Delivering on the Promise of RNA- Based Therapeu;cs

Transcription

1 Delivering on the Promise of RNA- Based Therapeu;cs Parent Project Muscular Dystrophy Webinar June 20, 2011

2 Forward- Looking Statements This presenta,on includes forward- looking statements, including statements about expecta,ons regarding the development of our product candidates, including eteplirsen, and including pre- clinical development, NDA- enabling ac,vi,es, the commencement, dura,on and,ming or availability of clinical trials and analyses of trial results; efficacy, safety and clinical benefit of product candidates in the treatment of rare and infec,ous diseases, and their poten,al to treat a broad number of human diseases; the poten,al market for our product candidates; the efficacy of our PMO chemistries and other RNA- based technology; availability and amount of funding from the U.S. government; and adequacy of funds to support our future opera,ons and our future capital needs. Although we believe that the forward- looking statements contained in this presenta,on are reasonable, we can give no assurance that our expecta,ons are correct. All forward- looking statements are expressly qualified in their en,rety by this cau,onary statement. For a detailed descrip,on of risks and uncertain,es we face, you are encouraged to review the official corporate documents filed with filed with the Securi,es and Exchange Commission. We do not undertake any obliga,on to publicly update these forward- looking statements based on events or circumstances aoer the date hereof. 2

3 2011 YTD: Suppor;ng DMD Clinical Development Strengthened Management Team with Key Hires Ed Kaye, M.D., Chief Medical Officer Peter Linsley, Ph.D., Chief Officer Effie Toshav, J.D., General Counsel, SVP Advanced our DMD Program Re- aligned KOLs and thought leaders with AVI Ph II Clinical Study Design Long- Term Animal Toxicity CMC / GMP Scale- Up Strengthened balance sheet

4 Gene;c Mechanism Underlying Select Muscular Dystrophies: Dystrophin Gene Muta;on In Frame Dele;on Becker dystrophin produced Out of Frame Dele;on Duchenne No dystrophin produced removes a number of complete codons and retains the transla@on reading frame Dele@on may remove a number of complete codons but always begins or ends in an incomplete codon 4

5 AVI s Approach to Enable Protein Transla;on: Exon Skipping Dele@on of exons results in an out of frame dele@on in mrna In this example, AVI s therapeu@c compound, eteplirsen, skips exon 51 Successful skip allows for subsequent transcrip@on of in- frame mrna 5

6 Poten;al Broad Benefit to DMD Pa;ents via AVI s Protein Transla;on Enabling Technology ~31,300 Pa@ents (US, EU, JPN) ~85% Candidates for Exon Skipping (27,000) Exon 51 ~18% (~5,000) Exon 45 ~11% (~3,000) Exon 53 ~10% (~2,700) Exon 44 ~8% (~2,200) Exon 50 ~5% (~1,350) First 5 Exons >52% of Pa;ents 6

7 STUDY 28: Eteplirsen Phase 1b/2 Design Open label, mul,ple dose, dose- ranging study Weekly dosing for 12 weeks IV infusion over 60 minutes 14 week post dosing follow- up period Pre and post treatment biopsies Doses: 0.5, 1, 2, 4, 10 and 20 mg/kg Study Popula;on 19 Ambulatory DMD 5 and 15 years of age DMD amenable to treatment via exon 51 skip Pre- treatment biopsy analysis consistent with DMD Study Objec;ves Evaluate safety and tolerability Measure dystrophin expression via immunofluorescence and western blot Exploratory of clinical outcome measures 7

8 Eteplirsen: Demonstrated Proof of Concept Key Phase 1b/2 Study 28 Conclusions Well tolerated in all DMD pa;ents Adverse events generally mild/moderate, transient and not drug related Substan;al, novel and dose dependent dystrophin expression Up to 55% dystrophin fibers Up to 27% dystrophin intensity per fiber Up to 18% of normal protein expression on western blot Reduc;on in inflammatory markers and no immune response Generally stable measures of clinical performance 8

9 PMO: A Very Well Tolerated Chemistry Significant exposure in human clinical trials Studied in 436 subjects in Clinical Trials Normal Healthy Volunteers, as well as in HCV, West Nile Virus, Polycys@c Kidney Disease, Coronary Artery Disease, and DMD No MTD was reached in animal studies No known drug- related adverse events or contraindica@ons Dosed up to 320 mg/kg in primates (maximum feasible dose) Dosed up to 960mg/kg in mice (maximum feasible dose) FDA clearance to dose up to 100mg/kg in 12- week study Provides flexibility in exploring higher doses in DMD trial Wide safety margin should allow for con@nuous therapy for chronic disease 9

10 Eteplirsen: Novel and Substan;al Dystrophin Expression Post- treatment Pre- treatment 8 20mg/kg Cohort % 4 10mg/kg Cohort Dystrophin posi;ve muscle fibers (% of normal) Dystrophin intensity per fiber (% of normal) Sub- therapeu;c cohorts (1-4) not shown. 10

11 Increase in Dystrophin Detected by Immunofluorescence NORMAL SUBJECT PRE- TREATMENT POST- TREATMENT PATIENT 201 (2mg/kg) PATIENT 205 (20mg/kg) Mandys 106 stain = nominal 100% Mandys 106 An@body stain = nominal 100% Subject 205 before study, dystrophin posi@ve fibers, revertants ~3% Subject 201 before study, dystrophin posi@ve fibers, revertants ~1% Subject 205 aker 12 weekly infusions of eteplirsen at 20 mg/ kg, increase in dystrophin posi@ve fibers to ~55% Cumula@ve dose 10,788mg Subject 201 aker 12 weekly infusions of eteplirsen at 2 mg/kg, increase in dystrophin posi@ve fibers to ~21% Cumula@ve dose 1,113mg 11

12 Eteplirsen Dystrophin Restora;on Associated with Reduc;on in Inflammatory Infiltrate Cohorts 5 & 6 CD3 Cohorts 5 & 6 CD4 Cohorts 5 & 6 CD6 Pre- treatment Inflammatory cells reduced post treatment Post- treatment An;body stained (brown) inflammatory cells 12

13 Accelera;ng Plan by ~12 Months: 2012 Pivotal Trial Expected Ini;ated NDA Enabling Parallel Path Ac;vi;es GMP Manufacturing Scale- Up Plan in Place Achieve scale for pivotal trial Realize significant cost of goods Establish commercial process for CMC Phase 2 Study Supports pivotal trial design Exploring higher doses Evalua@ng longer treatment Con@nuous dosing poten@al Long- Term Animal Toxicology 9- month primate study 6- month mdx mouse study 10- week juvenile rat study 13

14 Planned Eteplirsen Phase 2 Study Double- blind, randomized and placebo controlled 24 week dosing Higher doses Pre and post treatment biopsies Biochemical endpoints Dystrophin measures Inflammatory infiltrate evalua;on Clinical endpoints Mul;ple measure of clinical benefit 6MW NSAM FVC QOL Others Phase 2 Study Ini;a;on: Third Quarter

15 DMD Milestones Re- aligned KOLs and thought leaders with AVI Long- Term Animal Toxicity CMC / GMP Scale- Up Op@mized Phase 2 Clinical Study Design Ini@ate eteplirsen DMD Phase 2 trial Phase 2 eteplirsen DMD Data 15

16 Delivering on the Promise of RNA- Based Therapeu;cs Parent Project Muscular Dystrophy Webinar June 20, 2011