FDA Division on Sarepta Gene Therapy Highlighted by Duchenne Approval

Peter Marks has once again become the focal point of a contentious decision by the Food and Drug Administration (FDA) regarding a gene therapy for Duchenne muscular dystrophy (DMD). This marks the second instance where the senior FDA official overruled objections from agency reviewers to approve a treatment from Sarepta Therapeutics for this muscle-wasting condition.

On Thursday, the FDA significantly expanded the use of Sarepta’s treatment, Elevidys, making it accessible to about 80% of DMD patients in the United States. Previously, Elevidys was only approved for boys aged 4 or 5. The new decision has not only broadened its use but also converted its status from accelerated approval to full approval, ensuring its continued presence in the market. DMD, a severe genetic disorder, has limited treatment options and no known cure.

According to Debra Miller, CEO of the patient advocacy group CureDuchenne, families dealing with DMD urgently need treatments to delay disease progression. Miller emphasized that the expanded use of Elevidys is a significant option for many affected boys and young men.

However, internal FDA documents reveal a significant divide within the agency regarding Elevidys. Three FDA review teams and two senior officials had recommended rejecting Sarepta’s application due to inconsistent and insufficient clinical data. Marks, head of the FDA center responsible for gene therapies, overruled these objections. He concluded that the data was sufficiently supportive to extend Elevidys' label. Now, the treatment is approved for DMD patients over the age of 4 with specific genetic mutations, regardless of their ambulatory status.

Marks has played a crucial role in the review of Elevidys. Before the initial approval last year, he advocated for an advisory meeting after learning that agency scientists were inclined to reject the treatment. He later overruled these reviewers to grant accelerated approval, while publicly promoting the FDA's flexibility in evaluating gene therapies for fatal diseases like DMD. Marks has spoken at various patient advocacy meetings, highlighting the agency's patient-focused approach and its willingness to expedite the development of rare disease treatments.

Despite Marks’ position, FDA reviewers continued to express skepticism. Elevidys failed to meet the primary endpoints in placebo-controlled trials, showing no significant improvement in motor function compared to a placebo after one year. FDA staff questioned the link between the microdystrophin protein produced by Elevidys and any consequential treatment benefit. They also found Sarepta's secondary evidence—such as improvements in how quickly a person can stand up—unconvincing.

Lola Fashoyin-Aje, director of clinical evaluation in the FDA’s gene therapy office, described these secondary findings as exploratory and potentially due to chance. She argued they should not be used as a basis for regulatory decisions. In her memo, Fashoyin-Aje supported the views of clinical, pharmacology, and statistical review teams, who stated that the evidence was insufficient to prove Elevidys' effectiveness or to justify its broader use.

Mike Singer and Xiaofei Wang, clinical reviewers, further argued that the secondary findings could not compensate for the failed primary outcome. They emphasized that these results might mislead patients, caregivers, and prescribers about Elevidys' potential benefits, as it was unclear whether these effects were due to the treatment or merely coincidental.

Contrarily, Marks found the secondary study results compelling and argued that historical data suggests even slight benefits can be meaningful for DMD patients. He asserted that making Elevidys widely available now could positively impact lives, especially given the urgent need for treatment options.

In making his decision, Marks mirrored a precedent set by former FDA official Janet Woodcock, who overruled reviewers to grant accelerated approval to another Sarepta drug, Exondys 51, eight years ago. Her decision, like Marks', was controversial and led to significant internal dissent within the FDA.

Tim Lugo, an analyst at William Blair, noted that Marks' decision might have lasting effects on the FDA and the gene therapy field. He predicted a more patient-focused and less adversarial review process for serious illnesses with few treatment options.