Duchenne muscular dystrophy, a degenerative disease mostly affecting young boys, is one of the top targets for gene therapy developers. Recently, however, the pace of research has slowed as reports of a worrisome side effect in a number of clinical trial participants have led to study halts and new questions.
Now, scientists may have some strong clues to the cause, due to an unusual collaboration between rival drugmakers competing to develop the first Duchenne gene therapy.
Patients who experienced the side effect — the main symptom of which has been accelerated muscle weakness —all had similar genetic mutations that triggered an immune response to the genetic material contained in the therapies, an analysis presented Tuesday at a top gene therapy conference showed. Researchers involved in the work described the reaction as most likely a "class effect," meaning something shared across similar therapies.
Even though some patients with the highlighted mutations didn't experience muscle weakness, the companies developing DMD gene therapies are now excluding new patients with those mutations from trials, said Carsten Bonnemann, a senior National Institutes of Health researcher who presented the analysis at the American Society of Gene and Cell Therapy meeting. The findings were previously disclosed in March at another conference and in a community webinar.
Pfizer, Sarepta, Solid Biosciences and the French non-profit Genethon contributed safety data to the analysis, which helped researchers identify the specific mutations. Pfizer's research, in particular, was recently delayed by months as it tried to work out why there patients experienced muscle weakness. A participant in an earlier trial also died, which led Food and Drug Administration to impose a clinical hold on testing, although it's not clear whether that case involved similar symptoms.
The FDA last month allowed Pfizer's clinical trial to resume, but the company will now monitor patients in a hospital for a week after infusion. Sarepta has also reported a case of muscle weakness following treatment with its therapy.
The research presented Tuesday involved a total of five similar cases, which appear to have been sparked by disease-fighting immune cells called T cells. The five individuals developed symptoms between 24 and 42 days after receiving a Duchenne gene therapy. According to Bonnemann, that timeline is consistent with the interval between treatment and when key muscle-building proteins would be stimulated.
The muscle weakness involved "peculiar" symptoms such as difficulty with speech or swallowing that are "very unusual for Duchenne muscular dystrophy at this point" in the disease's progression, Bonnemann said. Patients were able to recover following treatment with breathing assistance and immune-suppressing drugs.
While it's not clear why some of the patients had an immune reaction and others didn't, Bonnemann said the responses were directed to portions of the muscle-building protein that were corrected by the gene therapy. This could be because their immune systems hadn't developed tolerance for the "transgene," which describes the genetic material the therapies contain.
In an email to BioPharma Dive, Pfizer described the risk as related to the underlying mutation and a resulting inflammatory response to a portion of the transgene. The effect does not appear to be specific to any type of gene therapy delivery shell, or the DNA sequence used in the transgene, Pfizer said.
"We believe immune-mediated myositis should ultimately impact a very limited number of patients and is likely common to all constructs," added a Sarepta spokesperson, in an email, using the medical term for the observed muscle weakness.
Bonnemann noted how a similar response was observed with an early DMD gene therapy developed more than a decade ago by Jerry Mendell, the Ohio State University researcher who also developed Sarepta's treatment.
Mendell's research suggested the T cell attack made the gene therapy ineffective. Bonnemann said scientists will monitor the five patients that took part in this new analysis to see if something similar happened.
In addition to excluding at-risk patients, drugmaker trials will also now monitor patients for treatment-specific T cell responses, and use drugs to manage that alongside the gene therapy, according to Bonnemann.
Editor's note: This story has been updated with additional information from Pfizer.