Rebalancing the hemophilia teeter-totter Free

In this issue of Blood, Matino et al¹ demonstrate the safety and efficacy of the anti–tissue factor pathway inhibitor (TFPI) rebalancing agent marstacimab in severe hemophilia A (HA; ≤1%) or moderate-severe hemophilia B (HB; ≤2%) without inhibitory antibodies. Marstacimab joins concizumab as a US Food and Drug Administration (FDA)–approved monoclonal antibody agent directed against TFPI; both demonstrate superiority of anti-TFPI vs on-demand (OD) therapy in preventing bleeding and more patient-friendly subcutaneous (SC) administration.^2-4 

Hemophilia is defined by spontaneous and traumatic bleeding characterized by intracranial hemorrhage as well as joint, mucosal, soft tissue, and gastrointestinal/genitourinary bleeding. Treatment has progressed incrementally over the last 60 years with efforts to replace the missing factor VIII (FVIII) or FIX protein with either factor concentrates (plasma or recombinant), or extended half-life recombinant proteins, or gene therapy.^5,6 Though mostly successful, their weaknesses have opened the door for factor “mimetics” and coagulation rebalancing agents. This transition is rooted in several disruptive events, which have impacted persons with hemophilia: human immunodeficiency virus and hepatitis C, inhibitory antibodies to FVIII/FIX, debilitating joint disease, thrombosis, need for IV infusions, and spontaneous bleeding. This difficult landscape prompted a renewed focus to provide all persons with hemophilia, the opportunity to be free of bleeding, predominantly by prophylactic infusions of factor. However, the goal of achieving hemostatic levels of FVIII and FIX above 40% to 50% is difficult to achieve, short of sustained factor levels from gene therapy.

Additionally, the FVIII mimetic, emicizumab, can only be utilized in HA and only approximates “FVIII-like” levels of 20% to 25%.⁷ Enter the rebalancing agents whose goal is to produce thrombin to counterbalance the bleeding associated with HA and HB.⁸ Currently, there are 3 main coagulation pathway inhibitors being targeted in clinical trials: antibodies directed against protein C and protein S, the TFPI antibody agents, and fitusiran, a small molecule which inhibits antithrombin. Fitusiran is also FDA-approved for use in HA and HB either with or without inhibitory antibodies.^9,10 Each of these products are given SC and vary regarding dosing interval (daily, weekly, or bi-monthly). All are effective in preventing bleeding but carry a risk of thrombosis, especially when coagulation products are used concomitantly to treat breakthrough bleeding.

Subjects in this open label, multicenter, 1 way crossover phase 3 study, enrolling adolescents and adults with either HA or HB, received once-weekly SC marstacimab at 150 mg for 12 months after a 6-month observation period where subjects continued their OD or routine prophylaxis (RP) schedules. One hundred sixteen subjects entered the treatment phase, with 33 from the OD group and 78 from the RP group completing the 12-month treatment window. The primary efficacy end point was annualized bleeding rate comparing marstacimab treatment with either OD or RP during the observation period. There was a significant reduction in bleeding with marstacimab prophylaxis compared to OD (P < .0001) and a noninferior reduction in bleeding compared to RP (P = .04). Approximately 70% of patients entered the study with a target joint and although there was no improvement in target joints after 12 months for those subjects on marsticimab vs RP, there was improvement in target joint bleeding when compared to OD therapy. Fourteen subjects also had dose escalation from 150 mg to 300 mg weekly due to breakthrough bleeding but these were not included in the primary efficacy analysis. There were no deaths or thromboembolic events during the study period. Encouragingly, only 6 patients demonstrated neutralizing antimarstacimab antibodies and all were transient, resolving by treatment end. Interestingly, improvement in health-related quality of life measures were not significantly different between marstacimab and RP, despite less frequent SC administration and high treatment adherence with marstacimab use.

Although not novel, this study adds to the growing use of rebalancing agents and provides another therapeutic tool for patients with HA and HB with and without inhibitory antibodies. Marstacimab and concizumab display different epitope-binding sites and affinities for TFPI, which might contribute to the benefit of weekly vs daily dosing. Longer follow-up is needed to better define whether these molecular differences contribute to a difference in thrombosis.

The primary weakness of this investigation is the small number of patients enrolled and relatively short duration of treatment (1 year). The authors recognize this limitation, which is being addressed in an ongoing protocol extension. Thrombotic angiopathies and thromboembolism are a cause for concern for all rebalancing agents and investigators are focused on maintaining the correct dosing to lower the respective coagulation inhibitor, while still generating the right amount of thrombin to prevent bleeding. Additionally, the use of clotting factor concentrates to treat spontaneous bleeding or to prevent surgical bleeding may also contribute to unwarranted clotting.

Until FVIII/FIX levels after gene or other novel therapies are sustained in the hemostatic range, factor mimetics and rebalancing agents will continue to warrant strong therapeutic usefulness. Clinicians must always remain vigilant, however, to avoid tipping the bleeding/clotting teeter-totter toward thrombosis.

Conflict-of-interest disclosure: The author declares no competing financial interests.