Collaborative Analysis Reveals "Class Effect" in DMD Safety Issues


When the U.S. Food and Drug Administration approved Sarepta Therapeutics’ Exondis 31 (eteplirsen) for Duchenne Muscular Dystrophy (DMD) in 2016 after a year-long contentious review, it broke ground for other companies to enter the DMD space.

Pfizer, Sarepta Therapeutics, Genethon and Solid Biosciences are working on gene therapies for the disease, but all have been finding serious side effects. Now, the four companies have teamed up to find the answer and they presented their data at this week’s American Society of Gene and Cell Therapy Meeting.

DMD is a muscle-wasting disease caused by mutations in the dystrophin gene. The dystrophin gene is the largest gene in the body, and because of this, it does not fit into a typical viral vector for gene therapy. As a result, most approaches to gene therapies or treatments involve using a shortened version of the gene that produces a truncated version of the dystrophin protein, or some form of “gene-skipping” technology that does the same thing.

DMD is a progressive disease that typically causes death in early adulthood and includes serious complications including heart or respiratory problems. It mostly affects boys, about one in every 3,500 or 5,000 male children.

The presentation, “A Collaborative Analysis by Clinical Trial Sponsors and Academic Experts of Anti-transgene SAEs in Studies of Gene Therapy for DMD,” notes that all four sponsor companies utilize an adeno-associated virus (AAV), although of different serotypes, to deliver different versions of a shortened dystrophin transgene driven by different promoters.

The companies had observed serious adverse events (SAEs) marked by muscle weakness and variable cardiac involvement, all having similar clinical presentation and time course. The SAEs involved five patients across three trials, and all occurred about three to seven weeks after the initial gene infusion.

They noted, “Following the events, all four sponsors chose to collaborate and share relevant clinical and laboratory data and further convened an international panel of experts to analyze the SAEs, minimize their recurrence, and assess potential therapeutic and preventative strategies.”

The companies believe because similar SAEs were observed across multiple gene therapies using different capsids, promoters and transgene sequences, they are “most likely to be a specific transgene/genotype-related ‘class effect.’”

They theorize that the mechanism of the SAEs is a “T-cell mediated immune response to the expressed transgene protein in a cross-reactive immunological material (CRIM)-negative setting, determined by the patient’s genotype.”

The SAEs only occurred in patients with genomic deletions, including N-terminal epitopes, which are present in the transgene protein. When positive ELISpot (T-cell) tests were performed in the patients with SAEs, they were reactive to the corresponding N-terminal peptide pool. Early epitope mapping of anti-dystrophin antibodies from one of the patients suggested a prominent signal at the transgene Hinge1 segment within the dystrophin N-terminus.

Acting as academic advisers, the companies brought in Carsten Bonnemann, M.D., a senior investigator for the Neuromuscular and Neurogenetic Disorders of the Childhood Section at the National Institutes of Health’s National Institute of Neurological Disorders and Stroke, and Dr. Francesco Muntoni, M.D., director of the Dubowitz Neuromuscular Centre at the UCL Institute of Child Health and Great Ormond Street Hospital for Children in London.

The two consultants participated in a working group of other experts in neuromuscular disease, inflammation, genetics and cardiac disease to go over the data and determine what questions remained.

So far, Pfizer has reported that people with specific mutations that might affect them negatively will be excluded from studies. The company reported a death in December 2021 in the Phase Ib DMD study of its gene therapy, fordadistrogene movaparvovec. Pfizer paused screening and dosing in the study as a result. The hold was then lifted in April 2022.

The companies stated, “The unique and timely formation of an open, collaborative working group including four sponsors of the ongoing studies and multiple academic experts was instrumental in being able to quickly identify an anti-transgene mechanism and the associated risk factors for observed SAEs. A plan for further investigation is underway to comprehensively define the immune mechanism and associated risk factors. This collaborative approach and its conclusions may have implications to mitigate risks in gene therapy development programs beyond DMD.”

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