Alnylam Pharmaceuticals, Inc. · NASDAQ:ALNY
Alnylam Pharmaceuticals — Technical Presentation (June 2020)
19 slides from Alnylam Pharmaceuticals's technical presentation, Jun 30, 2020
Slide 1: Twelve-month Interim Analysis of Efficacy and Safety of Givosiran in ENVISION OLE
Twelve-month Interim Analysis of Efficacy and Safety of Givosiran, an Investigational RNAi Therapeutic for AHP, in the ENVISION Open Label Extension Sardh E1, Balwani M2, Rees DC3, Stein P3, Stölzel U4, Aguilera Peiro P5, Bissell DM6, Bonkovsky HL7, Keel S8, Parker C9, Phillips JD9, Silver S10, Wind
Slide 2: Disclosure Slide
Disclosure Slide I have previously been engaged as a consultant by Alnylam Pharmaceuticals with fees paid to Karolinska Institutet. I am also leading an investigator-initiated study for which Karolinska Institutet receives funding from Alnylam Pharmaceuticals 2
Slide 3: Acute Hepatic Porphyria (AHP)
Acute Hepatic Porphyria (AHP) Enzymes Intermediates AHP Disease Types Disease Overview Glycine + Succinyl CoA • Family of rare, genetic diseases due to a deficiency in one of the enzymes in heme biosynthesis in the liver1,2 ALA Synthase (ALAS1) • AIP is the most common type, with mutation in hydroxy
Slide 4: Givosiran: An RNAi Therapeutic for AHP
Givosiran: An RNAi Therapeutic for AHP1,2 Therapeutic Hypothesis • Reduction of Liver ALAS1 Enzyme to Lower ALA and PBG ALAS1 enzyme ALA/PBG induces porphyria symptoms Givosiran results in reduction ALAS1 enzyme of ALAS1 mRNA and lowers ALA/PBG accumulation to prevent attacks and disease symptoms Gi
Slide 5: ENVISION Phase 3 Study Design
ENVISION Phase 3 Study Design • 94 patients with AHP enrolled in ENVISION at 36 sites in 18 countries • All patients completed 6-month double-blind (DB) period; all eligible patients (n=93) entered 30-month open label extension (OLE) period 6-Month DB Period 30-Month OLE Periodb Primary Endpoint • C
Slide 6: Demographics and Baseline Characteristics of AHP Patients
Demographics and Baseline Characteristics of AHP Patients • Baseline characteristics were generally balanced between groups Placebo Crossover Givosiran Patients Patients Characteristic (n=46) (n=48) Age at screening, years, median (range) 36 (20, 60) 42 (19, 65) Female, n (%) Baseline Disease Charac
Slide 7: Sustained AAR Reduction
Sustained AAR Reduction with Long-Term Dosing • Continued givosiran treatment led to sustained AAR reduction during the OLE • Placebo crossover patients had similar AAR reduction in OLE period as givosiran patients in DB perioda – Trend towards increased efficacy in placebo crossover patients for 2.
Slide 8: Sustained and Rapid Reduction of Attacks Over Time
Givosiran Treatment Led to Sustained and Rapid Reduction of Attacks Over Time • Patients who continued givosiran treatment had sustained or enhanced reduction in attacks over time • Placebo crossover patients had similar attack reduction during OLE period as givosiran patients in DB period Average N
Slide 9: Increased Number of Patients With Zero Attacks
Increased Number of Patients With Zero Attacks with Long-Term Dosing • Proportion of patients with zero attacks (61.7%) increased with continued givosiran treatment • Proportion of placebo crossover patients with zero attacks (42.2%) increased with givosiran treatment in OLE period Patients with 0 A
Slide 10: Rapid and Sustained Lowering of ALA and PBG Levels
Rapid and Sustained Lowering of ALA and PBG Levels with Long-Term Dosing • Continued givosiran treatment led to sustained ALA and PBG reduction during OLE period • Placebo crossover patients had >75% reduction in median ALA and PBG levels compared to baseline, consistent with data in givosiran patie
Slide 11: Sustained Reductions in Hemin Use
Sustained Reductions in Hemin Use with Long-Term Dosing • Continued givosiran treatment led to sustained reductions in hemin use in OLE period, with 70% of patients requiring zero days of hemin • Placebo crossover patients had 100% reduction in median annualized days of hemin use during OLE period,
Slide 12: Daily Worst Pain Decreased with Long-Term Dosing
Daily Worst Pain Decreased with Long-Term Dosing • Continued givosiran treatment led to a further decrease in pain during the OLE period • Placebo crossover patients had a decrease in pain and proportion of days with analgesics use, consistent with data in givosiran patients during DB period1 Placeb
Slide 13: Improvement in Physical Health (SF-12)
Improvement in Physical Health (SF-12) with Long-Term Dosing Givosiran Patients Mean change from baseline 15 DB period (0−6 months) • Continued givosiran treatment 12 OLE period (6−12 months) resulted in improvements in SF- 9 9.0 8.6 7.3 7.3 6.4 12 scores, with most impact on 6 5.1 6.1 5.2 5.7 5.9 4
Slide 14: Improvement in PPEQ
Improvement in PPEQ with Long-Term Dosing Givosiran Patients Percent of patients with responses DB period (Month 6) • Custom questionnaire that 100 84.4 “Much Better” or “Always” OLE period (Month 12) 80.0 used global rating of change 80 65.2 72.2 72.2 scale, with questions asked 60 52.2 54.3 47.8 5
Slide 15: Safety in AHP Patients with Ongoing Dosing
Safety in AHP Patients with Ongoing Dosing Safety Profile of Givosiran Remained Acceptable with No New Safety Concerns • Overall exposure: 11.22 months (median; range 1.8 to 19.5 months); cumulative exposure of 84.5 person-yearsa • 87 patients treated for ≥6 months, 36 patients treated for ≥12 month
Slide 16: Hepatic Events in AHP Patients
Hepatic Events in AHP Patients • Hepatic AEs were reported in 16 patients (17%)a, all were mild or moderate in severity – Majority were elevations of serum aminotransferases • ALT >3×ULN in 10 patients (10.6%), of whom 3 (3.2%) had ALT >5×ULN – 1 patient with ALT >8×ULN, discontinued treatment due t
Slide 17: Renal Events in AHP Patients
Renal Events in AHP Patients • 10 patients (11%) had renal AEsa, characterized by increased serum creatinine and/or decreased eGFR – Majority of AEs mild or moderate in severity – None led to discontinuation of study treatment • Small increases in serum creatinine were observed at Month 6 and 12 – M
Slide 18: ENVISION 12-Month OLE Summary
ENVISION 12-Month OLE Summary • Reductions in annualized rate of composite porphyria attacks in patients with AHP were sustained or enhanced during the OLE – 61.7% of patients who continued on givosiran had zero attacks during the OLE period • Givosiran treatment led to sustained lowering of ALA and
Slide 19: Acknowledgements
Acknowledgements ENVISION Investigators • Tomohide Adachi • Aneta Ivanova • Gayle Ross • Paula Aguilera Peiro • David Kuter • Eliane Sardh • Karl Anderson • Raili Kauppinen • Appalanaidu Sasapu • Manisha Balwani • Sioban Keel • Samuel Silver • Montgomery Bissell • Hung-Chou Kuo • Penny Stein • Herb
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