Hepatocyte-Targeted RNAi Therapeutics: A Reproducible and Modular Platform for Innovative Medicines

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1 Hepatocyte-Targeted RNAi Therapeutics: A Reproducible and Modular Platform for Innovative Medicines Laura Sepp-Lorenzino January 28, Alnylam Pharmaceuticals, Inc.

2 Alnylam Forward Looking Statements This presentation contains forward-looking statements, within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 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 our ability to discover and develop novel drug candidates and delivery approaches, successfully demonstrate the efficacy and safety of our drug candidates, obtain, maintain and protect intellectual property, enforce our patents and defend our patent portfolio, obtain regulatory approval for products, establish and maintain business alliances; our dependence on third parties for access to intellectual property; and the outcome of litigation, as well as those risks more fully discussed 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. All forward-looking statements speak only as of the date of this presentation and, except as required by law, we undertake no obligation to update such statements. 2

3 RNAi Therapeutics New Class of Innovative Medicines Harness natural pathway Catalytic mechanism Silence any gene in genome Upstream of today s medicines Clinically proven approach 3

4 Overcoming the Delivery Challenge PK/Tissue Distribution Cellular Uptake and Trafficking RISC Loading 100 Plasma Liver Spleen RT-qPCR % Injected dose Time (h) 4

5 Addressing the Challenges Alnylam Platforms for Functional Delivery to Target Tissue (Liver) sirna Chemically-modified sirna Potent and durable activity Metabolically stable No innate immune activation Lipid Nanoparticles (LNPs) Multi-component lipid formulation with encapsulated sirna Administered intravenously Assisted endosomal escape Conjugates Single component system with defined sirna conjugate Administered subcutaneously Unassisted endosomal escape 5

6 GalNAc-siRNA Conjugates Subcutaneous Investigational RNAi Therapeutics GalNAc 3 GalNAc-siRNA conjugate Asialoglycoprotein Receptor (ASGPR) Highly expressed in hepatocytes High rate of uptake Recycling time ~15 minutes Conserved across species ASGPR (ph>5) protein Clathrin-coated pit Recycling ASGPR Clathrin-coated vesicle Revusiran, ALN-AT3, ALN-PCSsc, ALN-CC5 sirna conjugated to N-acetylgalactosamine (GalNAc) ligand Efficient delivery to hepatocytes following subcutaneous administration Wide therapeutic index Enhanced stabilization chemistry (ESC) used with all programs after Revusiran Significantly improved potency and durability RISC mrna Nucleus Endosome 6

7 First Ever Demonstration of Robust RNAi Activity with Conjugates in Humans by STC GalNAc-siRNA Revusiran Phase 1: Randomized, double-blind, placebo-controlled SAD and MAD study in healthy volunteers Rapid, dose-dependent, consistent, and durable knockdown of serum TTR» Significant knockdown of serum TTR (p<0.01) up to 94% TTR knockdown; mean knockdown up to 92.4% -20 % Mean TTR Knockdown Relative to Baseline (± SEM) Revusiran dose groups Placebo (n=3) 2.5 (n=3) 5.0 (n=3) 10.0 (n=3) Revusiran (mg/kg), qd x5; qw x5 Days 7 Zimmermann, Heart Failure Society of America, Sept. 2013

8 sirna Conjugates Encounter Various Metabolic Enzymes En Route to Site of Action GalNAc-siRNA conjugate SC Injection site Excretion Lymphatics Capillary Uptake Nucleases (5 exo, 3 exo, endo) Peptidases D/M Central Compartment (systemic circulation) D/M P-bodies and associated exonucleases Kinases - Clp1 Phosphatases Effect Site Liver Cytosol RISC Lysosome 1 Hepatocyte Endosome Kidney Biliary excretion Phosphatases Nucleases Peptidases N-acetylgalactosidase many others 8 Schröder et. al., The Proteome of the Lysosome, Proteomics.10: (2010) (adapted from Mark Cancilla, Merck)

9 ESC Leads to Higher Liver Exposure Liver Exposure and Metabolic Stability, Single SC Dose, 25 mg/kg in Mice Metabolic profiling in liver 8h post dose Liver Exposure Standard Template Chemistry (STC) (GalNAc) 3 S 5 AS 5 = 2 -F = 2 -O-methyl Liver Concentration (ng/g) STC SC ESC Time (h) Enhanced Stabilization Chemistry (ESC) Liver Exposure S 5 Target Compound T max (h) C max (µg/g) AUC 0-t (h µg/g) AUC 0-48 (h µg/g) AS 5 AT3 STC AT3 ESC ,546 9,697 = Enzymatic cleavage site (thickness reflects frequency of corresponding cleavage products observed) 9 Manoharan, TIDES, May 2014

10 Superior TTR Knockdown with ALN-TTRsc02 SD 1 mg/kg ALN-TTRsc02 Compared to MD 5 mg/kg Revusiran in NHP Cumulative Dose (mg/kg) eauc (ug/ml*day) Revusiran ± Meyers, OTS, October 2015 ALN-TTRsc ± 1774

11 Potent and Durable Target Silencing in Humans by ESC-GalNAc-siRNA Drug Candidates Mean (Sem) % AT Knockdown ALN-AT3 15 mcg/kg (N=3) 45 mcg/kg (N=6) 75 mcg/kg (N=3) Mean (SEM) PCSK9 Knockdown ALN-PCSsc Placebo 25 mg 100 mg 300 mg 500 mg 800 mg Time (Days) Time (Months) Mean (SEM) % C5 Knockdown ALN-CC5 Placebo 50 mg 200 mg 400 mg Mean (SEM) % ALA Change ALN-AS1 Placebo mg/kg 0.1 mg/kg 0.35 mg/kg 1.0 mg/kg Time (Days) Time (Days)

12 Continuous Improvements in Potency Through Optimization of Conjugate Design Conjugate potency in mouse (ED 50, single s.c. dose ) 100 Partial modification 10 STC ED 50 (mg/kg) 1 ESC Advanced ESC 0.1 projected Year 12

13 GalNAc-siRNA Conjugates Wide Therapeutic Index from Non-Clinical GLP Studies NOAEL 1 4 or 7 weeks (mg/kg) NOAEL 13 weeks (mg/kg) NOAEL 6 mos Rat (mg/kg) NOAEL 9 mos NHP (mg/kg) Expected Human Therapeutic Index (TI) 2 Rat NHP Rat NHP Revusiran N/A N/A >80 ALN-AT3 3, N/A N/A >10 5 ALN-PCSsc Planned Planned >500 ALN-CC Ongoing Ongoing >200 ALN-AS1 N/A N/A Planned Planned >500 ALN-AAT N/A N/A Planned Planned >500 1 No Adverse Event Level (NOAEL) 2 TI calculated as NOAEL in NHP/Expected dose in man 3 7 week studies 4 NOAEL in hemophilia mice >100 mg/kg, qw x 7 5 Secondary to exaggerated pharmacology In Vivo No evidence for cytokine induction, complement activation, changes in clotting parameters Single target organ in rat; liver (typically vacuolar changes at top dose) by light microscopy No EM changes of note (revusiran chronic toxicology studies), including mitochondrial ultrastructure In vitro assays PBMC stimulation screen Off target screen Safety evaluation of novel chemistries (e.g., 2 F) 13

14 Alnylam Reproducible and Modular Platform Strategic Framework for Innovative Medicines 1 Genetically validated, liverexpressed target gene High unmet need disease Opportunity for highly competitive profile Delivery with GalNAc conjugate platform 2 Biomarker for POC in Phase 1 Blood or urine based Informative disease correlation Establish dose/regimen for late-stage development 3 Definable path to approval and market Clinical development plans with established endpoints Demonstrable value for payers 14

15 Reproducible and Modular Platform Fundamentally New Approach to Drug Development Preclinical POC Excellent Translation Human POC Select Dose/ Regimen Start of Phase 3 Increased POS due to Genetically Validated Targets Phase 3 Data % Men KD in human % Mean KD % Mean KD in NHP Months 15

16 Reproducible and Modular Platform Rapid Path from Idea to Human POC with 100% Success to Date IDEA DEVELOPMENT CANDIDATE CTA/IND HUMAN POC 6 months months 6-9 months Success Rate at each stage to date: 100% 100% 100% 16

17 Alnylam Strategic Therapeutic Areas (STArs) Investigational pipeline focused in 3 STArs Genetic Medicines RNAi therapeutics for rare diseases Cardio-Metabolic Diseases RNAi therapeutics for dyslipidemia, NASH, type 2 diabetes, hypertension, and other major diseases Hepatic Infectious Diseases RNAi therapeutics for major liver infections beginning with hepatitis B & D 17

18 Alnylam Development Pipeline 18

19 19 19

20 Potential Multi-Year Pipeline Progression >10 Clinical readouts in

21 Potential Multi-Year Pipeline Progression >5 Programs in Phase 3 in

22 Potential Multi-Year Pipeline Progression 1 st Phase 3 data readout and, if positive, NDA in

23 Competitive and Differentiated Profiles Robust Human Experience to Date* Number of Programs 7 Number of Clinical Studies 16 Total Patients or Volunteers Dosed >300 Longest Duration of Exposure >24 months Total sirna Doses Administered >4,500 *Numbers are approximate as many studies are ongoing 16-January

24 Key Features of Alnylam Investigational RNAi Therapeutics Potential Attributes for Differentiation and Value MAXIMUM KNOCKDOWN (KD) EFFICACY Up to 99% CLAMPED PHARMACODYNAMICS (PD) NOT UNDRUGGABLE TARGETS ROOM TEMP As few as 2 DURABILITY VS. 26 doses per year or more doses per year SUBCUTANEOUS (SC) ROUTE 24

25 RNAi Therapeutics Pave the Way for New Oligo Platforms Lessons Learned Exciting new biology therapeutic platform Significant multi-functional, R+D effort required Specificity, robustness, reproducibility, species translation Therapeutic window after single and chronic exposure Manufacturing, controls, quality, cost of goods Delivery Liver delivery presents many, many opportunities Tremendous progress on < drug exposure for > effects Other tissues/organs present additional upside Product clinical development and commercialization strategy Early focus on clinical and commercial differentiation Transformational medicines Successful, high impact products on market define ultimate validation 25

26 Thank you! 26

27 Competitive and Differentiated Profiles RNAi vs. Monoclonal Antibody (MAb) Potential resurgence of disease symptoms MAbs Transiently block protein in stoichiometric process, consumed by ongoing protein synthesis Saw-tooth effect 26 doses/year Protein Synthesis GalNAc mrna Nucleus RNAi sirna durably blocks protein synthesis in catalytic process Sustained suppression of disease symptoms Clamped effect 2 doses/year 27

28 RNAi Delivery to Liver Solved IV and SC Platforms (NHP) Enables advancement of innovative medicines to patients Liver target gene silencing with lipid nanoparticle (LNP) technology and IV dosing Advancement of proprietary conjugate platform for clinical translation and SC dosing Initial conjugates with Standard Template Chemistry (STC) achieve target knockdown with qw SC dosing Improvements with conjugates employing Enhanced Stabilization Chemistry (ESC) platform with qm/qq SC dosing LNP STC-Conjugate ESC-Conjugate % TTR mrna Silencing (Relative to Control) % TTR mrna Silencing (Relative to Control) % AT mrna Silencing (Relative to Pre-dose) Control Patisiran (MC3-LNP) mg/kg 100 Control Revusiran (STC-GalNAc-conjugate) mg/kg 100 Control ALN-AT3 (ESC-GalNAc-conjugate) mg/kg 28 Sah, Keystone: Adv in Biopharm., Jan. 2010; Maier et al., Oligo Ther Soc., Sep. 2011; Akinc, ISTH, July 2013

29 ESC Significantly Enhances Efficacy and Duration Reduction of AT Protein After Single SC Dose in NHP Potent and durable silencing achieved after single SC dose >10-fold improvement in efficacy over standard template chemistry Substantially extended duration of effect % Knockdown serum AT (Relative to pre-dose) STC-AT3 (10 mg/kg) ESC-AT3 (1 mg/kg) ESC-AT3 (10 mg/kg) Single SC dose Day 29 Manoharan, TIDES, May 2014