Pfizer’s vision for a banner 2022 in gene therapies is over. Having previously expected to post interim data on a trio of phase 3 programs next year, Pfizer has now delayed all the readouts, setting back its plans in hemophilia and Duchenne muscular dystrophy (DMD).
Multiple forces are behind the delays (PDF). In hemophilia A, Pfizer and partner Sangamo Therapeutics have voluntarily paused a phase 3 trial of their factor VIII gene therapy to change the protocol. The protocol change was prompted by the discovery that some patients had factor VIII activity of 150% or more, potentially raising their risk of blood clots.
The patients are taking anticoagulants to cut the risk of clotting, and nobody has had a thrombotic event so far. Even so, Pfizer and Sangamo have stopped dosing while they amend the protocol to give guidelines for the clinical management of elevated factor VIII levels.
It is unclear when Pfizer will have data from the study. The uncertainty is a consequence of both the protocol amendment and recent discussions with the FDA, which led Pfizer to abandon plans to run interim analyses of data from its phase 3 trials in hemophilia A and hemophilia B. The analyses were scheduled for next year.
Pfizer now expects to deliver pivotal hemophilia B data, based on an analysis of 40 patients, in the first quarter of 2023. That study has enrolled enough patients to assess the primary endpoint. The paused hemophilia A study is further from completion, with more than half of subjects enrolled, and Pfizer is yet to commit to a timeline for reporting results.
The delays could have consequences for the commercial prospects of Pfizer’s hemophilia therapies. UniQure and CSL Behring plan to file for FDA approval of their hemophilia B gene therapy in the first quarter of 2022, suggesting the treatment could enjoy a sizable head start over Pfizer’s candidate. In hemophilia A, BioMarin plans to seek approval for its once-rejected Roctavian in the second quarter of 2022.
Questions about durability torpedoed BioMarin’s original attempt to get Roctavian to market. Talking to investors on a quarterly conference call after disclosing the delays, Mikael Dolsten, M.D., Ph.D., chief scientific officer at Pfizer, pointed to durability as a potential positive of having a gene therapy that drives very high factor VIII levels.
“Having high factor VIII level has also some potential longer-term advantage on sustainability of gene therapy. The factor VIII data that you have seen also from others in the field have shown some more attenuation over time for the factor VIII molecules. To be in the upper range where we are, on average 60% to 70%, may be something that allows much longer gene therapy benefit than if you were on the lower end of the spectrum,” Dolsten said.
Pfizer added a data point in support of the proverb that bad things come in threes with an update on its DMD gene therapy, which was supposed to be the other candidate to deliver data next year. Pfizer now expects the pivotal study to read out in the first quarter of 2023, reflecting a forecast that it will take until early next year to fully enroll the study.
The DMD delay follows Pfizer’s decision to tighten the enrollment criteria after seeing three cases of muscle weakness including inflammation of the heart tissue in recipients of its gene therapy. All the patients were treated with higher doses of steroids and improved within a few weeks, but only a few sites have resumed new patient activities. Pfizer expects activity to resume at nearly all ex-U.S. sites by the end of the month.