Alnylam Pharmaceuticals, Inc. · NASDAQ:ALNY
Alnylam Pharmaceuticals — ASCO 2011
21 slides from Alnylam Pharmaceuticals's conference presentation, Jun 4, 2011
Slide 1: Phase I Dose Escalation Study of ALN-VSP02
ASCO June 2011 Phase I Dose Escalation Study of ALN-VSP02 A Novel RNAi Therapeutic for Solid Tumors with Liver Involvement June 4, 2011
Slide 2: Mechanism for RNA Interference (RNAi)
Mechanism for RNA Interference (RNAi) Synthetic siRNA dsRNA dicer Cleavage Strand separation Targeted Gene RISC Complementary pairing Silencing mRNA (A)n Cleavage mRNA degradation (A)n 2 ASCO, June 2011
Slide 3: ALN-VSP02 Scheme
ALN-VSP02 Scheme Lipid nanoparticle* (LNP) components: N O O DLi nDMA KSP O O O O P O siRNA N+ O H O- O VEGF DPP C H O O O N O O n O m P E G2000-C-DMA H H ALN-VSP02 HO Chol esterol *Lipid nanoparticle formulation from Tekmira Pharmaceuticals 3 ASCO, June 2011
Slide 4: ALN-VSP02 Phase I Study
ALN-VSP02 Phase I Study Objectives Primary Evaluate the safety and tolerability of ALN-VSP02 Secondary Characterize PK Assess for evidence of antitumor/antiangiogenic activity » Tumor response rate, change in tumor blood flow on DCE-MRI Exploratory Analyze voluntary tumor biopsies for drug l
Slide 5: Key Inclusion and Exclusion Criteria
Key Inclusion and Exclusion Criteria ALN-VSP02 Phase I Key Inclusion Criteria Patients must have histologically or cytologically confirmed advanced solid tumors that have recurred or progressed following standard therapy, or that have not responded to standard Each patient must therapy, or for whi
Slide 6: ALN-VSP02 Phase I Study Design
ALN-VSP02 Phase I Study Design Screening Cycle 1 Cycle 2 Cycle 3 Cycle 4 W1 W2 W3 W4 W1 W2 W3 W4 W1 W2 W3 W4 W1 W2 W3 W4 Rx Rx Rx Rx Rx Rx Rx Rx DCE-MRI d3-5 d8-10 Tumor biopsy d3-6 CT scan for tumor measurement Adverse events Dose levels and dosing schedule 0.1, 0.2, 0.4, 0.7, 1.0, 1.25, 1.5, 1.7
Slide 7: Demographics and Dosing
Demographics and Dosing N=41 » Dose escalation (0.1-1.5 mg/kg): N=31 » Expansion phase at 1.0 and 1.25 mg/kg: N=10 (5 per dose level) Median age 57 (range 34-78) Male: Female = 17:24 ECOG performance status 0/ 1 (%): 44 / 56 Average # of prior regimens for metastatic disease: 4.3 (range 1-
Slide 8: Treatment Emergent Adverse Events
Treatment Emergent Adverse Events Number of Patients with Grades 1, 2, 3, 4 ALN-VSP02 Dose Level (mg/kg) % of Patients 0.10 0.20 0.40 0.70 1.00 1.25 1.50 Toxicity** (n=41) (n=3) (n=3) (n=6) (n=7†) (n=9) (n=11‡) (n=2) Fatigue 24% 1, 0, 0, 0 0, 0, 0, 0 0, 2, 0, 0 2, 1, 0, 0 1, 0, 0, 0 1, 1, 0, 0 1, 0,
Slide 9: Serious Adverse Events
Serious Adverse Events Dose Patient Tumor Level # Type (mg/kg) Event(s) Relatedness 1. Liver failure Pancreatic 2. Hepatic encephalopathy 003-012 0.70 Possibly related neuroendocrine Both arising 5 days post-dose 2, resulting in death 1. Elevated WBC 2. Fever 001-021 Endometrial 0.70 Possibly relate
Slide 10: Plasma PK Data Summary
Plasma PK Data Summary VEGF and KSP siRNAs 100000 100000 Cycle 1 (mg/kg) Cycle 1 (mg/kg) 0.10 1.00 0.10 1.00 0.20 1.25 10000 0.20 1.25 10000 VEGF siRNA (ng/mL) 0.40 1.50 0.40 1.50 KSP siRNA (ng/mL) 0.70 0.70 1000 1000 100 100 10 10 1 1 0 200 400 600 800 1000 1200 1400 1600 0 200 400 600 800 1000 120
Slide 11: Safety Summary
Safety Summary ALN-VSP02 was generally well-tolerated » 1 patient has so far received 24 doses over 1 year No dose-dependent changes in liver function tests Grade 1-2 fatigue (24%), nausea (17%) and fever (15%) most common AEs with no clear dose dependence Grade 2 infusion-related reactions
Slide 12: Tumor Response Summary
Tumor Response Summary Dose N Avg # of # Pts with Stable # Pts Who Went Level (evaluable for Doses Received Disease or Better on to Extension Study (mg/kg) response) (range) for ≥ 2 mos (>8 doses) to Date 0.10 3 3 (2-4) 0 0 0.20 3 4 (4-4) 0 0 0.40 7* 4.6 (2-11) 1 1 3 (includes 1 PR with 0.70 5 9.6 (
Slide 13: Characteristics of Patients with SD or PR
Characteristics of Patients with SD or PR Dose Level Tumor Best # of Patient # (mg/kg) Type Response Doses 016 0.40 Squamous Cell Head and Neck SD 11 019 0.70 Colorectal SD 8 020 0.70 Angiosarcoma SD 10 021 0.70 Endometrial PR 24 (ongoing) 022 1.00 Colorectal SD 8 025 1.00 Synovial Sarcoma SD 7 037
Slide 14: Major Response in Endometrial Cancer
Major Response in Endometrial Cancer Patient 021, 70% Regression of Liver Metastases Pre-Treatment After 12 Doses ALN-VSP02* *Response ongoing after 24 doses 14 ASCO, June 2011
Slide 15: DCE-MRI Results on Evaluable Patients
DCE-MRI Results on Evaluable Patients # of tumors: 1 3 1 1 3 3 1 1 3 1 2 2 1 1 3 3 2 1 3 3 3 1 3 1 3 1 1 1 20 Average Ktrans Change 0 From Baseline (%) -20 -40 40%↓ -60 -80 -100 Dose Level (mg/kg): 0.1 0.2 0.4 0.7 1.0 1.25 1.5 n=2 n=1 n=4 n=6 n=7 n=6 n=2 46% (13/28) of patients with average Ktrans
Slide 16: DCE-MRI in PNET Patients with Liver Metastases
DCE-MRI in PNET Patients with Liver Metastases Pre-Treatment Day 7 Post-Dose 1 T1 Pt 012 Avg Ktrans↓=49% (n=3 tumors, T1-T3) (0.7 mg/kg) T2 T3 T1 Pt 044 Avg Ktrans↓=86% (n=3 tumors, only T1 shown) (1.0 mg/kg) T: liver tumor PNET: pancreatic neuroendocrine tumor 16 ASCO, June 2011
Slide 17: Voluntary Tumor Biopsies
Voluntary Tumor Biopsies CT-guided core needle biopsies obtained pre- and post-dose 1 in patients on voluntary basis » Analyses: – Drug levels – 5’ RACE – qPCR 29 Tumor biopsies obtained from 15 patients across multiple dose levels » 0.4 mg/kg (n=3), 0.7 mg/kg (n=2), 1.0 mg/kg (n=6), 1.25 mg/kg
Slide 18: Drug Levels in Tumor Biopsies Post-Dose
Drug Levels in Tumor Biopsies Post-Dose 1 Post-Dose Drug Levels** Biopsy (%) (ng/g tissue) Dose Tumor Type Viable Fibrosis/ VEGF KSP Pt # mg/kg (Biopsy Site, Day of Post-Dose Biopsy) Tumor Liver Necrosis siRNA siRNA 007 0.40 Colorectal (liver, d7) 17 80 3 25.7 12.5 017 0.40 Ovarian (liver, d2) 0 95
Slide 19: VEGF 5' RACE Assay
VEGF 5’ RACE Assay RNA cleavage Method for Demonstrating RNAi site VEGF mRNA Step 1 In vivo RNAi Step 2 RNA adaptor Ligation of adaptor Step 3 Amplification of GR5N VEGF Rev2 RNAi-specific product Sequence Analysis % Specific RNAi Cleavage Cleavage Pre-treatment Fraction of Total 1.4% Illustrative E
Slide 20: Tumor Biopsies Positive By VEGF 5' RACE
Tumor Biopsies Positive By VEGF 5’ RACE Pre-Dose Post-Dose Tumor Type Biopsy (%) Biopsy (%) (Biopsy Site, Dose VEGF Day of Post-Dose Viable Fibrosis/ Viable Fibrosis/ Pt # mg/kg Biopsy) Tumor Liver Necrosis Tumor Liver Necrosis 5’ RACE SCC H&N (liver, 016 0.40 10 0 90 0 100 0 Pos* d2) Ovarian 017 0.
Slide 21: Clinical Activity/PD Summary
Clinical Activity/PD Summary Evidence of antitumor activity in heavily pre-treated patients at doses ≥0.7 mg/kg Major ongoing response (PR with ~70% tumor reduction) in patient with endometrial cancer and multiple liver metastases treated at 0.7 mg/kg » Patient treatment continuing after one full