Pfizer setback brings questions for Duchenne gene therapy ahead of Sarepta decision

Phase 3Gene Therapy
The failure of a Pfizer medicine for Duchenne muscular dystrophy adds new uncertainty around the effectiveness of gene therapy for the muscle-wasting condition, days before the Food and Drug Administration is expected to decide on expanding use of a similar treatment from Sarepta Therapeutics.
On Wednesday, Pfizer said the treatment missed its mark in a definitive Phase 3 study of boys between 4 and 7 years of age with Duchenne. Pfizer didn’t disclose specifics, but said the therapy didn’t lead to a significant difference versus placebo on a measure of motor function, or on key secondary measures such as timed tests for how quickly study participants could stand or walk. The results will be presented at future medical and patient advocacy meetings.
The study’s failure makes it much less likely there will soon be a second gene therapy option for people with Duchenne, a progressive and deadly condition with no cure and limited treatment options. Pfizer had previously expected to file for a regulatory approval of its medicine if study results were positive. Now the company says it is “evaluating appropriate next steps” for the program. Multiple Wall Street analysts expect Pfizer to discontinue research.
The results are “a discouraging blow to our community, particularly devastating to those who participated in the study,” said Parent Project Muscular Dystrophy, a patient advocacy group, in a statement.
The setback also has important implications for Sarepta, whose therapy, Elevidys, is the only approved gene therapy for the disease. The Food and Drug Administration is currently reviewing whether to broaden use of Elevidys. A decision is expected by June 21.
The FDA last year granted an accelerated approval to Elevidys, a milestone clearance built on decades of scientific research into how to correct the genetic errors that cause Duchenne. Yet that approval was narrower than Sarepta had hoped, a reflection of mixed study results that led some FDA scientists to question Elevidys’ effectiveness. The therapy was only approved after Peter Marks, the head of the FDA office that reviews gene therapies, overruled other agency reviewers.
Pfizer and Sarepta’s treatments deliver into the body instructions to make a tiny version of a muscle-protecting protein that people with Duchenne lack. Researchers engineered this so-called microdystrophin because it’s small enough to pack into the benign viruses used to deliver gene therapies. It is designed to imitate a form of the protein found in people with a milder type of muscular dystrophy.
The FDA has established dystrophin production as a biological marker likely to predict a benefit in Duchenne patients, and has used it to approve multiple therapies in the last decade. Developers and researchers similarly believe microdystrophin can be helpful, and that the substantial levels gene therapies produce can halt or even reverse Duchenne’s course.
But evidence in testing of Sarepta and Pfizer’s therapies hasn’t shown that, leading to uncertainty about the connection between protein production and functional benefits. Sarepta’s treatment missed the main goal of two placebo-controlled trials, one of which was meant to provide confirmatory evidence for Elevidys’ approval. A dystrophin-boosting medicine from Japanese drug developer Nippon Shinyaku also recently failed a trial that was supposed to validate earlier results. Now Pfizer’s therapy has fallen short, too.
The findings “could perpetuate some questions about correlation between micro/mini-dystrophin expression and functional improvements, which could be important for the FDA’s comfort around accelerated approval for Elevidys in broader populations, ” wrote RBC Capital Markets analyst Brian Abrahams in a note to clients.
“Having a second gene therapy with a relatively similar approach show efficacy could have helped reassure that Elevidys's effects are real [or] replicable,” Abrahams added.
Baird analyst Brian Skorney noted how skeptics believe the stumbles for dystrophin and microdystrophin-producing drugs “should lead to the agency rethinking the suitability” of the proteins as predictive markers.
Sarepta has argued the “totality of the evidence” in its clinical trials makes clear the benefits of treatment. Unlike Pfizer, Sarepta reported consistent benefits on multiple secondary measures in its latest trial — effects that, it claims, persuaded the FDA to consider a broader label. Sarepta’s treatment is also made of different gene therapy components and testing hasn’t been slowed by safety concerns, as Pfizer’s therapy has.
As a result, analysts have expected the FDA to widen Elevidys’ availability, and many still do following Pfizer’s setback. Skorney contended, that rather than change its view of Elevidys, the agency and companies should re-evaluate the viability of designing Duchenne trials with one-year study goals. Because Duchenne is a heterogeneous condition, that “just isn’t enough” time to detect a treatment effect, he wrote.
In a separate note to clients, Mizuho Securities’ Uy Ear wrote the FDA has likely already made its decision, rendering Pfizer's results irrelevant to Sarepta’s case.
The “consistency of Pfizer’s negative data provide support” for Sarepta's “consistently positive” secondary results, according to Ear, who added that his team believes ”the key secondary endpoints demonstrate that Elevidys has activity in [Duchenne] and that these positive data were unlikely to be a coincidence.”
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