Food and Drug Administration scientists evaluating what could be the first gene therapy for Duchenne muscular dystrophy appear skeptical of the treatment’s benefit, adding to questions about its approval prospects days before a crucial regulatory meeting.
On Friday, the FDA will convene a panel of experts to discuss use of therapy, developed by biotechnology company Sarepta Therapeutics, for Duchenne patients who can still walk. Panelists will be asked to vote on whether an “accelerated” approval should be granted based on the therapy’s ability to help produce a potentially helpful protein called microdystrophin. Sarepta believes increases in this protein are “reasonably likely” to translate to clinical benefits.
The agency will also ask the panel to discuss, but not vote on, the impact an approval would have on an ongoing Phase 3 study of the therapy. Sarepta expects results in about six months from that study, which will represent a more definitive test of the treatment’s effects and potentially complicates the FDA’s decision.
The FDA doesn’t always follow the advice of its advisory panels, though it typically does. The agency is set to make a decision by May 29.
Documents released on Wednesday summarize the position of FDA scientists, giving a window into their view of the data Sarepta has compiled to date. They show that agency staff believe Sarepta has not provided “unambiguous evidence” its treatment can help Duchenne patients.
“It is challenging to conclude with reasonable certainty from the data provided by the applicant either that [the therapy] is likely effective for younger patients, or that it is likely ineffective for older patients or those with somewhat poorer functional status,” FDA staff wrote.
They also expressed concerns about approving a gene therapy that might be ineffective. Because treatment elicits an immune response to the engineered virus that delivers it, patients are expected to have only one opportunity to receive a therapy like Sarepta’s.
While the type of virus used by Sarepta is generally considered safe, some rare and serious adverse events, including liver damage and death, have occurred in trials of gene therapies that contain it.
The most frequent side effects reported in Sarepta’s studies were vomiting, nausea and liver injury. FDA reviewers also flagged five serious cases of acute liver injury, one instance of muscle weakness and a type of heart inflammation that occurred in clinical testing. The case of muscle weakness, myositis, is thought to be a shared effect of microdystrophin gene therapies and caused Sarepta to exclude patients with certain genetic mutations from testing.
“The documents create a shaky backdrop for the panel,” wrote Joseph Schwartz, an analyst at SVB Securities, in a Wednesday note to clients. They also undermine some of Sarepta’s past statements on the therapy’s benefit, he added.
Schwartz still anticipates the panel voting in favor of Sarepta's therapy, as do analysts at the investment bank Baird, who wrote in a note that the documents include “valid critiques” but give "a clear path for [a] yes vote."
Duchenne is a rare, progressive and fatal condition caused by a genetic mutation that stops the body from producing the muscle-protecting protein dystrophin. The disease, which is usually diagnosed in childhood and almost exclusively affects boys, slowly wastes away muscles. Patients typically lose the ability to walk in their teens and die from heart or lung weakness around 30 years old.
Several drugs known as “exon skippers,” including three from Sarepta, produce a shortened form of dystrophin and are thought, but not proven, to modestly slow the disease. However, most patients rely on steroids, which delay the disease’s progression but cause a variety of side effects and stunt growth.
Sarepta’s gene therapy is meant to be a one-time treatment that halts the disease for years, if not permanently. It spurs the body to produce microdystrophin, a diminutive version of the protein Duchenne patients lack.
Sarepta designed its treatment based on the shortened dystrophin genes of those with Becker muscular dystrophy, a milder form of the disease. Trial data to date from about 150 patients show the treatment can do so, increasing microdystrophyin levels to well beyond what is thought to change the trajectory of the disease. Sarepta is also leaning on evidence showing some treated patients are doing better than medical history suggests they should.
"We're going to ensure that the science is properly presented in an objective and rigorous way," Sarepta CEO Doug Ingram said in a recent interview, "and I think the science is going to speak very loudly."
Patients and doctors have been waiting on a Duchenne gene therapy for years. Several interviewed by BioPharma Dive in recent weeks believe the treatment is working and are expected to speak at Friday’s meeting.
“Time is muscle, and the alternative — doing nothing and letting the disease progress as we 100% know it will — when we could have this option made available is simply unacceptable," Jennifer Handt, whose five-year-old son Charlie has Duchenne and is involved in one of Sarepta’s trials, wrote in an email.
Yet there are questions about the impact of microdystrophin. In the documents, FDA scientists cautioned that it “differs in important ways” from the shortened dystrophin found in Becker patients or made by exon-skipping drugs. Reviewers also noted how Sarepta’s measurements of microdystrophin levels aren’t proof of a “pharmacologic effect” on a surrogate, or “biomarker,” of disease trajectory.
Notably, the gene therapy failed in the only placebo-controlled test Sarepta has completed so far. In that study, the therapy didn’t improve patients’ function compared to a placebo after one year. FDA staff also noted there wasn’t a clear correlation between their performance and microdystrophin expression in that portion of the trial.
When all of Sarepta’s human studies were pooled together, the correlation between expression and benefit appeared more compelling, the reviewers wrote. “However, the persuasiveness of such associations is uncertain,” they added, noting that most of the data comes from patients in open-label studies and “would be expected” to favor Sarepta’s treatment.
Sarepta originally had not expected the FDA to call an advisory committee meeting to review its therapy. But the agency apparently changed its mind in March, a reversal that Stat News reported was at the request of Peter Marks, who leads the FDA division in charge of reviewing gene therapies. According to Stat, agency staff were poised to reject the treatment before Marks intervened.
Marks recently argued in favor of using the accelerated approval pathway to bring new gene therapies to market. “We can’t be so careful about our approvals under accelerated approval that we prevent potentially life-saving therapies from getting to market in a timely manner,” he said at a March meeting held by the nonprofit Muscular Dystrophy Association.
Editor’s note: This story has been updated with additional detail on FDA views of Sarepta’s gene therapy, as well as patient and analyst comment.