Patients with hemophilia A or B can manage the inherited bleeding disorders with regular infusions of the clotting proteins they lack. This treatment helps—until it doesn’t. One problem with these infused factor replacement therapies is patients can develop inhibitors, which are antibodies that render the clotting proteins ineffective.
Experimental Pfizer drug marstacimab takes a different approach to both forms of hemophilia. Results from a pivotal study show the subcutaneously injected drug met the main goals of reducing bleeding episodes. The company also has some additional long-term data showing continuing improvement beyond the initial clinical trial evaluation period.
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The full Phase 3 results and preliminary follow-up data were presented Saturday evening during the annual meeting for the American Society of Hematology in San Diego. Davide Matino, assistant professor of medicine at McMaster University and the principal investigator of the Phase 3 study, told MedCity News on Sunday that while factor replacement therapy can be effective, intravenous administration poses a burden, particularly to pediatric patients as well as those who have poor veinous access.
“All new options that are not required to be given intravenously are welcomed,” Matino said. “Having an alternative is important for the hemophilia community because it gives more options to the treaters and the patients.”
Hemophilia B is rarer than A, but in both forms of the disease, patients lack certain key clotting proteins called factors. Factor replacement therapy, comprised of clotting proteins that are either engineered in a lab or derived from human plasma, has been a standard hemophilia treatment for decades. However, in addition to the potential for developing inhibitors, factor replacement therapies don’t last long in the body so patients need to receive treatment every two to three days.
Marstacimab is an antibody designed to block anti-tissue factor pathway inhibitor, an anticoagulant protein in the body. This protein is a very strong negative regulator of coagulation, Matino said. Blocking it allows for significant generation of thrombin, an enzyme important in the clotting process. The drug has the effect of enhancing coagulation, Matino said.
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Marstacimab is administered as a subcutaneous injection once a week. Pfizer evaluated this drug in an open-label Phase 3 study enrolling about 145 adolescents and adults with either hemophilia A or B. Participants included those who had developed inhibitors to factor replacement therapy as well as those who had not. Results showed an average 35.2% reduction in annualized bleeding rates compared to routine prophylactic factor replacement therapy in the 12-month active-treatment period. Compared to on-demand factor replacement therapy, the Pfizer drug reduced annualized bleeding rates by an average of 91.6% in the 12-month period.
One patient developed peripheral swelling—a serious adverse event deemed related to the study drug. Matino said the concern was that this could be a sign of a blood clot. The swelling was a case of cellulitis, a bacterial infection of the skin, Matino said. The patient was treated with antibiotics and the swelling resolved within 36 hours. There were no signs of thrombosis, Matino said.
Participants in the Phase 3 clinical trial had the option of continuing to receive the Pfizer drug in a long-term extension study. A total of 87 participants elected to do so. Results so far after 16 months show continued reductions in annualized bleeding rates. These are preliminary results and the extension study will continue for seven years or until the product is on the market, Matino said.
Some non-factor therapy alternatives are already available, but not for all hemophilia patients. Hemlibra, the blockbuster hemophilia A drug marketed by Roche, is a bispecific antibody designed to mimic the function of the clotting protein factor VIII. This drug is approved for treating patients with or without inhibitors. Dosed according to patient weight, Hemlibra starts with a once-weekly loading dose for the first month. Maintenance dosing can range from an injection every week to every four weeks.
Novo Nordisk has the only other drug that, like marstacimab, blocks anti-tissue factor pathway inhibitor. This antibody, concizumab, brand name Alhemo, won its approvals in Canada this year for treating both hemophilia A and hemophilia B patients who have inhibitors. However, the FDA turned down Novo Nordisk’s application for this drug and asked for more data about the monitoring and dosing of patients.
Sanofi’s Altuviiio is a new entrant in the hemophilia A market, having won its FDA approval in early 2023. The therapy is a version of factor VIII. It’s a fusion protein that combines engineered factor VIII with part of another protein called von Willebrand factor. This pairing has the effect of stabilizing factor VIII and helping it last longer in the body. Intravenously infused Altuviiio is administered once weekly.
A new, long-lasting treatment alternative is available from BioMarin Pharmaceutical. In June, the company received FDA approval for the gene therapy Roctavian as a treatment for adults with severe hemophilia A. Pfizer also has hemophilia gene therapy candidates. Fidanacogene elaparvovec is in development for the treatment of adults with hemophilia B; the company’s hemophilia A gene therapy is giroctocogene fitelparvovec. Pfizer is scheduled to present four-year Phase 1/2 results for the hemophilia A gene therapy on Monday evening during the ASH meeting.
[Paragraph updated with information about regulatory submissions.] A Pfizer spokeswomen said the company has been in active discussions with regulators about marstacimab. On Monday, the company announced that the FDA had accepted a biologics license application for marstacimab for the treatment of hemophilia A and B patients who do not have inhibitors; a regulatory decision is expected in the fourth quarter of 2024. Pfizer added that a marketing authorization application for the drug is under review in Europe and a regulatory decision there is expected by the first quarter of 2025.
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