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Background: Emicizumab, a bispecific monoclonal antibody, bridges activated factor (F) IX and FX, replacing the function of missing activated FVIII in persons with hemophilia A (PwHA). The Phase IIIb, multicenter, single-arm STASEY study (NCT03191799) assessed the safety and efficacy of emicizumab prophylaxis in PwHA with FVIII inhibitors. Surgical experiences in STASEY are reported here. Methods: Following informed consent and ethics committee approval, PwHA aged ≥12 years with FVIII inhibitors received 3 mg/kg/week emicizumab for 4 weeks (loading dose), then 1.5 mg/kg/week for the remaining 2-year treatment period. Minor and major surgeries were managed per the investigators' discretion. The type and number of procedures performed, additional prophylaxis, and frequency and management of postoperative bleeds were analyzed. Surgeries occurring up to 28 days after the last dose of emicizumab were included, due to emicizumab's ~28-day half-life (Emicizumab Prescribing Information, United States Food and Drug Administration, 2017). Surgeries were documented using an electronic case report form by the treating physicians and classified as minor or major based on manual medical review (Santagostino, et al. Haemophilia, 2015). Bleed and prophylactic hemophilia medication data were recorded in the electronic Bleed Medication Questionnaire by participants. Case narratives were provided by trial investigators. Results: Overall, 46 patients reported ≥1 on-study surgery. Thirty-seven patients had 56 minor surgeries (central venous access device [CVAD], n=9; dental, n=20; joint, n=4; other, n=23) (Figure), one of which (skin laceration and suture insertion on Day 9) was performed during the loading phase. Twenty-four surgeries (42.9%) were managed with additional prophylactic medications (Table). Of these, 11/24 (45.8%) resulted in postoperative bleeds, of which 6/11 were treated (54.5%). Of surgeries managed without additional prophylactic medications, 15/32 (46.9%) resulted in postoperative bleeds, of which 5/15 (33.3%) were treated. A total of 13 patients had 22 major on-study surgeries (arthroplasty, n=13; other, n=9). 'Other' included hemorrhoid operations, coronarography, sigmoidectomy, colostomy, laparotomy and polypectomy. Eighteen (81.8%) major surgeries, including all arthroplasties, were managed with additional prophylactic medications (Table). Of these, 12/18 (66.7%) resulted in postoperative bleeds (including 10/13 arthroplasties), of which six (50.0%) were treated (all arthroplasties). Four (18.2%) major surgeries were managed without additional prophylactic medication, including three hemorrhoid operations in one patient, and a coronarography in a patient with acute myocardial infarction. One hemorrhoid operation resulted in a postoperative treated bleed. Major surgeries included a 55-year-old male with Grade 4 device dislocation of left knee prosthesis on Day 7, who was diagnosed with recurrent infection and prosthesis misalignment on Day 62. Amputation of the left leg above the knee was performed, with treatment including tranexamic acid and rFVIIa. A 61-year-old male with left knee prosthesis infection underwent left knee arthrodesis on Day 457, vacuum-assisted closure therapy on Day 495, skin grafting on Day 512, and left knee arthrodesis with skin flap placement on Day 527. Throughout these surgeries, the individual experienced recurrent joint bleeding and received rFVIIa. Neither of these individuals had a change in their study treatment due to these events. No thrombotic events (TEs) or thrombotic microangiopathies (TMAs) related to surgeries were observed. Conclusions: In the STASEY study of PwHA with FVIII inhibitors receiving emicizumab prophylaxis, most minor surgical procedures were performed without additional prophylactic coagulation factor and did not result in postoperative treated bleeds. Therefore, emicizumab alone provided adequate hemostatic coverage for some PwHA undergoing certain types of minor surgery, such as tooth extraction and CVAD removal. Major surgeries were safely performed with additional coagulation prophylaxis. Management of surgeries with rFVIIa did not result in TE or TMA. In case of bleeds, a bleed management plan should be in place. Effects of emicizumab on coagulation and assays may persist for up to 6 months after the last dose, which may be relevant when planning postoperative treatment. Figure 1 Figure 1. Disclosures Castaman: Uniqure: Honoraria; Bayer: Honoraria; Sobi: Honoraria; CSL Behring: Honoraria; Novo Nordisk: Honoraria; Kedrion: Honoraria; LFB: Honoraria; Grifols: Honoraria; Werfen: Honoraria; Biomarin: Honoraria; Sanofi: Honoraria; F Hoffmann-La Roche Ltd: Honoraria. Windyga: Swixx BioPharma: Honoraria; Octapharma: Honoraria, Research Funding; Sobi: Honoraria, Research Funding; Sanofi-Aventis: Honoraria, Research Funding; Werfen: Honoraria; Bayer AG: Honoraria; Aspen: Honoraria; Alfasigma: Honoraria; Takeda: Honoraria, Research Funding; Shire: Honoraria, Research Funding; Alnylam Pharmaceuticals: Research Funding; Sanofi/Genzyme: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Alexion: Honoraria; CSL Behring: Honoraria; Rigel Pharmaceuticals: Research Funding; Novo Nordisk: Honoraria, Research Funding; Baxalta: Honoraria, Research Funding. Alzahrani: Sobi: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria; King Faisal Specialist Hospital and Research Centre: Current Employment. Robson: F. Hoffmann-La Roche Ltd: Current Employment, Ended employment in the past 24 months. Sanabria: F. Hoffmann-La Roche Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Howard: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Jiménez-Yuste: Octapharma: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Sobi: Consultancy, Honoraria, Research Funding; BioMarin: Consultancy; CSL Behring: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; NovoNordisk: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding.

Background: Emicizumab is indicated for routine prophylaxis in persons with congenital hemophilia A (PwcHA) with/without factor (F)VIII inhibitors in >100 and >80 countries, respectively. Emicizumab has been used by >11,400 persons across the globe (data cut-off 15 May 2021). The pivotal HAVEN 1-4 trials established the efficacy and safety of emicizumab prophylaxis; however, the HAVEN 1 trial identified an increased risk of thrombotic events (TEs) and thrombotic microangiopathies (TMAs) when used in conjunction with >100 U/kg/24 hours activated prothrombin complex concentrate (aPCC) for ≥24 hours (Oldenburg, et al. New Engl J Med 2017). Here we report an updated safety evaluation of emicizumab prophylaxis focusing on TEs and TMAs. Methods: All individual safety reports for emicizumab from clinical trials, registries, expanded access programs, compassionate use and the post-marketing setting were collated with a cut-off date of 15 May 2021 and analyzed for TEs and TMAs. Number of TEs/TMAs, clinical factors (indication, age, FVIII inhibitor status, comorbidities) and drug factors (co-exposure to medications affecting coagulation) are presented in aggregate. Individual case reports (cases) were reviewed to exclude non-TEs and any duplicate reports. TEs were identified using the Medical Dictionary for Regulatory Activities (MedDRA) search strategy: 'Embolic and Thrombotic Events' Standardized Medical Query ([SMQ] Wide) and Preferred Term 'Acute Coronary Syndrome'. TMAs were defined as hemolytic uremic syndrome, microangiopathic hemolytic anemia, microangiopathy, thrombotic microangiopathy and thrombotic thrombocytopenic purpura. Results: In total, 52 cases (56 events) meeting the search criteria were identified on the Roche Global Safety Database as of 15 May 2021 (Figure). After review, 39 cases were reported in PwcHA and 10 cases were determined to be off-label (acquired hemophilia A, n=7; or unknown indication, n=3). Two additional cases were determined to be duplicates. One case of 'hemiparesis' was identified through SMQ review, but did not fit the clinical definition of a true TE. Six cases occurred with concomitant aPCC use, of which four were TMAs. In total, 33 cases were not associated with concomitant aPCC use, and these comprised 37 TEs and no TMAs in PwcHA. No new TEs or TMAs associated with aPCC were reported since the last update (Lee, et al. Haemophilia 2020). For the 37 TEs reported in PwcHA and not associated with aPCC, the median age (range) at time of event was 49 years (0.42-84) and the median (range) emicizumab treatment duration at time of event was 330 days (0-1076). In total, 36 (97.3%) TEs were medically confirmed and one (2.7%) was patient reported. Seventeen (45.9%) TEs occurred in PwcHA with FVIII inhibitors. Seven (18.9%) TEs were associated with central venous access devices (CVADs), of which four were reported to be resolving/recovering at last report. All except for two (with limited information) non-aPCC associated TEs in PwcHA were associated with ≥1 cardiovascular (CV) risk factors (e.g. previous myocardial infarction, ischemic heart disease, coronary artery disease, hypertension, hyperlipidemia, smoking, advanced age) or other risk factors for thrombosis (e.g. sepsis/bacteremia, device use, coinciding injury, hepatitis C). Of the non-aPCC and non-CVAD associated events reported, six (20.0%) TEs led to the discontinuation of emicizumab. Across all non-aPCC associated events, an evaluation of latency or duration of treatment did not reveal any patterns or trends. In total, four TEs were fatal: two myocardial infarctions, both in medically complex patients; and two disseminated intravascular coagulation events in patients >70 years of age with pneumonia. Where reported, 20/31 (64.5%) TEs were recovered/resolving at the time of this analysis, with the majority of these cases reporting no change to emicizumab prophylaxis as a result of the event. Conclusions: The reporting rate for TEs without concomitant aPCC remains low as exposure increases. Notably, all cases with adequate information available were associated with CV risk factors and/or risk factors for thrombosis. All TMAs were associated with concomitant use of aPCC. This post-marketing analysis does not support TEs and TMAs without concomitant aPCC as an identified risk for PwcHA receiving emicizumab prophylaxis. The risk-benefit profile of emicizumab remains unchanged. Figure 1 Figure 1. Disclosures Howard: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. McKinley: Pro Unlimited: Current Employment. Sanabria: F. Hoffmann-La Roche Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Ko: Genentech, Inc.: Current Employment; Genentech, Inc.-Roche: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Nissen: Novartis: Consultancy; Actelion: Consultancy; F. Hoffmann-La Roche Ltd: Current Employment, Current holder of stock options in a privately-held company. OffLabel Disclosure: The enclosed analysis of the Roche Hemlibra internal database was produced by submitted safety reports, including reports of off-label use. These data will be discussed in aggregate, and not individually described.