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| Emicizumab Prophylaxis for the Treatment of Infants with Severe Haemophilia A without Factor VIII Inhibitors: Primary Analysis of the HAVEN 7 Study Steven W.Pipe1, Peter Collins2, Christophe Dhalluin3, Gili Kenet4, 5, Christophe Schmitt3, Muriel Buri3, Víctor Jiménez-Yuste6, Flora Peyvandi7, 8, Guy Young9, Johannes Oldenburg10, Maria Elisa Mancuso11, 12, Kaan Kavakli13, Anna Kiialainen3, Markus Niggli3, Tiffany Chang14, Michaela Lehle 3, Karin Fijnvandraat15. 1University of Michigan, Ann Arbor, MI, USA.2School of Medicine, Cardiff University, Cardiff, United Kingdom.3F.Hoffmann-La Roche Ltd, Basel, Switzerland.4Sheba Medical Center, Ramat Gan, Israel.5Tel Aviv University, Tel Aviv, Israel.6Hospital Universitario La Paz-IdiPaz, Universidad Autónoma, Madrid, Spain.7Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy.8Università degli Studi di Milano, Milan, Italy.9Children’s Hospital Los Angeles, Los Angeles, CA, USA.10Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Medical Faculty, University of Bonn, Bonn, Germany.11IRCCS Humanitas Research Hospital, Rozzano, Italy.12Humanitas University, Pieve Emanuele, Milan, Italy.13Ege University Faculty of Medicine Children's Hospital, Izmir, Turkey.14Spark Therapeutics, Inc., San Francisco, CA, USA.15University of Amsterdam, Amsterdam, Netherlands |
Abstract
Introduction: Venous access presents a significant challenge in infants with hemophilia A (IwHA) requiring prophylaxis. Subcutaneous emicizumab enables prophylaxis from birth, reducing bleed risk. Objectives: The HAVEN 7 (NCT04431726) primary analysis evaluates emicizumab prophylaxis over ≥52 weeks in IwHA. Methods: IwHA in the Phase 3b, open-label study were aged ≤12 months without factor (F)VIII inhibitors. They received emicizumab 3mg/kg maintenance dose every 2 weeks (Q2W) for 52 weeks, continuing emicizumab for 7 years’ planned follow-up. Endpoints include efficacy (negative binomial regression model-based annualized bleed rates [ABR] for treated, all, treated spontaneous, and treated joint bleeds), safety, pharmacokinetics, anti-emicizumab antibodies (ADAs), FVIII inhibitors, and biomarkers. Results: At data cut-off (May 22, 2023), 55 male IwHA had received emicizumab for ≥52 weeks (54.5% previously minimally treated [≤5 exposure days, EDs], and 45.5% previously untreated [PUP]). Median (range) age: 4 months (9 days–11 months 30 days) at enrollment; 29 (12–39) months at cut-off. Median (range) treatment duration: 100.3 (52–118) weeks. ABRs (95% confidence interval) for treated, all, and treated joint bleeds were 0.4 (0.30–0.63), 2.0 (1.49–2.66), and 0.0 (0.01–0.09), respectively. Overall, 207 bleeds occurred in 46 IwHA (83.6%), 87.9% of which were traumatic. Of the 207 total bleeds, 42 bleeds in 25 IwHA were treated, all traumatic. Thirty (54.5%) IwHA had zero treated bleeds, and no IwHA had >3 treated bleeds. No intracranial hemorrhage occurred. One IwHA was up-titrated (Day 374) to 3mg/kg weekly per investigator request based on locally assessed decreasing emicizumab levels. Nine IwHA (16.4%) had ≥1 treatment-related adverse event (AE), all Grade 1 injection-site reaction. No AE led to emicizumab change/withdrawal. No deaths/thrombotic events/thrombotic microangiopathies occurred. Mean steady-state emicizumab concentrations were 57–66µg/mL, above those with the same regimen in HAVEN 2 and 3 (46–48µg/mL). No IwHA developed ADAs. Two PUPs developed confirmed inhibitors after three and ten FVIII EDs, respectively. Mean FIX and FX concentrations were not impacted by emicizumab treatment. Activated partial thromboplastin time was shortened to within reference range by Day 15 (the first time point at which blood samples were obtained) in most participants. Mean thrombin generation peak height increased during loading and was maintained between 67 and 88nmol/L thereafter. Mean FVIII-like activity increased from baseline, and was then sustained between 21 and 26U/dL. Conclusions: This analysis suggests that emicizumab is efficacious and well tolerated in IwHA without FVIII inhibitors.
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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.