NEW YORK — Five patients with Duchenne muscular dystrophy enrolled in three separate gene therapy trials developed similar serious adverse reactions, prompting the trial sponsors to form a working group to share data and investigate the cause of the reactions.
The five boys, all between 7 and 9 years of age, were enrolled in clinical trials testing three different gene therapies for Duchenne muscular dystrophy. The condition, which primarily affects boys, stems typically from loss-of-function mutations in the DMD gene that lead to a deficiency in the dystrophin protein critical for strengthening muscle fibers, causing progressive muscle weakness.
A number of companies are developing gene therapies to treat Duchenne by delivering functional microdystrophin transgenes. Last week, the US Food and Drug Administration granted accelerated approval to the first gene therapy for this condition, Sarepta Therapeutics' Elevidys (delandistrogene moxeparvovec). In approving the drug, the FDA cautioned that some patients who received Elevidys in clinical trials had severe muscle inflammation, particularly of the heart muscle, known as myocarditis, and elevated troponin-I, a protein associated with heart muscle injury; the agency advised doctors to monitor troponin-I levels before starting the gene therapy and for a month after administering it.
The five boys who were taking part in the three different gene therapy trials — one sponsored by Pfizer, one by Sarepta, and one by Genethon — developed similar, unexpected adverse reactions. As the working group that formed described recently in the New England Journal of Medicine, all the boys experienced severe muscle weakness and inflammation, including myocarditis, and three patients required ventilation. The symptoms for all resolved within three months with immunomodulatory treatments.
"It was really very, very frightening," said Serge Braun, the director of neuromuscular strategy at Genethon, a French not-for-profit organization that is developing a gene therapy for Duchenne.
While the trials were all testing gene therapies to treat Duchenne, the drugs varied in formulation and used different microdystrophin transgenes under different promoters and were packaged into different adeno-associated virus serotypes. Still, the timing of symptom onset — three to six weeks after the therapy was administered — suggested that patients' adverse reactions to these different drugs were linked to transgene expression.
According to Braun, Genethon halted its trial in April 2021 after the first patient dosed with its gene therapy developed myocarditis. After speaking with the principal investigator of the study, Francesco Muntoni, a pediatric neurologist at Great Ormond Street Hospital for Children in the UK, Braun learned there could be similar cases in other Duchenne gene therapy trials.
"[Muntoni and I] had an overview of more than one of the clinical trials happening, just by being either investigators or advisers, [and] just by knowing the trial landscape," added Carsten Bönnemann, the chief of the Neuromuscular and Neurogenetic Disorders of Childhood Section at the National Institute of Neurological Disorders and Stroke. "It had occurred to Francesco that there were very similar things happening around the same time and in more than one trial."
Bönnemann and Muntoni reached out to the other Duchenne gene therapy trial sponsors with, what Bönnemann called, a "very carefully phrased letter" encouraging them all to work together to investigate these cases. "We were concerned that there could be a common element to these [adverse events] that needs to be identified quickly," he said.
"The response was just immediately accepting and positive," he added.
The sponsors — Genethon, Pfizer, Sarepta, and also Solid Biosciences — formed a working group with Bönnemann and Muntoni as academic experts to better understand what was happening in these patients who were having these serious adverse reactions. Bönnemann noted that the group came together quickly and without complicated data sharing or confidentiality agreements.
By sharing their data and experiences, the trial sponsors and the working group determined these events were a class effect — it was unrelated to AAV serotype, promoter type, or transgene sequence, Pfizer said in an email.
"It was important to exchange freely our observations," Genethon's Braun added, noting that he was not aware of another instance in which four competing drugmakers had collaborated in this way to openly discuss adverse reactions to their products.
Testing of the affected patients found that they were likely experiencing a cytotoxic T-cell immune response against dystrophin. The group traced the adverse reactions to patients' underlying DMD gene mutations. The five patients all had similar mutations in the DMD gene: large, overlapping deletions between exon 8 and exon 21.
Mapping this back to the microdystrophin constructs being used in the gene therapy trials, the group found that epitopes encoded by exons 8 through 11 were present in all the constructs but missing in the affected patients. This region of the DMD gene encodes the hinge 1 domain — an exposed part of the protein — and the beginning of the spectrin-like repeat domain.
Bönnemann noted that though Duchenne patients lack functional DMD proteins, portions of the protein can still be expressed at low levels. However, because the patients who had these adverse events completely lacked this stretch of the DMD gene, they had never been exposed to the portion of protein it produces. As such, when these drugs introduced this segment of the protein in these patients for the first time, it triggered their immune systems to respond.
These findings prompted the sponsors to alter their trial criteria to minimize risk to trial participants. Patients who have deletions that overlap the transgene sequences were excluded.
Braun added that this cooperation has helped the trial sponsors. He noted that an adverse event mitigation plan his organization filed with French regulatory authorities to exclude patients with those exon deletions enabled Genethon to restart its gene therapy trial. The group also added a few months of transgene immunosuppressor treatment as an extra cautionary step.
Sarepta also discussed this safety issue for patients with these deletions as well as their risk mitigation approach during the FDA advisory committee meeting on Elevidys. Based on this information, the agency has contraindicated Elevidys for patients with DMD exon 8 or 9 deletions.
Both Braun and Bönnemann noted that the working group is continuing to meet and investigate adverse reactions to the transgene. The group is also looking into other safety concerns common across the gene therapy trials like thrombotic microangiopathy, which can occur after high-dose AAV exposure, and liver injuries.
"It's for the sake of the patients, but also in the interest of the sponsor to do this," Braun said of the working group's efforts. "It takes all of us."