Experience in Developing a Treatment for Duchenne Muscular Dystrophy

Transcription

1 Experience in Developing a Treatment for Duchenne Muscular Dystrophy Pleae Edward M. Kaye MD Chief Medical Officer & SVP

2 The Cause of Duchenne Muscular Dystrophy is the Lack of Dystrophin (<5%) The Dystroglycan Complex protects the muscles during contrac;on and relaxa;on. DMD Muscle Tissue Healthy Muscle Tissue Dystrophin 2

3 Dystrophin Gene MutaLons in Muscular Dystrophy Becker MD In Frame DeleLon Because dele;on retains the transla;on reading frame, parlally funclonal dystrophin is produced. Duchenne MD Out of Frame DeleLon Because dele;on always begins or ends in an incomplete codon, no dystrophin is produced Milder disease Majority of pa;ents retain ambula;on into late adulthood and have a normal lifespan 77 X X Degenera;ve, invariably fatal Majority of pa;ents lose the ability to walk around age 13, survival beyond 30s is rare

4 Eteplirsen Restores Dystrophin ProducLon by Repairing the mrna through Exon- skipping X Dystrophin Dele;on of exons results in an out of frame delelon in mrna ü Dystrophin In this example, eteplirsen causes the transla;on machinery to skip exon 51 By skipping exon 51, in- frame mrna transcriplon is restored, enabling dystrophin produc;on 4

5 Eteplirsen Clinical Program Phase 1 Phase 1/2 Study 33 Intramuscular, Dose Escala;on, Single Blind (N=7) Study Systemic Delivery, Mul;ple Dose, Open Label, 12 Weeks (N=19) Phase 2b Study Systemic Delivery, Mul;ple Dose, Double Blind, Placebo Controlled, 12 and 24 Weeks (N=12) Study Open Label Extension Study, Ongoing (N=12). 5 5

6 Phase 2b (Study 201) n=4 30 mg/kg 24- wk Biopsy n=4 50 mg/kg 12- wk Biopsy n=4 Pre- Treatment Biopsy Placebo Control 12- wk Biopsy n=2 24- wk Biopsy n=2 12 Weeks 12 Weeks 24 Weeks ¾ Randomized, Double Blind, Placebo Controlled IV infusion over 60 minutes, weekly Single site: Na;onwide Children s Hospital (Ohio) MulLple Endpoints Biochemical Markers: Dystrophin and Immune- Inflammatory Response Clinical Outcomes: Various Tests of Muscle Func;on, Strength, and Endurance Cardiac and Pulmonary Func;on Tests, Safety 6

7 Phase 1 (Study 33) o Study Design Intramuscular injec;on in foot (extensor digitorum brevis EDB muscle). Candidate drug in one foot, saline in other Doses: Low dose (N=2): 0.09 mg (0.09 mg in 900 µl) High dose (N=5): 0.9 mg (0.9 mg in 900 µl) Muscle biopsy of both EDBs at 3 or 4 weeks o Study PopulaLon Ambulatory boys with DMD and out- of- frame dele;ons addressable by the skipping of exon 51 Ages 12 to 17 (inclusive) Site in the U.K. 7

8 Phase 1 (Study 33): ProducLon of Novel Dystrophin Control Pa;ent 3 Pa;ent 4 Pa;ent 5 Pa;ent 6 Pa;ent 7 Saline Drug 40 random fields per slide, Varia<ons in slide thickness normalised by spectrin baseline 8

9 Phase 1 (Study 33): Key Findings Eteplirsen produced expression of novel, funclonal dystrophin. Significant amount of dystrophin per muscle fiber High percentage of dystrophin posi;ve muscle fibers Eteplirsen- produced dystrophin localized to the correct place, as part of the dystroglycan- complex. No increase in T and B cell infiltralon (anl- CD3, - CD4, - CD8 and CD20 anlbodies), No anl- dystrophin anlbodies 9

10 Phase 1/2 (Study 28) ¾ Study Design Open label IV infusion over 60 minutes, weekly for 12 weeks Dose Ranges: 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 4 mg/kg, 10 mg/kg and 20 mg/kg Pre and post treatment biopsies ¾ Study PopulaLon Ambulatory boys with DMD and out- of- frame dele;ons addressable by the skipping of exon 51 Ages 5 to 15 (inclusive) Two sites in the U.K. 10

11 Phase 1/2 (Study 28) July

12 Phase 1/2 (Study 28): No Treatment- Related Adverse Events Treatment-Emergent Adverse Event Number (%) URTI 8 42 Headache 8 42 Rhinitis 7 37 Back pain 7 37 Fall 5 26 Myalgia 4 21 Tachycardia 3 16 Abdominal pain 3 16 Nausea 3 16 Vomiting 3 16 Influenza like illness 3 16 Arthralgia 3 16 Dizziness 3 16 Upper abdominal pain 2 11 Disease progression 2 11 Fatigue 2 11 Vessel puncture site bruise 2 11 Bronchitis 2 11 Viral infection 2 11 Lumbar vertebral fracture 2 11 Procedural pain 2 11 Pain in extremity 2 11 Haematoma 2 11 Two SAEs reported, both unrelated to drug One post- opera;ve nausea and vomi;ng; One ankle fracture both in 14 week follow- up 12

13 Phase 1/2 (Study 28): ProducLon of Novel Dystrophin RT-PCR - + Western Blot CT Post Pre ug 205 Immunofluorescence 205: ~ 10 fold increase pre to post Rx at 20mg/kg PRE-TREATMENT POST-TREATMENT NORMAL SUBJECT ¾ Mandys 106 Antibody stain = nominal 100% PATIENT 205 (20mg/kg) ¾ Subject 205 before study, dystrophin positive fibers, revertants ~3% ¾ Subject 205 after 12 weekly infusions of eteplirsen at 20 mg/ kg, increase in dystrophin positive fibers to ~55% ¾ Cumulative dose 10,788mg 13 Source: Lancet Aug 13;378(9791):

14 Phase 1/2 (Study 28): Key Findings Eteplirsen produced novel, dose dependent dystrophin expression Eteplirsen was well tolerated in all DMD palents Adverse events mild/moderate, transient and not drug related No increase in inflammatory markers, no immune response 14

15 Phase 2b (Study 201): No Treatment- Related Adverse Events Treatment-Emergent Adverse Event Treated N=8 (%) Placebo N=4 (%) Hypokalemia 4 (50.0%) 2 (50.0%) Procedural pain 4 (50.0%) 3 (75.0%) Balance disorder 3 (37.5%) 0 Vomiting 3 (37.5%) 0 Cough 2 (25.0%) 2 (50.0%) Dermatitis Contact 2 (25.0%) 0 Hematoma 2 (25.0%) 1 (25.0%) Back pain 1 (12.5%) 2 (50.0%) Fall 1 (12.5%) 1 (25.0%) Headache 1 (12.5%) 2 (50.0%) Diarrhea 1 (12.5%) 1 (25.0%) Polyuria 1 (12.5%) 0 Nausea 1 (12.5%) 1 (25.0%) Rhinitis 1 (12.5%) 1 (25.0%) Muscle Spasms 1 (12.5%) 0 Musculoskeletal Pain 1 (12.5%) 0 Pyrexia 1 (12.5%) 2 (50.0%) Proteinuria 0 1 (25.0%) Abdominal pain 0 2 (50.0%) No proteinuria No change in blood coagula;on profiles No evidence of treatment- related inflammatory responses No infusion- associated reac;ons No thrombocytopenia No change in liver- specific enzymes No change in kidney func;on 15

16 Phase 2b (Study 201): Significant Increase in Novel Dystrophin Change in % Dystrophin PosiLve Fibers 16 Change in % Dystrophin PosiLve Fibers Placebo Mean- 4% ± 6 ns (p 0.002) 12 weeks 50 mg/kg, Mean= 0.8% ± 7 24 weeks 30 mg/kg, Mean=23% ± 6* 1 0 Outcome *Sta;s;cally significant increase in dystrophin produc;on at 24 weeks with the low dose (30 mg/kg) eteplirsen rela;ve to placebo. PaLent Immunohistochemistry Pre- Tx At 24 Weeks 30 mg/kg/wk Membrane intensity post treatment mean: 21.2 ± 4.7% Methodology: Muscle biopsy pre- & post. Two ;ssue blocks cut and stained with Mandys 106. Quan;fied in 12 fields photographed at 20X from 3 levels in each block (n=24 fields).

17 Phase 2b (Study 201): Significant Increase in Novel Dystrophin (Cont.) Western Blots RT- PCR Products of Exon Skipping 51 Mandys106 AcLn Skipped Product 17

18 Eteplirsen- Produced Consistent RestoraLon of the Dystroglycan- Complex: Study 33 and Study 201 Study Cirak., S. et al Restora<on of the Dystrophin- associatedglycoprotein Complex AKer Exon Skipping Therapy in Duchenne Muscular Dystrophy Mol Ther 2012 Feb; 20(2):462-7 Study 201 βsg 18 γsg Components of the sarcoglycan complex restored with dystrophin expression induced by eteplirsen (example shown (#6) similar in all cases receiving 30 mg/kg )

19 6 Minute Walk Test (6MWT) meters Treated Placebo Oldest pa;ent (10.95 yr) Youngest pa;ent (7.29 yr) weeks Average baseline score across all pa;ents (using only best of) was 382 meters. meters weeks Placebo (N=4) Treated (N=6) Benefit Over Placebo 6MWT Adjusted Mean Change from Baseline at 24 Wks* m m 17.8 m 19 *This analysis excludes two pa;ents on 30 mg/kg that exhibited a rapidly progressive decline on this measure (> 50 meters by week 12).

20 Phase 2b (Study 201): Key Findings Eteplirsen produced a stalslcally significant increase in dystrophin at 24 weeks, relalve to placebo. 22.5% mean increase in dystrophin- posi;ve fibers (levels ranging from 15.9% to 29.0%) at 24 weeks (30 mg/kg). p- value < vs. placebo (no increase from baseline) Scoring was blinded and based on mul;ple samples from each biopsy Shorter dura;on of treatment, 12 weeks, did not show a significant increase in novel dystrophin despite administra;on at a higher dose (50mg/kg). Indicates that a longer dura;on of dosing is required before meaningful levels of dystrophin are produced. Eteplirsen proved safe at both dose levels (up to 50mg/kg/wk over 28 weeks), with no treatment- related adverse events. No dose missed in any study subject over the 28 week course of administra;on. Favorable safety profile supports con;nuing/long- term treatment 20

21 n=4 n=4 21 Study Eteplirsen Phase IIb Extension Study: Open Label Long Term Safety and Efficacy Assessing Long- Term Safety and Efficacy Pre- Treatment Biopsy n=4 Study 201: Blinded Phase IIb 12 Weeks 24 Weeks ¾ Long- term safety and efficacy assessed Muscle Biopsies Pre- Treatment, 12 Weeks, 24 Weeks and 48 Weeks Biochemical Markers: Dystrophin and Immune- Inflammatory Response Clinical Outcomes: Various Tests of Muscle Func;on, Strength, and Endurance, Cardiac and Pulmonary Func;on Tests Safety 12- wk Biopsy 12- wk Biopsy n=2 24- wk Biopsy 24- wk Biopsy n=2 n=6 n=6 48- wk Biopsy Study 202: Open Label Long- Term Safety and Efficacy Study 48 Weeks * Pa;ents who were originally on placebo will be 24 weeks behind the ;meframe shown 30 mg/kg/wk 50 mg/kg/wk Placebo Control: Rolled Over to Open- Label Eteplirsen*

22 Beyond Eteplirsen: AddiLonal Exon- Skipping Therapies for DMD ~31,300 DMD Pa;ents (US, EU, JPN) Eteplirsen Phase 2b Extension Trial Ongoing Exon 51 ~15% (~4,000) 22 ~85% of DMD Pa;ents are Candidates for Exon Skipping (27,000) Exon 53 ~9% (~2,500) Exon 45 ~9% (~2,500) Exon 44 ~7% (~1,890) Exon 50 ~5% (~1,350) IND- enabling studies IND- enabling studies Collabora;ve Funding: Collabora;ve Funding:

23 AVI BioPharma/Advocacy Partnerships Scien;fic advisory boards CureDuchenne CureCMD (Congenital Muscular Dystrophy) Spinal Muscular Atrophy Founda;on advisory boards. Past funding by: Ac;on Duchenne CureDuchenne Charley s Fund PPMD Founda;on to Eradicate Duchenne - - NORD Recent Events Rare Disease Pa;ent Advocacy Day (FDA, March 1 st, 2012) PPMD Race for our Sons (Seayle Rock- n- Roll Marathon, June 23 rd 2012) MDA conference, PPMD conference 23