The four companies working on gene therapies for Duchenne muscular dystrophy (DMD) have had another thing in common besides the modality and disease they’re working on: serious adverse events.
Rather than continue to plug away at individual studies and try to figure out why these side effects were happening in certain patients, Pfizer, Sarepta, Genethon and Solid Biosciences teamed up for a pooled safety analysis (PDF) that was presented this week at the American Society of Gene and Cell Therapy meeting. The companies shared clinical and laboratory data and put together a panel of experts to take a look with the goal of minimizing further medical complications.
The group brought in Carsten Bönnemann, M.D., and Francesco Muntoni, M.D., as academic advisors, according to Pfizer. Bönnemann is a senior investigator for the Neuromuscular and Neurogenetic Disorders of Childhood Section at the National Institutes of Health’s National Institute of Neurological Disorders and Stroke. Muntoni serves as director of the Dubowitz Neuromuscular Centre at the UCL Institute of Child Health and Great Ormond Street Hospital for Children in London.
Of the four companies, serious adverse events have occurred in five patients across three clinical trials. All were “strikingly similar,” according to the abstract, characterized by muscle weakness with variable cardiac involvement. The events happened about three to seven weeks after receiving a gene therapy. The patients were provided with immunosuppressive and supportive therapies and regained muscle strength and cardiac enzyme levels about six to eight weeks after onset, according to the analysis.
Bönnemann and Muntoni, through a working group, convened experts in neuromuscular disease, inflammation, genetics and cardiac disease to discuss the events and come up with questions that are still outstanding, Pfizer said.
All four companies use an adeno-associated virus to provide patients with a copy of the dystrophin transgene, although each delivery mechanism differs slightly. The therapies also employ different transgene sequences, which suggested that the events were tied to a “class effect,” or some sort of T-cell-mediated immune response from the expressed transgene that is determined by the patient’s genotype. The events only occurred in patients that had certain genomic deletions.
Pfizer said that the events did not appear to be tied to any AAV serotype, promoter type or transgene sequence, but instead resulted from the patients’ inflammatory response to a specific region of the mini-/micro-dystrophin that is delivered using these gene therapies.
The collaborative approach was “instrumental” in helping quickly identify an anti-transgene mechanism and the risk factors that could lead to the adverse events in patients, the study says. Investigation is continuing to better define the problematic immune mechanism behind the events and the risk factors, which can help inform future gene therapy studies in DMD and beyond. The work will continue, with more details on exactly what happened to come, Pfizer said.
Pfizer has already announced study exclusions for related at-risk mutations that will impact a portion of DMD patients.
The Big Pharma reported a patient death in an early-stage trial of its experimental gene therapy called fordadistrogene movaparvovec, or PF-06939926, in December 2021. The young male patient was participating in the phase 1 study featuring both non-ambulatory and ambulatory patients, meaning patients who need a wheelchair or not. The death triggered an FDA clinical hold for the therapy, which was also being studied in a separate late-stage test.
That phase 3 trial, which involved ambulatory patients, was cleared to continue in April after Pfizer addressed the agency’s requests regarding a potency assay and implemented a protocol amendment. Patients will now be monitored in a hospital for seven days after receiving the gene therapy.
But Pfizer is continuing to think over restarting testing in more advanced patients, even though the Big Pharma has received regulatory and ethics approvals to proceed with studying fordadistrogene movaparvovec in the ambulatory population.
Sarepta also reported a case of muscle weakness in a phase 3 trial of SRP-9001 in October 2021, which was attributed to the patient’s particular mutation.
Genethon, a nonprofit organization formed by a patient association, is working with Sarepta on GNT 0004. In April 2021, a study for the med was suspended due to a serious adverse event in a patient. After an investigation and a protocol amendment, the study was once again cleared in March by regulators in France and the U.K.