Safety and Efficacy of Emicizumab in Persons with Hemophilia a with or without FVIII Inhibitors: Pooled Data from Four Phase III Studies (HAVEN 1-4)
Authors: Callaghan Michael U. , Négrier Claude , Paz-Priel Ido , Chang Tiffany , Chebon Sammy , Lehle Michaela , Mahlangu Johnny , Young Guy , Kruse-Jarres Rebecca , Mancuso Maria Elisa , Niggli Markus , Kuebler Peter , Selak Bienz Nives , Shima Midori , Jimenez-Yuste Victor , Schmitt Christophe , Asikanius Elina , Levy Gallia , Pipe Steven W. , Oldenburg Johannes 
Published: November 2020

Introduction: Emicizumab-a subcutaneously administered, bispecific, humanized, monoclonal antibody-promotes effective hemostasis in people with hemophilia A (PwHA). The primary efficacy and safety of emicizumab were reported previously, but long-term data are limited. Here, data from a wide age-range of PwHA with/without factor (F)VIII inhibitors enrolled in the Phase III HAVEN 1 (NCT02622321), HAVEN 2 (NCT02795767), HAVEN 3 (NCT02847637), and HAVEN 4 (NCT03020160) studies are pooled to establish the durable efficacy and safety of emicizumab.
Methods: The studies enrolled pediatric and adult PwHA with/without FVIII inhibitors. Participants received emicizumab prophylaxis 1.5 mg/kg weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks. All participants assigned to receive emicizumab (including those assigned to control arms who later switched) are included in this analysis.
Participants and/or caregivers recorded outcomes of bleeding events via the Bleed and Medication Questionnaire (BMQ). Data from HAVEN 1-4 were pooled for an aggregate analysis of emicizumab efficacy and safety. Efficacy endpoints include calculated mean annualized bleed rates (ABRs; discrete, consecutive 24-week treatment intervals), model-based ABRs (calculated via negative binomial regression for full study period), percentage of participants with zero and 1-3 treated bleeds, and annualized cumulative dose of coagulation factor (ACD). Safety endpoints include incidence of adverse events (AEs) and AEs of special interest.
Results: Overall, 400 PwHA in HAVEN 1, 2, 3 and 4 (n=113, 88, 151, and 48, respectively) are included in the efficacy analysis for a total of 970.3 patient years (cutoff: 15 May 2020). The safety population comprises 399 PwHA who received ≥1 dose of emicizumab (1 PwHA was randomized to receive emicizumab but did not start treatment). The median age at baseline was 28.5 (range 1-77) years. The majority of participants were White (66.8%) or Asian (18.8%); 52.3% had FVIII inhibitors. In the 24 weeks prior to study entry, 60.9% of participants had target joints. The median duration of efficacy period was 120.4 (interquartile range 89.0-164.4) weeks; 85.0% of participants had an efficacy period of ≥74 weeks; 11 participants (2.8%) discontinued study treatment. Across all 4 studies, 90.9-94.8% of the observation period was covered by completed BMQs.
Across all studies, the model-based treated bleed ABR was 1.4 (95% confidence interval 1.1-1.7); treated bleed ABRs remained low throughout, and were seen to decrease with successive 24-week treatment intervals (Table 1). During Weeks 121-144 (n=170), 82.4% of participants had zero treated bleeds, and 15.3% of participants had 1-3 treated bleeds. During the same period, 91.8% and 90.0% had zero treated spontaneous/joint bleeds respectively (Figure 1). The proportion of participants with target joints reduced from 60.9% prior to study entry to 4.6% at Weeks 1-24, then &lt;1.5% in all subsequent treatment intervals.
ACD of FVIII (Table 2), activated prothrombin complex concentrate (aPCC) and activated recombinant FVII (rFVIIa, Table 3) generally decreased across each 24-week treatment interval.
Emicizumab was well tolerated (Table 4), and no participants discontinued due to AEs beyond the five previously described (Oldenburg et al. N Engl J Med 2017; Young et al. Blood 2019; Mahlangu et al. N Engl J Med 2018; Pipe et al. Lancet Haem 2019). At data cut, 1 fatality, 3 thrombotic microangiopathies (TMAs), and 4 thromboembolic events (TEs) have been reported; all but 1 occurred in HAVEN 1. All TMAs and 2 of 4 TEs were associated with concomitant aPCC use. The percentage of participants with ≥1 drug-related AE in Weeks 1-24, 25-48 and 49-72 were 28.8%, 6.8%, and 3.0% respectively; over the same intervals, injection site reactions were observed in 23.3%, 4.8%, and 2.5% of participants.
Conclusions: With nearly 3 years of follow-up, emicizumab maintained low bleed rates in PwHA of all ages, with/without FVIII inhibitors. ABRs continued to decrease and the proportion of participants with zero treated bleeds increased with each consecutive 24-week period; the trend was the same for the proportion of participants with zero joint bleeds and almost all target joints resolved. The ACDs of FVIII, aPCC, and rFVIIa decreased with successive treatment intervals. Emicizumab remains well tolerated over long-term follow-up, and no new safety concerns have been identified to date.

Disclosures
Callaghan: Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biomarin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Speakers Bureau; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Research Funding; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Hema Biologics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alnylum: Current equity holder in publicly-traded company; Spark: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Speakers Bureau; Roche/Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Speakers Bureau; NovoNordisk: Other, Speakers Bureau; Sancillio: Other. Négrier:CSL Behring, Octapharma, Shire/Takeda, Sobi: Research Funding; CSL, F. Hoffmann-La Roche Ltd, Sobi: Other: Travel support; Bayer, Biomarin, CSL Behring, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann-La Roche Ltd, Sanofi, Shire/Takeda, Sobi, Spark: Consultancy. Paz-Priel:Genentech, Inc: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company, Other: All authors received editorial support for this abstract, provided by Scott Battle, PhD, of Health Interactions and funded by F. Hoffmann-La Roche.. Chang:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Chebon:F. Hoffmann-La Roche Ltd: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Lehle:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in private company. Mahlangu:CSL Behring, Catalyst Biosciences, Freeline Therapeutics, Novo Nordisk, F. Hoffmann-La Roche Ltd, Sanofi, Spark and Takeda: Consultancy; South Africa Medical Research Council, Wits Health Consortium, Colleges of Medicine of South Africa: Membership on an entity's Board of Directors or advisory committees; CSL Behring, Catalyst Biosciences, Novo Nordisk, F. Hoffmann-La Roche Ltd, Sanofi, Spark and Takeda: Speakers Bureau; BioMarin, CSL Behring, Freeline Therapeutics, Novo Nordisk, Novartis, Pfizer, Sanofi, F. Hoffmann-La Roche Ltd, uniQure: Research Funding. Young:Bayer, CSL Behring, Freeline, UniQure: Consultancy; Genentech/Roche, Grifols, and Takeda: Research Funding; BioMarin, Freeline, Genentech/Roche, Grifols, Kedrion, Novo Nordisk, Sanofi Genzyme, Spark, Takeda, and UniQure: Honoraria. Kruse-Jarres:Biomarin, Chugai Pharmaceutical Co., CSL Behring, CRISPR Therapeutics, Genentech, Inc.: Consultancy; CSL Behring, Genentech, Inc., Spark: Research Funding; Biomarin, Chugai Pharmaceutical Co., CSL Behring, CRISPR Therapeutics, Genentech, Inc.: Honoraria; F. Hoffmann-La Roche Ltd: Speakers Bureau. Mancuso:Bayer, CSL Behring, Novo Nordisk, Pfizer, F. Hoffmann-La Roche Ltd, Octapharma, Kedrion, Grifols, Sobi, PedNet Foundation: Consultancy; Bayer, CSL Behring, Novo Nordisk, F. Hoffmann-La Roche Ltd, Octapharma, Grifols, Sobi: Speakers Bureau; Bayer, CSL Behring, Novo Nordisk, Pfizer, F. Hoffmann-La Roche Ltd, Octapharma, Kedrion, Grifols, Catalyst, Kedrion, Sobi: Membership on an entity's Board of Directors or advisory committees; Center for Thrombosis and Hemorrhagic Diseases, Humanitas Clinical and Research Center - IRCCS, Rozzano, Milan, Italy: Current Employment. Niggli:F Hoffmann-La Roche Ltd: Current Employment. Kuebler:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Selak Bienz:F. Hoffmann-La Roche Ltd: Current Employment. Shima:Chugai Pharmaceutical Co., F. Hoffmann-La Roche Ltd, BioMarin, Bayer, Sanofi: Membership on an entity's Board of Directors or advisory committees; Chugai Pharmaceutical Co. , Sanofi, Bayer, Sysmex: Speakers Bureau; Patents related to anti-FIXa/FX bispecific antibodies: Patents & Royalties; Chugai Pharmaceutical Co.: Honoraria; Chugai Pharmaceutical Co. , F. Hoffmann-La Roche Ltd, Sanofi, CSL Behring, KM Biologics, Novo Nordisk, Shire/Takeda: Research Funding; Chugai Pharmaceutical Co.: Consultancy. Jimenez-Yuste:F. Hoffman-La Roche Ltd, Novo Nordisk, Takeda, Sobi, Pfizer, Grifols, Octapharma, CSL Behring, Bayer: Honoraria; F. Hoffman-La Roche Ltd, Novo Nordisk, Takeda, Sobi, Pfizer: Consultancy; Grifols, Novo Nordisk, Takeda, Sobi, Pfizer: Research Funding. Schmitt:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Asikanius:Fimea: Current Employment; F Hoffman-La Roche Ltd: Ended employment in the past 24 months; F Hoffmann-La Roche Ltd: Divested equity in a private or publicly-traded company in the past 24 months. Levy:F Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Genentech, Inc.: Ended employment in the past 24 months; Spark Therapeutics: Current Employment; Baxalta US: Patents & Royalties: Royalties from ADAMTS13 patent . Pipe:Medical and Scientific Advisory Council to the National Hemophilia Foundation; Medical Advisory Board to World Federation of Hemophilia: Membership on an entity's Board of Directors or advisory committees; Apcintex, Bayer, BioMarin, Catalyst Biosciences, CSL Behring, HEMA Biologics, Freeline, Novo Nordisk, Pfizer, F. Hoffmann-La Roche Ltd/Genentech, Inc., Sangamo Therapeutics, Sanofi, Takeda, Spark Therapeutics, uniQure: Consultancy; Siemens: Research Funding. Oldenburg:Bayer, BioMarin, Biotest, Chugai Pharmaceuticals Co., CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann-La Roche, Ltd, Spark, Swedish Orphan Biovitrum and Takeda: Speakers Bureau; Bayer, BioMarin, Biotest, Chugai Pharmaceuticals Co., CSL Behring, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann-La Roche. Ltd, Spark, Swedish Orphan Biovitrum and Takeda: Other; Bayer, BioMarin, Biotest, Chugai Pharmaceuticals Co., CSL Behring, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann-La Roche, Ltd, Spark, Swedish Orphan Biovitrum and Takeda: Membership on an entity's Board of Directors or advisory committees; University Clinic Bonn: Current Employment; Bayer, Biotest, CSL Behring, Novo Nordisk, Octapharma, Pfizer and Takeda: Research Funding; Bayer, BioMarin, Biotest, Chugai Pharmaceuticals Co., CSL Behring, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann-La Roche, Ltd, Spark, Swedish Orphan Biovitrum and Takeda: Honoraria.