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Pfizer gene therapy research delayed by trial changes, safety questions

In both hemophilia and Duchenne, unexpected findings have led Pfizer to redraw its development plans.

The company recently paused patient screening and dosing in a Phase 3 study of its hemophilia A gene therapy, which is being developed together with Sangamo Therapeutics, after some participants experienced higher-than-normal levels of the clotting factor that’s missing in that disease.

While the gene therapy is designed to replace that clotting factor, thereby reducing or eliminating bleeding, levels that are too high raise the potential for blood clots.

No patients in the study have experienced a clot, Pfizer said, but some are now being treated with oral blood thinners.

Pfizer is now working to change the trial protocol to include measures for monitoring and responding to elevated clotting factor levels.

The company also scrapped plans to conduct an early analysis of data from both the hemophilia A study and another trial testing a gene therapy for hemophilia B. “This will push out the timing of readouts of those trials compared to our previous expectations,” Pfizer said.

In hemophilia B, results are now expected in early 2023. Pfizer is still assessing the impact on the testing timeline in hemophilia A.

A month ago, meanwhile, Pfizer announced it would narrow a key clinical trial of its Duchenne gene therapy to exclude certain patients after investigators observed muscle weakness in three study participants. At the time, Pfizer indicated its therapy was the cause, noting that genetics seemed to play a role in which patients experienced the adverse reaction.

Pfizer is now disclosing more information. According to Mikael Dolsten, the company’s top scientist, an immune response to the dystrophin protein encoded by its gene therapy — and otherwise missing or defective in DMD patients — led to a type of muscle inflammation called myositis. All three were treated with a high dose of steroids and improved within a few weeks.

Dolsten also suggested the problem might not be limited to Pfizer’s therapy.

“This type of reaction is a risk potentially inherent to any gene replacement therapy, and similar severe adverse events reported in other programs support the notion that this is a class effect,” he said in prepared remarks delivered on a Tuesday conference call.

In response, Pfizer has proposed excluding patients with certain Duchenne-causing mutations and expects that “nearly all” trial sites outside of the U.S. will have resumed enrolling participants by the end of November. In the U.S., however, the company is still working with the FDA to get regulator sign-off on a new laboratory test for the treatment’s potency.

Behind these two programs, however, is a growing pipeline of 12 preclinical gene therapies. Pfizer expects to start human testing on one to two of them each year, beginning with treatments for Wilson and Gaucher diseases next year.