A Phase 1b/2 Study of the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of PF-06741086, an anti-TFPI Monoclonal Antibody, in Patients with Severe Hemophilia A or B
ISTH Academy. Mahlangu J. Jul 7, 2019; 273864; OC 11.2 Topic: Hemophilia - Clinical
Johnny Mahlangu
Johnny Mahlangu
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OC 11.2

A Phase 1b/2 Study of the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of PF-06741086, an anti-TFPI Monoclonal Antibody, in Patients with Severe Hemophilia A or B

J. Mahlangu1, J.L. Lamas2, J.C. Morales2, D.R. Malan3, S. Zupancic-Salek4, M. Wang5, L.N. Boggio6, I. Hegemann7, A. Mital8, M. Cardinal9, T. Zhu9, P. Sun9, S. Arkin9
1Haemophilia Comprehensive Care Center, Faculty of Health Sciences, University of the WitWatersrand and NHLS, Johannesburg, South Africa, 2Complejo Assitencial Dr Sotero Del Rio, Santiago, Chile, 3Phoenix Pharma, Mount Croix, Port Elizabeth, South Africa, 4University Hospital Centre Zagreb, Zagreb, Croatia, 5Hemophilia and Thrombosis Center, University of Colorado, Aurora, United States, 6Rush Hemophilia & Thrombophilia Center, Rush University Medical Center, Chicago, United States, 7Haemophilia Comprehensive Care Center, University Hospital, Zurich, Switzerland, 8Medical University of Gdańsk, Gdańsk, Poland, 9Pfizer Worldwide Research and Development, Cambridge, United States

Main Topic: Hemophilia and Bleeding (including Transfusion)
Category: Hemophilia - Clinical

Background: PF-06741086, a monoclonal antibody, targets tissue factor pathway inhibitor (TFPI) to augment clotting activity.
Aims: Evaluate safety/tolerability of PF-06741086, administered subcutaneously (SC), for 3 months prophylactically in hemophilia A (hemA) and B (hemB). Efficacy, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity were also assessed.
Methods: This open-label, phase 1b/2, ascending dose study was approved by ethics committees and, with consent, enrolled patients with severe (FVIII or FIX ≤1%) hemA or hemB (± inhibitors), aged 18-64y, receiving on-demand treatment, with ≥6 bleeding episodes during the prior 6 months. Patients were assigned to PF-06741086 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. Safety parameters included adverse events (AEs), laboratory assessments, and vitals. Efficacy assessments used the annualized bleeding rate (ABR). A negative binomial model-based ABR was compared with historic controls.
Results: Twenty-six patients were enrolled: C1, n=7 (6 hemA, 1 hemB); C2, n=6 (5 hemA, 1 hemB); C3, n=6 (5 hemA, 1 hemB); and C4, n=7 (7 hemA, with inhibitors). All received ≥1 PF-06741086 dose. Four serious AEs unrelated to treatment occurred. No thrombotic events occurred. Three patients discontinued because of AEs. Four subjects had grade 3 AEs; all other AEs were grade ≤2. Most common treatment-related AEs were injection site reactions. Model-based ABR was 4.2 (C1), 1.5 (C2), 4.2 (C3), and 0.7 (C4). Percent reduction versus historical controls (ABR=27.6) was 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.
Conclusions: PF-06741086 was safe and efficacious in hemA and hemB patients, with or without inhibitors.

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