Entrance to Pfizer’s office in Cambridge, Massachusetts
The death of a patient receiving Pfizer’s experimental gene therapy for Duchenne muscular dystrophy caused the FDA to stop clinical trials. The death is still under investigation, but because the patient’s complications have raised questions about safety, cessation is one of several clinical shelving in the field of gene therapy in the past year.
Pfizer disclosed the death of the patient in a report on December 20 letter Sent to the patient group Parent Project Muscular Dystrophy. The company said it does not have complete information yet, but is working with clinical trial investigators to understand what happened. At the same time, screening and dosing for the Phase 1b study have been suspended.
Duchenne is a genetic disease that prevents the body from producing a key muscle protein called dystrophin. Without it, the patient will gradually worsen muscle weakness and eventually lead to death. FDA-approved drugs from Sarepta Therapeutics and NS Pharma can be used to slow the progression of the disease, but these therapies can only target certain patients with specific genetic characteristics. Even so, the benefits of these therapies are limited. Gene therapies from Pfizer and other companies are expected to provide the prospect of better and possibly lasting solutions.
Pfizer’s Duchenne gene therapy PF-06939926 carries the dystrophin gene into cells, with the purpose of restoring some dystrophin production. The gene in Pfizer’s therapy is a “shortened” version of the dystrophin gene because the conventional gene is too large for the adeno-associated virus used to transport the genetic cargo to its cellular destination.
Pfizer Gene Therapy is being evaluated in an open-label Phase 1b study that recruited Duchenne patients who were still able to walk (defined as the ability to walk 10 meters independently) and unable to walk. Non-ambulatory patients received higher doses than the ambulatory group. According to Pfizer’s letter, the patients who died belonged to the non-ambulatory group of the study.
In Pfizer’s third-quarter financial performance report released last month, the company stated that the phase 1b results so far show that after one year of experimental treatment, the expression of dystrophin is robust and durable, and that it is measured by exercise Ability test to measure functional improvement. The study treated 19 ambulatory boys in the United States. One year’s data is being prepared for presentation at a scientific conference.
About a year ago, Pfizer was determined to forge ahead. dose It can support the first patient in a large placebo-controlled study approved by the regulatory authorities. But this research also has some mistakes.exist Ready comments In the third-quarter conference call, Pfizer Chief Scientific Officer Mikael Dolsten stated that the reports of muscle weakness and myocardial inflammation observed in the Phase 3 study so far are in three patients with a subset of dystrophin-specific mutations. Developed on the patient’s body. These patients received steroid therapy, improved within a few weeks, and have recovered or are recovering.
Dolsten added that the test supports the hypothesis that an immune response to micro-dystrophin causes these cases, which he said is a potential risk for any gene therapy. To avoid this situation, Pfizer proposed a change to exclude patients with certain mutations.
Pfizer is not the only Duchenne gene therapy developer facing clinical shelving. Due to complications reported in the Phase 1/2 test, Solid Biosciences handled two clinical holds.This The company is approved to resume testing in 2020 After changing the manufacturing process to remove the empty virus capsid, the protein coat of gene therapy is wrapped. Solid also reduced the maximum weight of the patients in the study. Solid treatment is administered based on the weight of the patient; by reducing the maximum weight, the exposure level of the virus used in gene therapy is also reduced.
AAV delivery of genetic drugs has known safety risks, which may include dangerous immune responses and cancer. In April, Adverum Bio reported diabetic macular edema Blindness in patients receiving gene therapy treatment provided by AAVAfter four other patients had vision problems, the biotech company decided Stop further development of gene therapy in this indication. In September, the study of gene therapy provided by AAV was clinically shelved Astellas after the death of the patient, and BioMarin Pharmaceutical suspected of increased risk of cancer Observed in animal experiments.
Photo: Dominique Reuters/AFP, via Getty Images
