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Presentation Details
| NXT007 prophylaxis in people with hemophilia A with or without FVIII inhibitors: A global Phase I/II multiple-ascending-dose study Maria Elisa Mancuso1, 2, Davide Matino3, Dan Hart4, Francisco José López-Jaime5, Christophe Schmitt6, Sanjay Ahuja7, Giuliana Ventriglia6, Anna Kiialainen6, Laura Young8, Olivier Catalani6, Mark Belletrutti9, Tom Chu 10, Jerzy Windyga11, Víctor Jiménez-Yuste12, Michaela Lehle6, Janice M.Staber13. 1Humanitas University, Pieve Emanuele, Milan, Italy.2Center for Thrombosis and Hemorrhagic Diseases, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.3McMaster University, Hamilton, Ontario, Canada.4Roche Products Ltd, Welwyn Garden City, United Kingdom.5Hospital Universitario Regional de Málaga, Málaga, Spain.6F.Hoffmann-La Roche Ltd, Basel, Switzerland.7Indiana Hemophilia and Thrombosis Center, Indianapolis, IN, USA.8Auckland City Hospital, Auckland, New Zealand.9Department of Pediatrics, University of British Colombia, Vancouver, British Columbia, Canada.10Genentech, Inc., South San Francisco, CA, USA.11Department of Hemostasis Disorders and Internal Medicine, Laboratory of Hemostasis and Metabolic Diseases, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.12La Paz University Hospital-IdiPAZ, Autónoma University, Madrid, Spain.13Stead Family Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA, USA |
Abstract
Introduction: NXT007 is a next-generation bispecific antibody, based on emicizumab, that mimics the cofactor function of activated factor (F)VIII in people with hemophilia A (PwHA). We report on the first three cohorts of the Phase I/II global, open-label, non-randomized, multicenter, multiple-ascending-dose study of NXT007 (NCT05987449) in PwHA. Methods: Eligible participants are males aged 12–59 years with severe (FVIII activity <1 IU/dL) or moderate (FVIII activity 1–5 IU/dL) congenital HA with/without FVIII inhibitors. The primary treatment phase was 24 weeks. Cohorts 1, 2, and 3 received two loading doses (on Days 1 and 15) of subcutaneous NXT007 at 0.42 mg/kg, 1.05 mg/kg, and 1.62 mg/kg, respectively. Maintenance doses were 0.28 mg/kg, 0.70 mg/kg, and 1.08 mg/kg, respectively, every 4 weeks. The primary measure is safety, assessed through documentation of adverse events (AEs). Other measures include annualized bleeding rates (ABRs), pharmacokinetics, pharmacodynamics, and immunogenicity (incidence of anti-drug antibodies [ADAs]). Results: At data cut-off (April 21, 2025), 22 participants had been treated with NXT007: seven in Cohort 1, nine in Cohort 2, and six in Cohort 3. No participants discontinued NXT007 treatment. The median (range) age was 36 (15–49) years; 20 (90.9%) participants had severe HA. Two (9.1%) had history of FVIII inhibitors and one (4.5%) had current FVIII inhibitors. Median (range) observation periods in Cohorts 1, 2, and 3 were 68.9 (61.1–80.0), 44.1 (42.1–46.1), and 21.6 (20.1–24.1) weeks, respectively. At data cut-off, 19/22 (86.4%) participants had experienced 96 AEs in total. Five (22.7%) participants reported an injection-site reaction; all were Grade 1 and most resolved within 24 hours. One participant, in Cohort 2, experienced transient Grade 2 aspartate aminotransferase increase, deemed related to NXT007. Two participants experienced serious AEs; both resolved and were considered unrelated to NXT007. No thrombotic events or thrombotic microangiopathies were reported. The ABR (95% confidence interval) for treated bleeds in the maintenance period was 0.55 (0.11–2.83); 19/22 (86.4%) participants had zero treated bleeds. One notable outlier, in Cohort 3, reported multiple spontaneous treated bleeds considered secondary to direct vessel trauma in a replaced left knee joint. ADAs were detected by ELISA in most participants but had no impact on pharmacokinetics, efficacy, or safety, and had no cross-reactivity with emicizumab. Conclusion: NXT007 had a favorable safety profile at all doses. Overall treated bleed ABR was low. The presence of ADAs did not impact pharmacokinetics. These data support progression to Phase III trials.
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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.