April 18, 2024

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FDA Questions Efficacy and Safety of DMD Gene Therapy SRP-9001

FDA Questions Efficacy and Safety of DMD Gene Therapy SRP-9001


FDA Questions Efficacy and Safety of DMD Gene Therapy SRP-9001.

The U.S. Food and Drug Administration (FDA) issued a briefing document ahead of an expert advisory committee meeting for Sarepta Therapeutics’ Duchenne muscular dystrophy (DMD) gene therapy SRP-9001 this Friday (May 12). concerns about the ability to treat patients safely and effectively.


After reviewing all the evidence, the FDA noted that clinical studies conducted to date have not provided clear evidence that SRP-9001 may benefit outpatients with DMD.

“Concluding with reasonable certainty from the data presented by the applicants that SRP-9001 is likely to be effective in younger patients, or not in older patients or those with poorer functional status, is challenging.”

The agency also noted safety concerns related to SRP-9001 “related to the potential for ineffective gene therapy.”


FDA Questions Efficacy and Safety of DMD Gene Therapy SRP-9001



The Cell, Tissue and Gene Therapy Advisory Committee meets to discuss four key topics. However, only one overarching question will be voted on: Given the uncertainty, does the available evidence support accelerated approval of SRP-9001, using surrogate endpoints for the treatment of DMD patients with confirmed DMD gene mutations?




Question 1: Are there predictable clinical benefits for surrogate endpoints that warrant accelerated approval

Whether it is possible to predict clinical benefit from the surrogate endpoint proposed by Sarepta that would qualify SRP-9001 for accelerated approval.

Sarepta has requested early approval based on the gene therapy’s ability to stimulate microdystrophin expression at week 12.

The FDA doubts that there is any evidence that this biomarker demonstrates the pharmacological effect of SRP-901, but it simply indicates that the protein is expressed in the target cells.

SRP-901 is designed to change the disease of DMD to a milder form called Becker Muscular Dystrophy (BMD). To do this, gene therapy is said to correct dystrophin expression in muscles, which Sarepta believes will correct the underlying cause of DMD.

The FDA raised concerns about the clinical benefit of SRP-9001 back in December 2018, when the agency questioned the surrogate endpoint and recommended that Sarepta choose an endpoint that “assesses clinically meaningful benefit, such as how the patient is feeling, functioning, or surviving”. The issue was brought up again in various meetings with the company in September 2020, July 2021 and April 2022.

In its last interaction before submitting a biologics license application (BLA), Sarepta cited regulatory precedent allowing accelerated approval for drugs that promote expression of the shortened form of dystrophin. The FDA countered that this does not necessarily equate to predicting clinical benefit to support accelerated approval.

BLA due September 28, 2022 .

In its submission, Sarepta argued that protein replacement, as demonstrated by natural history studies, has clinical benefits and slows disease progression.

“The restoration of functional dystrophin in DMD patients has long been considered a key and widely accepted therapeutic goal in the treatment of DMD,” said Sarepta, who believes SRP-9001 has already been shown to do just that. The company came up with several different preclinical studies to back this up.



Question 2: Data from only one clinical study is available

The second question concerns the only randomized, double-blind, placebo-controlled clinical study of SRP-9001 for which data are available so far, the first part of a Phase 2 Phase 102 study.

The primary objective was to assess the effect of treatment on the North Star Ambulatory Assessment (NSAA), a commonly used rating scale used to assess functional movement capacity, progression, and treatment effectiveness in children with DMD.


The study showed no statistically significant change in this measure at week 48 compared to placebo. The group that received gene therapy showed no improvement from baseline.


Instead, Sarepta pointed to a subgroup analysis that showed better outcomes for outpatients aged 4 to 5 years. But the 6- to 7-year-old patients did not show any improvement. At the time, the company blamed it on an apparent imbalance between the two parts of the trial, arguing that placebo patients had higher functional scores on NSAIDs at baseline.


According to the FDA, Sarepta claimed that the mean change from baseline in NSAA scores in patients treated with SRP-901 was “greater at all time points.”

“FDA’s assessment was that the differences between the SRP-901 and placebo groups at all time points were within the uncertainty limits, even as evidenced by a lack of statistical significance for trends,” the agency wrote.


Later, the FDA said that while age was an important factor in disease progression in DMD, the post hoc analysis was not prespecified.


“Ad hoc subgroup testing after an overall nonsignificant test in the entire population should be considered hypothetical only, so this subgroup analysis must be interpreted with caution,” the FDA said.


Sarepta provided evidence from the entire clinical program of SRP-901 to support clinical efficacy, including Studies 103, 102 and 101, and performed a combined analysis of the trials.

Study 103 is an ongoing open-label Phase 1, which means patients know they are receiving gene therapy, and NSAA score assessment is an exploratory goal. Patients in group 1 had a mean increase in NSAA score at week 52, with a significant increase in score after one year, Sarepta said.


Study 101—an open-label, single-arm phase 1/2 test—likewise showed an increase in scores that was sustained over four years.

As for Study 102, Sarepta again pointed to the NSAA’s baseline imbalance and said the results were “difficult to interpret”

“The overall pattern of treatment effects and NSAA total scores across the three trials was consistent, durable and attributable to SRP-9001,” Sarepta explained.



Question 3: Risk Uncertainty

The FDA has asked the committee to consider the risks of SRP-9001 gene therapy in outpatients on a third issue.

The FDA is flagging the overall safety of the AAV gene therapy category, which has been associated with treatment-emergent serious adverse events, including liver toxicity, organ damage, anemia and even death. Some animal studies have also shown the potential for cancer, although human tumor formation has not yet been demonstrated.

This type of risk must be considered in the risk-benefit analysis of SRP-901, the FDA said.

According to FDA statistics, “a total of 1,230 treatment-emergent adverse events occurred in 85 subjects,” but no deaths were observed in the study. Serious adverse events occurred in 11 patients, with the most commonly reported problems being vomiting, nausea, acute liver injury, fever, and low platelets.

Sarepta noted class effects and said liver damage was observed between weeks 4 and 8 of SRP-901 treatment, but these resolved without complications. These events were predictable, the company said.

Noting the rarity of DMD, Sarepta said the three studies represented “182.75 patient-years of exposure” and demonstrated that “SRP-9001 was generally safe and well tolerated.”

SRP-9001 was put on hold for two clinical trials during the development process that began in October 2017. In June 2018, the FDA first suspended the project because human patients “have been or may be exposed to an unreasonable risk of significant disease or injury” and the application for human testing does not have sufficient risk assessment information. Three months later, the clinical hold was lifted.

The second hold occurred in August 2021, when the FDA again pointed to the lack of risk assessment information. Meanwhile, a serious adverse event was reported in a 9-year-old patient who required hospitalization and respiratory support after taking SRP-9001.




Question 4: Can a confirmatory study be completed if listed

Last week, Sarepta executives previewed the problems they might face during the first-quarter earnings call. Chief Executive Doug Ingram anticipated the clinical benefit discussion, but also said the FDA may have questions about Sarepta’s ability to complete a confirmatory study.

The FDA did ask the committee to review the confirmatory study, which Sarepta is conducting through the first part of a Phase 3 Phase 301 study known as EMBARK. But the agency more specifically asked the committee to consider the impact that early market access might have had on completing the trial.

The study was a comprehensive study of 120 patients aged 4 to 8 years and tested SRP-901 against a placebo in a randomized, double-blind, 52-week period. There is also a crossover called Part Two that will start in June 2023.

Once SRP-9001 hits the market, the risk of patient withdrawal is “extremely low,” Sarepta said, because there are 45 patients in the trial outside the United States, which will be the only place where the gene therapy will be available.

Uy Ear, an analyst at Mizuho Securities, said the briefing document “could make it difficult to have a positive vote” at the advisory committee meeting.

The FDA does not have to follow the votes of advisory committees, but rather uses discussions to make decisions.

“Overall, we think the FDA briefing is a very poor read, with the FDA essentially stating that the currently available data do not support accelerated approval,” Ear wrote in a note to clients on Wednesday.

But investors apparently viewed the single-vote issue as a positive sign, since the FDA didn’t ask the committee to consider whether it should wait until EMBARK is complete before approving it.

Investors still think the FDA could approve the drug by May 29.





FDA Questions Efficacy and Safety of DMD Gene Therapy SRP-9001.

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