Alnylam Pharmaceuticals, Inc. · NASDAQ:ALNY
Alnylam Pharmaceuticals — Technical Presentation (March 2015)
28 slides from Alnylam Pharmaceuticals's technical presentation, March 2015
Slide 1: Disease Progression in Patients with Familial Amyloidotic Cardiomyopathy
Disease Progression in Patients with Familial Amyloidotic Cardiomyopathy Results of a Multi-center International Study March 2015 1
Slide 2: Agenda
Agenda • Disease Background • FAC Natural History Study Results • Overview of Revusiran Program in FAC 2
Slide 3: Transthyretin (TTR) Amyloidosis
Transthyretin (TTR) Amyloidosis TTR Protein >100 defined mutations Liver-derived TTR Sensorimotor Restrictive Polyneuropathy Cardiomyopathy Familial Amyloidotic Familial Amyloidotic Senile Systemic Polyneuropathy (FAP) Cardiomyopathy (FAC) Amyloidosis (SSA) • Age of onset 30-50 • Age of onset > 60 •
Slide 4: Familial Amyloidotic Cardiomyopathy (FAC)
Familial Amyloidotic Cardiomyopathy (FAC) Disease Overview Epidemiology • Orphan disease • Estimated >40,000 FAC patients WW ◦ Currently underdiagnosed • Cardiac-predominant TTR genotypes in US/EU ◦ Most common mutation is V122I; occurs in ~4% of African- Americans ◦ T60A most common mutation in UK/
Slide 5: Disease Progression in FAC
Disease Progression in FAC Published Prospective and Retrospective Studies TRACS* Connors et. al.** Sattianayagam et. al.*** Prospective study Yes No Yes Mutation V122I V122I T60A S77Y T60A N=11 N=35 N=48 N=13 N=60 Median Survival from diagnosis 25.6 41 59 62 40.8 (months) Median time to first CV 26
Slide 6: Agenda
Agenda • Disease Background • FAC Natural History Study Results • Overview of Revusiran Program in FAC 6
Slide 7: Study of Disease Progression in FAC
Study of Disease Progression in FAC Multi-center Retrospective Analysis Goal • Characterization of disease severity and rate of progression in multinational population of FAC patients Methods • Demographics, overall survival collected retrospectively on 137 FAC patients in 2 countries with 2 study i
Slide 8: Demographics
Demographics All Patients NAC Columbia Total Pooled (N=88) (N=49) (N=137) Mutation, n (%) V122I 88 (100%) 29 (59%) 117 (85%) T60A 0 10 (20%) 10 (7%) V30M 0 2 (4%) 2 (1%) Other types (frequency per type <2) 0 8 (16%) 8 (6%) Total N=88 N=49 N=137 Median Age (yrs) 76 66 72 [Min, Max] [57,88] [41,84] [4
Slide 9: Baseline Characteristics
Baseline Characteristics All Patients NAC Columbia Total Pooled Characteristics N (n=88) N (N=49) N (N=137) Median BMI (kg/m2) 25.7 25.3 26.0 75 49 122 [min, max] [15.9, 38.5] [19.3, 36.6] [15.9, 38.5] Median eGFR (mL/min/ 51.5 54.7 55.3 76 47 123 1.73m2) [min, max] [20, 90] [20,115] [20, 115] Media
Slide 10: Survival Probability
Survival Product-Limit Survival Estimates (with number of subjects at risk) Survival Probability NAC Columbia Pooled Months NAC Columbia Group N Deaths Censored Median Survival* (months) (95% CI) Columbia 49 17 32 38.5 (34.5, Not Reachable) NAC 88 33 55 29.4 (26.4, 35.1) Pooled 137 50 87 34.1 (28.6,
Slide 11: Probability of CV Hospitalization
CV Hospitalizations Time to first CV Hospitalization Frequency of CV Hospitalizations 60% Probability of CV Hospitalization 50% Percent of Patients (%) 40% 30% 20% 10% 0% 0 1 2 3 4 5 Total number of CV hospitalizations Months from first visit No. of CV Number of # (%) of Patients with Median Time to
Slide 12: Demographics and Baseline Characteristics
Demographics and Baseline Characteristics Patients in 6-MWD Analysis FAC with 6MWD Data Characteristics N (N=39*) Mutation, n (%) V122I 39 39 (100%) Median Age (yrs) 76 37 [Min, Max] [60,87] Baseline NYHA Class, n (%) I 1 (3%) II 32 19 (59%) III 12 (38%) IV 0 Stabilizer Use 39 9 (23%) Median Baselin
Slide 13: Change in 6-MWD Over Months
Change in 6-MWD Over 18 Months 0 0 10 Change From Baseline (m) Change From Baseline (%) -30 0 -30 -10 -60 -60 -20 -90 -90 -30 -120 -120 -40 -150 -150 -50 -180 -180 -60 0 6 12 18 0 6 12 18 Months from 1st visit Months from 1st visit Visit Actual Value Change from Baseline Percentage Change (meters) (
Slide 14: Change in 6-MWD Over Months: Comparison to TRACS
Change in 6-MWD Over 18 Months Comparison to TRACS* 400 350 Mean [+/-SEM] 6-MWD (meters) 300 250 200 150 100 NAC (n=39) 50 TRACS* (n=10)** 0 0 2 4 6 8 10 12 14 16 18 Months since first visit *Ruberg et al., Am Heart J. 2012 14 **Note: of 11 total V122I patients in TRACS, n=10 with 6-MWD data reporte
Slide 15: NT-proBNP Change Over Time
NT-proBNP Change Over Time 40000 5 NTproBNP (ng/L) Changes from Baseline NTproBNP Relative to Baseline Value 30000 4 20000 3 10000 2 0 1 -10000 0 0 10 20 30 40 50 0 10 20 30 40 50 Months from First Visit Months from First Visit • V122I patients from NAC with available serial NT-proBNP data (N=78) •
Slide 16: Summary
Summary Clear decline in 6-MWD in FAC patients with mild-moderate heart failure over an 18-month period • Mean decline of 106 m at 12 months and 140 m at 18 months compared to baseline is consistent with the 91 m and 118 m decline compared to baseline at 12 and 18 months, respectively, observed in t
Slide 17: Agenda
Agenda • Disease Background • FAC Natural History Study Results • Overview of Revusiran Program in FAC 17
Slide 18: Revusiran for Treatment of FAC
Revusiran for Treatment of FAC Revusiran in clinical development • Subcutaneous delivery • Well tolerated with > 90% TTR knockdown in Phase 1 healthy volunteer study1 • Phase 2 study in FAC and SSA completed ◦ Interim data presented at ABC meeting November 2014 ◦ Final data presented at ACC March 20
Slide 19: GalNAc-siRNA Conjugates
GalNAc-siRNA Conjugates Targeted Delivery to Hepatocytes and SC Dosing GalNAc-siRNA Conjugates GalNAc-siRNA conjugate • GalNAc ligand conjugated to chemically modified siRNA to mediate ASGPR (pH>5) targeted delivery Clathrin-coated pit • Trivalent GalNAc carbohydrate cluster has nM affinity for ASGP
Slide 20: Therapeutic Hypothesis for Revusiran in FAC
Therapeutic Hypothesis for Revusiran in FAC Revusiran acts to knock down hepatic mutant and wild-type TTR production Production of mutant and wild type TTR Reduction of Unstable circulating TTR unstable circulating TTR tetramers tetramers Prevention of organ Organ deposition of monomers, deposition
Slide 21: Revusiran Phase 2 Study Results: Demographics
Revusiran Phase 2 Study Results Demographics FAC SSA Total (n=14) (n=12) (n=26) Characteristics Mean Age 65.0 71.8 68.1 Gender (M/F) 11/3 12/0 23/3 Race 10 White, 4 African 12 White 22 White, 4 African American American Mean Weight [kg] 77.8 83.1 80.3 TTR Type T60A (7) WT (12) T60A (7) V122I (5) V12
Slide 22: Revusiran Phase 2 Study Results: Safety and Tolerability
Revusiran Phase 2 Study Results Safety and Tolerability Treatment Emergent Adverse Events Possibly or Definitely Related ≥10% 5.0 mg/kg 7.5 mg/kg Total (n=23) (n=3) (n=26) LFT elevation^ 4 (17%) 0 4 (15%) Injection site erythema 3 (13%) 0 3 (12%) ^ Preferred Terms: LFT abnormal (1), ALT increased (2
Slide 23: Serum TTR Lowering at 5.0 mg/kg by TTR Type
Revusiran Phase 2 Study Results Serum TTR Lowering at 5.0 mg/kg by TTR Type 1.1 Treatment N Individual Mean ± SD Max KD (%) Max KD (%) 1.0 FAC 13 97.7 84.5 ± 9.1 0.9 SSA 10 96.6 85.8 ± 10.1 0.8 Relative to Baseline 0.7 0.6 0.5 0.4 0.3 0.2 FAC (n=13) 0.1 SSA (n=10) 0.0 0 10 20 30 40 50 60 70 80 90 10
Slide 24: Revusiran Phase 2 Study Results: Summary
Revusiran Phase 2 Study Results Summary Multiple doses of revusiran generally well tolerated in TTR cardiac amyloidosis patients with low incidence of reported adverse events • Transient mild injection site reactions in 15% of patients • Transient mild LFT changes in 15% of patients, resolved with c
Slide 25: Phase 3 Trial Design Summary
Phase 3 Trial Design Summary Design Feature Proposal Patient Population • Age 18-90 • TTR mutation • Presence of amyloid deposits in tissue. In patients with monoclonal gammopathy, TTR protein identification by IHC, mass spectrometry or scintigraphy • Clinical evidence of HF with at least 1 prior HF
Slide 26: ALN-TTR-NT-002 Screening Study
ALN-TTR-NT-002 Screening Study Rationale: • Determine frequency of TTR mutations in subjects suspected of having cardiac amyloidosis • Subjects diagnosed with FAC may be eligible for enrollment in Phase 3 study Design: • Sequencing of TTR gene in subjects with HF suspected to have cardiac amyloidosi
Slide 27: Acknowledgments
Acknowledgments Investigators for FAC Natural History Study: • Julian Gilmore ◦ National Amyloidosis Centre, London, UK • Philip Hawkins ◦ National Amyloidosis Centre, London, UK • Mathew Maurer ◦ Columbia University, New York, NY, USA Investigators for Phase 2 Study • Julian Gilmore ◦ National Amyl
Slide 28: Thank You
Thank You ZL Alnylan.
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