The entrance to a Pfizer office in Cambridge, Massachusetts

A patient treated with an experimental Pfizer gene therapy for Duchenne muscular dystrophy has died, leading the FDA to stop the clinical trial. The death is still under investigation, but the halt is one of several clinical holds to hit the gene therapy field in the past year as patient complications raise questions about safety.

Pfizer disclosed the patient death in a Dec. 20 letter sent to the patient group Parent Project Muscular Dystrophy. The company said it did not yet have complete information, but is working with the clinical trial investigator to understand what happened. In the meantime, screening and dosing in the Phase 1b study have been paused.

Duchenne is an inherited disorder that results in the body being unable to produce a key muscle protein called dystrophin. Without it, patients develop progressively worsening muscle weakness that eventually leads to death. FDA-approved drugs from Sarepta Therapeutics and NS Pharma are available to slow the disease’s progression, but these therapies can only address certain patients who fit particular genetic profiles and even then, the therapies offer limited benefit. Gene therapies from Pfizer and others are hoped to offer the prospect of a better and potentially long-lasting fix.

Pfizer’s Duchenne gene therapy, PF-06939926, carries a dystrophin gene into cells with the goal of restoring some dystrophin production. The gene in the Pfizer therapy is a “shortened” version of the dystrophin gene because the regular gene is too large for the adeno-associated virus that is used to carry the genetic cargo to its cellular destination.

The Pfizer gene therapy is being evaluated in an open-label Phase 1b study enrolling Duchenne patients who are still ambulatory (defined as the ability to walk 10 meters unassisted) as well as those who are can no longer walk. Non-ambulatory patients received a higher dose than those in the ambulatory group. According to Pfizer’s letter, the patient who died was in the non-ambulatory group of the study.

In Pfizer’s report of third quarter financial results last month, the company said that the Phase 1b results to date show robust and durable expression of dystrophin after one year of receiving the experimental therapy, as well as functional improvement as measured by test that measures motor abilities. A total of 19 ambulatory boys in the U.S. have been treated in the study and one-year data are being readied for presentation at a scientific meeting.

About a year ago, Pfizer forged ahead and dosed the first patient in a larger, placebo-controlled study that could support regulatory approval. But that study has had some stumbles as well. In prepared remarks for the third quarter conference call, Mikael Dolsten, Pfizer’s chief scientific officer, said that the reports of muscle weakness and heart muscle inflammation observed in the Phase 3 study so far developed in three patients with a specific subset of mutations to the dystrophin protein. Those patients were treated with steroids, improved within a few weeks, and have recovered or are recovering.

Dolsten added that tests support the hypothesis that an immune response to the mini-dystrophin protein caused these cases, a reaction that he said is a potential risk of any gene therapy. To avoid it, Pfizer proposed a change to exclude patients who have certain mutations.

Pfizer isn’t the only Duchenne gene therapy developer that has faced a clinical hold. Solid Biosciences dealt with two clinical holds due to complications reported in Phase 1/2 testing. The company was cleared to resume testing in 2020 after changing manufacturing process to remove empty viral capsids, the protein shells that envelop a gene therapy. Solid also lowered the maximum weight of patients in the study. Solid’s therapy is dosed according to patient weight; by reducing the maximum weight, exposure levels to the virus used in the gene therapy are also reduced.

AAV delivery of genetic medicines has known safety risks that can include dangerous immune responses as well as cancer. In April, Adverum Bio reported that a diabetic macular edema patient treated with its AAV-delivered gene therapy lost vision. After vision problems developed in four additional patients, the biotech decided to halt further development of the gene therapy in that indication. September saw clinical holds placed on studies of AAV-delivered gene therapies from Astellas Pharma after a patient death, and BioMarin Pharmaceutical following a suspected increased cancer risk observed in animal testing.

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