Introduction Emicizumab is a recombinant humanized bispecific monoclonal antibody mimicking the cofactor function of activated factor VIII. Aim In this multicentre, open‐label study (HOHOEMI), we evaluated the efficacy, safety and pharmacokinetics of emicizumab in Japanese paediatric patients aged <12 years with severe haemophilia A without factor VIII (FVIII) inhibitors. Methods Emicizumab was administered subcutaneously, with four loading doses of 3 mg/kg every week followed by maintenance doses of 3 mg/kg every 2 weeks (Q2W) or 6 mg/kg every 4 weeks (Q4W) in 6 and 7 patients, respectively. Results All patients completed at least 24 weeks of treatment. Baseline ages ranged from 4 months to 10 years, and all patients had been treated with FVIII prophylaxis prior to enrolment except a 4‐month‐old patient untreated with FVIII previously. In the respective Q2W and Q4W cohorts, 2/6 and 5/7 patients experienced no treated bleeding events, and annualized bleeding rates for treated bleeding events were 1.3 (95% confidence interval [CI], 0.6‐2.9) and 0.7 (95% CI, 0.2‐2.6). All caregivers preferred emicizumab to the patient's previous treatment. Only one related adverse event (injection site reaction) was observed. There were no thromboembolic events or thrombotic microangiopathy. Individual trough plasma concentrations of emicizumab were within the variability observed in preceding adult/adolescent studies. All patients tested negative for anti‐emicizumab antibodies. Conclusions Emicizumab administered Q2W or Q4W was efficacious and safe in paediatric patients with severe haemophilia A without inhibitors. This study was registered at http://www.clinicaltrials.jp (JapicCTI‐173710).

Introduction Safety and efficacy results of the phase 1 study and phase 1/2 extension study of the bispecific antibody emicizumab in patients with severe haemophilia A with or without factor VIII inhibitors for up to 2.8 years were reported previously. Aim To evaluate further longer‐term data including patients’ perceptions at study completion. Methods Emicizumab was administered subcutaneously once weekly at maintenance doses of 0.3, 1 or 3 mg/kg with potential up‐titration. All patients were later switched to the approved maintenance dose of 1.5 mg/kg. Results Eighteen patients received emicizumab for up to 5.8 years. Most adverse events were mild and unrelated to emicizumab. Annualized bleeding rates (ABRs) for bleeds treated with coagulation factors decreased from pre‐emicizumab rates or remained zero in all patients. The median ABRs were low at 1.25, 0.83 and 0.22 during the 0.3, 1 and 3 mg/kg dosing periods, respectively. Of 8 patients who decreased their doses from 3 to 1.5 mg/kg, ABRs decreased in 4, remained at zero in 2, and increased in 2. Total time spent with symptoms associated with treated bleeds decreased in all patients except 2. All patients answered ‘improved’ for bleeding severity and time until bleeding stops, except 1 answering ‘slightly improved’. Most patients answered ‘improved’ or ‘slightly improved’’ for daily life and feelings; in particular, all patients except 1 answered ‘improved’ or ‘slightly improved’ for anxiety. Conclusions Long‐term emicizumab prophylaxis for up to 5.8 years was safe and efficacious, and may improve patients’ daily lives and feelings, regardless of inhibitor status.

Emicizumab is a bispecific antibody mimicking the cofactor function of activated coagulation factor VIII to prevent bleeds in patients with hemophilia A. The dose selection for the first-in-child phase III study of emicizumab was addressed by pediatric pharmacokinetic prediction using an adult/adolescent population pharmacokinetic model developed in phase I-I/II studies. The model was modified to incorporate functions describing the age-dependent increase in body weight (BW) with or without clearance maturation to account for the differences in emicizumab pharmacokinetics between adults/adolescents and children. A minimal dose anticipated to achieve in children the same target efficacious exposure as for adults/adolescents was identified when considering BW and clearance maturation. It was the same BW-based dose as for adults/adolescents and was selected for the starting dose for the pediatric study. Whether considering clearance maturation or not in addition to BW led to uncertainty in the pediatric pharmacokinetic prediction and dose selection, which informed implementation of a dose-adapting scheme in the study design. Exposure matching to adults/adolescents was ultimately achieved in children with the starting dose, indicating that consideration of clearance maturation in addition to BW provided adequate pediatric pharmacokinetic predictions for emicizumab. This pharmacokinetic finding in conjunction with exposure-response information served as a basis for the efficacy demonstrated in children, avoiding a time-consuming process for exploring an optimal pediatric dose of emicizumab. This experience indicates that a model-based framework helped optimize the pediatric dose selection and study design, thereby streamlining the development process with extrapolation, of emicizumab for children.

Introduction: Emicizumab is a novel, subcutaneously injectable, recombinant humanized bispecific monoclonal antibody which mimics the function of activated coagulation factor VIII. Due to its mechanism of action and lack of sequence homology, emicizumab is not expected to induce or be affected by anti-factor VIII (FVIII) antibodies (inhibitors). Emicizumab once-weekly dosing has been approved for hemophilia A patients with inhibitors of all ages in several countries. A clinically meaningful prophylactic effect and favorable safety of emicizumab given every 2 weeks (Q2W) and every 4 weeks (Q4W) in adult/adolescent patients has been demonstrate in HAVEN3 study (NCT02847637) and HAVEN4 study (NCT03020160). This is the first report to assess emicizumab prophylaxis in pediatric patients without inhibitors including a patient previously untreated with FVIII. Methods: The present study (JapicCTI-173710) enrolled Japanese patients aged <12 years with hemophilia A without inhibitors. Patients received a loading dose of 3 mg/kg weekly for the first 4 doses, followed by a maintenance dose of 3 mg/kg Q2W or 6 mg/kg Q4W. This interim analysis was performed after at least 6 patients in each dosing cohort had completed at least 12 weeks of treatment with emicizumab prophylaxis. Results: A total of 13 male patients were enrolled in 2 cohorts. The numbers of patients aged 0 - < 2, 2 - < 6, and 6 - < 12 years were 1, 2, and 3 in the Q2W cohort and 2, 2, and 3 in the Q4W cohort. All patients had been previously treated with FVIII prophylaxis except for 1 patient aged 4 months in the Q4W cohort who was previously untreated. As of the data cutoff date of March 14, 2018, the medians (range) of treatment duration were 21 (18.3 - 22.1) and 16 (4.3 - 16.6) weeks in the Q2W and Q4W cohorts, respectively. The interim analysis results showed a clinically meaningful effect of emicizumab prophylaxis with the Q2W and Q4W regimens. As of the data cutoff date, 3/6 patients in the Q2W cohort and 5/7 patients including 1 patient previously untreated with FVIII in the Q4W cohort experienced no treated bleeds. There were no treated spontaneous bleeds and a total of 6 treated bleeds were traumatic. Two out of them were treated joint bleeds. Model-based annualized bleeding rates for treated bleeds with FVIII products under emicizumab prophylaxis were 1.6 (95% CI, 0.60 to 4.25) and 1.0 (95% CI, 0.25 to 4.06) in the Q2W and Q4W cohorts, respectively. All 13 patients experienced at least 1 adverse event (AE) and a total of 78 AEs were reported. There were no AEs that were grade 3 or higher, serious, led to withdrawal from treatment, or resulted in dose modification or interruption. None of the AEs were considered related to emicizumab. Neither thromboembolic events, thrombotic microangiopathy, systemic hypersensitivity reactions, nor local injection site reactions were reported. The most frequent AEs were contusion in 10 (76.9%) patients, excoriation and nasopharyngitis in 4 (30.8%) patients each, and ligament sprain and influenza in 3 (23.1%) patients each. The emicizumab exposures observed in this study were within the observed variability in preceding studies. No effects of age or body weight on emicizumab exposure were evident. Conclusions: This interim analysis results suggested clinically meaningful efficacy and favorable safety of the emicizumab Q2W and Q4W regimens in patients aged <12 years with severe hemophilia A without inhibitors. This suggests that it should be appropriate to apply the same dosing regimens of emicizumab for pediatric patients without inhibitors and other patient populations of hemophilia A. The updated results of primary analysis after completing at least 24 weeks on emicizumab treatment will be presented at the meeting. Disclosures Shima: Chugai Pharmaceutical Co., Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Anti-FIXa/X bispecific antibodies , Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees. Nogami:Chugai Pharmaceutical Co., Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Anti-FIXa/X bispecific antibodies , Research Funding, Speakers Bureau. Nagami:Chugai Pharmaceutical Co., Ltd: Employment, Equity Ownership. Yoshida:Chugai Pharmaceutical Co., Ltd: Employment. Yoneyama:Chugai Pharmaceutical Co., Ltd: Employment, Patents & Royalties: Anti-FIXa/X bispecific antibodies . Ishiguro:Chugai Pharmaceutical Co., Ltd: Research Funding, Speakers Bureau. Suzuki:Chugai Pharmaceutical Co., Ltd: Research Funding, Speakers Bureau. Taki:Chugai Pharmaceutical Co., Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

INTRODUCTION: Emicizumab is a bispecific antibody that mimics the cofactor function of activated factor VIII and is currently indicated for routine prophylaxis of bleeds in patients with congenital hemophilia A (CHA) regardless of factor VIII (FVIII) inhibitor status. Nonclinical investigations suggest that emicizumab would be efficacious for preventing bleeds also in patients with acquired hemophilia A (AHA) (J Thromb Haemost 2020;18:825-33). However, no dedicated investigations have been performed to explore the optimal dosing algorithm of emicizumab for AHA. We present herein a proposed dosing algorithm of emicizumab potentially appropriate for AHA. METHODS: The dose selection for AHA aimed to achieve trough levels of plasma emicizumab concentration (Ctrough) of &gt;30 μg/mL in most patients, at which the effect of emicizumab for preventing bleeds is expected to be almost maximized as in patients with CHA (Res Pract Thromb Haemost 2019;3[Suppl 1]:315). Because the time spent with a high risk of bleeding in AHA is much shorter than in CHA due to the immunosuppressive therapy (IST) given to eradicate FVIII inhibitors (a reported median is 31 days [Blood 2015;125:1091-7]), and because bleeding symptoms in AHA can be severer than in CHA, the loading dose duration of 4 weeks for the current approved subcutaneous dosing regimens of emicizumab for CHA (i.e., 3 mg/kg once weekly [QW] for first 4 weeks [loading dose] followed by 1.5 mg/kg QW, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks from the 5th week onwards [maintenance dose]) was considered too long to maximize the effect of emicizumab in AHA. In addition, the potential risk of hypercoagulation associated with coexistence of emicizumab and FVIII restored as a consequence of successful IST was concerning. Modification of the loading dose together with definition of an appropriate timing for the dosing completion of emicizumab were therefore considered necessary. Exploration of a modified dosing regimen was performed by pharmacokinetic (PK) simulations using a population PK model developed in patients with CHA (Clin Pharmacokinet 2020 Jun 5) with the covariates adjusted for patients with AHA. The given dose per administration was capped at the maximum one approved for CHA. The dosing frequency of the maintenance dose was set to QW, aiming to keep the maximum plasma emicizumab concentration at steady state low for minimizing the potential risk of hypercoagulation after FVIII activity is restored. Development of the dosing completion criteria for emicizumab was addressed by a literature review. RESULTS: A modified subcutaneous dosing regimen of 6 mg/kg and 3 mg/kg on the 1st and 2nd days of the 1st week, respectively (loading dose), followed by 1.5 mg/kg QW from the 2nd week onwards (maintenance dose) was found to meet the defined requirements for AHA. With the modified dosing regimen, the median Ctrough was predicted to achieve &gt;30 μg/mL by the 2nd week and to reach steady state by the 3rd week, which would allow for rapider maximization and stabilization of the effect of emicizumab than with the current approved QW dosing regimen (Figure). However, there remained uncertainty in the PK predictions in association with the older age and severer disease conditions in AHA than in CHA, which may require further adaptation of the dosing regimen in case of insufficient exposure or efficacy. In reference to the lower limit of the normal range of FVIII activity and the definitions of partial remission employed in previous researches, an endogenous FVIII activity of &gt;50 IU/dL measured in the absence of interference by emicizumab was selected for a criterion for guiding the dosing completion of emicizumab. In addition, taking into account a standardized definition of a bleeding event (J Thromb Haemost 2014;12:1935-9) together with the bleeds in AHA possibly occurring even if FVIII is restored, absence of using coagulation factor products for &gt;72 hours after the last episodic use of coagulation factor products was considered as another dosing completion criterion to be met. CONCLUSIONS: A dosing algorithm of emicizumab potentially appropriate for prophylaxis in AHA was proposed leveraging literature information and PK simulations. The appropriateness of the selected dosing regimen together with the developed dosing completion criteria is currently under investigation with possibility of data-driven adaptations in a clinical study (AGEHA; JapicCTI-205151). Disclosures Shima: Patents related to anti-FIXa/FX bispecific antibodies: Patents & Royalties; Chugai Pharmaceutical Co. , Sanofi, Bayer, Sysmex: Speakers Bureau; 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.: Consultancy; Chugai Pharmaceutical Co. , F. Hoffmann-La Roche Ltd, Sanofi, CSL Behring, KM Biologics, Novo Nordisk, Shire/Takeda: Research Funding; Chugai Pharmaceutical Co.: Honoraria. Nagami:Chugai Pharmaceutical Co., Ltd.: Current equity holder in publicly-traded company, Ended employment in the past 24 months, Patents & Royalties: Inventor of patents related to anti-FIXa/FX bispecific antibodies. Yoneyama:Chugai Pharmaceutical Co., Ltd.: Current Employment, Patents & Royalties: Inventor of patents related to anti-FIXa/FX bispecific antibodies. Nomura:Chugai Pharmaceutical Co., Ltd.: Current Employment. Ogawa:Chugai Pharmaceutical Co., Ltd.: Consultancy; Bayer AG: Research Funding. Amano:Pfizer Inc.: Speakers Bureau; Novo Nordisk A/S: Speakers Bureau; F. Hoffmann-La Roche Ltd.: Research Funding; CSL Behring: Speakers Bureau; Japan Blood Products Organization: Speakers Bureau; Chugai Pharmaceutical Co., Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; KM Biologics Co., Ltd.: Research Funding, Speakers Bureau; Sanofi S.A.: Speakers Bureau; Bayer AG: Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Speakers Bureau. Nogami:Chugai Pharmaceutical Co., Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor of patents related to anti-FIXa/FX bispecific antibodies, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire Plc: Research Funding, Speakers Bureau; Bioverativ Inc.: Research Funding, Speakers Bureau; Novo Nordisk A/S: Research Funding, Speakers Bureau; Bayer AG: Research Funding, Speakers Bureau. OffLabel Disclosure: Emicizumab for acquired hemophilia A