The United States (US) Food and Drug Administration (FDA) has approved marstacimab-hncq, an anti-tissue factor pathway inhibitor, for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients 12 years of age and older with hemophilia A (HA) without factor VIII inhibitors or hemophilia B (HB) without factor IX inhibitors (neutralizing antibodies).¹ The approval was based on results from the phase 3 BASIS trial, which showed a reduction in the annualized bleeding rate (ABR) with marstacimab-hncq compared to on-demand treatment and routine prophylaxis in patients with HA or HB without inhibitors.^1,2

HA and HB are rare, X-linked bleeding disorders resulting from mutations in the clotting factor genes, FVIII and FIX respectively.³ Hemophilia is estimated to impact more than 800,000 people worldwide, with HA being much more common than HB.² Factor replacement therapy is the most common treatment for hemophilia, and its use in prophylactic regimens helps to reduce bleeding and prevent resultant joint damage.² However, the time-consuming nature of these infusions poses a significant challenge for adherence to this regimen.²

Marstacimab-hncq is a monoclonal antibody that targets the tissue factor pathway inhibitor protein (TFPI), a natural anti-clotting protein that inhibits the extrinsic blood coagulation pathway.⁴ It is administered subcutaneously once weekly via a pre-filled auto-injector pen._² Its recent approval by the FDA is based on an open-label, multicenter study involving 116 adult and pediatric male patients aged ≥12 to <75 years with severe HA (FVIII <1%) or moderately severe to severe HA (FIX ≤2%) without inhibitors.⁴

In this study, 128 participants first entered a 6-month observational phase (OP) and received either on-demand (OD) therapy (HA n=29, HB n=8) or routine prophylaxis (RP; HA n=72, HB n=19).⁴ Among these, 116 patients completed the OP and crossed over to a 12-month active treatment phase (ATP), during which they received a single subcutaneous loading dose of 300mg followed by once weekly 150mg marstacimab-hncq.⁴ A further 88 participants who completed the ATP enrolled in the long-term extension (LTE) study (OD: HA n=22, HB n=7; RP: HA n=45; HB n=13).⁴ The primary endpoints of the trial were the annualized bleeding rate (ABR) for treated bleeds and safety outcomes, while the secondary endpoints included the incidence of various types of breakthrough bleeds and health-related quality of life (HR-QoL) measures.⁴

In patients who received OD factor replacement (n=33), the mean ABR was 38.00 (95% CI: 31.03-46.54) during OP, which was reduced to 3.18 (95% CI: 2.09-4.85) during ATP with marstacimab-hncq, resulting in a 91.6% (95% CI: 88.1-94.1;

p<0.001) reduction in ABR.4 Among those who received RP (n=83), the mean ABR was 7.85 (95% CI: 5.09-10.61) during OP, which was reduced by 35.2% (95% CI: 5.6-55.6; p=0.0376) over the 12-month ATP to 5.08 (95% CI: 3.40-6.77).⁴ These reductions were maintained during the LTE phase, with the OD group (mean treatment duration=8.0 months [range: 1.2-14.5]) having a mean ABR of 3.86 (95% CI: 2.02-7.37) and the RP group (mean treatment duration=6.5 months [1.1-16.1]) having a mean ABR of 2.27 (95% CI: 1.40-3.67).⁴

vMarstacimab-hncq was also associated with significant reductions in ABR across all breakthrough bleed categories compared to OD treatment, with numerical reductions observed compared to RP, demonstrating non-inferiority.⁴ The decrease in ABR observed with marstacimab-hncq during ATP was also consistent across hemophilia types and age groups.⁴ Moreover, HR-QoL parameters showed non-significant improvements compared to OD therapy and were non-inferior to RP.⁴

For safety outcomes, all-cause adverse events (AEs) were higher during ATP compared to during OP for both the OD group (36.4% vs. 24.3%) and the RP group (74.7% vs 22.0%).⁴ Treatment-related AEs were reported in 12.1% of patients in the OD group during ATP and 22.9% in the RP group, of which only 1 was a serious AE.⁴ The most commonly reported AEs of special interest which were more frequent with marstacimabhncq included COVID-19, hemorrhages, hypersensitivity, and injection site reactions.⁴ No deaths or serious AEs related to thromboembolism were reported during the study.4 Anti-drug antibodies developed in 20.5% of participants, but titers were low and resolved in 22 of 23 participants by the end of the study.⁴

In summary, the phase 3 BASIS trial showed that once-weekly subcutaneous marstacimab-hncq was safe and effective in reducing bleeding events in hemophilia patients compared to previous OD or RP therapies.⁴ The FDA’s approval of this drug offers patients a less time-consuming, subcutaneous alternative to traditional intravenous infusion treatments.^1,2