RNAi Roundtable: ALN-AS1 for the Treatment of Hepatic Porphyrias. August 21, 2014

Transcription

1 RNAi Roundtable: ALN-AS1 for the Treatment of Hepatic Porphyrias August 21, 2014

2 Welcome Josh Brodsky Manager, Investor Relations and Corporate Communications Introduction Barry Greene President and Chief Operating Officer Overview of Hepatic Porphyrias Karl Anderson, M.D., FACP, Professor, Departments of Preventive Medicine and Community Health (Division of Human Nutrition) and Internal Medicine (Division of Gastroenterology), and Director, Porphyria Laboratory & Center at the University of Texas Medical Branch Q&A Session with Dr. Anderson ALN-AS1 Program Rachel Meyers, Ph.D. Vice President, Research and RNAi Lead Development Q&A Session Agenda 2

3 Reminders Event will run until ~5:00 p.m. ET Q&A session at end of each presentation» Submit questions at bottom of webcast screen» Questions may be submitted at any time Replay, slides, and audio available at 3

4 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 forwardlooking statements speak only as of the date of this presentation and, except as required by law, we undertake no obligation to update such statements. 4

5 Welcome Josh Brodsky Manager, Investor Relations and Corporate Communications Introduction Barry Greene President and Chief Operating Officer Overview of Hepatic Porphyrias Karl Anderson, M.D., FACP, Professor, Departments of Preventive Medicine and Community Health (Division of Human Nutrition) and Internal Medicine (Division of Gastroenterology), and Director, Porphyria Laboratory & Center at the University of Texas Medical Branch Q&A Session with Dr. Anderson ALN-AS1 Program Rachel Meyers, Ph.D. Vice President, Research and RNAi Lead Development Q&A Session Agenda 5

6 Alnylam 5x15 TM Strategy A Reproducible and Modular Path for Genetic Medicines GCCCCUGGAGGG 2. POC achieved in Phase 1 Blood-based biomarker with strong disease correlation» e.g., Serum TTR, thrombin generation, hemolytic activity, LDL-C, HBsAg levels 1. Liver-expressed target gene Involved in disease with high unmet need Validated in human genetics GalNAc-siRNA enables SC dosing with wide therapeutic index 3. Definable path to approval and market Established endpoints Focused trial size Large treatment effect Collaborative approach with physicians, regulators, patient groups, and payers 6

7 Alnylam Development Pipeline Discovery Development Phase 1 Phase 2 Phase 3 TTR-Mediated Amyloidosis ALN-TTRsc Patisiran (ALN-TTR02) Hemophilia and Rare Bleeding Disorders ALN-AT3 Complement-Mediated Diseases Hepatic Porphyrias Hypercholesterolemia Alpha-1 Antitrypsin Deficiency Hepatitis B Virus Infection Beta-Thalassemia and Iron-Overload Disorders Mixed Hyperlipidemia and Hypertriglyceridemia Hypertriglyceridemia Additional Genetic Medicine and Other Programs ALN-CC5 ALN-AS1 ALN-PCSsc ALN-AAT ALN-HBV ALN-TMP ALN-ANG ALN-AC3 Delivery Technology: LNP (IV) Standard Template Chemistry (STC)-GalNAc Conjugate (SC) Enhanced Stabilization Chemistry (ESC)-GalNAc Conjugate (SC) 7

8 Alnylam Development Pipeline Discovery Development Phase 1 Phase 2 Phase 3 TTR-Mediated Amyloidosis ALN-TTRsc Patisiran (ALN-TTR02) Hemophilia and Rare Bleeding Disorders ALN-AT3 Complement-Mediated Diseases Hepatic Porphyrias Hypercholesterolemia Alpha-1 Antitrypsin Deficiency Hepatitis B Virus Infection Beta-Thalassemia and Iron-Overload Disorders Mixed Hyperlipidemia and Hypertriglyceridemia Hypertriglyceridemia Additional Genetic Medicine and Other Programs ALN-CC5 ALN-AS1 ALN-PCSsc ALN-AAT ALN-HBV ALN-TMP ALN-ANG ALN-AC3 IND Filing late 14 / early 15 Delivery Technology: LNP (IV) Standard Template Chemistry (STC)-GalNAc Conjugate (SC) Enhanced Stabilization Chemistry (ESC)-GalNAc Conjugate (SC) 8

9 Welcome Josh Brodsky Manager, Investor Relations and Corporate Communications Introduction Barry Greene President and Chief Operating Officer Overview of Hepatic Porphyrias Karl Anderson, M.D., FACP, Professor, Departments of Preventive Medicine and Community Health (Division of Human Nutrition) and Internal Medicine (Division of Gastroenterology), and Director, Porphyria Laboratory & Center at the University of Texas Medical Branch Q&A Session with Dr. Anderson ALN-AS1 Program Rachel Meyers, Ph.D. Vice President, Research and RNAi Lead Development Q&A Session Agenda 9

10 Acute Intermittent Porphyria Alnylam RNAi Roundtable Karl E. Anderson, MD August 21, 2014

11 Definition of porphyrias Disorders of heme biosynthesis Each is due to the altered activity of one of the 8 enzymes in the heme biosynthetic pathway Large amounts of heme pathway intermediates accumulate Porphyrin precursors (ALA and PBG) Porphyrins Intermediates affect the nervous system and skin 11

12 Each porphyria: deficiency of a specific enzyme Erythropoietic protoporphyria (X-linked) Mitochondrial enzymes (in red) from: Anderson, Cecil Textbook of Medicine, 2012 Cytosolic enzymes (in brown) 12

13 Heme Biosynthetic Pathway Begins with 2 simple molecules Ends with insertion of iron into protoporphryin IX 13

14 Heme Biosynthetic Pathway Begins with 2 simple molecules Ends with insertion of iron into protoporphryin IX All tissues Most active in Bone marrow hemoglobin Liver cytochrome P450 enzymes

15 Classification of porphyrias Site of initial accumulation of intermediates (liver or marrow): Erythropoietic (n=2) Hepatic (n=6) Based on major symptoms Neurological acute porphyrias Photosensitivity cutaneous porphyrias 15

16 Acute intermittent porphyria (AIP) Classified Hepatic Acute Prevalence ~5/100,000 (including latent cases) 2 nd most common porphyria Most common acute porphyria Attacks with neurological manifestations No skin symptoms Autosomal dominant inheritance, low penetrance e.g. after the index case was diagnosed in this family, 15 asymptomatic heterozygotes were identified

17 Metabolic defect in AIP Half-normal activity of PBG deaminase AKA hydroxymethylbilane synthase (HMBS) Heterozygous PBG deaminase mutations Most remain asymptomatic carriers HOOC H 2 N COOH HOOC HOOC N H COOH HOOC COOH Porphobilinogen Porphobilinogen deaminase COOH HOOC COOH HO N H N H N H Hydroxymethylbilane N H 17

18 Pathophysiology Enzyme defect + Environmental or physiologic trigger * Imbalance in heme biosynthetic pathway Induction of ALAS1 & Overproduction of intermediates Porphyrin precursors may cause neurologic symptoms Porphyrins react with sunlight causing skin photosensitivity (VP and HCP) *Could be a drug, dietary restriction, alcohol use, progesterone, etc. 18

19 Pathophysiology of AIP ALAS1 (rate-limiting in liver) plays a key role, and is induced: Directly by drugs, steroids ALAS1 and hepatic CYP genes share upstream enhancer elements By depletion of free heme pool PGC-1 (peroxisome proliferator-activated receptor-γ coactivator-1) Up-regulated by fasting or CHO restriction Reversed by administration of carbohydrate ALAS1 induction accentuated by partial deficiency of PBGD Limits heme supply to the regulatory free heme pool LIVER Free Heme Pool Succinyl CoA ALAS1 + ALA PBG HMB Uro Copro Proto Heme Glycine PBGD ~50% Negative Feedback Control 5 4 Hemoproteins (CYPs, etc) 19

20 Pathophysiology of AIP Neurologic manifestations Result from the liver Cured by liver transplantation Toxic effects of δ-aminolevulinic acid (ALA)? Heme deficiency hemoprotein dysfunction?? e.g. vasospasm due to NOS deficiency??? LIVER Free Heme Pool Succinyl CoA ALAS1 + ALA PBG HMB Uro Copro Proto Heme Glycine PBGD ~50% Negative Feedback Control 5 4 Hemoproteins (CYPs, etc) 20

21 Clinical manifestations of AIP Symptoms occur in some heterozygotes Onset after puberty Most commonly 20~40 years of age More commonly in women Symptoms & signs are nonspecific mimic many other medical conditions diagnosis may not be considered Readily diagnosed selected laboratory tests 21

22 Clinical manifestations of AIP Factors that precipitate attacks Drugs especially those that induce ALAS1 and hepatic heme synthesis Progesterone & luteal phase of the menstrual cycle Fasting and CHO restriction? Stress? Other genetic factors Most precipitating factors induce ALAS1 22

23 Clinical manifestations of AIP Symptoms usually occur as acute attacks May occur only once or twice Attacks can recur frequently Symptoms can become chronic All symptoms & signs are neurological Autonomic and enteric systems Tachycardia, hypertension Abdominal pain & ileus (visceral neuropathy) Bladder dysfunction Peripheral neuropathy Primarily motor may progress of quadraparesis & bulbar paralysis Central nervous system Agitation, hallucinations, seizures Syndrome of inappropriate ADH secretion (SIADH) 23

24 AIP-posterior reversible encephalopathy syndrome (PRES) During an attack Hyperintensities in the subcortical white matter of the frontal and parietal and occipital lobes Recovered 1 year later May be due to vasospasm Kuo et al, Eur Neurol 2011;66:

25 Clinical Features of the Acute Attack Signs and Symptoms Abdominal pain Vomiting Tachycardia Constipation Pain in the extremities, back, neck, or head Paresis Mental symptoms Systemic arterial hypertension Convulsions Respiratory paralysis Diarrhea Estimated Incidence (%) Adapted from Anderson et al. Ann Intern Med 2005;142:439-50, based on several published series 25

26 Other manifestations of AIP Hepatic Transaminase elevations Risk of hepatocellular carcinoma (long term) Cardiovascular Arrhythmias Chronic hypertension Renal Chronic kidney disease Dialysis and transplantation 26

27 Diagnosis of acute porphyrias Urinary PBG: Sensitive Specific Rapid kit available Urinary porphyrins also increased Sensitive Nonspecific Not rapid CO 2 H CO 2 H H 2 C H 2 N N H Porphobilinogen

28 Treatment for acute attacks Specific (repress hepatic ALAS1) Glucose loading Mediated by PGC-1 (peroxisome proliferator-activated receptor-γ coactivator-1) Recommended only for mild attacks Intravenous hemin Repletes the regulatory heme pool More potent and effective Supportive Narcotic analgesics Phenothiazines Fluids, electrolytes Etc. 28

29 Hemin therapy Two products Panhematin (Recordati) Lyophilized hematin (heme hydroxide) Available in U.S. Normosang (Orphan Europe) Heme arginate Available in Europe & South Africa Differ in stability and side effects Both are effective (Grade IC* - based on numerous case reports and uncontrolled trials) * Sood & Anderson, in Crowther MA, Ginsberg J, Schunemann H, Meyer RM, Lottenberg R (eds): Evidence-Based Hematology, Wiley,

30 Hemin therapy Single daily infusion Dose: 3-4 mg/kg body weight/day Duration of treatment: 4 days Longer in severe cases Lowers PBG rapidly Duration of action is short Heme is rapidly degraded by hepatic heme oxygenase Hematin is reconstituted with albumin Stabilizes hemin fewer side effects Off-label method, cumbersome, adds expense Porphobilinogen (mcg/ml serum) Days 9 10 Five patients with acute attacks treated with heme arginate 3 mg/kg/day for 4 days

31 Prevention of acute attacks Avoid harmful drugs & diets For frequent cyclic premenstrual attacks GnRH analogues interrupt ovulation Evidence: Grade 1B Case reports and case series For frequent noncyclic attacks Hemin single infusions weekly or biweekly 31

32 Prevention of acute attacks For frequent attacks not responsive to or prevented by hemin Liver transplantation is curative Severely paralyzed patients are poor candidates Of interest Domino transplantation Recipient develops AIP 32

33 Management long term includes Monitor liver imaging after age 50 liver function tests kidney function Control hypertension Identify mutation & screen relatives 33

34 Unmet need Therapy that is: Specific (i.e. down-regulates hepatic ALAS1) Long lasting (more than 1 week) Convenient (e.g. subcu injection) Few side effects RNAi approach may have these features. 34

35 Porphyria Centers Mt. Sinai School of Medicine, New York U of Utah, Salt Lake City UC San Francisco Carolinus Medical Center, Charlotte NC U of Alabama Birmingham U Texas Medical Branch, Galveston 35

36 R. Desnick, PhD, MD Mount Sinai School of Medicine, NYC ; K. Anderson, MD Univ. of Texas Medical Branch, Galveston ; M. Bissell, MD Univ. of California, San Francisco ; J. Bloomer, MD Univ. of Alabama, Birmingham ; H. Bonkovsky, MD Carolinas Medical Center, Charlotte, NC ; J. Phillips, PhD Univ. of Utah, Salt Lake City ; D. Lyon Howe American Porphyria Foundation, Houston 866-APF

37 Questions? 37

38 Welcome Josh Brodsky Manager, Investor Relations and Corporate Communications Introduction Barry Greene President and Chief Operating Officer Overview of Hepatic Porphyrias Karl Anderson, M.D., FACP, Professor, Departments of Preventive Medicine and Community Health (Division of Human Nutrition) and Internal Medicine (Division of Gastroenterology), and Director, Porphyria Laboratory & Center at the University of Texas Medical Branch Q&A Session with Dr. Anderson ALN-AS1 Program Rachel Meyers, Ph.D. Vice President, Research and RNAi Lead Development Q&A Session Agenda 38

39 Welcome Josh Brodsky Manager, Investor Relations and Corporate Communications Introduction Barry Greene President and Chief Operating Officer Overview of Hepatic Porphyrias Karl Anderson, M.D., FACP, Professor, Departments of Preventive Medicine and Community Health (Division of Human Nutrition) and Internal Medicine (Division of Gastroenterology), and Director, Porphyria Laboratory & Center at the University of Texas Medical Branch Q&A Session with Dr. Anderson ALN-AS1 Program Rachel Meyers, Ph.D. Vice President, Research and RNAi Lead Development Q&A Session Agenda 39

40 Targeting ALAS1 to Lower Heme Intermediates ALN-AS1 Therapeutic Hypothesis ALN-AS1 GalNAc 3 Neurotoxicity Altered GABA Signaling Iron mediated oxidation and ROS production γ-aminolevulinic Acid (ALA) γ-aminobutric Acid (GABA) Brennan et al. Nature 1979, Hermes-Lima et al. Biochem Biophys Acta

41 RNAi Therapeutic Targeting ALAS-1 Potential Use for Acute Treatment and Prophylaxis Recurrent Attack Setting (Prophylaxis) ALAS-1 mrna Months ALN-AS1 Blunted Up-regulation Months Mild chronic suppression will blunt recurrent ALAS-1 upregulation that drives attacks Reduction in number and severity of attacks Acute Attack Setting (Treatment) ALN-AS1 ALAS-1 mrna Days Rapid Suppression Days Release of pathway bottleneck Quick reduction in ALA/PBG Rapid improvement in clinical symptoms 41

42 Rodent Models of AIP Mouse AIP Model PBGD compound heterozygous KO ~30% Residual PBGD activity ~30-100X increase in ALA/PBG following qd x 3-4 phenobarbital (PB) POC with LNP published Rat AIP Model (At Alnylam) Transient PBGD sirna KD in liver ~15% Residual PBGD mrna 10-50x increase in ALA/PBG following qd x3 phenobarbital induction PB PB Lindberg et al., Nature Genetics.; 12: (1996) PB PB Yasuda et al. PNAS

43 rpbgd/rgapdh, Relative to PBS=1 ralas1/rgapdh, Relative to PBS=1 ALN-AS1 Treatment in Rat AIP Model PBGD KD sirna PB IP x 4 D D1 D2 D3 D4 Liver PBGD mrna 4.5 D5 Urine ALA/PBG Liver ALAS1 mrna sirna PB 0.0 PBS 10mg/kg 5mg/kg 2.5mg/kg ALN-AS1 Control sirna PB 0.0 PBS 10mg/kg 5mg/kg ALN-AS1 2.5mg/kg PBGD LNP PBGD LNP

44 Rat Urine PBG (mmol/mol Creatinine) Relative to PBS=1 Rat Urine PBG (mmol/mol Creatinine) Relative to PBS=1 ALN-AS1 Treatment in Rat AIP Model PBGD KD sirna PB IP x 4 D-3 D1 D2 D3 D4 D5 Urine ALA/PBG 16 PBG 16 ALA sirna 0 PBS 10mg/kg 5mg/kg ALN-AS1 2.5mg/kg 0 sirna PBS 10mg/kg 5mg/kg ALN-AS1 2.5mg/kg PB PBGD LNP PB PBGD LNP

45 ralas1/rgapdh, (PBS=1) Urinary ALA or PBG (mmol/mol creatininine) PBS=1 ALN-AS1 Multidose Prophylaxis in Rat AIP Model D0 D7 D14 D21 D25 (sac) 3, 1, or 0.3mg/kg (QWx4) Phenobarb 4.0 D18 PBGD LNP ALAS1 mrna 10 8 ALA/PBG ALA PBG PBS 3mg/kg 1mg/kg 0.3mg/kg ALN-AS1 0 PBS 3 mg/kg 1 mg/kg 0.3 mg/kg ALN-AS1 PB PB PBGD LNP PBGD LNP

46 ALA(μmol/L) PBG(μmol/L) ALN-AS1 Acute Tx vs. Heme in Mouse AIP Model ALA PBG Saline 10 Hemin ALN-AS Hours after sirna or Hemin Saline Hemin ALN-AS Hours after sirna or Hemin 46

47 Normalized ALAS-1 Circulating Extracellular RNA Detection (cerd) Method for Circulating ALAS1 mrna Detection AS1 Transcript by cerd by liver biopsy Monitoring RNAi Activity in Liver mrna or 5 RACE product in tissue Circulating secreted protein Detection of Circulating ALAS1 mrna Exosomes are shed into bodily fluids from many different cell types and contain mrna and mirna derived from tissue of origin Exosomes can be used to monitor ALAS1 mrna levels after ALN-AS1 dosing in serum/urine without need for biopsy PBS ALAS-GalNAc (mg/kg) QDx5, EOD, d15 (not DC) Sehgal et al. RNA

48 % Mean AS1 Knockdown (Fraction Pre-dose) ALN-AS1 NHP Pharmacology Study Repeat dose, Serum ALAS1 mrna via cerd ALN-AS1 2.5 mg/kg qw x8 ALN-AS1 5.0 mg/kg qd x3; 2.5 mg/kg qw x7 Days 48

49 Initial Safety Studies of ALN-AS1 Wide Therapeutic Index GalNAc Conjugate Platform Tolerability Cytokine assessment» No evidence of inflammation (cytokine or complement) in vitro or in vivo, including NHP Preliminary toxicology findings (QWx3, or QWx5 up to 300mg/kg)» No in-life findings or injection site reactions» No significant changes in serum chem, or liver function (ALT/AST)» No adverse histopath findings Minimal hepatocyte vacuolization in rat but not NHP (more predictive species) On Target Analysis of Liver Heme Depletion Evaluation of p450 panel in mice, rats, NHP after ALN-AS1 dosing» With QWx5 at 300mg/kg (~100X above efficacious dose) in NHP, no impact on p450 activity of CYP1A, CYP2E, CYB2B, CYP2D, CYP3A in liver microsomes 13-week studies ongoing to evaluate p450s after longer dosing 49

50 AIP Potential Clinical Populations Acute Intermittent Porphyria Known PBGD mutations Autosomal dominant Incomplete penetrance Asymptomatic No increase in ALA/PBG levels ~50% of all gene carriers Recurrent attack patients Monthly or multiple attacks per year Require prophylaxis Highest unmet need Poor Quality of life Spontaneous attack patients Episodic attacks with asymptomatic periods ~10-15% all gene carriers Primarily need acute treatment Proper diagnosis can be a challenge High Excreters Elevated ALA/PBG compared to normal ~25-50% gene carriers May never have attacks, some infrequently Possible chronic pain, nerve degeneration, though poorly studied Increased risk of HCC seen in Sweden 50

51 Potential Clinical Indications for ALN-AS1 Significant Unmet Needs Remain in Acute Hepatic Porphyrias Acute Intermittent Porphyria Population Prophylaxis for patients with acute attacks Current Treatment: Heme (US) Heme Ariginate (EU) IV Glucose Major Unmet Medical Needs Diagnosis Effective prophylaxis Unstable heme products causes side effects Potential for tachyphylaxis Variegate Porphyria Population Treatement of patents with acute attacks Current Treatment: Heme (US) Heme Ariginate (EU) IV Glucose Photoprotection Major Unmet Medical Needs Diagnosis Rapid resolution of attack symptoms Impact of cutaneous symptoms to lifestyle Unstable heme products causes side effects Hereditary Coproporphyria Population Treatment of patients with acute attacks Current Treatment: Heme (US) Heme Ariginate (EU) IV Glucose Photoprotection Major Unmet Medical Needs Diagnosis Rapid resolution of attack symptoms Impact of cutaneous symptoms to lifestyle Unstable heme products causes side effects 51

52 Number of patients Potential Target Patient Segments Symptomatic Hepatic Porphyria patients could benefit from ALN-AS1 40,000 30,000 37K 18.5K Total Population ALN-AS1 Initial Opportunity 20, K 10,000 - All Acute Hepatic Porphyria 5K 1.5K Asymptomatic AIP Symptomatic AIP Variegate Varigate Porphyria Hereditary Coproporphyria A large portion of the patient population likely has not been diagnosed (mean time to diagnosis ~15 years) 52

53 ALN-AS1 Commercial Opportunity Significant opportunity to treat and prevent porphyric attacks Orphan disease with substantial morbidity» IV Heme products have poor stability, limited efficacy and significant side effects» Prophylaxis with heme is controversial due to safety profile and potential tachyphylaxis Potential for long-term growth through improved diagnosis» Significant number of patients are undiagnosed or poorly managed» Porphyria Centers of excellence (i.e., American Porphyria Consortium) support rapid adoption of new therapies Value supported by significant burden of disease (hospital visits, impact to productivity) Strong patient advocacy from the American Porphyria Foundation 53

54 ALN-AS1 Clinical Development Plan Initial Focus on Prophylaxis in Recurrent AIP Patients Phase 1/2 SAD/MAD AIP Patients (latent and manifest) Phase 2/3 Prophylaxis AIP Patients with Recurrent Attacks Objective: Establish POC and active dose/regimen for future studies Placebo-controlled SAD, MAD qw SC Additional multidose cohort in recurrent attack patients Endpoints: ALA/PBG levels in blood and urine, safety, tolerability, PK Objective: Show efficacy in prophylaxis Q weekly chronic dosing Endpoints: Reduction in attack frequency post-treatment; reduction in Hematin use and hospitalization, improvement in QOL, safety EXPLORE Natural History Study Recurrent Attack Patients 54

55 ALN-AS1 Porphyria Program Summary Alnylam is developing ALN-AS1 for treatment of AIP and other acute hepatic porphyrias Generated pre-clinical proof of concept for targeting ALAS1 with RNAi therapeutics» Effective with prophylaxis or acute treatment in rodent models Identified ALN-AS1, an ESC-GalNAc-siRNA conjugate, as Drug Candidate» Expect human SC doses <1 mg/kg, weekly (< 1mL volume) Plan to start EXPLORE Natural History study in late 14 On track to file IND or IND equivalent in late 14 or early 15» Start Phase 1 in early 15 Rapid clinical development plan focused on prophylaxis in recurrent attack patients with highest unmet need 55

56 Welcome Josh Brodsky Manager, Investor Relations and Corporate Communications Introduction Barry Greene President and Chief Operating Officer Overview of Hepatic Porphyrias Karl Anderson, M.D., FACP, Professor, Departments of Preventive Medicine and Community Health (Division of Human Nutrition) and Internal Medicine (Division of Gastroenterology), and Director, Porphyria Laboratory & Center at the University of Texas Medical Branch Q&A Session with Dr. Anderson ALN-AS1 Program Rachel Meyers, Ph.D. Vice President, Research and RNAi Lead Development Q&A Session Agenda 56

57 Summer RNAi Roundtable Series Patisiran and ALN-TTRsc for the treatment of Transthyretin-Mediated Amyloidosis (ATTR) Tuesday, July 12:30 p.m. 2:00 p.m. ET Advances in Delivery of RNAi Therapeutics with Enhanced Stabilization Chemistry (ESC)-GalNAc-siRNA Conjugates Tuesday, July 11:00 a.m. 12:00 p.m. ET ALN-HBV for the treatment of Hepatitis B Virus (HBV) Infection Tuesday, July 9:30 a.m. 10:30 a.m. ET ALN-AT3 for the treatment of Hemophilia and Rare Bleeding Disorders Thursday, August 9:30 a.m. 10:30 a.m. ET ALN-CC5 for the treatment of Complement-Mediated Diseases Wednesday, August 9:30 a.m. 10:30 a.m. ET ALN-PCSsc for the treatment of Hypercholesterolemia Thursday, August 4:00 p.m. 5:00 p.m. ET ALN-AAT for the treatment of Alpha-1 Antitrypsin Deficiency-Associated Liver Disease Wednesday, August 12:30 p.m. 1:30 p.m. ET ALN-AS1 for the treatment of Hepatic Porphyrias Thursday, August 4:00 p.m. 5:00 p.m. ET Replays, presentations, and transcripts of all RNAi Roundtables available at 57

58 Alnylam 5x15 ALN-CC5 Patisiran Alnylam 5x15 GalNAc Conjugates ALN-HBV ALN-PCSsc ALN-TTRsc ALN-AT3 ALN-CC5 Select Scientific and Clinical Meetings Mid to Late 14 High Blood Pressure Research (HBPR)» September 9-12, San Francisco, CA International Complement Society Workshop (ICSW)» September 14-18, Rio de Janeiro, Brazil American Neurological Association (ANA)» October 12-14, Baltimore, MD Oligonucleotide Therapeutics Society (OTS)» October 12-15, San Diego, CA AASLD (The Liver Meeting)» November 7-11, Boston, MA American Heart Association (AHA)» November 15-19, Chicago, IL Venue TBD» November American Society of Hematology (ASH)*» December 6-9, San Francisco, CA * Pending acceptance of abstracts 58

59 Speaker Biographies Barry Greene President and Chief Operating Officer, Alnylam Pharmaceuticals, Inc. Barry Greene joined Alnylam in 2003, and brings over 25 years of experience in healthcare, pharmaceutical, and biotechnology industries. Prior to Alnylam, he was General Manager of Oncology at Millennium Pharmaceuticals, Inc., where he led the company s global strategy and execution for its oncology business including strategic business direction and execution, culminating in the successful approval and launch of VELCADE (bortezomib) in mid Prior to joining Millennium in February 2001, Barry served as Executive Vice President and Chief Business Officer for Mediconsult.com. Prior to Mediconsult.com, his past experiences include Vice President of Marketing and Customer Services for AstraZeneca, formerly AstraMerck; Vice President Strategic Integration with responsibility for the AstraZeneca North American post merger integration; and Partner, Andersen Consulting responsible for the pharmaceutical/biotechnology marketing and sales practice. Barry received his B.S. in Industrial Engineering from University of Pittsburgh and served as Senior Scholar at Duke University, Fuqua School of Business. Barry also serves on the Boards of Acorda Therapeutics and Karyopharm Therapeutics. Karl Anderson, M.D., FACP Professor, Departments of Preventive Medicine and Community Health (Division of Human Nutrition) and Internal Medicine (Division of Gastroenterology), and Director, Porphyria Laboratory & Center at the University of Texas Medical Branch A graduate of the Johns Hopkins University School of Medicine, Dr. Anderson completed his residency and postgraduate training in gastroenterology at the New York Hospital-Cornell Medical Center. He was a member of the faculty at the Rockefeller University, Cornell University Medical College and New York Medical College before coming to UTMB in He directs the Division of Human Nutrition in the Department of Preventive Medicine and Community Health, and is an active clinical investigator particularly on the General Clinical Research Center (GCRC), where he is also Associate Program Director. He is PI for UTMB's NIH K30 grant that supports a variety of clinical research education programs, Director of the Clinical Research Education Office, and Director of the Graduate Program (PhD or MS) in Clinical Science, which is suited particularly for physicians seeking advanced training in clinical research. Dr. Anderson's research interests include (i) pathogenesis of human porphyrias and identification of factors that increase susceptibility; (ii) development of new therapies for porphyrias; (iii) effects of diet on drug metabolism in humans, especially by cytochrome P450 enzymes, and on circulating hormone levels; and (iv) collaborative work on effects of soy feeding in humans on breast cancer risk. His clinical interests include human porphyrias, metabolic and nutritional aspects of liver disease, and general clinical gastroenterology and hepatology. Rachel Meyers, Ph.D. Vice President, Research and RNAi Lead Development, Alnylam Pharmaceuticals, Inc. Dr. Rachel Meyers is Vice President of Research and RNAi Lead Development (RLD) at Alnylam. In this capacity, she plays a key role in the advancement of Alnylam s RNAi therapeutic programs, from early discovery through clinical development and her team is responsible for program leadership for most of Alnylam s preclinical and clinical stage programs. In addition to leading the research organization, Dr. Meyers has worked closely with Alnylam s business development group, playing an integral part in establishing important collaborations, and has functioned as a scientific lead in collaborations with Novartis, Takeda, Isis, Roche and Genzyme. She also led the scientific diligence resulting in Alnylam s acquisition of the Sirna assets from Merck. Prior to taking on the leadership of the Research and RLD Groups, Dr. Meyers was one of Alnylam s Research Directors, focusing her efforts on the development of RNAi therapeutics to target infectious diseases, and was the project lead for the company s RSV program, where she was responsible for advancing ALN-RSV01 from inception, through preclinical development and into the clinic. Dr. Meyers was honored by Mass High Tech as one of 10 Women to Watch 2007 and by R & D Directions as one of its Top 20 Scientists Before joining Alnylam in April of 2003, Dr. Meyers was a Senior Scientist at Millennium Pharmaceuticals ( ) where she was involved in the bioinformatics, molecular and cell biology of target discovery. Dr. Meyers completed her postdoctoral training at Harvard Medical School in the field of signal transduction, and received her Ph.D. from MIT in the field of in vitro transcription. 59

60 Thank You