs or discontinuations due to AEs o dose-dependent AEs or clinically significant changes in vital signs, EKG, clinical laboratory parameters or physical examination Cohort 3: one unlikely related fatal SAE of acute pancreatitis complicated by a pulmonary embolism Givosiran showed robust clinical activity in AIP patients with recurrent attacks Data suggest modest lowering, and/or blunting of further increases during attacks, of ALA/PBG may be sufficient for clinical activity Cohort 1 Data in Givosiran-treated patients: 74% reduction in annualized attack rate compared to run-in 75% reduction in annualized hemin usage compared to run-in 10.5x maximum attack free interval (~82 days longer on average) compared to run-in Aggregated Cohort 2 Blinded Data: Supportive data demonstrating reduction in attack rate and hemin usage compared to run-in Study ext Steps Complete dosing of Cohorts 3 and 4 Ongoing open label extension study for longer term safety and clinical activity data 34 *Data transfer date: 07 ov 2016

35 atural istory Study Results Demonstrate Severe Disease Burden Design Observational, multinational, prospective natural history study 112 patients across 13 countries Diagnosis of acute hepatic porphyria (AP), including AIP, CP, VP Recurrent attacks (>3+ attacks/last 12M) or using prophylactic treatment >70% Attacks requiring hemin or treatment in hospital or healthcare setting >65% Patients experience chronic symptoms between attacks 4.6 Average hospital stays per year, ranging 1-60 days Severe Disease Burden; Impact on QOL measures comparable to AE 35

36 RADOMIZATIO Potential Phase 3 Study Design for Givosiran* Initial Focus on ophylaxis for Recurrent AIP Patients Patient Population Biochemical and genetic diagnosis of AIP 4 attacks per yr if not on hemin prophylaxis If on hemin prophylaxis, willing to stop for study duration = Givosiran OR Placebo Endpoints Change in annualized attack rate compared to baseline ALA, PBG and ALAS1 levels emin usage ospitalization EQ-5D-5L QoL Safety and tolerability All completers eligible for givosiran treatment in Phase 3 OLE study 36 *eliminary plans subject to further diligence and health authority feedback

37 Patient Advocacy & Scientific Leadership Patient Advocacy Education Collaboration Support of American Porphyria Foundation (APF) o Advocacy team presence at multiple APF patient events in 2016 o Patient advisory board scheduled for early 2017 to better understand patient needs Building relationships with leading European advocacy groups such as the British Porphyria Association (BPA) EXPLORE atural istory Study o Largest prospective study ever conducted in AP Data presentations at SSIEM, AASLD, and AS conferences in 2016 Disease awareness and education initiatives ongoing Long standing collaboration with the American Porphyria Consortium and European Porphyria etwork Investigators otect the Future initiative for porphyria physician training 37

38 ute epatic Porphyria Market Landscape Major Unmet eed o approved therapy for attack prevention o significant investigational drugs in development Only available therapy (hemin) has modest efficacy and safety limitations In EXPLORE study, mean of 3.3 attacks per year on hemin prophylaxis vs. 5.1 attacks per year without Short duration of drug activity and reports of decreased effectiveness over time Side effects including nausea, vomiting, headache, phlebitis Risk of iron overload Risk of venous destruction or complications from venous port (e.g. infection, clots) 38 Bissell DM, Wang B. J Clin Transl epatol. 2015;3: Anderson KE, Bloomer JR, Bonkovsky L, et al. Ann Intern Med. 2005;142: Balwani M, Desnick RJ. Blood. 2012;120: Bonkovsky L. Am Soc ematol Educ ogram. 2005: Wahlin S, arper P. In: Ferreira GC, Kadish KM, Smith KM, Guilard R, eds. andbook of porphyrin science. Vol

39 ute epatic Porphyria Market Opportunity AP represents a global opportunity with potential for continuous expansion ute intermittent porphyria (AIP) Variegate porphyria (VP) ereditary coproporphyria (CP) Asymptomatic high excreters (ASE) Launch Target AIP patients with recurrent attacks Disease Expansion VP, CP patients with recurrent attacks AIP Patient Expansion All AP patients with sporadic attacks Life Cycle Management ute attacks; ASE subjects 39

40 Commercial Opportunity - igh Unmet eed Supported by Close Analogue: AE ute epatic Porphyria could be a significant growth market AP has many similarities to ereditary angioedema (AE) prior to the advent of effective prophylactic treatments Underdiagnosed rare disease with low consensus prevalence AE: 2:100,000 AP: 2-5:100,000 (AIP only) ute, life-threatening episodes requiring urgent medical attention Suboptimal on-demand therapies ophylaxis primary endpoint of reduction in attack frequency igh burden on the healthcare system and patient QoL 800 M 400 M 0 M Cinryze Global Sales Cinryze Launch Date: October 2008 WAC ice: >$500K pppy 40

41 Givosiran ogram Summary & ext Steps Phase 1 data providing initial evidence of clinical activity in AIP patients experiencing recurrent attacks 74% decrease in annualized attack rate, 75% decrease in annualized hemin doses, >10X increase in maximum attack free interval in Part C cohort 1 Attractive global commercial opportunity Substantial unmet need and potential for continuous expansion ext Steps Additional Phase 1 data planned for mid-2017, likely at ICPP in June 2016 Rapid acceleration to Phase 3 Plan to engage in regulatory discussions to align on pivotal study design for late 2017 start 41