Emicizumab in people with moderate or mild haemophilia A (HAVEN 6): a multicentre, open-label, single-arm, phase 3 study.

Autor:	Négrier C; Claude Bernard Lyon 1 University, Lyon, France. Electronic address: claude.negrier@univ-lyon1.fr., Mahlangu J; University of the Witwatersrand and NHLS, Johannesburg, South Africa., Lehle M; F Hoffmann-La Roche, Basel, Switzerland., Chowdary P; Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London, London, UK., Catalani O; F Hoffmann-La Roche, Basel, Switzerland., Bernardi RJ; Genentech, San Francisco, CA, USA., Jiménez-Yuste V; La Paz University Hospital, Autonomous University of Madrid, Madrid, Spain., Beckermann BM; F Hoffmann-La Roche, Basel, Switzerland., Schmitt C; F Hoffmann-La Roche, Basel, Switzerland., Ventriglia G; F Hoffmann-La Roche, Basel, Switzerland., Windyga J; Department of Hemostasis Disorders and Internal Medicine, Laboratory of Hemostasis and Metabolic Diseases, Institute of Hematology and Transfusion Medicine, Warsaw, Poland., d'Oiron R; Bicêtre Hospital AP-HP, University of Paris-Saclay and UMR_S1176 INSERM, Le Kremlin-Bicêtre, Paris, France., Moorehead P; Memorial University of Newfoundland, St John's, NL, Canada., Koparkar S; Genentech, San Francisco, CA, USA., Teodoro V; F Hoffmann-La Roche, Basel, Switzerland., Shapiro AD; Indiana Hemophilia and Thrombosis Center, Indianapolis, IN, USA., Oldenburg J; Institute of Experimental Haematology and Transfusion Medicine, University of Bonn, Bonn, Germany., Hermans C; University Clinic of Saint Luke, Catholic University of Louvain, Brussels, Belgium.
Jazyk:	angličtina
Zdroj:	The Lancet. Haematology [Lancet Haematol] 2023 Mar; Vol. 10 (3), pp. e168-e177. Date of Electronic Publication: 2023 Jan 27.
DOI:	10.1016/S2352-3026(22)00377-5
Abstrakt:	Background: Clinical trial data are scarce for the use of prophylaxis in people with non-severe haemophilia A. The HAVEN 6 study aims to assess safety and efficacy of emicizumab prophylaxis in people with non-severe haemophilia A without factor VIII (FVIII) inhibitors. Methods: HAVEN 6 is a multicentre, open-label, single-arm, phase 3 study taking place in 22 specialty clinics and hospitals in Europe, North America, and South Africa. Eligible participants were people of all ages weighing at least 3 kg with a diagnosis of moderate (FVIII activity ≥1%-≤5%) or mild (FVIII >5%-<40%) haemophilia A without FVIII inhibitors requiring prophylaxis as assessed by the treating physician. Participants received subcutaneous emicizumab 3 mg/kg of bodyweight once weekly for 4 weeks, followed by the participant's choice of maintenance dose: 1·5 mg/kg once weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks. Safety was the primary objective of the study. Safety endpoints included adverse events, serious adverse events, and adverse events of special interest including thromboembolic events and thrombotic microangiopathies. The primary efficacy endpoint was the annualised bleed rate for treated bleeds. Analyses were done for participants who received at least one dose of emicizumab. This study is registered with ClinicalTrials.gov, number NCT04158648, and is active but not recruiting. Findings: Between Feb 10, 2020, and Aug 31, 2021, we assigned 73 people to treatment. 72 participants received at least one dose of emicizumab (51 moderate [71%]; 21 mild [29%]; 69 male [96%]; three female [4%]; and 61 White [85%]). Median age was 23·5 years (IQR 12·0-36·0); median follow-up was 55·6 weeks (IQR 52·3-61·6) weeks. At baseline, 24 participants (33%) had target joints and 37 (51%) were receiving FVIII prophylaxis. 60 participants (83%) had at least one adverse event; the most common adverse events were headache (in 12 participants [17%]), injection-site reaction (12 [17%]), and arthralgia (11 [15%]). 15 (21%) had at least one emicizumab-related adverse event; no adverse events led to treatment withdrawal, modification, or interruption. Eight participants (11%) reported ten serious adverse events in total, none emicizumab-related. There were no deaths or thrombotic microangiopathies. One participant had grade 1 thrombosed haemorrhoids (classified as a thromboembolic event), unrelated to emicizumab. The annualised bleed rate was 0·9 (95% CI 0·55-1·52) for treated bleeds. 48 participants (67%) had no treated bleeds. All-bleed annualised bleed rates were 10·1 (95% CI 6·93-14·76) from 24 weeks pre-study and 2·3 (1·67-3·12) on-study after a median follow-up of 55·6 weeks. Interpretation: These data show efficacy and a favourable safety profile of emicizumab in people with non-severe haemophilia A without FVIII inhibitors who warrant prophylaxis, confirming emicizumab as a valuable treatment option in this population. Funding: F Hoffmann-La Roche. Competing Interests: Declaration of interests CN has served as a consultant to BioMarin, Novo Nordisk, F Hoffmann-La Roche/Genentech, Sanofi, Sobi, and Shire/Takeda; received research funding from Novo Nordisk, F Hoffmann-La Roche/Genentech, and Sobi; received honoraria from Bayer, Novo Nordisk, F Hoffmann-La Roche /Genentech, Sanofi, Sobi, Spark Therapeutics, and Shire/Takeda; and has been a member of a board of directors or advisory committee for Bayer, BioMarin, CSL Behring, Novo Nordisk, Pfizer, F Hoffmann-La Roche/Genentech, Sanofi, Sobi, Spark Therapeutics, Shire/Takeda, and UniQure. JM is an employee of University of the Witwatersrand; has received grant or research support from BioMarin, Baxalta, Catalyst Biosciences, CSL, Novartis, Novo Nordisk, Pfizer, F Hoffmann-La Roche, Sanofi, Spark Therapeutics, and UniQure; consultant fees from BioMarin, Baxalta, CSL Behring, Catalyst Biosciences, Novo Nordisk, F Hoffmann-La Roche, Spark Therapeutics; and speaker bureau fees from Novo Nordisk, Pfizer, F Hoffmann-La Roche, Sanofi, Takeda, WFH, ISTH, and Springer. ML is an employee and holds stock in F Hoffmann-La Roche. PC has received research funding from Bayer, CSL Behring, Freeline, Novo Nordisk, Pfizer, Sobi, and Takeda; honoraria from ApcinteX, Bayer, Boehringer Ingelheim, CSL Behring, Chugai Pharmaceutical, Freeline, Novo Nordisk, Pfizer, F Hoffmann-La Roche, Sanofi, Spark Therapeutics, Sobi, and Takeda. OC is an employee of F Hoffmann-La Roche. RJB is an employee of Genentech, and stockholder in F Hoffmann-La Roche/Genentech. VJ-Y has received grant or research support from Grifols, Novo Nordisk, F Hoffmann-La Roche, Takeda, Bayer, CSL Behring, Pfizer, Sanofi, Sobi, and Octapharma; consultancy fees from Grifols, Novo Nordisk, F Hoffmann-La Roche, Takeda, Bayer, CSL Behring, Pfizer, BioMarin, Sanofi, Sobi, Spark Therapeutics, and Octapharma; honoraria from Grifols, Novo Nordisk, F Hoffmann-La Roche, Takeda, Bayer, CSL Behring, Pfizer, Sanofi, Sobi, Spark Therapeutics, and Octapharma. BMB is an employee and stockholder in F Hoffmann-La Roche. CS is an employee and stockholder in F Hoffmann-La Roche, and is co-inventor of a patent related to an anti-factor IXa/factor X bispecific antibody. GV is employee and stockholder in F Hoffmann-La Roche. JW is an employee at Institute of Hematology and Transfusion Medicine; received research funding from Baxalta, Novo Nordisk, Rigel Pharmaceuticals, F Hoffmann-La Roche, Shire, and Takeda; and received honoraria from Alfasigma, Bayer AG, Baxalta, CSL Behring, Novo Nordisk, Octapharma, Pfizer, F Hoffmann-La Roche, Sanofi-Aventis, Shire, Sobi, Swixx BioPharma, Takeda, and Werfen. Rd'O has received research funding from Takeda, CSL Behring, LFB, Novo Nordisk, Octapharma, F Hoffmann-La Roche, BioMarin, Sobi, and Sanofi; and honoraria from Takeda, CSL Behring, LFB, Novo Nordisk, Octapharma, F Hoffmann-La Roche, BioMarin, Sobi, Sanofi, and UniQure. PM is a member of a board of directors or advisory committee for F Hoffmann-La Roche Canada and Bayer. SK is an employee of Genentech. VT is an employee of F Hoffmann-La Roche. ADS is an employee of Indiana Hemophilia and Thrombosis Center,; received consultancy fees from Sangomo Biosciences, Prometic Life Sciences, and Sigilon; research funding from Bioverativ, Sanofi, Genentech, Kedrion Biopharma, Novo Nordisk, Pfizer, Sigilon, Takeda, ProMetic Life Sciences, and Freeline; and honoraria from Genentech, Sigilon, Novo Nordisk, Pfizer, and Catalyst Biosciences; speaker's bureau fees from Genentech and Novo Nordisk; and is a member of a board of directors or advisory committee for Hemophilia Foundation, Genentech, Sigilon, Novo Nordisk, and Sanofi. JO has received research funding from Bayer, Biotest, CSL Behring, Octapharma, Pfizer, Swedish Orphan Biovitrum, and Takeda; and consultancy, speaker's bureau, honoraria, scientific advisory board, and travel expenses from Bayer, Biogen Idec, BioMarin, Biotest, Chugai Pharmaceutical, CSL Behring, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, F Hoffmann-La Roche, Sanofi, Spark Therapeutics, Swedish Orphan Biovitrum, and Takeda. CH has received research funding from Bayer, Shire/Takeda, Pfizer, Novo Nordisk, CSL Behring, and Sobi; honoraria and speaker's bureau fees from Bayer, Shire/Takeda, Pfizer, Novo Nordisk, CSL Behring, Octapharma, Sobi, LFB, CAF-DCF, F Hoffmann-La Roche, UniQure, and BioMarin. (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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