Marstacimab trumps FRT for severe haemophilia without inhibitors

The novel, investigational anti-tissue factor pathway inhibitor marstacimab outdid factor replacement therapy (FRT) in reducing bleeds in patients with severe haemophilia A (HA) or moderately severe to severe haemophilia B (HB) without inhibitors beyond 12 months in the phase III BASIS trial.

“Marstacimab met the primary objectives and significantly reduced annualized bleeding rates (ABR) of treated bleeds,” said Dr Davide Matino from McMaster University, Hamilton, Ontario, Canada, at ASH 2023.

Over 12 months, mean ABR dropped significantly with marstacimab vs routine prophylaxis (RP; 5.1 vs 7.9), representing a 35-percent reduction in ABR and noninferiority and superiority of the former over the latter (p=0.0376). Compared with on-demand treatment (OD), marstacimab achieved superiority as evidenced by the significant 92-percent drop in mean ABR (3.2 vs 38.0; p<0.0001). [ASH 2023, abstract 285]

The long-term extension (LTE) phase (additional 16 months) saw a further drop in ABR with marstacimab in the RP subgroup (mean ABR, 2.3); in the OD subset, the 12-month reduction in mean ABR was sustained (mean ABR, 3.9).

About a third of participants did not have any treated bleeds with marstacimab during the active treatment phase (ATP), said Matino. Moreover, marstacimab efficacy was generally consistent across all subgroups.

Marstacimab achieved superiority over OD across all bleed categories (p<0.0001 for joint, spontaneous, target joint, and total bleeds) and noninferiority to RP (p=0.1680, p=0.0596, p=0.2811, and p=0.0406, respectively).

There were also greater numerical reductions in Haem-A-QoL Total scores with marstacimab vs OD (median estimate [ME], -4.8 vs -1.5) and RP (ME, -3.7 vs -1.2). A similar trend was seen in the Haem-A-QoL Physical Health Domain score (ME, -12.4 vs -1.1 [OD] and ME, -6.1 vs -3.9 [RP]).

The most common adverse events of special interest (AESI) with marstacimab were COVID-19, hepatic disorder, and injection site reaction. Most AEs were mild to moderate in severity.

Twenty-three patients tested positive for antidrug antibodies (ADAs), but this did not influence the safety of marstacimab. ADA titres in 22 patients were low and resolved eventually. Six ADA-positive patients tested positive for neutralizing antibodies, but these were transient and resolved by end of study, noted Matino.

May improve treatment adherence

BASIS included 128 patients (median age 30 years, 48 percent Asian) with severe HA (FVIII <1 percent; 79 percent) or moderately severe to severe HB (FIX ≤2 percent; 21 percent) with or without inhibitors. Participants received RP or OD in the 6-month observational phase (OP). After which, the 12-month ATP ensued, wherein 116 patients received a single loading 300-mg dose of marstacimab subcutaneously followed by 150 mg once weekly. Of these, 87 continued treatment in the LTE.

In a press release, Matino noted that the results are “particularly encouraging” as the ABR reductions seen in the ATP were retained in the LTE. [www.pfizer.com/news/press-release/press-release-detail/marstacimab-phase-3-data-presented-ash-2023-demonstrate, accessed December 23, 2023]

“For [over] 5 decades, the most common treatment for HA and HB has been IV infusions that are often administered multiples times per week,” said Dr James Rusnak, Senior Vice President, Chief Development Officer, Internal Medicine and Infectious Diseases, Research and Development, Pfizer.

Marstacimab may address the time-consuming nature of HA and HB treatment by providing an alternative that could be delivered subcutaneously and weekly in a flat dose that is not weight-based, and with low monitoring requirements. [Patient Prefer Adherence 2017;11:1677-1686; Haemophilia 2001;7:392-396]

“Based on the results, and if approved, we believe marstacimab could offer a subcutaneous option with a compelling combination of efficacy and safety that may significantly reduce the risk of bleeding. We look forward to potentially bringing this treatment option to people living with HA and HB without inhibitors,” said Rusnak.