DMD: Sarepta Updates Community on Eteplirsen Plans, Pipeline

Sarepta Therapeutics announced it is on track to submit an application to the U.S. Food and Drug Administration (FDA) for approval of eteplirsen in the first half of 2014.

In parallel with that application, the company is preparing to conduct a large-scale, confirmatory trial of eteplirsen. It plans to open the trial during the first quarter of 2014.

Eteplirsen is an experimental drug designed to treat approximately 13 percent of patients with Duchenne muscular dystrophy (DMD). Its mechanism of action is exon skipping, and its target is exon (section) 51 of the dystrophin gene, which is mutated in DMD.

In September 2013, Sarepta announced that walking distance of trial participants continued to show stabilization 96 weeks (1.8 years) into a phase 2b trial. The stabilized walking distance, measured in a "six-minute walk test," contrasts with the expected decline in walking distance that would be expected in untreated DMD patients over this period of time.

The trial includes 12 participants, although only 10 could be assessed on the six-minute walk test, because two lost the ability to walk early in the study. An additional participant sustained a leg fracture late in the trial and could not be evaluated at all time points. (The two who lost walking ability continue to be treated with eteplirsen and are being evaluated on measures other than walking.)

In an Oct. 17, 2013, webcast, available for replay on the Sarepta site, the DMD community received a comprehensive update about Sarepta's plans for eteplirsen and "follow-on" compounds that target other parts (exons) of the dystrophin gene.

Chris Garabedian, Sarepta's president and CEO, and Ed Kaye, Sarepta's senior vice president and chief medical officer, provided an overview of the company's plans and answered questions from the community.

Representing DMD patients and families on the webcast were: Jane Larkindale, MDA's vice president of research; Sharon Hesterlee and Holly Peay of Parent Project Muscular Dystrophy; Marissa Penrod from Duchenne Alliance; and Debra Miller from Cure Duchenne.

Listeners also were directed to Let's Skip Ahead, Sarepta's new online resource center for families with DMD.

A summary of the Oct. 17 webcast, including a question-and-answer session with representatives from patient organizations, follows.

Sarepta's plans for eteplirsen: FDA application, confirmatory trial

Chris Garabedian and Ed Kaye said:

  • The company plans to meet with the FDA in October and November 2013 and plans to submit its new drug application (NDA) for eteplirsen in the first half of 2014. It is not known whether or not the FDA will consider eteplirsen eligible for its accelerated approval program.
  • Sarepta is setting up a confirmatory trial of eteplirsen during the remainder of 2013 and is on track to begin patient dosing in the first quarter of 2014. An accelerated approval for eteplirsen would mean the drug could be made available to patients prior to completion of the confirmatory trial, although the confirmatory trial would still be required of Sarepta to confirm eteplirsen's clinical benefit and safety.
  • The preliminary plan for the confirmatory eteplirsen trial does not include a placebo group, though Sarepta will seek additional feedback from the FDA before it finalizes the study design.
  • In the confirmatory trial, 60 participants with DMD who are ages 7 and older with dystrophin mutations that can potentially be treated by skipping exon 51 of the dystrophin gene will receive eteplirsen. At the same time, 60 participants ages 7 and older who cannot be helped by eteplirsen, because they have mutations that can be treated by skipping exons 44, 45, 50 or 53, will not receive an exon-skipping drug and will be the comparison group. All participants will need to be on a stable regimen of corticosteroid medication.
  • The untreated participants with mutations in parts of the dystrophin gene near exon 44, 45, 50 or 53 could potentially become candidates for later trials of drugs in Sarepta's pipeline that target these exons; "natural history" data gathered during the confirmatory eteplirsen trial is likely to help with these trials.
  • Sarepta is exploring the possibility for U.S. and Canadian participants in the placebo group of a previous trial of drisapersen (a different DMD exon-skipping drug) to participate in the confirmatory eteplirsen trial; Sarepta also may explore whether there is an option for patients who have previously received drisapersen, but a decision has not yet been made.

Sarepta's plans for additional exon-skipping drugs

Chris Garabedian and Ed Kaye said:

  • Sarepta has four follow-on exon-skipping drugs in its pipeline, targeting exon 45, exon 53, exon 50 and exon 44.
  • The company hopes to seek approval from the FDA to conduct a clinical trial of one of these drugs by mid-2014 and of an additional one by the end of 2014.
  • The company hopes to see drug development for all patients with DMD who can be helped by exon skipping, which it estimates to be about 80 percent of those with DMD.
  • DMD patients with mutations that can potentially be helped by exon skipping but not by skipping exon 51, 45, 53, 50 or 44 are too few in number for standard clinical trials to be conducted. Based on potential success with eteplirsen and its follow-on exon-skipping drug candidates, the company hopes to ask the FDA in the future for "class approval" for drugs targeting additional exons, based on evidence of safety, production of dystrophin protein and functional effectiveness of drugs designed for the more common mutations.
  • The company plans to use the same technology to develop approximately 20 exon-skipping drugs in addition to the five drugs in its current pipeline; these are the drugs for which FDA class approval will be sought.

Question-and-answer highlights

Chris Garabedian and Ed Kaye answered questions from representatives of four DMD organizations, including MDA. The questions were based on feedback from the DMD community. Here are some of the questions and answers; they have been lightly edited for clarity and brevity.

Q: What are the repercussions from the recent failure of drisapersen to show efficacy in a phase 3 trial? How do you think this will affect the approval process for eteplirsen or the use of the six-minute walk test?

A: We can't comment on the drisapersen study, because we were not participants, and we do not understand all the aspects of it. [Drisapersen is in development by Prosensa and GlaxoSmithKline.]

That study has caused concern about whether the six-minute walk test is appropriate for boys with DMD. We believe it is a good test. In our review of the data, we found it to be a sensitive endpoint.

We focus on patient selection for this endpoint [the six-minute walk test]. We're not trying to improve the six-minute walk distance but to maintain it. We have a cohort [group] expected to deteriorate on the six-minute walk distance, with children who are older than 7 years. By having a homogeneous population that should decline [without treatment] and being able to show that they are stable, we think we have a good study design.

We think these two drugs [drisapersen and eteplirsen] are very different. They are different chemical entities, with very different chemical backbones. We do not think the drisapersen failure is an indictment of exon skipping. Our plans for an NDA submission are intact.

Q: Most of those with DMD develop cardiomyopathy. Has eteplirsen shown any benefit on cardiac measures? What are the expectations on this?

A: Cardiomyopathy is an important part of the disease, but we chose boys for this study who were younger and did not have cardiac problems at the outset of this trial. We have followed them with EKGs and echocardiograms, and we have not seen any changes. However, they were normal to begin with. We will continue to follow these boys long-term. It's too early to tell about the effect.

Q: Do you plan to address patients with duplications in the dystrophin gene or who need to have multiple exons skipped?

A: Currently we do not have a product candidate or effort in place to address duplications or multiple exon skipping. Our current focus is to have every patient with a deletion that could benefit from our technology have a drug available to them. There are some expert scientists and clinicians looking at the possibility of applying exon skipping to other types of mutations such as duplications. This work is at a very early stage, and we will be following it to see how it progresses. We remain committed to exploring the potential of our exon-skipping technology.

Q: Will nonambulatory patients be included in subsequent trials?

A: We are focused on the six-minute walk test [as an outcome measure] for now, as it has been validated for regulatory approval. A lot of outcome measures for the upper extremity have not been validated. Initially we are focusing for our confirmatory study for exon 51 on the six-minute walk test. But as we gain more information about how to look at arm function, we will consider looking at nonambulatory patients. We need more understanding of how to evaluate effectiveness in this patient group, and we need to obtain more safety data.

We have two nonambulatory boys in the current trial who showed dystrophin production at 24 and 48 weeks. They lost ambulation early in the study and could not do the six-minute walk test, but the data suggest stabilization on pulmonary function and on other measures, and safety has been shown.

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