Wave Life Sciences Enters FDA's Clinical Trial Pilot Program to Develop DMD Drug

animation of dystrophin muscle protein domain

Dystrophin muscle protein domain (N-terminal actin binding domain). Defects cause Duchenne muscular dystrophy (DMD).

WAVE Life Sciences is working to get its nucleic acid treatment, suvodirsen, for Duchenne muscular dystrophy (DMD) approved. DMD is a rare muscle-wasting disease that affects mostly boys, about 15,000 in the U.S. There is already a drug, Sarepta Therapeutics’ Exondys 51, on the market for DMD, although the drug is controversial and expensive.

Because of the low number of patients available, it is difficult to design appropriate clinical trials. Wave was chosen earlier this month into the U.S. Food and Drug Administration (FDA)’s Complex and Innovative Trial Design pilot program. Wave and the FDA will work to design a Phase II/III clinical trial with a lower number of trial participants.

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Suvordirsen focuses on 13 percent of DMD patients with the most common gene mutation. DMD is caused by mutations to the dystrophin gene, which is involved in muscle development. There are approximately 2,000 known mutations causing the disease. Wave believes that suvodirsen will induce significantly higher levels of dystrophin expression than Sarepta’s Exondys 51. Both drugs target the same gene mutation.

The Exondys 51 approval was both dramatic and controversial. There was significant controversy within the agency. There were at least three major opponents to approval within the FDA. Ronald Farkas, clinical team leader, left the agency just prior to approval. The agency’s acting chief scientist, Luciana Borio, and Ellis Unger, director of the office of drug evaluation, strongly opposed approval, arguing that Sarepta did not provide substantial evidence of Exondys 51’s effectiveness.

Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research (CDER), pushed it through, overruling her staff. The final decision went to Robert Califf, then FDA Commissioner. Evidence suggests Califf had similar reservations as Borio and Unger, but sided with Woodcock.

Some of the concerns about the Exondys 51 trial revolved around the very small size of the trial—about 12 patients—and the lack of controls, and the use of separate trial data. As part of the approval, Sarepta was required to conduct a two-year, randomized controlled trial to verify the drug’s benefits.

In fact, in September 2018, the European Medicines Agency (EMA) rejected Sarepta’s application for Exondys 51.

It appears that Wave’s application to the Complex and Innovative Trial Design pilot program bears similarities to Sarepta’s approach in 2016. The FDA looked at two key criteria, the innovative features of the trial design and the therapeutic need. Wave’s application included a plan to leverage DMD historical control data to add to the placebo arm of the Phase II/III clinical trial, among other elements.

Part of the goal of the program and Wave’s design is to reduce the number of patients needed to deliver conclusive results. 

“In designing our clinical trials, we are constantly looking to maximize the probability of a definitive result, incorporate the feedback of patients and their families, and reduce the burden on those who are already bravely enduring the challenges associated with serious, genetically-defined diseases,” stated Michael Panzara, Wave’s chief medical officer. “The FDA’s recognition of our plan reflects the thoughtful and collaborative way in which we approach clinical development.”

The FDA CID pilot program falls under the 21stCentury Cures Act, which has, among other things, a goal of modernizing clinical trial design. It also hopes to streamline and advance drug development and make for less complex regulatory decision-making.

Comparing their approach to that of Sarepta’s, Panzara told the Boston Business Journal, “When you have an open-label study with no control group and then post-hoc say, we’re going to compare this to historical data, it’s hard to know how that allows you to access efficacy. We’re using historical information from the beginning.”

Reportedly Wave has already recruited 40 DMD patients for the trial; the Phase I extension study began in August 2018.

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