Pfizer Revises DMD Gene Therapy Trial Protocol Following Three Serious Adverse Events

Compiled and Translated | Aspirin

On September 29, 2021, in a letter to Parent Project Muscular Dystrophy (PPMD), the largest U.S. non-profit organization dedicated to finding a cure for Duchenne muscular dystrophy, Pfizer announced that it would narrow the scope of the trial protocol for an ongoing clinical trial of a gene therapy for Duchenne muscular dystrophy (DMD) following three serious adverse medical events.

Among these three adverse events, Pfizer reported three cases of muscle weakness, two of which involved cardiac inflammation (myocarditis). These clinical trials are evaluating fordadistrogene movaparvovec, an investigational gene therapy under development by Pfizer. Pfizer’s External Data Monitoring Committee determined that these three adverse events were related to the investigational treatment received by the participants, and that specific mutations in the dystrophin gene may predispose these participants to a higher risk of side effects and adverse events.

Following an adverse event, to enhance trial safety, newly enrolled participants must not carry any mutations affecting exons 9 through 13 (inclusive) or any mutations concurrently affecting both exon 29 and exon 30. This criterion excludes approximately 15% of patients with Duchenne muscular dystrophy from participating in this clinical trial. Meanwhile, regulatory authorities and ethics committees in countries where the trial is already underway are reviewing these latest protocol amendments.

Pfizer stated in a statement: "We understand that this change will be very difficult news for patients and their families. However, upon becoming aware of new safety concerns and risk information, we must take this step to protect the safety of clinical trial participants."

Currently, this clinical trial is being conducted in Italy, Spain, Israel, the United Kingdom, South Korea, Japan, Russia, and Canada. The trial will not be conducted in the United States until the U.S. Food and Drug Administration (FDA) approves Pfizer's clinical trial application.

In a May 2021 letter to Cure Duchenne (a California-based nonprofit organization), Pfizer stated that it had already opened 14 clinical trial sites across eight countries. Currently, regulatory authorities in each country must review and approve the amended protocol before the clinical trials can proceed.

Pfizer also stated in the announcement, “In the United States, we are actively collaborating with the FDA to resolve issues pertaining to our Investigational New Drug (IND) application, including the technical aspects of our drug potency assay, so that we can begin patient enrollment for the U.S. Phase III clinical trial. While we maintain full confidence in our current overall quality control and potency testing, and these assays have been accepted by countries and regions outside the United States, the FDA has additional technical requirements, which we are also working diligently to address as quickly as possible.”

Additionally, Sarepta Therapeutics, a competitor of Pfizer in the field of gene therapy, was the first company to receive approval for a Duchenne muscular dystrophy therapy. In 2016, Sarepta's Exondys 51 (eteplirsen) received FDA approval, with positive results reported from the first 11 participants in its gene therapy trial. Exondys 51 is used to treat, but not cure, certain types of Duchenne muscular dystrophy caused by specific mutations. It targets only specific mutations and can be used to treat approximately 14% of cases.

Roche is conducting a clinical trial named ENDEAVOR. Its SRP-9001 is a gene transfer therapy designed to deliver a micro-dystrophin-encoding gene to muscle tissue. One of the challenges in gene therapy for Duchenne muscular dystrophy (DMD) is that the dystrophin gene is the largest in the human genome, making it impossible to package into a conventional gene therapy vector. Sarepta is testing the delivery of a smaller, modified version of the dystrophin gene via a vector. Another company in this field is Solid Biosciences, which has encountered a series of safety issues with its DMD gene therapy.

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Pfizer Modifies MD Gene Therapy Trial Following Three Serious Adverse Events