Today was a historic day for the Duchenne community: the first FDA Advisory Committee meeting for a gene therapy intended to treat Duchenne. This meeting was held as part of the regulatory review process for SRP-9001 (delandistrogene moxeparvovec), Sarepta’s investigational gene therapy, which has applied for FDA approval through the Accelerated Approval pathway, with the requested indication for the treatment of ambulatory patients with Duchenne.

Advisory Committee meetings offer the opportunity for the FDA to include a variety of perspectives before making the final regulatory decision for the therapy under review. Today’s meeting does not reflect the final decision of the FDA for SRP-9001 – the final decision remains the responsibility of the Center for Biologics Evaluation and Research (CBER) review division and is expected on or around SRP-9001’s PDUFA date of May 29th.

However, PPMD is optimistic as the majority of today’s Advisory Committee members (8 of 14) voted favorably, echoing the overwhelming sentiment shared in testimonies throughout the day – “time is muscle.”

We are grateful that the FDA agreed to hold today’s Advisory Committee meeting so that Duchenne families, clinicians, and scientists could share their perspectives, preferences, and priorities. We thank FDA and CBER for their consideration of these views and hope they are all carefully considered when reviewing SRP-9001.

Thank you to everyone – families, physicians, scientists – who raised their voices today to deliver a clear, concise message about the importance of gene therapy and its relevance to treatments for Duchenne. Whether you sent in written testimony or provided an oral testimony, we thank you for sharing your story so that the FDA can make their decision fully understanding the perspectives of our community.

Our Duchenne community stands ready to support the continuing progress on SRP-9001’s ongoing review, between now and the PDUFA date of May 29th. We are hopeful CBER will exercise regulatory flexibility as they weigh the benefits and risks of SRP-9001, which is a source of hope for our Duchenne community.

Join the Virtual Town Hall

Along with our community partners, PPMD will host a Virtual Town Hall on Thursday, May 18th, at 4 PM ET where we will debrief on today’s FDA Advisory Committee meeting and provide next steps leading up to the SRP-9001 PDUFA date on May 29th. You can register to participate here and submit questions in advance.

What We Learned Today

FDA Advisory Committee meetings consist of presentations from both the applicant and the FDA around the product’s application which is under review, an open public hearing portion, and questions and votes which are presented to facilitate discussion around the findings and complexities of the clinical study and related matters (such as manufacturing and preclinical studies) that has been presented throughout the day.

Sarepta’s Testimony

The focus of Sarepta’s testimony during the advisory committee was to provide additional context on SRP-9001 to the voting members. Sarepta laid out the requirements for meeting accelerated approval and how the data they have collected since their initial study could be supportive of granting approval through that pathway, in addition to having completed enrollment of their confirmatory study. Dr Jerry Mendell provided background on Duchenne and educated the committee on the clinical meaningfulness of changes in the NSAA. Dr. Rodino-Klapac highlighted the development process for Sarepta’s micro-dystrophin including key regions of the dystrophin protein seen in Becker patients and maintained in their micro-dystrophin. Drs. Mason, Signorovitch, and McDondald outlined the clinical trial results and comparison to external controls that demonstrate the efficacy of SRP-9001. Safety data, including monitoring plans and proposed mutation restrictions involving exons 9-13, was presented by Dr. Darton.

Open Public Hearing

During the open public hearing, families, clinicians and experts in the Duchenne community shared their experiences. Families participating in SRP-9001 clinical trials repeatedly expressed how increased function allows independence and the ability to keep up with their peers. Clinicians highlighted their personal experiences caring for children who received SRP-9001 and observing the change in their function over time and the significance of those functional impacts on patient quality of life. They also stressed the need to build the infrastructure needed to ensure delivery to patients and long-term monitoring.

FDA Presentation

The FDA presented their concerns following reviewing Sarepta’s application. The four areas of concern expressed with the application were:

• The FDA felt that they could not compare data from two different methods used to produce SRP-9001, as SRP-9001 transitioned from product made at Nationwide Children’s Hospital to their commercial product. Additionally, they discussed concerns about translating preclinical animal models to humans.
• The micro-dystrophin transgene used by Sarepta does not exist in nature, though it was rationally designed, which limits their ability to make predictions on its effects
• The FDA expressed concerns about safety for SRP-9001, including effects seen in other gene therapy products not necessarily witnessed in SRP-9001 clinical trials. They also raised concern about potential efficacy of SRP-9001 and limiting access to future gene therapies.
• Finally the FDA raised concerns about the impact of accelerated approval compromising the ability of Sarepta to complete their confirmatory study.

Voting & Discussion

One question was presented to the Advisory Committee today, with discussions followed by a vote on that discussion. The question posed to the committee was if they would support accelerated approval of SRP-9001 based on micro-dystrophin as a surrogate at 12-weeks given the uncertainties and overall considerations of benefit/risk.

In an 8-6 vote, the Advisory Committee voted in favor of supporting Accelerated Approval for SRP-9001.

• Those that voted against cited the challenge of evaluating SRP-9001 with limited data from the three studies presented.
• Members voting in support referenced the potential benefit of SRP-9001 outweighing the risk with the known course of Duchenne disease progression.

While this is exciting and hopeful news, it is important to remember that it does not guarantee that the FDA will grant Accelerated Approval for SRP-9001. The result of the votes today should be viewed as Committee advice to CBER and do not reflect the final decision of the FDA. Discussions from today’s Advisory Committee meeting will be used to help further inform regulators before a decision is made, on or before SRP-9001’s PDUFA date of May 29th.

A Community United

PPMD, our community partners, and many others are optimistic that gene therapy could be a potential treatment for Duchenne. Despite the advances made with five prior drug approvals for Duchenne and a full, promising therapeutic pipeline, our community continues to have significant unmet needs. A gene therapy that targets both skeletal muscle and the heart and delivers a smaller but functional version of the protein holds promise. These kinds of therapeutic advancements further build upon, and extend, the positive impact of Duchenne therapy development to date.

We are optimistic that the majority of voting members voted yes today and we hope that, factoring in both the clinical evidence and the available data regarding patient-family perspectives and preferences, the FDA will apply appropriate regulatory flexibility in the review of SRP-9001. It is critical for our community that new, safe therapies that can modify the course of this disease are accessible at the earliest possible opportunity.

PPMD’s Submissions to the Advisory Committee

While PPMD is disappointed that we were not selected to speak during the Open Public Hearing (OPH) portion of the meeting, our written testimony submissions reflect our belief that the patient voice must be captured and reflected in regulatory decisions, including during FDA’s review of SRP-9001:

• PPMD submitted a summary of our work with Duchenne UK, a UK-based patient advocacy group, and social scientists at RTI International, through which we conducted a scientific, rigorous study capturing the Duchenne community’s views on risk tolerance to gene therapy. In our written testimony to the Advisory Committee, this summary of unpublished data highlights the high risk tolerance of our community in exchange for a slowing of disease progression, a view we hope the agency will reflect on in weighing benefit-risk.
• PPMD’s Pat Furlong also submitted written testimony to the Advisory Committee, reflecting on the incredible progress made to date since her sons were diagnosed in 1984, including the well-documented natural history of Duchenne, a better understanding of mutations in the DMD gene and their relationship with phenotype, and how the micro-dystrophin construct, while not found in human nature, has been deliberately developed based on sequencing the variants from individuals with functional dystrophin to fully exploit critical domains of the dystrophin protein.

What’s Next?

PPMD will continue to work alongside our community partners to discuss how we can further support the FDA’s review of SRP-9001, between now and the PDUFA date of May 29th. During this time, PPMD will also continue to communicate with the FDA to help better inform the review process in any way we can.

We urge the FDA to exert maximal regulatory flexibility to allow incremental innovations that also encourage new research in order to extend such advances. We also encourage the FDA to consider the Accelerated Approval criteria in gene therapy content developed by research, clinical, and advocacy leaders set forth in the Community-led draft drug development guidance submitted to the Agency in October 2022.

Together, we hope for a positive outcome on May 29th to move us closer as a community to the day that every person with Duchenne will have access to the full array of treatment options that cutting-edge scientific and clinical research can provide. Advancing us toward the day when we can – and will – end Duchenne.