Presentation Details
| Individual Pharmacokinetic Evaluation of Fixed-Sequence Single-Dose Octocog Alfa, Rurioctocog Alfa Pegol, and Efanesoctocog Alfa in Adults With Severe Hemophilia A Janice M.Staber1, Toshko Lissitchkov2, Anthony Chan3, Andrew Wilson4, Jennifer Dumont4, Annemieke Willemze 5. 1Division of Hematology/Oncology, Department of Pediatrics, Carver College of Medicine, University of Iowa Stead Family Children's Hospital, Iowa City, IA, USA.2Specialized Hospital for Active Treatment of Hematological Diseases, Department of Chemotherapy, Hemotherapy and Hereditary Blood Diseases at Clinical Hematology Clinic, Sofia, Bulgaria.3McMaster Children’s Hospital, McMaster University, Hamilton, ON, Canada.4Sanofi, Cambridge, MA, USA.5Sanofi, Amsterdam, Netherlands |
Abstract
Background
Efanesoctocog alfa (formerly BIVV001) is a first-in-class high-sustained factor VIII (FVIII) replacement therapy uniquely designed to increase recombinant FVIII (rFVIII) half-life in part by decoupling FVIII from endogenous von Willebrand factor. The Phase 1 sequential pharmacokinetic (PK) study (NCT05042440; EudraCT 2021-000228-37) assessed PK and safety outcomes for rFVIII in previously treated patients following sequential single doses of standard half-life FVIII (SHL, octocog alfa), extended half-life FVIII (EHL, rurioctocog alfa pegol), and efanesoctocog alfa. Efanesoctocog alfa had a 2.8–3.9-fold longer elimination half-life and 3.6–6.0-fold greater area under the curve (AUC) versus rurioctocog alfa pegol and octocog alfa, respectively.
Objective
To analyze individual patient-level PK profiles in the sequential PK study.
Methods
The study included previously treated male patients (≥150 exposure days of prior FVIII treatment with any recombinant and/or plasma-derived FVIII and/or cryoprecipitate products), 18–65 years of age, with severe hemophilia A (<1 IU/dL endogenous FVIII). Patients received sequential single 50 IU/kg doses of octocog alfa, rurioctocog alfa pegol, and efanesoctocog alfa after appropriate washout. Here, demographics/baseline characteristics, time points above 15% and 40% FVIII levels, and PK parameters (half-life [t1/2], AUC, clearance [CL], maximum FVIII activity [Cmax], incremental recovery [IR]) were assessed at the individual patient level for octocog alfa, rurioctocog alfa pegol, and efanesoctocog alfa.
Results
Thirteen male patients were enrolled, aged 26–47 years (mean [standard deviation, SD] 36.8 [6.5] years), with a mean (SD) weight of 87.8 (18.9) kg. In individual patient level comparisons, all patients experienced a longer t½ and greater AUC with efanesoctocog alfa than with octocog alfa or rurioctocog alfa pegol (geometric mean [geometric SD] t1/2: octocog alfa, 11.0 [1.5] h; rurioctocog alfa pegol, 15.4 [1.4] h; efanesoctocog alfa, 43.3 [1.3] h; Figure 1). All patients experienced more days above 15%, and 40% FVIII activity levels with efanesoctocog alfa compared with octocog alfa or rurioctocog alfa pegol (average of ~4 days above 40% activity with efanesoctocog alfa vs <1 and 1 day for octocog alfa and rurioctocog alfa pegol, respectively; Figure 2). Clearance was lower with efanesoctocog alfa than with octocog alfa or rurioctocog alfa pegol in all patients. The spread of clearance data indicates lower interpatient variability with efanesoctocog alfa (geometric mean [geometric SD] CL: octocog alfa 3.0 [1.5] mL/h/kg; rurioctocog alfa pegol 1.8 [1.4] mL/h/kg; efanesoctocog alfa: 0.5 [1.2] mL/h/kg). Cmax and IR were similar for all 3 FVIII therapies tested (Figure 1). There were 3 treatment-emergent adverse events (TEAEs) while receiving efanesoctocog alfa in 1 patient (2 mild and 1 moderate) and none reported for other treatments. No TEAEs were serious, led to treatment discontinuation, or were deemed related to efanesoctocog alfa treatment.
Conclusion
Consistent superiority regarding time over 40% FVIII activity, half-life, clearance, and FVIII exposure were observed with efanesoctocog alfa compared with SHL and EHL FVIII in all patients. No serious TEAEs or inhibitor development were reported for efanesoctocog alfa.
Study funded by Sanofi and Sobi. Editorial assistance by Timothy Davies, PhD (Fishawack Communications Ltd., part of Avalere Health) funded by Sanofi.
No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.
Efanesoctocog alfa (formerly BIVV001) is a first-in-class high-sustained factor VIII (FVIII) replacement therapy uniquely designed to increase recombinant FVIII (rFVIII) half-life in part by decoupling FVIII from endogenous von Willebrand factor. The Phase 1 sequential pharmacokinetic (PK) study (NCT05042440; EudraCT 2021-000228-37) assessed PK and safety outcomes for rFVIII in previously treated patients following sequential single doses of standard half-life FVIII (SHL, octocog alfa), extended half-life FVIII (EHL, rurioctocog alfa pegol), and efanesoctocog alfa. Efanesoctocog alfa had a 2.8–3.9-fold longer elimination half-life and 3.6–6.0-fold greater area under the curve (AUC) versus rurioctocog alfa pegol and octocog alfa, respectively.
Objective
To analyze individual patient-level PK profiles in the sequential PK study.
Methods
The study included previously treated male patients (≥150 exposure days of prior FVIII treatment with any recombinant and/or plasma-derived FVIII and/or cryoprecipitate products), 18–65 years of age, with severe hemophilia A (<1 IU/dL endogenous FVIII). Patients received sequential single 50 IU/kg doses of octocog alfa, rurioctocog alfa pegol, and efanesoctocog alfa after appropriate washout. Here, demographics/baseline characteristics, time points above 15% and 40% FVIII levels, and PK parameters (half-life [t1/2], AUC, clearance [CL], maximum FVIII activity [Cmax], incremental recovery [IR]) were assessed at the individual patient level for octocog alfa, rurioctocog alfa pegol, and efanesoctocog alfa.
Results
Thirteen male patients were enrolled, aged 26–47 years (mean [standard deviation, SD] 36.8 [6.5] years), with a mean (SD) weight of 87.8 (18.9) kg. In individual patient level comparisons, all patients experienced a longer t½ and greater AUC with efanesoctocog alfa than with octocog alfa or rurioctocog alfa pegol (geometric mean [geometric SD] t1/2: octocog alfa, 11.0 [1.5] h; rurioctocog alfa pegol, 15.4 [1.4] h; efanesoctocog alfa, 43.3 [1.3] h; Figure 1). All patients experienced more days above 15%, and 40% FVIII activity levels with efanesoctocog alfa compared with octocog alfa or rurioctocog alfa pegol (average of ~4 days above 40% activity with efanesoctocog alfa vs <1 and 1 day for octocog alfa and rurioctocog alfa pegol, respectively; Figure 2). Clearance was lower with efanesoctocog alfa than with octocog alfa or rurioctocog alfa pegol in all patients. The spread of clearance data indicates lower interpatient variability with efanesoctocog alfa (geometric mean [geometric SD] CL: octocog alfa 3.0 [1.5] mL/h/kg; rurioctocog alfa pegol 1.8 [1.4] mL/h/kg; efanesoctocog alfa: 0.5 [1.2] mL/h/kg). Cmax and IR were similar for all 3 FVIII therapies tested (Figure 1). There were 3 treatment-emergent adverse events (TEAEs) while receiving efanesoctocog alfa in 1 patient (2 mild and 1 moderate) and none reported for other treatments. No TEAEs were serious, led to treatment discontinuation, or were deemed related to efanesoctocog alfa treatment.
Conclusion
Consistent superiority regarding time over 40% FVIII activity, half-life, clearance, and FVIII exposure were observed with efanesoctocog alfa compared with SHL and EHL FVIII in all patients. No serious TEAEs or inhibitor development were reported for efanesoctocog alfa.
Study funded by Sanofi and Sobi. Editorial assistance by Timothy Davies, PhD (Fishawack Communications Ltd., part of Avalere Health) funded by Sanofi.
No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.
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