Efanesoctocog Alfa Half-Life and Clearance Are Independent of von Willebrand Factor in Severe Hemophilia A: A Post Hoc Analysis from Phase 1/2a Studies

Abstract Introduction: Scientific evidence increasingly suggests that, for many patients with severe hemophilia A, targeting higher sustained factor VIII (FVIII) levels is required to improve protection from bleeds, preserve joint health, and advance closer to the goal of a functional cure and health equity (Skinner MW, et al. Haemophilia. 2020). However, achieving high sustained factor activity levels with once-weekly dosing is not possible with currently approved FVIII therapies due to the FVIII half-life ceiling imposed by endogenous von Willebrand factor (VWF). Efanesoctocog alfa (rFVIIIFc-VWF-XTEN; BIVV001) is a novel fusion protein designed to decouple recombinant FVIII (rFVIII) from endogenous VWF and thereby overcome the VWF-imposed half-life ceiling (Chhabra ES, et al Blood. 2020). Once-weekly efanesoctocog alfa (50 IU/kg) has a geometric mean half-life of 41 hours and provides high sustained FVIII activity levels in the normal to near-normal range (>40%) for 3-4 days post dose and 10% at Day 7 (Lissitchkov T, et al. Blood. 2019). Therefore, efanesoctocog alfa has the potential to offer extended bleed protection with less frequent dosing in patients with severe hemophilia A (Konkle B, et al. N Engl J Med. 2020). In the Phase 1/2a and Phase 1 studies (EXTEN-A single-dose and repeat-dose, respectively), efanesoctocog alfa was well tolerated in previously treated adults with severe hemophilia A and no safety concerns were identified (Konkle B, et al. N Engl J Med. 2020; Lissitchkov T, et al. Blood. 2019). The aim of this post hoc analysis is to evaluate the relationship between endogenous VWF antigen levels and efanesoctocog alfa half-life and clearance in patients with severe hemophilia A from the single- and repeat-dosing studies. Methods: A total of 40 previously treated adult males (N=16 and N=24, respectively) with severe hemophilia A (<1 IU/dL [<1%] endogenous FVIII at screening) and ≥150 exposure days of prior FVIII treatment enrolled in the EXTEN-A single-dose (NCT03205163) and repeat-dosing (EudraCT No: 2018-001535-51)studies (Konkle B, et al. N Engl J Med. 2020; Lissitchkov T, et al. Blood. 2019). Subjects received either a single IV dose of 25 IU/kg (n=7) or 65 IU/kg (n=9) efanesoctocog alfa in EXTEN-A (Konkle B, et al. N Engl J Med. 2020) or 4 once-weekly doses of either 50 IU/kg (n=10) or 65 IU/kg (n=14) efanesoctocog alfa in the repeat-dosing study (Lissitchkov T, et al. Blood. 2019). Each study assessed safety and tolerability as its primary objective, with pharmacokinetics (PK) evaluated as a secondary objective (Konkle B, et al. N Engl J Med. 2020; Lissitchkov T, et al. Blood. 2019). All subjects with evaluable PK profiles were included in this post hoc analysis. The half-life and clearance of efanesoctocog alfa were evaluated as a function of pre-dose endogenous VWF antigen levels. VWF antigen levels were also assessed at various time points after dosing through end of study. Linear correlations were calculated using Pearson's correlation coefficient. Results : Of 40 enrolled subjects, mean (range) age was 39 (19-63) years. Mean (range) pre-dose VWF antigen levels were 151% (74%-297%; n=14) and 128% (49%-265%; n=24) for the single- and repeat-dose studies, respectively. Individual patient antigen levels of endogenous VWF were relatively stable over time, from screening and pre dose through 336 hours post dose and end of study (Figure 1A). Similar results were observed for VWF:RCo levels. A total of 37 subjects were eligible for inclusion in the pooled correlation analyses; 3 subjects had missing values and were excluded from analysis. Efanesoctocog alfa half-life showed no correlation with VWF antigen levels (R 2=0.0007; P=0.88) (Figure 1B). A similar result was observed for clearance of efanesoctocog alfa, which showed no correlation with VWF antigen levels (R 2=0.0493; P=0.19). Conclusions: Endogenous VWF levels are unaffected during and after treatment with single- or repeat-dosing of efanesoctocog alfa in previously treated patients with severe hemophilia A. Furthermore, the half-life and clearance of efanesoctocog alfa are independent of endogenous VWF levels. This is consistent with previous findings from preclinical data and supports the continued evaluation of efanesoctocog alfa as a VWF-independent rFVIII in ongoing Phase 3 clinical trials in hemophilia A (XTEND-1, NCT04161495; XTEND-Kids, NCT04759131; XTEND-ed, NCT04644575). This analysis was funded by Sanofi and Sobi. Figure 1 Figure 1. Disclosures Staber: Bayer, CSL Behring, Sanofi, Takeda: Membership on an entity's Board of Directors or advisory committees. Lissitchkov: Catalist: Other: Principal Investigator of Clinical Trials; Grifols: Other: Principal Investigator of Clinical Trials; Bayer: Other: Principal Investigator of Clinical Trials. Konkle: BioMarin Pharmaceutical Inc.: Other: Data and safety monitoring; Sigilon Therapeutics: Honoraria; CSL Behring: Other: Data and safety monitoring; Genentech USA Inc.: Honoraria. Shapiro: OPKO: Research Funding; Prometric BioTherapeutics: Research Funding; Sangamo: Other: Advisory board fees, Research Funding; Takeda: Research Funding; Sigilon Therapeutics: Other: Advisory board fees, Research Funding; Glover Blood Therapeutics: Research Funding; Genentech: Other: Advisory board fees, Research Funding, Speakers Bureau; Octapharma: Research Funding; Pfizer: Research Funding; Novo Nordisk: Other: Advisory board fees, Research Funding, Speakers Bureau; Novartis: Research Funding; Kedrion Biopharma: Research Funding; BioMarin: Research Funding; Bioverativ (a Sanofi company): Other: Advisory board fees, Research Funding; Daiichi Sankyo: Research Funding; Agios: Research Funding. Quon: Orthopaedic Institute for Children: Current Employment. Kulkarni: Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire/Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hamilton: Sobi: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Chhabra: Sanofi: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Katragadda: Sanofi: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Altincatal: Sanofi: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Willemze: Sanofi: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Dumont: Sanofi: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Ragni: Takeda Therapeutics: Membership on an entity's Board of Directors or advisory committees; Spark Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bioverativ (Sanofi): Membership on an entity's Board of Directors or advisory committees; BioMarin Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Alnylam (Sanofi): Membership on an entity's Board of Directors or advisory committees; University of Pittsburgh: Research Funding.