DUCHENNE MUSCULAR DYSTROPHY CLINICAL DEVELOPMENT PROGRAM

Transcription

1 DUCHENNE MUSCULAR DYSTROPHY CLINICAL DEVELOPMENT PROGRAM Dana R. Martin, PharmD Sarepta Therapeutics PPMD ANNUAL CONNECT CONFERENCE ORLANDO, FLORIDA JUNE 27, 2016

2 FORWARD LOOKING STATEMENTS This presentation, contains forward- looking statements. These forward- looking statements generally can be identified by the use of words such as believes or belief, anticipates, plans, expects, will, intends, potential, possible, advance and similar expressions. These forward- looking statements include statements about gathering western blot dystrophin data, our plans to submit such data to the FDA and a prompt decision by the FDA; our plans for our clinical development programs and other pipeline plans; the safety and efficacy of eteplirsen and other exon- skipping investigational therapies and the use and/or impact of the data collected; the potential market for our exon skipping product candidates and Sarepta s mission, commitments and business plans and strategies. Forward- looking statements also include those made during the presentation regarding future business developments and actions and the timing of the same. Each forward- looking statement contained in this presentation is subject to risks and uncertainties, including those outside of Sarepta s control, which could cause actual results to differ materially from those expressed or implied by such statement. Applicable risks and uncertainties include, among others: we may not be able to successfully gather all the data we currently plan to provide to the FDA or may not be able to otherwise comply with FDA requests, to the FDA s satisfaction, with respect to the additional dystrophin data requested by the FDA in a timely manner or at all; even if we provide the FDA with the additional dystrophin data requested, we do not know what the results will show and they could be inconsistent with prior data or result in an FDA finding that the data does not support approval of the eteplirsen NDA, on an expedited timeframe or at all, and the FDA may further delay its approval decision, make additional requests relating to the eteplirsen NDA, provide a complete response letter or otherwise decline to provide marketing approval for eteplirsen; we may not be able to comply with any other FDA requests relating to the eteplirsen NDA submission and the addendums we have submitted to the FDA or with respect to our ongoing or planned clinical trials, in a timely manner or at all; the FDA may further delay its decision on the eteplirsen NDA or may not provide marketing approval for eteplirsen; we may not be able to complete clinical trials required by the FDA for approval of our products or any submissions made in connection with our pipeline of product candidates; the results of our ongoing research and development efforts and clinical trials for our product candidates including eteplirsen and our technologies may not be positive or consistent with prior results or demonstrate a safe treatment benefit or support an NDA filing, positive advisory committee recommendation or marketing approval by the FDA or other regulatory authority; we may not be able to execute on our business plans including meeting our expected or planned regulatory milestones and timelines, clinical development plans and bringing our product candidates to market, including the planned commercialization of eteplirsen, for various reasons, including factors outside of the Company s control, including possible limitations of Company financial and other resources, manufacturing limitations that may not be anticipated or resolved for in a timely manner or at all, and regulatory, court or agency decisions, such as decisions by the United States Patent and Trademark Office with respect to patents that cover our product candidates; and those risks identified under the heading Risk Factors in Sarepta s most recent Annual Report on Form 10- K for the year ended December 31, 2015 or Quarterly Report on Form 10- Q for the quarter ended March 31, 2016 filed with the Securities and Exchange Commission (SEC) as well as other SEC filings made by Sarepta which you are encouraged to review. Any of the foregoing risks could materially and adversely affect Sarepta's business, results of operations and the trading price of Sarepta's common stock. For a detailed description of risks and uncertainties Sarepta faces, you are encouraged to review the Company's filings with the SEC. We caution investors not to place considerable reliance on the forward- looking statements contained in this press release. Sarepta does not undertake any obligation to publicly update its forward- looking statements based on events or circumstances after the date hereof. 2

3 ETEPLIRSEN NEW DRUG APPLICATION (NDA) Current Status Gathering Western blot dystrophin data from the PROMOVI confirmatory study 1 Consists of 13 biopsy samples and will compare baseline values to week 48 values Data will be submitted to FDA over the coming weeks to facilitate a prompt decision on the NDA by the FDA 1 What should you do? Keep in touch and engaged with Duchenne advocacy organizations and other advocates Reach out to Sarepta directly at any time if you have any questions Trial related questions: trialinfo@sarepta.com skipahead@sarepta.com or call DMD- SKIP 1. Sarepta Press Release June 6,

4 OUR CURRENT PLANS SUPPORTING OUR COMMITMENT TO DUCHENNE Sarepta s Phosphorodiamidate Morpholino Oligomer (PMO) Pipeline As per previous slide, NDA for eteplirsen under review by FDA Expand clinical development of SRP and SRP for skipping exons 45 and 53 Planning to have clinical sites in US, Europe, and Canada Continue evaluation of exon- skipping candidates for other amenable exons Other Evaluate next generation exon- skipping therapeutics To continuously evaluate potential combination therapeutic approaches with exon- skipping and other development platforms (e.g., gene therapy) 4

5 AGENDA The Importance of Genetic Testing Exon Skipping Simplified Clinical Development Program Conclusions 5

6 The Importance of Genetic Testing 6

7 DIAGNOSTICS GENETIC TESTING IS ALWAYS NECESSARY 1 Required to determine eligibility for drugs targeted to specific mutations 2 Examples: Exon skipping and nonsense mutation specific therapeutics Enables more thorough understanding of genotype- phenotype 2 Provides additional clinical information to enable proper genetic counseling 1 It is the current standard of diagnosis for Duchenne 1 1. Bushby, K. et al. Lancet Neurol. 2010;9(1): FDA Draft Guidance DMD and Related Dystrophinopathies,

8 GENETIC TESTING FOR DUCHENNE: CURRENT STATUS IN THE UNITED STATES 1 Approximately 40% of boys/men with Duchenne have not received genetic testing Even when genetic testing is performed there remains a significant knowledge gap to interpret the results further to determine amenability to mutation- specific investigational therapies 5,000 % Genotyped by Center Size 4,500 Number of Patients 4,000 3,500 3,000 2,500 2,000 1,500 69% Overall % Genotyped 60% 40% 1, > 100 patients 51% > 50 - < 100 patients 35% < 50 patients Genotyped Not Genotyped 1 Sarepta Therapeutics Data on File 8

9 HOW TO ACCESS GENETIC TESTING Speak to your/your son s doctor about genetic testing for DMD. Was it performed? If Yes Has genetic counseling been offered? Has amenability to mutation- targeted investigational therapeutics been determined? If No Has insurance denied coverage? Was it determined not necessary? PPMD s Decode Duchenne program provides free genetic testing, interpretation, and counseling for people with Duchenne or Becker muscular dystrophy. 1 Example: PPMD resource for physicians to determine exon- skipping amenability 1 duchenneconnect.org. [Internet] [cited 25 June 2016]. Available from: 9

10 Exon Skipping Simplified 10

11 EXON SKIPPING SIMPLIFIED The dystrophin protein acts as a molecular shock absorber, protecting muscle during muscle contraction Boys/men with DMD have little to no dystrophin protein, many with out- of- frame exon deletions, impacting the ability to produce any functional dystrophin The goal of exon skipping is to restore the DMD gene reading frame, allowing for production of a shortened but functional dystrophin protein in patients with out- of- frame deletions 11

12 DYSTROPHIN (DMD) GENE EXON MAP The different shapes represent specific sequences where exons connect to each other The exons need to fit together like a jigsaw puzzle in order to produce dystrophin protein 12

13 DYSTROPHIN (DMD) GENE EXON MAP This is an example of out- of- frame deletions of exons 49 and 50 As you can see, the pieces do not line up and the reading frame is disrupted 13

14 DYSTROPHIN (DMD) GENE EXON MAP PMO Sarepta s PMO technology targets a specific exon to skip, in this case exon 51 14

15 DYSTROPHIN (DMD) GENE EXON MAP PMO Skipping exon 51 allows the reading frame to line up and the potential for production of shortened dystrophin protein 15

16 UNDERSTANDING GENE MUTATIONS This represents DMD gene mutations amenable to skipping exon What is wrong with exon 51? 16

17 Sarepta s Duchenne Clinical Development Program 17

18 DUCHENNE CLINICAL DEVELOPMENT 6 ON- GOING TRIALS, 1 PLANNED Study Name/No. Exon target Length of Study # of Patients (approx.) Key Inclusion Enrollment Status US- 202 Exon weeks year old male Ambulatory Complete Exon weeks ~40 ~20 treated ~20 untreated 4 6 year old male Ambulatory Enrolling (Untreated) Exon weeks ~24 ~24 treated 7 21 year old male Limited to no ambulation Complete (PROMOVI) Exon weeks (plus 48 week extension) ~160 ~80 treated ~ 80 untreated 7 16 year old male Ambulatory Enrolling (Treated and Untreated) Exon 53 Part 1: 12 weeks Part II: 48 weeks 12 (Part I); 48 (Part II) Part I: 8 placebo, 4 treated Part II: 24 treated (12 Part I), 24 untreated 6 15 year old male Ambulatory Complete Exon weeks (plus 108 weeks extension) ~12 ~12 treated (extension phase) 7 21 year old male Limited to no ambulation Complete (ESSENCE) Exon 45 or Exon weeks (plus 96 week extension) ~ year old male Ambulatory Enrolling soon 18

19 EXON 51 SKIPPING (ETEPLIRSEN) CLINICAL DEVELOPMENT Strong consideration of FDA guidance and input from advocates Patients should not be unnecessarily excluded from enrollment in clinical trials due to age or disease stage unless scientifically justified 1 Based on current clinical trials, approximately 135 males in total, amenable to exon 51 skipping, expected to enroll Age 4 6 years (~20 males) Ambulant Age 7 16 years (~92 males) Ambulant Age 7 21 years (~24 males) Limited to no ambulation Study Study US- 202 Study (PROMOVI) Study FDA Draft Guidance DMD and Related Dystrophinopathies,

20 EXON 45 SKIPPING (SRP- 4045) AND EXON 53 SKIPPING (SRP- 4053) CLINICAL DEVELOPMENT Strong Consideration of FDA Guidance and input from advocates Based on current clinical trials, approximately 140 boys/men amenable to exon 45 skipping or 53 skipping expected to enroll Age 6 15 years (~24 males, exon 53) Ambulant Study Age 7 13 years (~ 50 males, exon 45; ~50 males, exon 53) Ambulant Study (ESSENCE) Age 7 21 years (~12 males, exon 45) Limited to no ambulation Study

21 ESSENCE TRIAL DESIGN FOR MUTATIONS AMENABLE TO EXON 45 SKIPPING OR EXON 53 SKIPPING Overview ~ 99 males to enroll 96 week, double- blind, placebo controlled Roll over to open- label for 96 weeks Randomized 2:1 (66 active treatment:33 placebo) Conducted at sites in US, Europe, Canada Inclusion/Exclusion Age 7 13 years Amenable to skipping exon 45 or 53 Average 6MWT (2 consecutive days) meters Stable corticosteroid dose Minimum 24 weeks prior to entry Considerations 2:1 randomization designed to mitigate number of boys on placebo Interim analysis planned when 75% of boys enrolled reach week 48 All boys may roll over to open- label study at end of 96 weeks for 96 weeks For more information go to clinicaltrials.gov/show/nct or contact Sarepta at trialinfo@sarepta.com 21

22 ESSENCE CLINICAL TRIAL (EXON 45 AND 53 SKIPPING) IMPORTANCE/RELEVANCE 1. Confirmatory clinical trial for eteplirsen if granted accelerated approval SRP- 4045and SRP have the same PMO chemistry backbone 2. Pivotal Phase 3 study for SRP and SRP The intent is to file for regulatory approval of both investigational products based on the data from this trial to potentially enable broadest availability for patients with mutations amenable to exon 45 skipping or exon 53 skipping 3. Data to serve as foundation to the advancement of all follow- on exon programs 22

23 ESSENCE TRIAL Q&A (1 OF 2) Why a double- blind, placebo- controlled trial? Following FDA guidance will provide the most efficient pathway to approval To serve as a foundation to the advancement of our follow- on exon skipping products Why was the placebo- control extended from 48 weeks to 96 weeks? A statistically significant divergence (or separation) in 6MWT between boys on eteplirsen versus an external control was not demonstrated at 48 weeks in boys participating in study 201/202 FDA guidance states that efficacy studies of 18 to 24 months duration may substantially increase statistical power while only modestly increasing overall development time We believe that increasing to 96 weeks will increase the likelihood of meeting the primary endpoint leading to broader access to Duchenne populations amenable to these investigational candidates 23

24 ESSENCE TRIAL Q&A (2 OF 2) Why was the age range reduced from age 7 16 years to age 7 13 years? To enroll a very homogenous (similar) population We used the most current understanding of Duchenne to ensure data are interpretable Less predictable disease course in boys > 13 years who walk further than 300 meters on the 6MWT What can the community do? Stay informed with your doctor and other members of the community Sarepta will work closely with investigators, study staff and advocacy organizations to expedite enrollment Contact your doctor or genetic counselor about genetic testing if unsure it has been completed 24

25 CONCLUSIONS Sarepta is committed to continuing our focus on development of potential exon- skipping therapeutics for Duchenne muscular dystrophy Genetic testing is an important first step to determining eligibility for mutation- specific clinical trials Sarepta has ongoing clinical trials actively enrolling in treated and untreated cohorts Phase 3 ESSENCE clinical trial is 1) a confirmatory study for eteplirsen (if granted accelerated approval) 2) aims to demonstrate potential safety and efficacy of SRP- 4045, SRP and 3) may serve as a foundation to the advancement of our future DMD development programs 25

26 WE ARE EXTREMELY GRATEFUL FOR THE CONTINUED SUPPORT OF THE ADVOCACY COMMUNITY, DUCHENNE EXPERTS, TREATERS AND OTHER HEALTHCARE PROFESSIONALS, PARENTS AND FAMILIES, AND MOST OF ALL THE BOYS AND MEN WHO PARTICIPATE IN OUR CLINICAL TRIALS. THANK YOU! 26