Marstacimab Reduces Patients’ Bleeds, Even With Inhibitors

The treatment's safety is still being tested in an ongoing Phase 3 trial

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Treatment with marstacimab (PF-06741086), an experimental antibody-based therapy developed by Pfizer, reduced the number of bleeds in patients with severe hemophilia who took part in a Phase 1b/2 clinical study.

This held true regardless of whether patients had hemophilia A or hemophilia B, or had inhibitors in their blood. Some patients who are on replacement therapy with the clotting factors they are missing can develop inhibitors to those factors, which usually lowers treatment effectiveness.

Researchers also observed that marstacimab, given once a week as a subcutaneous (under-the-skin) injection, was generally safe across a range of doses.

They continue to test marstacimab’s safety in an ongoing Phase 3 trial (NCT03938792) that has dosed the first patient and remains open for enrollment in locations worldwide. Its findings may provide an “opportunity to establish a wide therapeutic index,” the researchers wrote.

The study, “A Phase 1b/2 clinical study of marstacimab, targeting human tissue factor pathway inhibitor, in haemophilia,” was published in the British Journal of Haematology.

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Hemophilia occurs when the body does not make enough of the clotting factors that help the blood to clot. The type of hemophilia depends on the clotting factor that’s missing.

To prevent or reduce the number of bleeds, patients receive regular into-the-vein injections of the clotting factor they’re missing. This is called replacement therapy. However, frequent injections increase the treatment burden and reduce adherence to it. Sometimes, a thin tube called a catheter is needed to deliver the injections, but this can be complicated by an infection or blood clots (thrombosis).

Marstacimab is an antibody that binds to and blocks the tissue factor pathway inhibitor (TFPI), a protein that normally prevents blood clotting. By releasing this molecular brake, it’s expected to help prevent or reduce the number of bleeds, making it a possible alternative to replacement therapy.

Dosing with marstacimab

The Phase 1b/2 clinical study (NCT02974855) tested how safe marstacimab is and how well it works when given once a week for up to three months. The study was conducted at eight locations in North America, South America, Europe, and Africa, and included 26 male patients ranging in age from 19 to 63.

Sixteen (61.5%) had hemophilia A without inhibitors; seven (26.9%) had hemophilia A with inhibitors; and three (11.5%) had hemophilia B. Most (92.3%) had joints with multiple bleeds, called target joints, and 22 (84.6%) had joint disease associated with hemophilia.

Patients were divided into four groups, and each group was given a different treatment dose. Because this was an open-label study, they all knew which dose they were receiving. Researchers waited at least four weeks before giving a new dose to the next group. This was done to check for side effects and to see if treatment was working as expected.

Patients in the first group, which had seven participants, received 300 mg of marstacimab once a week. The second group (six patients) received a single loading dose of 300 mg, followed by 150 mg once a week. The third group (also six patients) received the highest dose of 450 mg once weekly. The fourth group, which included all seven patients with hemophilia A who tested positive for inhibitors, received the 300 mg dose.

Twenty-four patients (92.3%) finished the study. Two (7.7%) left due to side effects.

Marstacimab side effects

A total of 56 side effects in 21 (80.8%) patients were logged. These included the two patients who left the study (one had high blood pressure, the other had a large a drop in the level of fibrinogen, a protein that helps the blood to clot).

The most common side effects were pain and swelling at the site of the injection, followed by high blood pressure. Most were mild or moderate. Four (15.4%) patients had serious side effects.

“Marstacimab treatment was generally safe and well tolerated at all dose levels,” the researchers wrote.

While the study did not include a control group, researchers drew on data from an external group of 65 patients who received on-demand replacement therapy with ReFacto (moroctocog alfa) or BeneFIX (nonacog alfa) to to compare marstacimab’s effectiveness.

The mean annualized bleeding rate was roughly 10 times lower in marstacimab-treated patients than in controls (2.67 vs. 27.62). A similar finding was observed when researchers compared the mean annualized bleeding rate before the study (18.83). This reduction was observed across all doses.

The higher the dose of marstacimab, the higher its levels in the blood. Steady-state levels were reached by day 57 (about two months after the first injection). This was observed for both patients “with and without inhibitors.”

Blood tests revealed both TFPI and peak (highest-level) thrombin — a protein that causes the blood to clot — increased with the treatment, indicating “effective targeting of TFPI,” the researchers wrote. They said the “safety, efficacy, [and pharmacological profile] of marstacimab support further evaluation of once-weekly … dosing in patients with severe hemophilia, with or without inhibitors.”