Evaluating BIVV001, a New Class of Factor VIII Replacement Therapy: A Phase 3 Study (XTEND-1) Design

Introduction
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 15–19 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 registered trademark of Amunix Pharmaceuticals, Inc.) 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; Konkle et al. Blood. 2018). 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 (34.2–50.1) hours. The efficacy, safety, and pharmacokinetics of BIVV001 are currently being evaluated in this Phase 3 trial (XTEND-1). An ongoing observational study is collecting pre-study baseline data for subjects anticipated to enroll in XTEND-1.

Study Design and Methods
XTEND-1 (NCT04161495) is a multicenter, open-label, nonrandomized Phase 3 trial. Previously treated subjects (≥150 exposure days) ≥12 years of age with severe hemophilia A (<1 IU/dL [<1%] endogenous FVIII) are eligible for inclusion. XTEND-1 will evaluate bleed events and factor usage, and patient-centric and novel endpoints such as patient-reported outcome measurements, including physical activity monitoring via wearable devices and longitudinal joint health assessments with musculoskeletal ultrasound imaging.

Subjects on a pre-study prophylaxis regimen will switch to prophylaxis with BIVV001 50 IU/kg once weekly (Arm A [n~124]), whereas those receiving pre-study 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 1). The primary efficacy objective is to evaluate BIVV001 as a prophylactic treatment. The primary and key secondary efficacy outcome measures are annualized bleed rate (ABR) and intra-patient comparison of ABR (pre-study [from the observational study] versus BIVV001 prophylaxis), respectively, in Arm A (Figure 1). 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.

For the primary endpoint, mean ABR and confidence interval for the weekly prophylaxis treatment arm (Arm A) will be estimated using a negative-binomial regression model. Intra-patient ABR comparison of BIVV001 weekly prophylaxis treatment to historical prophylaxis will be performed.

Conclusions
XTEND-1 will investigate the efficacy, safety, and pharmacokinetics of 50 IU/kg once-weekly prophylactic dosing of BIVV001, a new class of FVIII replacement with high sustained FVIII activity, in severe hemophilia A. The study has initiated and is currently recruiting.