Alnylam RNAi Roundtable. May 13, 2011

Transcription

1 Alnylam RNAi Roundtable May 13, 2011

2 Agenda & Introductions Welcome Cynthia Clayton» Senior Director, Investor Relations and Corporate Communications Program Overview Akshay Vaishnaw, M.D., Ph.D. (Moderator)» Senior Vice President, Clinical Research Jared Gollob, M.D.» Senior Director, Clinical Research 2

3 RNAi Roundtable In-depth discussion around key topics relating to Alnylam and the development of RNAi therapeutics Interactive environment Recurring event Virtual and on-site RNAi Roundtables 3

4 Reminders Event will run until ~2:00 PM Q&A session will be held at end of presentation» Submit questions at bottom of webcast screen» Questions may be submitted at any time Replay, slides and audio available at 4

5 Alnylam Forward Looking Statements This presentation contains forward-looking statements. There are a number of important factors that could cause actual results to differ materially from the results anticipated by these forward-looking statements. These important factors include those that we discuss in our most recent quarterly report on Form 10-Q under the caption Risk Factors. If one or more of these factors materialize, or if any underlying assumptions prove incorrect, our actual results, performance or achievements may vary materially from any future results, performance or achievements expressed or implied by these forward-looking statements. 5

6 Akshay Vaishnaw, M.D., Ph.D., SVP Clinical Research An Overview of RNAi in Man Proof of Mechanism Data from Alnylam s ALN-VSP Program 6

7 RNA Interference (RNAi) A Discovery that Happens Only Every Decade or So Potential for a whole new class of drugs Harness natural pathway» Catalytic mechanism» Mediated by small interfering RNAs or sirnas Achieve therapeutic gene silencing» Any gene in genome Major breakthroughs in delivery achieved Including systemic RNAi with formulations and chemistries Now enables advancement of products to clinic and market 7

8 Alnylam Development Pipeline Discovery Development Phase I Phase II Phase III TTR-Mediated Amyloidosis Severe Hypercholesterolemia ALN-TTR02 ALN-PCS ALN-TTR01 Refractory Anemia ALN-HPN Program 4 (TBA) Program 5 (TBA) Respiratory Syncytial Virus Liver Cancers Huntington s Disease ALN-HTT ALN-VSP ALN-RSV01 Alnylam 5x15 Programs Partner Programs 8

9 Partner Programs Alnylam 5x15 Programs Pipeline Goals ALN-TTR01 R2D IND Phase I Human POC Q3 11 ALN-TTR02 H2 11 H1 12 Alnylam Goals Phase II Start 2012 Phase II Data ALN-PCS H1 11 H2 11 ALN-HPN 2012 Program 4 Q3 11 Program 5 Q4 11 ALN-RSV ALN-VSP / Q2 11 Partner/2012 ALN-HTT 2012 Additional Corporate Goals 2011 Additional partnerships Year-end cash >$275M 9

10 Jared Gollob, M.D., Sr Director Clinical Research An Overview of RNAi in Man Proof of Mechanism Data from Alnylam s ALN-VSP Program 10

11 ALN-VSP Agenda ALN-VSP Background Phase I Trial Safety Data Pharmacodynamic Data» Molecular Proof of Mechanism» DCE-MRI Summary 11

12 Liver Cancer Program ALN-VSP RNAi to treat primary and secondary liver cancers Prevalent solid tumor and common site of metastatic disease» ~700,000/yr: Incidence of HCC worldwide» ~500,000/yr: Patients with liver metastasis ALN-VSP is first dual-targeted RNAi drug» Targets two distinct genes involved in cancer pathways Proliferation: Kinesin Spindle Protein (KSP) Angiogenesis: VEGF» Lipid nanoparticle (LNP) formulation From Tekmira Pharmaceuticals Phase I clinical trial for liver cancer» Encouraging initial data and RNAi POM» Enrollment completed >40 patients Doses range: mg/kg Multiple patients continuing therapy» Data to be presented at ASCO, June 3-7, 2011 Poster Session: Developmental Therapeutics Experimental Therapeutics; June 4, 2pm-6pm CDT Poster Discussion; June 4, 5pm-6pm CDT VEGF KSP ALN-VSP 12

13 Tumor Targeting Murine Liver Cancer Model Orthotopic tumor model with intrahepatic Hep3B seeding in SCID mice Single IV bolus injection of ALN-VSP or control sirna Mitotic arrest (monoasters) clearly detected in VSP-treated animals KSP and VEGF target mrnas cleaved in tumors confirming RNAi mechanism Control sirna hksp mrna hvegf mrna RNA adapter GR5N hksp mrna 3 cleavage product RNA adapter GR5N hvegf mrna 3 cleavage product ALN-VSP hksp mrna 3 cleavage product Rev3 PCR product 380 nt Rev2 VSP m g / k g cdna hvegf mrna 3 cleavage product Rev4 Rev3 cdna PCR product 210 nt VSP m g / k g Keystone: RNAi, Feb 2009

14 Systemic Delivery to Liver Tumors Efficacy in Pre-clinical Orthotopic Liver Cancer Model Orthotopic tumor model with intrahepatic Hep3B seeding in pre-clinical studies ALN-VSP demonstrates clear anti-tumor activity compared with controls Control sirna, n=6 ALN-VSP, n=7 Keystone: RNAi, Feb

15 Survival (%) Prolonged Survival With ALN-VSP Treatment Study 1 Study ALN-VSP SNALP-Ctrl 100 ALN-VSP SNALP-Ctrl Survival (%) Days After Tumor Seeding Days After Tumor Seeding Orthotopic Tumor Model (Hep3B) Treated 18 days post seeding; IV bolus injections of 4 mg/kg VSP or control sirna 2x/wk for 3 wks Keystone Symp: Ther. Mod. of RNA Using Oligos, Feb

16 ALN-VSP Agenda ALN-VSP Background Phase I Trial Safety Data Pharmacodynamic Data» Molecular Proof of Mechanism» DCE-MRI Summary 16

17 ALN-VSP 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 DCE-MRI Tumor biopsy Plasma samples for VEGF/PLGF CT scan for tumor measurement Rx Rx Rx Rx Rx Rx Rx Rx d3-5 d8-10 d3-6 Adverse events Dose levels and dosing schedule 0.1, 0.2, 0.4, 0.7, 1.0, 1.25, 1.5, 1.7 mg/kg cohort design, expansion phase at MTD 15-min IV infusion q2 wks; premed with steroids, H1 and H2 blockers, acetaminophen Cycle = 2 doses (1 month), tumor measurements after every 2 cycles, treat until disease progression» ALN-VSP extension study for pts remaining on study beyond 4 cycles 17

18 ALN-VSP Phase I Study Status Enrollment completed» >40 patients at doses ranging from 0.1 to 1.5 mg/kg Tumor types include:» Colorectal cancer» Pancreatic neuroendocrine tumor» Papillary renal cell cancer» Squamous cell cancer of head and neck» Pancreatic cancer» Esophageal cancer» Endometrial cancer» Angiosarcoma» Ovarian cancer» Synovial sarcoma» Mullerian stromal tumor All patients treated with multiple prior anti-angiogenic and/or chemotherapy regimens 18

19 ALN-VSP Phase I Safety Summary Interim Data as of November 2010 ALN-VSP generally well tolerated to date» 127 doses administered to 28 patients across 6 dose levels» Up to 13 doses given to single patient No dose-dependent trends in clinical or laboratory adverse events No dose-dependent changes in LFTs Human plasma PK showed dose-proportional Cmax and AUC with no evidence of drug accumulation» Animal PK studies accurately predicted for human Two dose-limiting toxicities» 0.7 mg/kg: Liver failure and death after 2 doses (possibly related to study drug) in patient with near complete replacement of liver by tumor and prior partial hepatectomy and splenectomy» 1.25 mg/kg: Grade 3 thrombocytopenia after dose 1 (related to study drug), resolved within 5 days Three grade 2 infusion reactions (one each at 0.4, 0.7 and 1.25 mg/kg), all 3 tolerated further treatment with prolongation of infusion duration Chemotherapy Foundation Symposium, November

20 ALN-VSP Agenda ALN-VSP Background Phase I Trial Safety Data Pharmacodynamic Data» Molecular Proof of Mechanism» DCE-MRI Summary 20

21 ALN-VSP Pharmacology Tumor Biopsies as of January Tumor biopsies obtained from 9 patients» 3 at 0.4 mg/kg» 2 each at 0.7, 1.0 and 1.25 mg/kg» Liver tumor biopsies in 6 patients» Extrahepatic tumor biopsies in 3 patients CT-guided core needle biopsies obtained preand post-dose 1» Analyses ongoing: Drug levels 5 RACE qpcr 21

22 CT-guided Core Needle Biopsy Tumor Core Biopsies Viable tumor Viable tumor Fibrosis Core biopsy Tumor necrosis 22

23 Tumor Core Biopsies Liver Liver Viable Tumor 23

24 Drug Levels in Tumor Biopsies Pt # Dose mg/kg Tumor Type (Biopsy Site, Day of Post- Dose Biopsy) Viable Tumor Post-Dose Biopsy (%) Liver Drug Levels (ng/g) Fibrosis/ Necrosis vegf ksp Colorectal (liver, d7) Ovarian (liver, d2) Colorectal (liver, d2) Colorectal (adrenal, d2) * Sarcoma (muscle, d2) Colorectal (liver, d6) <LLOQ Ovarian (abdomen, d4) LLOQ: lower limit of quantitation *Remaining 12% was normal adrenal (6%) and fat (6%) Remaining 15% was skeletal muscle Dana Farber Cancer Institute, January » Drug delivery to normal liver established» Delivery to hepatic and extrahepatic tumors also confirmed, with levels varying depending on location and tissue components in biopsy

25 ALN-VSP Pharmacology Tumor Biopsies as of January Tumor biopsies obtained from 9 patients» 3 at 0.4 mg/kg» 2 each at 0.7, 1.0 and 1.25 mg/kg» Liver tumor biopsies in 6 patients» Extrahepatic tumor biopsies in 3 patients CT-guided core needle biopsies obtained preand post-dose 1» Analyses ongoing: Drug levels 5 RACE qpcr 25

26 RNAi Produces Precise Cleavage of Target mrna Synthetic sirna dsrna Cleavage dicer Strand separation Targeted Gene Silencing RISC Complementary pairing mrna (A) n mrna degradation Cleavage (A) n 5 RACE 26

27 5 RACE Assay Method for Demonstrating RNAi Sequence Analysis (illustrative) 27

28 Factors Influencing Ability to Show RNAi By 5 RACE in Tumor Biopsies Expression level of target mrna Amount of tissue in biopsy that expresses target 28

29 Molecules VEGF-A and KSP mrna Levels in Normal Liver and Tumors VEGF KSP liver hcc crc Very low expression of KSP mrna in normal liver and tumors Relatively abundant expression of VEGF-A mrna in both normal liver and tumor 29

30 Tissue Components of Biopsies Analyzed to Date Pre-Treatment Biopsy (%) Post-Treatment Biopsy (%) Pt# Dose mg/kg Tumor Type site of metastasis Tumor Liver Necrosis/ Fibrosis Tumor Liver Necrosis/ Fibrosis Colorectal (liver) SCC H&N (liver) Ovarian (liver) N/A N/A N/A Pancreatic (liver) Colorectal (liver) N/A: Biopsy not performed Tumor biopsies from liver very heterogeneous with regards to amounts of tumor, normal liver, and dead tissue Post-treatment biopsies from 3 patients at 0.4 mg/kg:» Little to no tumor, abundant normal liver» Can be used for VEGF 5 RACE, since robust VEGF expression in liver» Not informative for KSP 5 RACE, as very little expression in normal liver Post-treatment biopsies from 2 patients at 0.7 mg/kg:» Little tumor, very little normal liver» Not informative for either VEGF or KSP 5 RACE Dana Farber Cancer Institute, January 2011

31 Dominant Band Seen in 5 RACE for VEGF in Two Post-Dose Clinical Samples Non-clin 0.4 mg/kg hcc liver crc pre post pre post post Predicted VEGF mrna cleavage product band Dana Farber Cancer Institute, January

32 reads/total reads mapping to the transcript per_obs Post-treatment Pre-treatment Untreated controls Patient Pre-treatment Human RNAi Proof of Mechanism Results from Blinded Molecular Analysis of Human Biopsy Samples Patient Post-treatment (2 days) Patient Post-treatment (2 days) Patient Pre-treatment Patient Post-treatment (7 days) Untreated control (colorectal cancer-crc) Untreated control (hepatocellular cancer-hcc) Untreated control (normal liver) *T-test Dana Farber Cancer Institute, January 2011 % Specific cleavage as proportion of all sequence reads 1.4% 29.2% 27.9% 0.66% 0.55% 0.64% 0.26% 0.1% p<0.0001* p< RNAi Cleavage Location along VEGF Transcript ---3 Evidence of RNAi NO YES YES NO NO NO NO NO

33 5 RACE Tumor Biopsy Data Conclusions In first 5 patients analyzed, 3 had abundant normal liver/total mrna that permitted VEGF 5 RACE analysis Predicted VEGF mrna cleavage product seen post-treatment in livers of 2/3 patients» p<0.0001» Biopsy from negative patient was obtained 7 days post treatment First demonstration of RNAi in man with LNP-formulated sirna 33

34 ALN-VSP Agenda ALN-VSP Background Phase I Trial Safety Data Pharmacodynamic Data» Molecular Proof of Mechanism» DCE-MRI Summary 34

35 ALN-VSP Pharmacology DCE-MRI DCE-MRI (dynamic contrast-enhanced MRI) established as radiologic test for assessing anti-vegf effect of novel drugs in clinical trials Ktrans is key parameter» Measure of blood flow and blood vessel permeability in tumors» 40% or greater drop in Ktrans post-treatment considered a significant drop in tumor blood flow Example of Ktrans drop in patient treated with oral anti-vegfr drug AG Liu G et al. JCO 2005;23:

36 Ktrans and IAUGC Change from Baseline (%) DCE-MRI Result at 0.7 mg/kg Patient 012: Pancreatic Neuroendocrine Tumor Baseline MRI, coronal view Patient T1 T2 T T1 T2 T3 Ktrans2 IAUGC2 Ktrans3 IAUGC3 T: liver tumor number Ktrans2/IAUGC2: Δ DCE-MRI #1 (BL) to DCE-MRI #2 (Day 4) Ktrans3/IAUGC3: Δ DCE-MRI #1 (BL) to DCE-MRI #3 (Day 7) Ktrans Baseline (BL) Pre-Dose Day 4 Post-Dose 1 Day 7 Post-Dose 1 T1 T1 T1 T2 T2 T2 T3 T3 T3 ASCO, June

37 Average Ktrans Change From Baseline (%) DCE-MRI Results Summary of Cohorts 1-4 # of evaluable liver tumors: %» 21 evaluable liver tumors in 12 patients» 19/21 tumors (90%) showed decline in Ktrans» 13 of 21 tumors (62%) had Ktrans of 40%» 8 of 12 patients (67%) had average Ktrans of 40% Patient Number Dose level: 0.1 mg/kg 0.2 mg/kg 0.4 mg/kg 0.7 mg/kg ASCO, June

38 ALN-VSP Agenda ALN-VSP Background Phase I Trial Safety Data Pharmacodynamic Data» Molecular Proof of Mechanism» DCE-MRI Summary 38

39 ALN-VSP Program Summary Safety of LNP delivery to liver established in ALN-VSP Phase I liver cancer trial Liver delivery and VEGF mrna target engagement with LNP-formulated sirna demonstrated through 5 RACE assay on liver tumor biopsies» Clear proof of RNAi activity in man Preliminary DCE-MRI data from imaged liver tumors further supportive of anti-vegf pharmacology with ALN-VSP Translatability of safety and pharmacology from NHP to man greatly de-risks LNP delivery platform» Also highlights potential of liver-directed programs currently in development including ALN-TTR and ALN-PCS 39

40 ALN-VSP Program Next Steps Report additional clinical and molecular biopsy data at ASCO Annual Meeting being held June 3 7, 2011» Poster Session: Developmental Therapeutics Experimental Therapeutics Saturday, June 4 from 2:00 p.m. 6:00 p.m. CDT» Poster Discussion Saturday, June 4 from 5:00 p.m. 6:00 p.m. CDT Partner prior to Phase II 40

41 Reads/Total Reads TTR mrna Levels (Relative to Control) 1. Delivery breakthroughs enable clinical translation Control Pre-Clinical Animal Studies sirna (MC3-LNP) mg/kg RNAi Therapeutics The Time is Now: 3 Reasons 2. Growing human experience: safety and predictable PK >500 Subjects/patients enrolled overall Systemic delivery in human trials» > 40 Patients dosed» Over 6 months of dosing RNAi therapeutics generally well tolerated Pharmacologically relevant human tissue levels achieved 3. Human RNAi proof of mechanism established Patient A Pre-treatment Patient A Post-treatment Patient B Post-treatment Untreated control colorectal cancer Untreated control hepatocellular cancer Untreated control normal liver % Specific cleavage 1.4% 29.2% 27.9% 0.6% 0.3% 0.1% Evidence of RNAi NO YES YES NO NO NO cleavage site...ataggagagatgagcttcctacacagcacacaaacaaatg... AGATGAGCTTCCT... CAGCACACAAACA... plot location vs. no of reeds p< Location along mrna 3 41

42 May 13, 2011 Alnylam RNAi Roundtable Q&A 42

43 43