Alnylam Pharmaceuticals, Inc. · NASDAQ:ALNY
Alnylam Pharmaceuticals — ERA-EDTA 2020
24 slides from Alnylam Pharmaceuticals's conference presentation, Jun 7, 2020
Slide 1: ILLUMINATE-A, a Phase 3 Study of Lumasiran in Children and Adults with PH1
ILLUMINATE-A, a Phase 3 Study of Lumasiran, an Investigational RNAi Therapeutic, in Children and Adults with Primary Hyperoxaluria Type 1 (PH1) Sander F. Garrelfs1,Yaacov Frishberg2, Sally A. Hulton3, Michael J. Koren4, William D. O’Riordan5, Pierre Cochat6, Georges Deschenes7, Hadas Shasha-Lavsky8,
Slide 2: Primary Hyperoxaluria Type 1
Primary Hyperoxaluria Type 1 Progressive disease mediated by hepatic overproduction of oxalate AGXT Homozygous or compound Excess oxalate results in insoluble As renal function declines In advanced disease, heterozygous AGXT calcium oxalate crystals, leading due to progressive disease, patients mani
Slide 3: Lumasiran: Investigational RNAi therapeutic for PH1
Lumasiran Investigational RNAi therapeutic for PH1 Defect in PH1 • RNAi is a natural pathway involved in regulation Peroxisome Cytosol of gene expression by targeting mRNA1 Pyruvate Alanine Glycolate • Lumasiran targets the mRNA for HAO1, which GO encodes GO in the liver1 AGT Glyoxylate Glyoxylate G
Slide 4: Lumasiran Clinical Development
Lumasiran Clinical Development Clinical pharmacology study Efficacy and safety studies in patients with PH1 Phase 1/2 Phase 3 STUDY 001 ILLUMINATE-A ILLUMINATE-B ILLUMINATE-C Healthy volunteers PH1 patients PH1 patients PH1 patients PH1 patients Part A: single ascending Part B: multiple ascending Do
Slide 5: Urinary Oxalate Assays Used in Clinical Trials of Lumasiran
Urinary Oxalate Assays Used in Clinical Trials of Lumasiran • Enzymatic assay used in the Phase 1/2 study 24 hr urinary oxalate corrected for BSA (mmol/24 hr/1.73m2) (samples from Phase 1/2 and Phase 2 studies of lumasiran) – Used clinically for diagnosis and clinical management – Available at multi
Slide 6: ILLUMINATE-A Phase 3 Study Design
ILLUMINATE-A Phase 3 Study Design 6-MONTH DOUBLE-BLIND PATIENT POPULATION (N=39) 54-MONTH EXTENSION PERIOD TREATMENT PERIOD Lumasiran • Adults and children ≥6 years 2:1 RANDOMIZATION qM × 3 loading dose, • Urinary oxalate excretion then q3Ma 3.0 mg/kg subcutaneously Lumasiran ≥0.7 mmol/24 hr/1.73 m2
Slide 7: Patient Disposition
Patient Disposition 39 Randomized 13 Placebo 26 Lumasiran 2 Discontinued lumasiran 1 Withdrew consent 1 Had adverse event 13 Completed 25 Completed • 1 patient discontinued study drug after receiving 1 dose and subsequently withdrew from study 6-month double-blind 6-month double-blind due to inabili
Slide 8: ILLUMINATE-A: Baseline Demographic Characteristics
ILLUMINATE-A: Baseline Demographic Characteristics Balanced between placebo and lumasiran groups Placebo Lumasiran Overall Demographic characteristic (N=13) (N=26) (N=39) Mean age at informed consent, years (range) 17.0 (6–60) 18.7 (6–47) 18.1 (6–60) Pediatric (0–18 years), n (%) 8 (61.5) 14 (53.8)
Slide 9: ILLUMINATE-A: Baseline Clinical Characteristics
ILLUMINATE-A: Baseline Clinical Characteristics Balanced between placebo and lumasiran groups Placebo Lumasiran Overall Clinical characteristic (N=13) (N=26) (N=39) Mean 24 hr urinary oxalate excretion corrected for BSAa (SD), mmol/24 hr/1.73 m2 1.79 ± 0.68 1.84 ± 0.60 1.82 ± 0.62 Mean 24 hr urinary
Slide 10: Primary and Secondary Endpoints
Primary and Secondary Endpoints ILLUMINATE-A met its primary endpoint and all tested secondary endpoints Placebo Lumasiran Difference, Endpoint p-value (N=13) (N=26) Lumasiran−Placebo Primary endpoint Percent change in 24 hr urinary oxalate excretion corrected for –11.8 –65.4 –53.5 1.7 × 10–14 BSA f
Slide 11: Primary Endpoint: Percent Change in 24 hr Urinary Oxalate to Month 6
Primary Endpoint: Percent Change in 24 hr Urinary Oxalate from Baseline to Month 6 Rapid and sustained reduction in 24 hr urinary oxalate levels Percent change from baseline in 24 hr 20 LS mean average of M3–M6 urinary oxalate corrected for BSA 0 −20 −11.8% Placebo (N=13) −40 −60 −65.4% Lumasiran (N
Slide 12: Subgroup Analysis: Percent Change in 24 hr Urinary Oxalate
Subgroup Analysis: Percent Change in 24 hr Urinary Oxalate from Baseline to Month 6 Consistent treatment effect across all subgroups, including baseline 24 hr urinary oxalate excretion, pyridoxine use, and eGFR Subgroup Lumasiran–Placebo Overall (n=39) Age at screening 6 to <12 years (n=16) 12 to <1
Slide 13: Secondary Endpoint: Absolute Change in 24 hr Urinary Oxalate
Secondary Endpoint: Absolute Change in 24 hr Urinary Oxalate Levels from Baseline to Month 6 Rapid and sustained reduction in 24 hr urinary oxalate levels 2.5 24 hr urinary oxalate corrected for LS mean average of M3–M6 (mmol/24 hr/1.73 m2) BSA (mmol/24 hr/1.73 m2) 2.0 1.5 −0.27 Placebo (N=13) 1.0 0
Slide 14: Secondary Endpoint: Percent Change in Urinary Oxalate:Creatinine Ratio
Secondary Endpoint: Percent Change in 24 hr Urinary Oxalate:Creatinine Ratio from Baseline to Month 6 Rapid and sustained reduction in 24 hr urinary oxalate:creatinine ratio 40 24 hr urinary oxalate:creatinine ratio Percent change from baseline in LS mean average of M3–M6 20 0 −10.8% Placebo (N=13)
Slide 15: Proportion of Patients with Urinary Oxalate ≤1.5 × ULN or ≤ULN
Secondary Endpoints: Proportion of Patients with 24 hr Urinary Oxalate Level ≤1.5 × ULN or ≤ULN at Month 6 Majority of patients achieved near normalization (≤1.5 × ULN) or normalization (≤ULN) in 24 hr urinary oxalate levels at month 6 p=8.3 × 10–7 100 84% p=0.0010 Lumasiran Patients (%) 52% Placebo
Slide 16: Secondary Endpoint: Percent Change in Plasma Oxalate
Secondary Endpoint: Percent Change in Plasma Oxalate from Baseline to Month 6 Rapid and sustained reduction in plasma oxalate levels 60 Percent change from baseline in LS mean average of M3–M6 40 plasma oxalate 20 −0.3% Placebo (N=10) 0 −20 −40 −39.8% Lumasiran (N=23) −60 0 20 40 60 80 100 Study vis
Slide 17: Secondary Endpoint: Absolute Change in Plasma Oxalate
Secondary Endpoint: Absolute Change in Plasma Oxalate from Baseline to Month 6 Rapid and sustained reduction in plasma oxalate levels 30 LS mean average of M3–M6 (µmol/liter) Plasma oxalate (µmol/liter) 25 20 1.3 Placebo (N=10) 15 10 −7.5 Lumasiran (N=23) 5 0 0 20 40 60 80 100 Study visit BL M1 M2 M
Slide 18: Secondary Endpoint: Change in eGFR from Baseline to Month 6
Secondary Endpoint: Change in eGFR from Baseline to Month 6 eGFR remained stable from baseline to month 6 100 90 eGFR (mL/min/1.73 m2) Placebo (N=13) 80 70 Lumasiran (N=26) 60 50 0 20 40 60 80 100 Study visit BL W2 M1 M2 M3 M4 M5 M6 Dosing 13 13 12 13 13 12 13 13 Patients (N) 26 24 25 25 25 25 25 25
Slide 19: Exploratory Endpoints: Renal Stone Events and Nephrocalcinosis
Exploratory Endpoints: Renal Stone Events and Nephrocalcinosis No apparent difference between treatment groups with regard to renal stone events; 3 patients with improvements in nephrocalcinosis Renal stone eventsa Nephrocalcinosisb Placebo Lumasiran Placebo Lumasiran Change from baseline to month 6
Slide 20: Exploratory Endpoint: Change in Plasma Glycolate
Exploratory Endpoint: Change in Plasma Glycolate from Baseline to Month 6 Plasma glycolate initially increased and then plateaued, consistent with reduction in hepatic GO activity Plasma glycolate (µmol/liter) 250 Lumasiran (N=26) 200 150 Placebo (N=13) 100 50 Study visit BL M1 M2 M3 M4 M5 M6 Dosing
Slide 21: Lumasiran Safety Profile
Lumasiran Safety Profile • There were no deaths, severe, or serious AEs Placebo Lumasiran Event, n (%) (N=13) (N=26) • All AEs were mild or moderate in severity AEs 9 (69) 22 (85) • Most common related AEs were injection-site AEs occurring in ≥10% of patients in either group reactions Injection-site
Slide 22: Conclusions
Conclusions • PH1 is a rare devastating disease, with high morbidity and mortality in all age groups • Current management options for PH1 are limited and there is an urgent need for new therapies that can reduce hepatic oxalate production, the key toxic metabolite in PH1 • Substantial reduction in u
Slide 23: Acknowledgments
Acknowledgments Thank you to the patients, investigators, and study staff who participated in the ILLUMINATE-A study ILLUMINATE-A study collaborators: • Samah Alasrawi • Lili Chan • Theresa Kwon • Pallavi Prasad • Spyridon Arampatzis • Hanh Chu • Kia Lee • Bruno Ranchin • Kenneth Aung-Din • Claire D
Slide 24: Challenge Accepted
To those who say “impossible, impractical, unrealistic,” we say: CHALLENGE ACCEPTED 24 © 2020 Alnylam Pharmaceuticals, Inc.