Author(s): Annemieke J. Willemze, MD, Sanofi; Annette von Drygalski, MD, PharmD, University of California San Diego; Barbara A. Konkle, MD, Bloodworks Northwest; Bent Winding, MD, Sobi AB; John Pasi, MB, ChB, PhD, Royal London Haemophilia Centre, Barts and the London School of Medicine and Dentistry; Marek Demissie, MD, PhD, Sanofi; Roshni Kulkarni, MD, Michigan State University; Stacey Poloskey, MD, Sanofi; Stella Lin, PhD, Sanofi; Suresh Katragadda, PhD, Sanofi; Toshko Lissitchkov, MD, Specialized Hospital for Active Treatment of Hematological Diseases

Research Category: Clinical Research/Clinical Trials

Description:

Objectives:

Factor VIII (FVIII) replacement enables comprehensive management of people with hemophilia A across clinical scenarios. Treatment goals in hemophilia are advancing toward functional cures and health equity (Skinner, et al. Haemophilia. 2019), which highlights the need for therapies that provide high sustained activity with longer prophylactic dosing intervals. Plasma half-life extension of current FVIII replacement products are constrained to 1519 hours by the chaperone effect of endogenous von Willebrand factor (VWF) on FVIII.
BIVV001 (rFVIIIFc-VWF-XTEN) is a novel, investigational recombinant FVIII therapy comprising single-chain FVIII, the Fc domain of human immunoglobulin G1, two XTEN®a polypeptides, and the FVIII-binding D?D3 domain of VWF. This new class of FVIII replacement is uncoupled from endogenous VWF, breaking the VWF-imposed half-life ceiling (Chhabra, et al. Blood. 2020). In a Phase 1 repeat-dose study, BIVV001 (four once-weekly infusions of 50 IU/kg) was associated with high sustained FVIII activity and was well tolerated with no identified safety concerns (Lissitchkov, et al. Blood. 2019). After final infusion, mean steady-state FVIII activity at 3 and 7 days was 46% and 10%, respectively, and FVIII geometric mean (range) half-life was 41.3 (34.250.1) hours. The efficacy, safety, and pharmacokinetics of BIVV001 are currently being evaluated in this Phase 3 trial (XTEND-1, NCT04161495). An ongoing observational study is collecting pre-study baseline data for subjects anticipated to enroll in XTEND-1.

Methods:

XTEND-1 is a multicenter, open-label, nonrandomized Phase 3 trial. Previously treated subjects (?150 exposure days), ?12 years old, with severe hemophilia A (<1 IU/dL [<1%] endogenous FVIII) are eligible for inclusion. Subjects on a prestudy prophylaxis regimen will switch to prophylaxis with BIVV001 50 IU/kg once weekly (Arm A, n~124), whereas those receiving prestudy on-demand treatment will receive BIVV001 50 IU/kg on demand for 26 weeks before switching to prophylaxis with BIVV001 50 IU/kg once weekly for 26 weeks (Arm B, n~26) (Figure).

Summary:

The primary efficacy objective is to evaluate BIVV001 as a prophylactic treatment. The primary and key secondary efficacy outcome measures are annualized bleed rate and intra-patient comparison of annualized bleed rate (prestudy [from the observational study] versus BIVV001 prophylaxis), respectively, in Arm A (Figure). Other secondary objectives include efficacy in bleed treatment and perioperative management, joint health outcomes, quality of life, and BIVV001 consumption. Safety, tolerability, and pharmacokinetics are additional objectives. Other novel endpoints include ultrasound assessment of joint health and physical activity tracking using wearable devices. The study has initiated and is currently recruiting.

Conclusions:

XTEND-1 will further investigate the efficacy, safety, and pharmacokinetics of once-weekly prophylactic dosing of BIVV001, a new class of FVIII replacement with high sustained FVIII activity, in severe hemophilia A.
aXTEN® is a registered trademark of Amunix Pharmaceuticals, Inc.