Tremendous progress has been made in the management of hemophilia with the introduction of recombinant proteins for treatment and prophylaxis, reducing the negative impact of hemophilia on morbidity. Despite this progress, there are still challenges to overcome to secure adequate prophylaxis and treatment, specifically related to regular and repeated intravenous administration. Although this approach has led to a reduced comorbidity, it does not yet represent an optimized approach to prevent hemophilic complications. One suggested alternative approach is the rebalancing of hemostasis through non-factor therapy. Dr. Johnny Mahlangu and others have conducted some preliminary research on PF-06741086, a monoclonal antibody that targets tissue factor pathway inhibitor (TFPI) to augment clotting activity.

The aim of this particular Phase 1b/2 study was to evaluate the safety of PF-06741086, administered subcutaneously (SC), for 3 months prophylactically in hemophilia A and B patients, along with an assessment of its efficacy via annualized bleeding rate (ABR), pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity. Individuals enrolled in this study had severe (Factor VIII or Factor IX ≤1%) hemophilia A or hemophilia B (plus or minus inhibitors); were between 18 and 64 years old; were receiving on-demand treatment; and had ≥6 bleeding episodes during the prior 6 months. They were assigned to 1 of 4 different cohorts (C): C1, 300 mg SC once weekly (QW); C2, 300 mg SC loading dose, 150 mg SC QW; C3, 450 mg SC QW; and C4 (inhibitor patients), 300 mg SC QW.

What did Dr. Mahlangu and his team find? Among the 26 patients enrolled who received PF-06741086, no thrombotic events occurred, and only 4 serious adverse events (AEs) occurred, unrelated to treatment. Three patients discontinued because of AEs. Four subjects had grade 3 AEs; all other AEs were grade ≤2. Injection site reactions occurred in only 1% of the subjects. Model-based ABR was 4.2 (C1), 1.5 (C2), 4.2 (C3), and 0.7 (C4). Percent reductions versus historical controls were 85% (C1), 95% (C2), 85% (C3), and 98% (C4). Across all cohorts, exposure levels were as predicted. Three patients had antidrug antibodies, with no impact on safety, PK, or PD. There were no confirmed neutralizing antibodies.

As Dr. Mahlangu stated, the findings clearly demonstrate that PF-06741086 was safe and efficacious in hemophilia A and B patients, with or without inhibitors. Further research is warranted around PF-06741086, but at first glance, the results suggest a promising future.

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