[Skip to main content](/content/review/5a736cdd-2b4b-48fe-ab15-d7447eec56f5/source/ss-34113138#main-content/index.html) Pharmacokinetics and Pharmacodynamics of Emicizumab in Hemophilia A Research reportView only Create alertChat May 5, 2026 # Pharmacokinetics/pharmacodynamics of emicizumab in hemophilia A ## Emicizumab exhibits predictable, dose-proportional pharmacokinetics with sustained plasma concentrations that produce FVIII-equivalent hemostatic activity and reduce bleeding rates by 94% through an exposure-response relationship plateauing above 30 µg/mL. # Abstract Emicizumab demonstrates dose-proportional, predictable pharmacokinetics across diverse hemophilia A populations, with subcutaneous administration achieving sustained trough concentrations of 42-66 µg/mL during maintenance dosing across weekly (1.5 mg/kg), every-2-weeks (3 mg/kg), and every-4-weeks (6 mg/kg) regimens. The median elimination half-life is 23-30 days, with time to steady-state of 12 weeks with loading doses and 24 weeks without. Interindividual variability in trough concentrations is moderate (32%), influenced primarily by body weight, age, albumin levels, and rarely by neutralizing antibodies. Infants achieve higher concentrations (60-65 µg/mL) than older individuals with identical dosing, while bioavailability decreases after age 65. Pharmacodynamically, emicizumab maintains FVIII-equivalent activity of 17-25 IU/dL, thrombin generation >100 nM, and normalized aPTT without affecting FIX, FX, or coagulation activation markers. Exposure-response modeling establishes that bleeding control plateaus above emicizumab concentrations of 30 µg/mL (IC50 3.58 µg/mL), explaining equivalent efficacy across dosing regimens that achieve mean concentrations of 53.5 µg/mL and produce a 94% reduction in annualized bleeding rates. Clinical studies demonstrate annualized bleeding rates for treated bleeds of 0.4-2.4, with 54-78% of patients achieving zero treated bleeds. The safety profile is favorable, with injection site reactions as the most common adverse event (16-22%), no thromboembolic events when used alone, and minimal immunogenicity. These pharmacokinetic and pharmacodynamic characteristics support body weight-based dosing without routine therapeutic drug monitoring, with potential for individualized dosing in patients maintaining concentrations substantially above the 30 µg/mL efficacy threshold. Methods We analyzed 10 sources from an initial pool of 200, using 8 screening criteria. Each paper was reviewed for 8 key aspects that mattered most to the research question. More on methods Records from Elicit search n = 200 Papers screened using: Population - Hemophilia A, Intervention - Emicizumab, Outcome - PK/PD Data, Study Population - Human Subjects, Study Design, Intervention Specificity, Population Specificity, Data Relevance n = 200 Papers screened out n = 190 Papers included for extraction n = 10 Press enter or space to select a node.You can then use the arrow keys to move the node around. Press delete to remove it and escape to cancel. Press enter or space to select an edge. You can then press delete to remove it or escape to cancel. ## Paper search We performed a semantic search across over 138 million academic papers from the Elicit search engine, which includes all of [Semantic Scholar](https://www.semanticscholar.org/) and [OpenAlex](https://openalex.org/). We ran this query: “Pharmacokinetics/pharmacodynamics of emicizumab in hemophilia A” The search returned 200 total results from Elicit. We retrieved 200 papers most relevant to the query for screening. ## Screening We screened in sources based on their abstracts that met these criteria: - **Population - Hemophilia A**: Does the study include patients diagnosed with hemophilia A? - **Intervention - Emicizumab**: Does the study investigate emicizumab as the primary intervention? - **Outcome - PK/PD Data**: Does the study report pharmacokinetic data (e.g., plasma concentrations, clearance, half-life, bioavailability) and/or pharmacodynamic data (e.g., factor VIII mimetic activity, bleeding rates, coagulation parameters)? - **Study Population - Human Subjects**: Is the study conducted in human subjects (not animal or in vitro studies)? - **Study Design**: Is the study a clinical trial (Phase I, II, III, IV), observational study, case series, case report, systematic review, or meta-analysis? - **Intervention Specificity**: Does the study include emicizumab as an intervention (not focusing solely on other hemophilia treatments without emicizumab)? - **Population Specificity**: Does the study include hemophilia A participants (not exclusively patients with hemophilia B or other bleeding disorders without any hemophilia A participants)? - **Data Relevance**: Does the study report pharmacokinetic and/or pharmacodynamic data (not only clinical efficacy or safety outcomes without PK/PD data)? We considered all screening questions together and made a holistic judgement about whether to screen in each paper. ## Data extraction We asked a large language model to extract each data column below from each paper. We gave the model the extraction instructions shown below for each column. - **Study Population**: Extract patient demographics and clinical characteristics relevant to emicizumab pharmacokinetics/pharmacodynamics in hemophilia A, including: - Age range and median/mean age - Body weight/BMI characteristics - Hemophilia A severity (mild, moderate, severe) - FVIII inhibitor status (presence/absence, titer levels if available) - Prior treatment history (treatment-naive, previously treated) - Geographic/ethnic population - Sample size for PK/PD analyses - Any other patient factors mentioned as potentially affecting emicizumab PK/PD - **Dosing Regimen**: Extract all details about emicizumab dosing and administration for PK/PD assessment, including: - Dose level(s) tested (mg/kg) - Dosing frequency (weekly, every 2 weeks, every 4 weeks) - Loading dose regimen if applicable - Maintenance dose regimen - Route of administration - Duration of treatment/observation - Any dose adjustments or individualization strategies - Sampling timepoints for PK/PD measurements - **PK Parameters**: Extract pharmacokinetic parameters and characteristics of emicizumab in hemophilia A patients, including: - Plasma/serum emicizumab concentrations (steady-state, peak, trough) - Clearance (CL/F) - Volume of distribution (V/F or Vss/F) - Half-life (t½) - Time to steady-state - Bioavailability or relative bioavailability - Dose-proportionality findings - PK variability (inter-patient, intra-patient) - Any population PK modeling results - Comparison across different dosing regimens if applicable - **PD Outcomes**: Extract pharmacodynamic outcomes and biomarkers for emicizumab in hemophilia A, including: - FVIII-equivalent activity levels (IU/dL or %) - Coagulation parameters (aPTT, thrombin generation, etc.) - Annualized bleeding rates (ABR) for treated bleeds, spontaneous bleeds, joint bleeds - Proportion of patients with zero bleeds - Time to first bleeding episode - Bleeding severity and location - Need for additional hemostatic treatment - Any other hemostatic efficacy measures - Methods used to assess each PD outcome - **PK/PD Relationships**: Extract any analyses of exposure-response or concentration-effect relationships for emicizumab in hemophilia A, including: - Correlations between emicizumab concentration and FVIII-equivalent activity - Exposure-efficacy relationships (concentration vs. bleeding rates) - Exposure-safety relationships - Population PK/PD modeling results - Threshold concentrations for efficacy - Model parameters (EC50, Emax, slope factors) - Goodness-of-fit assessments - Predictions or simulations of different dosing scenarios - **Safety Profile**: Extract safety and immunogenicity data relevant to emicizumab PK/PD in hemophilia A, including: - Injection site reactions - Thrombotic/thromboembolic events - Anti-drug antibodies (ADA) development and impact on PK/PD - Neutralizing antibodies - Other treatment-related adverse events - Laboratory safety parameters - Any safety findings that could affect dosing or PK/PD interpretation - Discontinuations due to safety concerns - **Covariates**: Extract factors identified as affecting emicizumab pharmacokinetics or pharmacodynamics in hemophilia A patients, including: - Age effects on PK/PD parameters - Body weight/size effects - Inhibitor status effects on efficacy - Prior treatment history effects - Genetic factors or ethnic differences - Concomitant medications effects - Disease-related factors affecting drug disposition - Any other identified sources of PK/PD variability - Magnitude and clinical significance of covariate effects - **Study Methods**: Extract methodological details relevant to PK/PD assessment of emicizumab in hemophilia A, including: - Study design and phase - PK sampling strategy and timepoints - Bioanalytical methods for emicizumab concentration measurement - Methods for measuring FVIII-equivalent activity and coagulation parameters - PK analysis methods (non-compartmental, population modeling software) - Statistical approaches for PK/PD analysis - Validation of bioanalytical and PD assays - Any limitations affecting PK/PD interpretation # Results ## Characteristics of Included Studies The review included 10 sources examining emicizumab pharmacokinetics and pharmacodynamics in hemophilia A, comprising clinical trial reports, a systematic review, and an exposure-response modeling study. The studies varied in design from Phase I dose-escalation trials to Phase III pivotal studies and represented diverse patient populations. Study Full text retrieved? Study Type Population Sample Size (PK/PD) Study Design C. Schmitt et al., 2020 Yes Primary study (Phase III) Adults/adolescents (12-75 years) with severe HA and FVIII inhibitors; multicenter (14 countries) 112 Open-label, multicenter, randomized A. Kiialainen et al., 2023 No (abstract only) Pooled analysis HAVEN 1-4 participants Not specified Phase III trials M. Shima et al., 2016 No (abstract only) Primary study (Phase I) Japanese adults with severe HA with/without inhibitors 18 Open-label, non-randomized, dose-escalation M. Shima et al., 2017 Yes Primary study (Phase I/II extension) Japanese adults (12-58 years) with severe HA with/without inhibitors 18 Open-label, long-term extension S. Pipe et al., 2022 No (abstract only) Primary study (Phase IIIb interim) Infants ≤12 months with severe HA without inhibitors 52 Multi-center, open-label (HAVEN 7) Qianqian Mao et al., 2025 No (abstract only) Primary study (retrospective) Chinese pediatric patients (0.93-16.25 years) with HA 46 Retrospective single-center S. Pipe et al., 2023 No (abstract only) Primary study (Phase IIIb primary) Infants ≤12 months with severe HA without inhibitors 55 Multi-center, open-label (HAVEN 7) A. Donners et al., 2021 Yes Systematic review Adults and children (0 to ≥12 years) with HA with/without inhibitors 469 PwHA, 140 volunteers Systematic review of 15 studies S. Pipe et al., 2019 No (abstract only) Primary study (Phase III) Adults/adolescents (≥12 years) with severe HA with/without inhibitors from 6 countries 41 (expansion cohort) Multi-center, open-label, two-stage (HAVEN 4) F. Jonsson et al., 2021 Yes Modeling study 445 PwHA with/without inhibitors (age 1-77 years) 385 emicizumab-treated Exposure-response modeling of pooled Phase III data toof Pageof The populations spanned a wide age range from infants (9 days old) to adults (up to 77 years), including specialized studies in infants ≤12 months and Chinese pediatric patients. Most studies included patients with severe hemophilia A, with variable inhibitor status across studies. Prior treatment history varied, with several studies including previously untreated or minimally treated patients. ## Dosing Regimens and Administration Emicizumab was administered subcutaneously across all studies, with various loading and maintenance regimens tested to optimize pharmacokinetic profiles. Study Loading Dose Maintenance Dose Dosing Frequency Duration C. Schmitt et al., 2020 3 mg/kg weekly for 4 weeks 1.5 mg/kg Once weekly Median 60.5 weeks (range 3.3-94.2) A. Kiialainen et al., 2023 3 mg/kg weekly for 4 weeks 1.5 mg/kg, 3 mg/kg, or 6 mg/kg Weekly, Q2W, or Q4W Not specified M. Shima et al., 2016 None mentioned 0.3, 1.0, or 3.0 mg/kg Weekly 12 weeks M. Shima et al., 2017 1 mg/kg (cohort 1), 3 mg/kg (cohort 2) 0.3, 1.0, or 3.0 mg/kg Once weekly Up to 33.3 months S. Pipe et al., 2022 3 mg/kg weekly for 4 weeks 3 mg/kg Every 2 weeks for 52 weeks ≥52 weeks with 7-year follow-up Qianqian Mao et al., 2025 Median 2.85 mg/kg per week (range 2.14-3.90) Median 5.21 mg/kg (range 2.54-6.46) Loading: weekly; Maintenance: every 28 days December 2023-July 2025 S. Pipe et al., 2023 3 mg/kg weekly for 4 weeks 3 mg/kg, 1.5 mg/kg, or 6 mg/kg Q2W for 52 weeks; then weekly or Q4W options ≥52 weeks with 7-year follow-up A. Donners et al., 2021 Not mentioned 1.5 mg/kg, 3 mg/kg, or 6 mg/kg Weekly (75%), Q2W (11%), Q4W (14%) ≥16 weeks S. Pipe et al., 2019 3 mg/kg weekly for 4 weeks 6 mg/kg Every 4 weeks ≥24 weeks F. Jonsson et al., 2021 3 mg/kg weekly for 4 weeks 1.5 mg/kg, 3 mg/kg, or 6 mg/kg Once weekly, Q2W, or Q4W 365.25 days for ABR calculation toof Pageof The standard loading regimen across recent studies was 3 mg/kg weekly for 4 weeks, designed to rapidly achieve therapeutic concentrations. Maintenance dosing flexibility allowed for once-weekly (1.5 mg/kg), every-2-weeks (3 mg/kg), or every-4-weeks (6 mg/kg) administration. Dose adjustments were permitted in some studies, with up-titration to 3 mg/kg weekly allowed for suboptimal efficacy after 6 months and individualized dose modifications implemented based on efficacy and safety committee review. In the HAVEN 7 study, one participant required dose up-titration from biweekly to weekly due to decreasing emicizumab levels. ## Pharmacokinetic Parameters Emicizumab demonstrated predictable, dose-proportional pharmacokinetics across diverse patient populations. ### Plasma Concentrations Study Steady-State Trough Concentrations Peak/Loading Concentrations Time to Steady-State C. Schmitt et al., 2020 ≥50 µg/mL maintained; mean 54.1 µg/mL after loading, sustained >50 µg/mL Not specified Not specified A. Kiialainen et al., 2023 42.1-52.3 µg/mL with maintenance dosing Mean 52.9 µg/mL (SD 13.6) at week 5 Not specified M. Shima et al., 2016 Increased in dose-dependent manner Not specified Not specified M. Shima et al., 2017 10.3 mg/mL (cohort 1), 29.9 mg/mL (cohort 2), 120 mg/mL (cohort 3) Not specified ~12 weeks with loading, 24 weeks without S. Pipe et al., 2022 60-65 µg/mL maintained Mean 63.2 µg/mL (95% CI: 59.5-66.8) at Week 5 Not specified Qianqian Mao et al., 2025 Maintenance: median 50.6 µg/mL (range 17.3-81.7) Loading: median 57.7 µg/mL (range 31.8-79.9) Not specified S. Pipe et al., 2023 Sustained at 57-66 µg/mL Mean 62.0 µg/mL (95% CI: 58.3-65.6) at Week 5 Not specified A. Donners et al., 2021 Moderate interindividual variability (32%) Not specified Not specified S. Pipe et al., 2019 Not specified Not specified Not specified F. Jonsson et al., 2021 ~50 µg/mL across regimens; trough: 28.4 (QW), 24.9 (Q2W), 17.7 (Q4W) µg/mL Not specified Not specified toof Pageof Trough concentrations increased during the loading phase, reaching mean values of 52.9-63.2 µg/mL by week 5, and were sustained at 42.1-66 µg/mL with maintenance dosing. The Chinese pediatric study reported somewhat lower median trough concentrations during maintenance (50.6 µg/mL). Dose-proportional increases in steady-state trough levels were observed across dose cohorts in the Phase I/II extension, with levels of 10.3, 29.9, and 120 mg/mL for 0.3, 1.0, and 3.0 mg/kg weekly dosing, respectively. Plasma concentrations increased in a dose-dependent manner across all dose escalation studies. A notable finding was higher emicizumab concentrations in infants compared to older populations. In HAVEN 7, infant concentrations (60-65 µg/mL) were higher than those observed with the same dosing regimen in HAVEN 1-4 studies of older patients (46.7 ± 14.9 µg/mL) and HAVEN 2-3 studies (46-48 µg/mL). ### Pharmacokinetic Model Parameters The Chinese pediatric study provided detailed estimates using the published population PK model. Median clearance (CL/F) was 0.0637 L/day (range 0.0421-0.1578), volume of distribution (V/F) was 2.1543 L (range 1.2629-6.2103), and elimination half-life was 23.44 days (range 20.79-27.28). The earlier Phase I study reported a longer half-life of 4-5 weeks, while another source cited approximately 30 days. The systematic review noted that clearance was comparable to other therapeutic IgG4-based monoclonal antibodies (0.2-0.5 L/day), but emicizumab demonstrated increased distribution volumes (10 vs. 6 L) and a longer half-life. Time to steady-state was approximately 12 weeks with a loading dose and 24 weeks without loading. ### Pharmacokinetic Variability Interindividual variability in trough concentrations was moderate at 32% and remained consistent across various subgroups including FVIII inhibitor status, age group, and dosing interval. Total PK interindividual variability was approximately 60%, influenced by body weight, neutralizing antidrug antibodies, age, and albumin levels. Children showed slightly less variability than adults and adolescents. The long half-life was expected to result in minimal variation in peak/trough plasma concentrations, supporting stable pharmacokinetics with minimal peak-trough fluctuation. Emicizumab demonstrated high subcutaneous bioavailability, with bioavailability decreasing with age, particularly after 65 years. The dose-linear pharmacokinetics supported body weight-based dosing, although individualized monitoring may allow for more cost-effective dosing. ## Pharmacodynamic Outcomes ### FVIII-Equivalent Activity and Coagulation Parameters Study FVIII-Equivalent Activity (IU/dL) aPTT Response Thrombin Generation (nM) Other Coagulation Parameters C. Schmitt et al., 2020 Remained above 20 U/dL Normalized at subtherapeutic concentrations Peak height above 100 nM FIX, FX, fibrinogen, PT, D-dimer, PF1.2 not significantly affected A. Kiialainen et al., 2023 25.2 IU/dL at week 5, sustained 17-23 IU/dL Shortened following first dose 115.2 nM at week 5, sustained >116 nM Not mentioned M. Shima et al., 2016 Not mentioned Remained short throughout Not mentioned No clinically relevant coagulation abnormalities M. Shima et al., 2017 Not mentioned Remained short, within or shorter than reference range Promotion of FXIa-triggered thrombin generation Not mentioned S. Pipe et al., 2022 21 U/dL during loading, sustained Normalized by Week 3 Increased to 100 nM from Week 17 onwards FIX and FX unaffected Qianqian Mao et al., 2025 Loading: 14.6 IU/dL (range 7.4-39.2); Maintenance: 20.2 IU/dL (range 8.9-39.6) Not mentioned Not mentioned Not mentioned S. Pipe et al., 2023 Not mentioned Not mentioned Not mentioned Not mentioned A. Donners et al., 2021 Not mentioned Not mentioned Not mentioned Not mentioned S. Pipe et al., 2019 Not mentioned Not mentioned Not mentioned Not mentioned F. Jonsson et al., 2021 Not mentioned Not mentioned Not mentioned Not mentioned toof Pageof FVIII-like activity increased during the loading period to 21-25.2 IU/dL and was sustained at 17-23 IU/dL with maintenance dosing, remaining consistently above 20 U/dL. The Chinese pediatric study reported median FVIII-equivalent activity of 14.6 IU/dL during loading and 20.2 IU/dL during maintenance. These levels theoretically convert patients with severe hemophilia A to a mild disease phenotype. Thrombin generation peak height increased during loading, reaching 100-115.2 nM by week 5-17, and was sustained above 100-116 nM thereafter. Activated partial thromboplastin time (aPTT) was normalized at subtherapeutic concentrations of emicizumab, shortened following the first dose, normalized by Week 3 in most participants, and remained short throughout studies. Importantly, emicizumab did not significantly affect plasma concentrations of target antigens FIX and FX, nor did it affect fibrinogen, prothrombin time (international normalized ratio), D-dimer, or prothrombin fragment 1.2 levels, indicating no induction of consumptive coagulopathy or coagulation activation. ### Bleeding Outcomes Study Treated Bleeds ABR (95% CI) All Bleeds ABR (95% CI) Treated Joint Bleeds ABR (95% CI) Zero Treated Bleeds (%) C. Schmitt et al., 2020 87% reduction vs. no prophylaxis Not specified Not specified 62.9% M. Shima et al., 2016 Cohort 1: 32.5→4.4; Cohort 2: 18.3→0.0; Cohort 3: 15.2→0.0 Not specified Not specified 73% (with inhibitors), 71% (without) M. Shima et al., 2017 Median: Cohort 1: 1.4; Cohort 2: 0.2; Cohort 3: 0 Not specified Not specified 8/18 patients (44%) S. Pipe et al., 2022 0.4 (0.23-0.65) 1.9 (1.35-2.68) 0.1 (0.01-0.22) 77.8% Qianqian Mao et al., 2025 Median ABR: 0 Not specified Not specified Not specified S. Pipe et al., 2023 0.4 (0.30-0.63) 2.0 (1.49-2.66) 0.0 (0.01-0.09) 54.5% A. Donners et al., 2021 At 30 µg/mL: 2.4; At 50 µg/mL: 1.9 Not specified At 30 µg/mL: 1.1; At 50 µg/mL: 1.0 70.8%→80.2% after 1 year S. Pipe et al., 2019 2.4 (1.4-4.3) 4.5 (3.1-6.6) 1.7 (0.8-3.7) 56.1% (39.7-71.5) F. Jonsson et al., 2021 Predicted mean: 1.28 at 53.5 µg/mL (94% reduction from baseline) Not specified Not specified Not specified toof Pageof Emicizumab prophylaxis demonstrated substantial efficacy in reducing bleeding rates across all studies. In the infant population (HAVEN 7), the model-based ABR for treated bleeds was 0.4 (95% CI: 0.23-0.65 in interim analysis and 0.30-0.63 in primary analysis), with ABR for all bleeds of 1.9-2.0 and treated joint bleeds of 0.0-0.1. No intracranial hemorrhage occurred in this vulnerable population. The proportion of patients achieving zero treated bleeds ranged from 54.5% to 77.8% in the HAVEN 7 analyses. In the Phase I dose-escalation study, median ABRs decreased from baseline values of 18.3-32.5 to 0.0-4.4 across cohorts receiving 0.3-3.0 mg/kg weekly, with 71-73% of patients experiencing no bleeding. The long-term extension showed median ABRs remaining low at 0.0-1.4. The HAVEN 4 study examining every-4-weeks dosing reported an ABR of 2.4 (95% CI: 1.4-4.3) for treated bleeds, with 56.1% of patients reporting no treated bleeds. The Chinese pediatric study achieved a median ABR of 0. Overall, the systematic review found that 70.8% of patients had no treated bleeds initially, increasing to 80.2% after 1 year of treatment. The majority of bleeds were traumatic (87.9% in HAVEN 7), with breakthrough bleeding episodes successfully treated with episodic FVIII or bypassing agents when needed. The episodic use of clotting factors to control bleeding was reduced. ## Exposure-Response Relationships Several studies characterized the relationship between emicizumab concentrations and clinical outcomes, demonstrating clear concentration-dependent effects on both pharmacodynamic biomarkers and bleeding control. ### Concentration-Biomarker Correlations FVIII-like activity and thrombin generation peak height correlated with emicizumab concentrations. The Chinese pediatric study quantified this relationship, finding a positive correlation between emicizumab concentration and FVIII-equivalent activity by linear regression (Y = 0.9569·X + 33.24, R² = 0.37, p < 0.01) and Spearman correlation (ρ = 0.56, p < 0.01). The relationship between emicizumab plasma concentration and aPTT was well described by an inhibitory Emax model. In the infant population, sustained FVIII-like activity and normalization of aPTT suggested a concentration-effect relationship, with higher emicizumab concentrations in infants compared to older individuals contributing to excellent bleeding control. ### Concentration-Efficacy Relationships The systematic review by Donners et al. performed detailed exposure-response modeling using an Emax model relating trough plasma concentrations to annualized bleeding rates. The EC50 for treated bleeds was 1.47 µg/mL with an Emax of 0.96, while for treated joint bleeds the EC50 was 1.09 µg/mL with an Emax of 0.98. Critically, the control of bleeds did not improve above emicizumab concentrations of 30 µg/mL, establishing an effectiveness plateau. At 30 µg/mL, the expected ABR was 2.4 for treated bleeds and 1.1 for treated joint bleeds, while at 50 µg/mL these values were 1.9 and 1.0, respectively. The comprehensive exposure-response analysis by Jonsson et al. using a generalized Poisson distribution and inhibitory Emax relationship found that emicizumab concentrations were inversely related to bleeding rates, with higher concentrations leading to reduced bleeding. The IC50 was estimated at 3.58 µg/mL, indicating the concentration required for half-maximal effect. Importantly, concentrations above 30 µg/mL provided clinically meaningful control of bleeding. At the average steady-state concentration across all regimens (53.5 µg/mL), the predicted mean annualized bleeding rate was 1.28, corresponding to a 94.0% reduction from baseline. Simulations demonstrated that the three dosing regimens (1.5 mg/kg QW, 3 mg/kg Q2W, 6 mg/kg Q4W) maintain concentrations near the plateau of effect. Visual predictive checks from the exposure-response model showed adequate prediction of bleeding onset over time, supporting the model’s validity. The PK profile of once-weekly emicizumab provided sustained therapeutic plasma levels consistent with population PK models. ## Factors Affecting Pharmacokinetics and Pharmacodynamics ### Body Weight and Size Effects Body weight was a significant covariate affecting emicizumab pharmacokinetics across multiple studies. Dosing regimens were universally based on body weight (mg/kg), and including body weight in population PK models significantly reduced interindividual variability in both clearance (CL/F) and volume of distribution (V/F). Body weight also affected apparent clearance and distribution volume in the exposure-response model. The Chinese pediatric study documented body size characteristics, with median weight of 14.5 kg (range 8.5-41.8 kg) and median BMI of 16.8 kg/m² (range 13.8-21.5 kg/m²). Plasma concentrations of emicizumab increased in a dose-dependent manner, and steady-state trough levels increased in a dose-proportional manner, supporting body weight-based dosing strategies. However, the systematic review suggested that individualized monitoring of emicizumab concentrations may allow for more cost-effective dosing. ### Age Effects Age emerged as an important covariate affecting emicizumab pharmacokinetics and potentially pharmacodynamics. Bioavailability decreased with age, particularly after 65 years. Conversely, infants demonstrated higher emicizumab concentrations compared to older individuals with the same dosing regimen, with concentrations of 60-65 µg/mL in HAVEN 7 versus 46.7 ± 14.9 µg/mL in older HAVEN 1-4 participants and 46-48 µg/mL in HAVEN 2-3. The Chinese pediatric study population had a median age at enrollment of 3.52 years (range 0.93-16.25 years) and a median age at emicizumab initiation of 1.40 years, with height (median 92.0 cm) also documented. The HAVEN 7 studies focused specifically on infants ≤12 months of age, demonstrating feasibility and efficacy in this youngest population. Studies in adults included participants from age 12 to 75 years. ### Inhibitor Status and Prior Treatment History FVIII inhibitor status did not significantly affect emicizumab PK variability or efficacy. Emicizumab was effective in patients with FVIII inhibitors as well as those without, with no significant difference in bleeding control between the two groups. Prior treatment history varied across studies and was considered as a potential covariate. Several studies included previously untreated or minimally treated patients (PUPs/MTPs). The Chinese pediatric study reported that 15 patients were previously untreated or minimally treated, and 9 had a history of inhibitors. In the exposure-response analysis, prior prophylaxis with FVIII significantly reduced bleeding hazard by 44.7%, representing the most clinically significant covariate effect identified. ### Other Covariates Albumin levels affected pharmacokinetics, with low albumin levels associated with decreased exposure and albumin affecting apparent clearance. The Chinese pediatric study documented median albumin levels of 46.1 g/L (range 41.4-49.6 g/L). Ethnic differences were observed, with African race mentioned as a factor affecting PK variability and ethnicity affecting distribution volume in population PK models. The Chinese pediatric study specifically noted that ethnic and developmental factors—such as body size, nutritional status, and earlier treatment initiation—may influence drug exposure and clinical response. Neutralizing antidrug antibodies represented a primary source of interindividual PK variability, though their actual occurrence was rare (discussed in safety section below). Age >30 years was also identified as a factor affecting PK variability. ## Safety and Immunogenicity Emicizumab demonstrated a favorable safety profile across all studies, with most adverse events being mild and not leading to treatment discontinuation. ### Injection Site Reactions and General Tolerability Injection site reactions were the most frequent treatment-related adverse event. In the Phase I/II extension, mild injection site reactions occurred in 38.9% of patients (7/18). In the infant studies, 16.4-16.7% of participants experienced emicizumab-related injection site reactions, all Grade 1. The HAVEN 4 study reported injection site reactions in 22% of patients. Most participants in infant studies experienced at least one adverse event (92.6-100%), but importantly, no adverse events led to treatment withdrawal, modification, or interruption. The long-term Phase I/II extension reported no discontinuations due to safety concerns, and the treatment was generally well tolerated with limited toxicity. ### Thrombotic Events Notably, no thromboembolic events or thrombotic microangiopathies occurred in the infant studies or the long-term Phase I/II extension. The HAVEN 4 study also observed no thrombotic events. In the HAVEN 1 study, two participants experienced thrombotic microangiopathy and thromboembolism, but these were associated with the use of bypassing agents (activated prothrombin complex concentrate) rather than emicizumab itself. The systematic review noted an increased thrombotic risk when emicizumab was used with high doses of activated prothrombin complex concentrate. ### Immunogenicity Emicizumab demonstrated minimal immunogenicity across studies. None of the participants in the HAVEN 7 studies tested positive for anti-drug antibodies (ADAs) at any timepoint (baseline, Week 5, or 12-weekly thereafter). The early Phase I study reported no development of antibodies to emicizumab. In the Phase I/II extension, 4 patients tested positive for ADAs, but these were nonneutralizing and did not affect PK/PD parameters. Similarly, the systematic review noted that neutralizing antidrug antibodies affected PK variability but their actual development was rare. The HAVEN 4 study observed no development of de-novo antidrug antibodies with neutralizing potential. Regarding development of FVIII inhibitors in previously untreated patients, one PUP in HAVEN 7 was confirmed positive for FVIII inhibitors on Day 603 after three FVIII exposure days (for traumatic bleed treatment), and another PUP tested positive on Day 428 after 10 FVIII exposure days (for post-tonsillectomy bleed management), with confirmatory titer pending at the analysis cut-off. ### Laboratory Safety Parameters Emicizumab did not significantly affect key laboratory safety parameters. Platelet count, fibrinogen, D-dimer, and prothrombin fragment 1.2 (PF1.2) levels were not significantly affected. FIX and FX plasma antigen levels, prothrombin time, and concentrations of exploratory safety markers of coagulation activation (D-dimer, prothrombin fragment 1 + 2, and fibrinogen) were not notably affected. In the infant study, aPTT was normalized by Week 3 and mean FIX and FX concentrations were unaffected by emicizumab. ### Serious Adverse Events Serious adverse events were infrequent and not attributed to emicizumab. In HAVEN 7, 29.1% of participants (16/55) reported 30 serious adverse events, all considered serious due to hospitalization, but none were considered emicizumab-related. The Phase I/II extension reported that 4 patients experienced serious adverse events, but none were related to emicizumab treatment. One participant in HAVEN 7 experienced an anaphylactic reaction following food allergy, not considered emicizumab-related. The systematic review noted joint pain episodes at high concentrations (90 µg/mL). Five participants were withdrawn from emicizumab treatment in HAVEN 1 due to adverse events or physician/patient decision, though specific details were not provided. ## Study Methodologies The studies employed diverse methodological approaches to assess emicizumab pharmacokinetics and pharmacodynamics, ranging from Phase I dose-escalation studies to large Phase III randomized trials and sophisticated modeling analyses. ### Study Designs The evidence base included open-label, non-randomized, dose-escalation Phase I studies, Phase III multicenter, open-label, randomized studies, Phase IIIb multi-center, open-label studies, and a two-stage Phase III study with run-in and expansion cohorts. The systematic review pooled data from 15 studies including 469 patients with hemophilia A and 140 volunteers. The exposure-response modeling study analyzed pooled Phase III trial data. One real-world study employed a retrospective single-center design. ### Pharmacokinetic Assessment Methods PK sampling strategies varied by study. The HAVEN 1 study collected blood samples before the first dose, weekly for the first month, every 2 weeks for the second month, every 4 weeks from the third to sixth month, every 8 weeks from the seventh to twelfth month, and every 12 weeks thereafter. HAVEN 7 measured plasma trough emicizumab concentrations at Week 5 and thereafter. The Chinese pediatric study collected peripheral blood samples during both loading and maintenance phases. Bioanalytical methods for emicizumab concentration measurement included validated enzyme-linked immunosorbent assay (ELISA) in Phase I-III studies and a modified one-stage clotting assay (OSA) in Phase IV studies. The HAVEN 1 study used a validated ELISA, while the Chinese pediatric study employed a modified one-stage assay. PK analysis approaches included graphical exploratory analyses and linear regressions, population pharmacokinetic modeling using NONMEM software, and application of published population PK models. The systematic review employed non-linear least squares regression using a maximum effect (Emax) model. Statistical approaches included descriptive analysis, negative binomial regression for calculating ABRs, generalized Poisson distribution and inhibitory Emax relationship for exposure-response modeling, and linear regression and Spearman correlation for PK/PD relationships. ### Pharmacodynamic Assessment Methods FVIII-equivalent activity was measured using chromogenic assays, including the Hyphen Biophen FVIII:C assay containing human factors and the HYPHEN chromogenic FVIII assay. Thrombin generation was assessed using the Calibrated Automated Thrombogram method. Efficacy endpoints in the infant studies were estimated using a negative binomial regression model for annualized bleeding rates. Assay precision and accuracy for emicizumab concentration measurement were validated in key studies, though detailed validation information for pharmacodynamic assays was not consistently reported across all studies. ### Study Limitations Several methodological limitations were noted. The Phase I/II extension was not randomized or controlled and had small patient numbers in each dose cohort. Sample sizes in some studies were based on clinical considerations rather than statistical power calculations. The systematic review cited limitations including a limited number of available studies, heterogeneous study populations, and lack of blinded, placebo-controlled studies. The exposure-response modeling study noted a limited range of exposure concentrations at the lower end of the dose-response curve. ## Synthesis The pharmacokinetic and pharmacodynamic characteristics of emicizumab demonstrate remarkable consistency across diverse populations and study designs, supporting its use as a prophylactic treatment for hemophilia A. Several key findings emerge from synthesis of the evidence. ### Dose-Concentration-Response Relationships The evidence establishes a clear hierarchy of dose-proportional pharmacokinetics leading to sustained therapeutic concentrations, which in turn correlate with pharmacodynamic biomarkers and translate to clinically meaningful bleeding control. The convergence of findings from mechanistic studies, clinical trials, and sophisticated modeling analyses provides robust evidence for a threshold effect, with bleeding control plateauing above concentrations of 30 µg/mL. This plateau has important implications: it explains why all three approved maintenance regimens (1.5 mg/kg weekly, 3 mg/kg every 2 weeks, 6 mg/kg every 4 weeks) achieve similar efficacy despite different trough concentrations, and it suggests that therapeutic drug monitoring could enable dose reduction in patients maintaining concentrations substantially above this threshold. ### Age-Related Pharmacokinetic Differences The consistently higher emicizumab concentrations observed in infants compared to older populations receiving identical dosing regimens represents a genuine population-specific difference rather than measurement artifact, as it was replicated across studies and correlates with known developmental changes in antibody pharmacokinetics. Infants have lower total body weight but proportionally higher body surface area and different tissue composition compared to adults, which may reduce volume of distribution relative to body weight. Additionally, the neonatal Fc receptor (FcRn), which protects IgG antibodies from catabolism, may function differently in infants, potentially reducing clearance and increasing bioavailability. These age-related differences in exposure did not translate to safety concerns, as thrombotic events remained absent in the infant population despite higher concentrations. This suggests the concentration-safety relationship may also plateau, or that young children have different thrombotic risk profiles. The decrease in bioavailability with age, particularly after 65 years, suggests older patients may require adjusted dosing to maintain therapeutic concentrations. ### Clinical Implications of PK/PD Variability The moderate 32% interindividual variability in trough concentrations remains consistent across FVIII inhibitor status, age groups, and dosing intervals, supporting body weight-based dosing without routine therapeutic drug monitoring. However, specific subpopulations may benefit from concentration monitoring: patients with low albumin or those who develop neutralizing antibodies, patients over 65 years with reduced bioavailability, and potentially African patients given ethnic effects on distribution volume. The finding that prior FVIII prophylaxis reduces bleeding hazard by 44.7%—the single largest covariate effect identified—suggests that the benefits of emicizumab may be partially additive to those of prior prophylaxis, possibly through prevention of joint damage that would otherwise increase bleeding risk. ### Reconciling Safety Findings The favorable safety profile, particularly the absence of thromboembolic events in most studies, requires reconciliation with the two thrombotic events in HAVEN 1. These events occurred specifically with concomitant use of high-dose activated prothrombin complex concentrate (aPCC), representing a drug-drug interaction rather than an inherent property of emicizumab. The mechanism likely involves emicizumab providing baseline hemostatic activity that, when combined with high doses of bypassing agents, creates excessive thrombin generation exceeding physiologic regulatory capacity. This context-specific risk led to modifications in clinical practice guidelines recommending caution with bypassing agents in emicizumab-treated patients. The very low immunogenicity likely reflects the humanized antibody design and subcutaneous route of administration, which promotes tolerance compared to intravenous dosing. ## References [C. Schmitt, J. Adamkewicz, Jin Xu, Claire Petry, O. Catalani, and 4 more\\ (2020).Pharmacokinetics and Pharmacodynamics of Emicizumab in Persons with Hemophilia A with Factor VIII Inhibitors: HAVEN 1 Study. Thrombosis and Haemostasis](/content/review/5a736cdd-2b4b-48fe-ab15-d7447eec56f5/source/ss-224819275/index.html) [A. Kiialainen, J. Adamkewicz, Claire Petry, J. Oldenburg, S. Pipe, and 9 more\\ (2023).Pharmacokinetics and coagulation biomarkers in children and adults with hemophilia A receiving emicizumab prophylaxis every 1, 2, or 4 weeks. Research and Practice in Thrombosis and Haemostasis](/content/review/5a736cdd-2b4b-48fe-ab15-d7447eec56f5/source/ss-266665861/index.html) [A. Donners, C. Rademaker, Lisanne A H Bevers, A. Huitema, R. Schutgens, and 2 more\\ (2021).Pharmacokinetics and Associated Efficacy of Emicizumab in Humans: A Systematic Review. Clinical Pharmacokinetics](/content/review/5a736cdd-2b4b-48fe-ab15-d7447eec56f5/source/ss-237005225/index.html) [S. Pipe, M. Shima, M. Lehle, A. Shapiro, S. Chebon, and 12 more\\ (2019).Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study. The Lancet Haematology](/content/review/5a736cdd-2b4b-48fe-ab15-d7447eec56f5/source/ss-124147356/index.html) [F. Jonsson, C. Schmitt, Claire Petry, F. Mercier, N. Frey, and 1 more\\ (2021).Exposure–Bleeding Count Modeling of Emicizumab for the Prophylaxis of Bleeding in Persons with Hemophilia A with/Without Inhibitors Against Factor VIII. Clinical Pharmacokinetics](/content/review/5a736cdd-2b4b-48fe-ab15-d7447eec56f5/source/ss-232202682/index.html) [M. Shima, H. Hanabusa, M. Taki, T. Matsushita, Tetsuji Sato, and 5 more\\ (2016).Factor VIII-Mimetic Function of Humanized Bispecific Antibody in Hemophilia A. New England Journal of Medicine](/content/review/5a736cdd-2b4b-48fe-ab15-d7447eec56f5/source/ss-205099251/index.html) [M. Shima, H. Hanabusa, M. Taki, T. Matsushita, Tetsuji Sato, and 5 more\\ (2017).Long-term safety and efficacy of emicizumab in a phase 1/2 study in patients with hemophilia A with or without inhibitors. Blood Advances](/content/review/5a736cdd-2b4b-48fe-ab15-d7447eec56f5/source/ss-34113138/index.html) [S. Pipe, P. Collins, C. Dhalluin, G. Kenet, C. Schmitt, and 10 more\\ (2022).Emicizumab Prophylaxis for the Treatment of Infants with Severe Hemophilia A without Factor VIII Inhibitors: Results from the Interim Analysis of the HAVEN 7 Study. Blood](/content/review/5a736cdd-2b4b-48fe-ab15-d7447eec56f5/source/ss-256774867/index.html) [Qianqian Mao, Zhengping Li, Zhenping Chen, Runhui Wu\\ (2025).Pharmacokinetic and pharmacodynamic characteristics of emicizumab in Chinese pediatric patients with hemophilia A: A retrospective single-center study. Blood](/content/review/5a736cdd-2b4b-48fe-ab15-d7447eec56f5/source/ss-283609058/index.html) [S. Pipe, P. Collins, C. Dhalluin, G. Kenet, C. Schmitt, and 12 more\\ (2023).Emicizumab Prophylaxis in Infants with Severe Hemophilia A without Factor VIII Inhibitors: Results from the Primary Analysis of the HAVEN 7 Study. Blood](/content/review/5a736cdd-2b4b-48fe-ab15-d7447eec56f5/source/ss-265563796/index.html) Download BIBDownload RISDownload TXT ## Report Status Gather sources 200 sources found Details Screen sources 10 sources included Details Extract data 80 data points extracted Details Generate report Save PDF BIBLaTeX, ZoteroRISZotero, MendeleyTXTAPA BibliographyPDFPDFDOCXMicrosoft Word Chat Got some follow-up questions? [Sign up](/content/users/auth?redirectToPath=%2Freview%2F5a736cdd-2b4b-48fe-ab15-d7447eec56f5%2Fsource%2Fss-34113138&show=signup/index.html) or [sign in](/content/users/auth?redirectToPath=%2Freview%2F5a736cdd-2b4b-48fe-ab15-d7447eec56f5%2Fsource%2Fss-34113138/index.html) to chat with this report. Back ## Long-term safety and efficacy of emicizumab in a phase 1/2 study in patients with hemophilia A with or without inhibitors. M. Shima, H. Hanabusa, M. Taki, T. Matsushita, Tetsuji Sato, K. Fukutake, R. Kasai, K. Yoneyama, Hiroki Yoshida, K. Nogami Blood Advances· 2017· 109 citations SourceDOI Plain textPDF Searching for PDF Unable to find PDF from source Back Study Population \- Age range: 12 to 58 years \- Geographic/ethnic population: Japanese \- Hemophilia A severity: Severe \- FVIII inhibitor status: Presence or absence of inhibitors \- Sample size for PK/PD analyses: 18 patients Dosing Regimen \- Dose level(s) tested: 0.3 mg/kg, 1 mg/kg, 3 mg/kg \- Dosing frequency: Once weekly \- Loading dose regimen: Cohorts 1 and 2 received a loading dose of 1 mg/kg and 3 mg/kg, respectively \- Maintenance dose regimen: Once-weekly subcutaneous administration \- Route of administration: Subcutaneous \- Duration of treatment/observation: Up to 33.3 months \- Dose adjustments: Individualized based on efficacy and safety evaluation committee review \- Sampling timepoints for PK/PD measurements: Not explicitly mentioned PK Parameters \- Plasma/serum emicizumab concentrations: Steady-state trough levels increased in a dose-proportional manner at 10.3, 29.9, and 120 mg/mL for cohorts 1, 2, and 3, respectively. \- Clearance (CL/F): Not mentioned. \- Volume of distribution (V/F or Vss/F): Not mentioned. \- Half-life (t½): 4 to 5 weeks. \- Time to steady-state: Approximately 12 weeks with a loading dose, 24 weeks without. \- Bioavailability or relative bioavailability: Not mentioned. \- Dose-proportionality findings: Plasma concentrations increased in a dose-proportional manner. \- PK variability (inter-patient, intra-patient): Not mentioned. \- Any population PK modeling results: Not mentioned. \- Comparison across different dosing regimens: Not mentioned. PD Outcomes \- FVIII-equivalent activity levels: Not mentioned \- Coagulation parameters: aPTT remained short; promotion of FXIa-triggered thrombin generation \- Annualized bleeding rates (ABR): Median ABRs remained low at 1.4, 0.2, and 0 in cohorts 1, 2, and 3, respectively \- Proportion of patients with zero bleeds: 8 out of 18 patients \- Time to first bleeding episode: Not mentioned \- Bleeding severity and location: Not mentioned \- Need for additional hemostatic treatment: All breakthrough bleeding episodes were successfully treated with episodic treatment (FVIII or bypassing agents) \- Other hemostatic efficacy measures: Reduction in ABR with dose up-titration; successful treatment of breakthrough bleeding episodes \- Methods used to assess each PD outcome: Monitoring of ABR, aPTT, and thrombin generation PK/PD Relationships \- Correlations between emicizumab concentration and FVIII-equivalent activity: Not mentioned. \- Exposure-efficacy relationships: Plasma concentrations increase in a dose-proportional manner; further reduction in ABRs with dose up-titration. \- Exposure-safety relationships: Not explicitly discussed. \- Population PK/PD modeling results: Not mentioned. \- Threshold concentrations for efficacy: Not mentioned. \- Model parameters (EC50, Emax, slope factors): Not mentioned. \- Goodness-of-fit assessments: Not mentioned. \- Predictions or simulations of different dosing scenarios: Not mentioned. Safety Profile \- Injection site reactions: Mild, 12 events in 7 patients (38.9%). \- Thrombotic/thromboembolic events: None reported. \- Anti-drug antibodies (ADA) development: 4 patients tested positive, but ADAs were nonneutralizing and did not affect PK/PD. \- Neutralizing antibodies: None developed. \- Other treatment-related adverse events: 4 patients experienced SAEs, but none were related to emicizumab. \- Laboratory safety parameters: Not mentioned. \- Safety findings affecting dosing or PK/PD interpretation: None mentioned. \- Discontinuations due to safety concerns: None reported. Covariates \- Inhibitor status effects on efficacy: No significant difference in efficacy between patients with and without inhibitors. \- Dose effects: Plasma concentrations increased in a dose-proportional manner; slight dose dependency observed in PD parameters. \- Dose up-titration effects: Further reduction in ABR observed with dose up-titration. \- ADA effects: Non-neutralizing ADAs did not affect PK/PD profiles. \- Other identified sources of PK/PD variability: Not explicitly mentioned. \- Magnitude and clinical significance of covariate effects: Not explicitly discussed. Study Methods \- Study design and phase: Open-label, long-term extension of a phase 1 study. \- PK sampling strategy and timepoints: Plasma concentrations measured; steady-state reached after 12 weeks in cohorts 1 and 2, and after 24 weeks in cohort 3. \- Bioanalytical methods for emicizumab concentration measurement: Described previously, but specific details not provided. \- Methods for measuring FVIII-equivalent activity and coagulation parameters: Activated partial thromboplastin time (aPTT) and activated factor XI (FXIa)-triggered thrombin generation (TG). \- PK analysis methods: Not specified (non-compartmental or population modeling software). \- Statistical approaches for PK/PD analysis: Not explicitly detailed. \- Validation of bioanalytical and PD assays: Not mentioned. \- Limitations affecting PK/PD interpretation: Not randomized or controlled; small patient numbers in each dose cohort. Emicizumab (ACE910), a recombinant humanized bispecific monoclonal antibody, provides factor VIII (FVIII) cofactor bridging function to restore hemostasis in people with hemophilia A. In a phase 1 trial involving 18 Japanese patients with severe hemophilia A, once-weekly subcutaneous administration of emicizumab 0.3, 1, or 3 mg/kg (cohorts 1, 2, and 3, respectively) was well tolerated and substantially reduced annualized bleeding rates (ABRs) in the presence or absence of FVIII inhibitors. The current study represents an open-label, long-term extension of the previously reported 12-week phase 1 study, in which 16 of 18 patients continued to receive emicizumab for up to 33.3 months. Long-term emicizumab treatment was well tolerated, with no thromboembolic events reported and no neutralizing antiemicizumab antibodies developing during the course of the study. Plasma concentrations of emicizumab increased in a dose-proportional manner, with activated partial thromboplastin times remaining short. In cohorts 1, 2, and 3, respectively, median ABRs remained low at 1.4, 0.2, and 0 compared with 4.4, 0, and 0 in the 12-week study. Overall, 8 patients experienced no bleeding events (6 patients with and 2 patients without FVIII inhibitors); dose up-titration resulted in further reduction in ABRs in patients with suboptimal bleeding control; and the episodic use of clotting factors to control bleeding was reduced. In conclusion, long-term emicizumab treatment demonstrated a favorable safety profile with encouraging efficacy, irrespective of the presence of FVIII inhibitors, in patients with hemophilia A. This study was registered at www.clinicaltrials.jp as #JapicCTI-132195. Introduction Hemophilia A, a deficiency of clotting factor VIII (FVIII) that results in frequent bleeding, is estimated to develop in 1 in 5000 males worldwide. 1 More than half the population of patients with hemophilia A have severe disease characterized by FVIII activity ,0.01 IU/mL. 2 These patients often experience frequent traumatic or spontaneous bleeding events, 2 including joint bleeding, 3 which leads to irreversible hemophilic arthropathy, the major cause of morbidity and reduced quality of life in patients with hemophilia. 4,5 ophylactic or episodic IV infusions of plasma-derived or recombinant FVIII are the current options for managing severe hemophilia A. 6,7 Prophylactic treatment reduces the risk of joint damage. 8 However, the short half-lives of approximately 12 to 15 hours \[9\]\[10\]\[11\]\[12\]\[13\] for currently available agents necessitate frequent (eg, 2-3 times per week), inconvenient, and time-consuming administration to maintain protective FVIII levels. 7,14 In infants, the need for frequent IV access can prove particularly difficult, and central venous access devices are often required. 15 The development of FVIII inhibitors (anti-FVIII antibodies), which render FVIII replacement therapy ineffective, is 1 of the most challenging complications of treatment. 16 Inhibitors develop in approximately 30% of patients with severe hemophilia A and lead to substantial morbidity and decreased quality of life. 17 or patients with FVIII inhibitors, treatment may involve inhibitor-eliminating immune tolerance induction therapy, which is burdensome and not successful in every patient. For patients undergoing or refractory to immune tolerance induction therapy, bleeding events are controlled with bypassing agents (eg, recombinant activated FVII \[rFVIIa\] or activated prothrombin complex concentrate \[aPCC\]). 16 Although these treatments can be efficacious for many patients, neither of these therapies is considered as effective as FVIII replacement. Emicizumab (ACE910) has been developed to address the burdens associated with current treatment options for patients with hemophilia A, such as frequent infusion, inconvenient IV administration, and FVIII inhibitor development. Emicizumab is a recombinant humanized bispecific monoclonal antibody that acts as an FVIII mimetic by binding simultaneously to activated factor IX (FIXa) and factor X (FX). 18,19 Because of its unique structure, emicizumab is not expected to induce FVIII inhibitor development or be affected by existing FVIII inhibitors. Subcutaneously administered emicizumab showed high bioavailability in cynomolgus monkeys, 20 and once-weekly administration significantly reduced spontaneous bleeding symptoms in a primate model of acquired hemophilia A. 21 In its first-in-human phase 1 study, emicizumab demonstrated a long half-life of 4 to 5 weeks, and single subcutaneous doses of #1 mg/kg had favorable safety and tolerability in healthy participants. 22 Subsequently, in the first-in-patient 12-week, phase 1 study, once-weekly subcutaneous emicizumab at 0.3, 1, or 3 mg/kg was well tolerated and substantially reduced annualized bleeding rates (ABRs) in patients with severe hemophilia A both with and without inhibitors. 23 rrently, an extension of the first-in-patient 12-week study is ongoing. The objective of this long-term study is to investigate safety and, in an exploratory manner, the prophylactic effect of emicizumab on bleeding events in patients with hemophilia A with or without inhibitors. Here we report long-term data up to a cutoff of February 2016 in combination with the complete data from the 12-week study, in which emicizumab treatment was initiated from May 2013. Methods This ongoing phase 1/2, open-label, multicenter extension study has been conducted since August 2013 in compliance with the International Conference on Harmonisation Guideline for Good Clinical Practice and was approved by institutional review boards. The 12-week study and this extension study were registered at www.clinicaltrials.jp/user/cteSearch\_e.jsp (#JapicCTI-121934 and #JapicCTI-132195, respectively). All patients and/or their legally authorized representatives provided written informed consent for study participation. Patients Eighteen Japanese patients aged 12 to 58 years, with severe hemophilia A with or without inhibitors, who enrolled in the 12-week phase 1 study 23 were candidates for the extension study. Eligibility criteria for the 12-week study have been described previously. 23 Inclusion criteria specific for the extension study included report of $3 bleeding episodes in the 6 months before the 12-week study enrollment (for patients without inhibitors). On the basis of inclusion and exclusion criteria for the extension study, investigators determined patient eligibility. The efficacy and safety evaluation committee for the study also determined patients' eligibility for the extension study based on their individual clinical findings, including laboratory tests, vital signs, 12-lead electrocardiogram (ECG) results, adverse events (AEs), pharmacokinetics (PK), pharmacodynamics (PD), and serum cytokine concentrations. Study design Patients started once-weekly subcutaneous emicizumab at 0.3 (cohort 1) or 1 mg/kg (cohort 2) from 1 week after receiving a loading dose of 1 (cohort 1) or 3 mg/kg (cohort 2) on the first day of the 12-week study (day 1); patients in cohort 3 received 3 mg/kg once weekly from day 1. 23 Each cohort included 6 patients. In the extension study, eligible patients continued on the assigned dose for their respective cohort from the 12-week study, with potential dose up-titration to 1 (cohort 1) or 3 mg/kg (cohorts 1 and 2; Figure 1 ). In cohort 3, patients remained on 3 mg/kg once weekly. Decisions on dose up-titration during the extension study were made by the efficacy and safety evaluation committee on an individual patient basis after reviewing all patient data from the phase 1 study at a dose considered for up-titration. If a bleeding event occurred, the committee determined the feasibility of dose up-titration within the dose range considered acceptable for the extension study based on clinical findings, including laboratory tests, vital signs, 12-lead ECG, AEs, PK/PD responses, serum cytokine concentrations, and the number of bleeding episodes over $12 consecutive emicizumab administrations in the patient. Approval of self-injection by a patient or caregiver was also made by the committee on a dose-level basis, similar to the assessments made for dose up-titration. For dose up-titration from 0.3 to 1 mg/kg, the initial subcutaneous dose was 3 mg/kg, followed by subsequent weekly doses of 1 mg/kg. At the discretion of the investigator, individual administrations of emicizumab could be suspended. If a patient's reduction in bleeding rate from pre-to postemicizumab treatment in the 12-week study was ,50%, the emicizumab dose was considered suboptimal. Such patients did not initially participate in the extension study, but instead transitioned to the postemicizumab follow-up observation period, during which reinitiation of prior treatment was allowed. Restarting emicizumab treatment with dose up-titration was at the discretion of the investigators. Once the efficacy and safety evaluation committee approved initiation of emicizumab treatment at a higher dose in the extension study, the patient could be enrolled in the extension study to restart emicizumab treatment at this up-titrated dose (supplemental methods). Breakthrough bleeding episodes that occurred during the study were treated with FVIII or a bypassing agent according to standard clinical practice. Outcome measures The primary end point of the extension study was safety, including AEs and treatment-related AEs, laboratory tests, clinical symptoms, vital signs, 12-lead ECG and chest X-ray, and immunogenicity (ie, plasma antiemicizumab (drug) antibodies \[ADAs\]). Secondary end points included PK profiles assessed with plasma concentrations of emicizumab, FIX and FX, and PD responses of activated partial thromboplastin time (aPTT) and activated factor XI (FXIa)-triggered thrombin generation (TG). The assay methods for the PK, PD, and ADAs have been described previously. 22 Coagulation factor use was allowed to treat breakthrough bleeding or bleeding related to procedure/surgery. The number of breakthrough bleeding episodes requiring coagulation factor treatment was an exploratory efficacy end point of the study. Statistical analysis All analyses were conducted using the combined data from the 12-week and extension studies. Although this study had no preplanned analysis, a data cutoff of February 2016 was chosen because the median follow-up time of the population was .2 years and considered long enough to assess long-term safety and exploratory efficacy. Summary statistics were calculated for demographic, PK, PD, and safety and tolerability outcomes. The ABRs during emicizumab treatment were compared with those during the 6 months before emicizumab treatment as captured from the patients' medical records. The ABR was calculated as 365.25 times the number of bleeding episodes divided by the number of days treated. The relationship between emicizumab dose and ABR was explored within each patient who had dose up-titration. Data after dose up-titration were excluded from summary statistical calculation of PK, PD, and ABR data. Results As of February 2016, 16 of 18 Japanese patients who enrolled in the 12-week study continued into the extension study: 6 patients in cohort 1, and 5 patients each in cohorts 2 and 3. Two patients from the 12-week study were not eligible for the extension study. One patient (inhibitor; cohort 2) discontinued emicizumab on day 29 of the 12-week study because of mild injection-site erythema, and the second patient (noninhibitor; cohort 3) had no bleeding event before emicizumab administration. One patient (noninhibitor; cohort 1) restarted emicizumab in the extension study at a higher dose (1 mg/kg) than in the 12-week study (0.3 mg/kg) after the postemicizumab follow-up observation. Demographics and baseline characteristics of patients enrolled in the initial 12-week study have been reported previously. 23 In brief, characteristics were similarly distributed across cohorts with the exception of ABRs in the 6 months before the study (ABRs for patients in cohort 1, particularly patients without inhibitors, were higher than for patients in cohorts 2 and 3) and prior bypassing agent use (episodic for cohorts 1 and 2 and prophylactic for cohort 3). Across the 12-week and extension studies, at a median follow-up of 32.6 (range, 32.2-33.3), 27.0 (range, 8.2-28.5), and 21.5 months (range, 11.1-22.6) for cohorts 1, 2, and 3, respectively, 16 patients had continued study treatment. Four patients had dose up-titration: 2 patients required up-titration from 0.3 to 1 mg/kg and then 3 mg/kg; 1 patient required up-titration from 0.3 to 1 mg/kg; and the fourth patient required up-titration from 1 to 3 mg/kg. Most patients self-administered emicizumab during the study; some patients received treatment from a caregiver or health care professional. PK/PD Plasma emicizumab concentrations reached steady state ;12 weeks after treatment initiation in cohorts 1 and 2, where an initial loading dose was administered, and after ;24 weeks in cohort 3, where no loading dose was administered (Figure 2A ). Mean (6 standard deviation) steady-state trough levels increased in a dose-proportional manner at 10.3 (6 4.54), 29.9 (6 6.88), and 120 (6 26.8) mg/mL in cohorts 1, 2 and 3, respectively. In the 4 patients with dose up-titrations, plasma emicizumab increased with increased doses (data not shown). Shortening of aPTT and promotion of FXIa-triggered TG were maintained with weekly emicizumab treatment; a slight dose dependency was observed (Figure 2B-C ). At steady state, mean (6 standard deviation) aPTT was 32.5 (6 5.5), 27.7 (6 3.5), and 24.0 (6 2.3) seconds in cohorts 1, 2, and 3, respectively. No obvious changes in plasma concentrations of FIX or FX were observed (data not shown). Dose up-titration resulted in slight or negligible shortening of aPTT and promotion of FXIa-triggered TG (data not shown). Safety It was not possible to conduct a comparison of different dose groups, because some patients experienced dose up-titration, and patients were not randomly assigned to dose groups. Therefore, all 18 patients were included in the safety analysis. Once-weekly subcutaneous emicizumab administration for a maximum of 33.3 months was well tolerated, even at steady state for the highest dose (3 mg/kg). In this patient population, no thromboembolic AEs were observed, even when FVIII or a bypassing agent was administered to treat breakthrough bleeding episodes. No deaths have been reported during the study. AEs that occurred in $2 patients are listed in Table 1 . All patients experienced $1 AE, with 150 AEs reported overall. The most frequently reported AEs were local injection-site reactions (erythema, hematoma, pruritus, discomfort, pain, or rash); 12 events, all mild, were reported in 7 patients (38.9%). All injection-site reactions occurred after .2 emicizumab doses. One patient in cohort 2 withdrew from treatment on day 29 of the 12-week study because of repeated mild injection-site erythema. The AE required approximately 489 nmol/L, respectively, which were derived from healthy Japanese participants. 22 All data collected after dose up-titrations were excluded; the number of patients for this summary was 6 per cohort. Data points where the number of patients with quantifiable measurement was $2 and not less than half of the number of observed patients were plotted. resulting from thrombosis was considered unlikely because the patient had experienced no acute abdominal condition, the hematoma developed slowly, there was no evidence of intestinal edema, and there were no clinically significant changes in laboratory coagulation markers to suggest thrombosis. Relevant computed tomography images are shown in supplemental Figure 1 . After an interruption of emicizumab from weeks 69 to 75 (equating to 7 missed doses), when episodic FVIII therapy was administered, the event resolved, with no further bleeding reported; the patient remained on emicizumab at the time of data cutoff. The fourth patient (inhibitor) required hospitalization for control of a subcutaneous hemorrhage of the proglossis on day 860 and also experienced a nosebleed (also on day 860). The nosebleed resolved by the time of hospitalization. Without any interruption to emicizumab treatment, the patient was administered a bypassing agent twice daily and was discharged the following day. The hemorrhage event resolved 9 days after onset, and the patient remained on emicizumab at the time of data cutoff. Efficacy Median ABRs for each cohort 6 months before starting emicizumab prophylaxis, during the 12-week phase 1 study, and during combined phase 1 and extension studies up to the data cutoff are shown in Figure 3 . The reduction in median ABRs (bleeding events at any site) from the prior 6 months to the 12-week study has been reported previously 23 ; this reduction continued in the extension study. In cohorts 1, 2, and 3, respectively, median (range) ABRs remained low at 1.4 (0.0-59.5), 0.2 (0.0-2.7), and 0.0 (0.0-0.6), vs 4.4 (0.0-59.5), 0.0 (0.0-4.3), and 0.0 (0.0-4.2) in the 12-week study. The low ABR overall in the extension study was reflected in the median (range) frequency of joint bleeding events vs the 12-week study: 1.1 (0.0-59.5) vs 4.3 (0.0-59.5) in cohort 1, 0.2 (0.0-1.9) vs 0.0 (0.0-0.0) in cohort 2, and maintained at 0 (0.0-0.0 for both periods) in cohort 3. Overall, 8 patients experienced no bleeding events with weekly emicizumab as of the data cutoff. These patients included 1 with inhibitors in cohort 1, 3 with inhibitors in cohort 2, and 2 with and 2 without inhibitors in cohort 3. The decrease in ABRs did not differ for patients with or without inhibitors (supplemental Figure 2 ). In all emicizumab dose cohorts, patients with inhibitors had a reduction in ABRs to nearly 0 after receiving treatment. The efficacy and safety evaluation committee allowed a small subset of 4 patients to have emicizumab dose up-titration because of suboptimal bleeding control. In each patient who had emicizumab dose up-titration, a further reduction in ABR was observed (supplemental Figure 3 ). These individual reductions in ABR ranged from 85% to 100% after dose up-titration. All breakthrough bleeding episodes were successfully treated with episodic treatment (FVIII or bypassing agents) according to standard clinical practice. The daily amounts of the various coagulation factors required to control breakthrough bleeding or bleeding related to a procedure postemicizumab are summarized in Table 2 . There were 83 FVIII treatment episodes, with a dose range of 12 to 98 IU/kg per day for breakthrough bleeding during emicizumab treatment in 5 of 7 noninhibitor patients. Most FVIII treatment episodes were for 1 day (63 episodes) or at #50 IU/kg per day (69 episodes). Among 11 inhibitor patients, 2, 1, and 3 patients used aPCC only, rFVIIa only, or both bypassing agents, respectively, with a dose range of 38 to 203 U/kg per day for aPCC and 86 to 504 mg/kg per day for rFVIIa. One patient used aPCC only for bleeding related to a procedure (ie, he experienced no breakthrough bleeding that required coagulation factors). No patient administered aPCC and rFVIIa on the same day. There were 23 aPCC and 35 rFVIIa treatment events. Most aPCC treatment episodes were for 1 day (20 episodes) or at #100 U/kg per day (21 episodes). Most rFVIIa treatment episodes were for 1 or 2 days (25 or 9 episodes, respectively) or at #270 mg/kg per day (33 episodes). The amount of coagulation factor required per breakthrough bleeding episode, pre-and postemicizumab, is shown in supplemental Figure 4 . The range of percent change in the intrapatient mean amount of each coagulation factor per bleeding episode from pre-to postemicizumab administration was 237.5% to 170.0% (for 4 of 5 patients) for FVIII products, 241.0% to 130.0% (n 5 4) for aPCC, and 220.0% to 121.4% (n 5 4) for rFVIIa. One patient required a large amount of FVIII products because of repeated treatments for a single SAE (mesenteric hematoma). None of the remaining patients required coagulation factor products during emicizumab administration (ie, the percent change was 2100%). A majority of patients, including those with no bleeding event, experienced a decrease in the mean use of coagulation factor products during emicizumab administration (supplemental Figure 4 ). Immunogenicity Four patients tested positive for ADAs: 1 tested positive before emicizumab initiation (baseline), and 3 tested positive only after emicizumab initiation. Two of the 4 patients underwent dose uptitration. Because the presence of ADAs had no effect on plasma concentrations of emicizumab, FIX or FX, PD markers (aPTT or TG), or reduction in ABR in any of the 4 patients (data not shown), the ADAs were considered nonneutralizing. One patient who received 0.3 mg/kg of emicizumab up to week 96, and 1 mg/kg thereafter, developed anti-emicizumab immunoglobulin E (IgE). This patient tested negative for ADAs at baseline and positive for ADAs at weeks 36, 48, 60, 68, 72, and 84, which included positive IgE tests at weeks 36 and 48. The patient also tested negative for ADAs at weeks 12, 24, 56, 64, 76, and 80 and every 4 weeks from week 88 until week 136. This patient experienced mild injectionsite reactions (discomfort, erythema) and several other AEs that were reported by .1 patient (Table 1 ). Overall, no specific AE As of February 2016, 16 of 18 Japanese patients enrolled in the 12-week study continued into the extension study: 6 patients in cohort 1, and 5 patients each in cohorts 2 and 3. All data collected after dose up-titrations were included. \*The patient 1-6 used 2000 IU of FVIII 3 times per day (98 IU/kg per day) to treat breakthrough bleeding during treatment with 3 mg/kg of emicizumab. This patient had 59 treatment events in total and was the only 1 who used .50 IU/kg per day of FVIII. †The patient 2-1 used 3000 U of aPCC 3 times per day (115 U/kg per day) to treat bleeding related to a procedure (not counted as breakthrough bleeding) during treatment with 1 mg/kg of emicizumab. ‡The patient 1-2 used 7000 U of aPCC twice per day (203 U/kg per day) for 2 days to treat breakthrough bleeding during treatment with 0.3 mg/kg of emicizumab. §The patient 1-3 used 15 mg of rFVIIa twice per day (504 mg/kg per day) to treat breakthrough bleeds during treatment with 0.3 and 1 mg/kg of emicizumab. occurrence patterns for the patient were observed, and no hypersensitivity, other than local injection-site reactions, was reported. Discussion This ongoing extension of the 12-week phase 1 study 23 was conducted to assess the long-term safety and efficacy of emicizumab in the management of patients with severe hemophilia A. Onceweekly subcutaneous emicizumab was well tolerated for up to 33.3 months, with tolerability of the highest dose of 3 mg/kg once weekly confirmed under steady-state conditions (mean trough level, 120 mg/mL). Treatment-related AEs were manageable and did not occur more often than AEs unrelated to study treatment (ie, nasopharyngitis, headache, and dizziness); treatment-related AEs were successfully treated with commonly available drugs or resolved without treatment. Injection-site reactions were the most frequently reported treatment-related AEs. A total of 4 patients experienced SAEs, all of which resolved and none of which were considered related to emicizumab treatment by the study investigators. Long-term emicizumab treatment showed encouraging efficacy in patients with hemophilia A, irrespective of the presence of FVIII inhibitors, as demonstrated by the substantial decrease in ABRs across dose cohorts. The low ABRs achieved during the first 12 weeks of emicizumab administration were maintained with longterm treatment. Joint bleeding was well controlled, especially in cohort 3, where an ABR of 0 was maintained in all 6 patients. Eight of 18 patients who enrolled in the 12-week study achieved 0 bleeding episodes; 1 additional patient achieved 0 bleeding episodes at an up-titrated dose. aPTT is a commonly used biomarker to monitor hemostatic activity. 24 The postemicizumab aPTT at steady state averaged 24.0 to 32.5 seconds and was within or shorter than the reference range of 25.4 to 37.2 seconds derived from healthy Japanese participants under the same assay conditions. 22 Results from the current study, where a majority of patients experienced bleeding events even with such apparently normalized aPTT, suggest that aPTT measurements overestimate the hemostatic activity of emicizumab. Nevertheless, monitoring aPTT may allow for the detection of neutralizing ADA development, as evidenced by data from 1 healthy participant in the first-in-human study. 22 In contrast to aPTT, there may be a potential relationship between plasma emicizumab concentrations and reductions in bleeding rate, as suggested by the PK and ABR findings in patients who had emicizumab dose up-titration. A linear PK profile of emicizumab has been demonstrated in patients with hemophilia A, as well as in healthy participants. 22 ithin the tested dose range of 0.3 to 3 mg/kg, steady-state trough levels of plasma emicizumab concentrations increased in a dose-proportional manner. In addition, emicizumab-dependent accumulation or depletion of FIX or FX was not observed, even at steady state for the highest dose (3 mg/kg). These findings suggest that antigen-antibody complex formation in plasma, which may affect the clearance of the antibody-based drugs and their antigens and may disturb the function of the antigen, 25 is unlikely to occur with emicizumab. This is probably because of the weak antigen-binding affinity of emicizumab to each factor. 26 isodic coagulation factors were effectively administered during this study and treated breakthrough bleeding. The daily amount of coagulation factor administered to treat breakthrough bleeding was considered within the standard therapeutic dose range, and the amount of coagulation factor required per bleeding episode decreased in 5 of 10 patients with bleeding events during emicizumab administration. Four of 10 patients required increased amounts of coagulation factor concentrate to resolve their bleeding events vs before starting the study. An additional patient required many episodic FVIII administrations to treat a mesenteric hematoma. It was demonstrated previously that emicizumab in combination with bypassing agents, particularly aPCC, results in enhanced TG in vitro and in vivo. 27 This suggests that episodic bypassing agents, especially aPCC, concomitant with emicizumab prophylaxis have a potential to induce thromboembolic events. In an ongoing phase 3 study in patients with inhibitors, thrombotic microangiopathy and thromboembolic events occurred after aPCC treatment, with doses averaging .100 U/kg per day for .1 day, during emicizumab prophylaxis. 28 However, no such events were observed in the current study. This may be because 22 of 23 aPCC administrations were at a lower dose than .100 U/kg per day for .1 day. Although 4 patients had ADAs, there was no impact on their PK or PD profiles of emicizumab, indicating that the ADAs were nonneutralizing and did not affect the efficacy of emicizumab. One patient did develop antiemicizumab IgE, but it was not persistently detected. AEs reported in this patient did not seem to include any specific events and were not unique to this patient. Moreover, because no hypersensitivity, other than local injectionsite reactions, occurred and the development of ADAs did not result in treatment discontinuation, no clinical relevance of ADAs was evident. Of note, although neutralizing ADAs developed in 1 healthy participant in the first-in-human study, no AEs related to either abnormal coagulability or allergic reaction were observed. 22 mitations to the current study include that it was not randomized or controlled, and the small patient numbers in each dose cohort restricted assessment of the incidence and characteristics of AEs. Disparity in the baseline severity of disease, based on ABRs in the 6 months before the study, hindered the assessment of a doseresponse relationship with emicizumab treatment in terms of bleeding prophylactic efficacy. Moreover, each patient's physical activity was not documented during the course of the study, which may have affected the interpretation of reported bleeding events. Considering that hemophilia A is a lifelong disease, further long-term assessment of the safety and efficacy of emicizumab is required. Nonetheless, the available clinical data highlight the potential for emicizumab to shift the treatment paradigm in hemophilia A. The long half-life of emicizumab has been predicted to result in minimal variation in peak/trough plasma concentrations at repeated subcutaneous injections, 22 which may result in fewer joint bleeds than with treatments with more fluctuating PK profiles. It also suggests potential for less frequent administration than once weekly, for more dosing convenience, which will be explored in future studies. The subcutaneous administration of emicizumab (vs IV administration for current agents) has the potential to further decrease the treatment burden for patients. Subcutaneous administration simplifies the initiation and introduction of regular prophylaxis and may in turn improve compliance with prophylaxis regimens, which could also improve efficacy and long-term health outcomes. Additionally, because emicizumab showed promising efficacy in patients with inhibitors and is not expected to induce inhibitors, it represents a potential solution to the unmet need in patients with hemophilia A who develop inhibitors to FVIII therapy. In conclusion, long-term emicizumab treatment demonstrated a favorable safety profile with encouraging efficacy, irrespective of the presence of FVIII inhibitors, in patients with hemophilia A. Emicizumab has the potential to provide an effective and convenient prophylactic therapeutic option with a lower treatment burden vs current prophylactic agents, including in patients with inhibitors and/or with venous access difficulty. Authorship Contribution: M.S. and R.K. wrote the manuscript; M.S., R.K., K.Y., and H.Y. designed the study; H.H., T.M., M.T., T.S., K.F., and K.N. conducted the study; K.Y. and H.Y. analyzed the data; all authors had access to the data and analysis and approved the final manuscript; and M.S. is the guarantor. ORCID profiles: R.K., 0000-0002-4720-4823; K.Y., 0000-0001-8166-6522; H.Y., 0000-0002-7705-2410. Conflict Correspondence: Midori Shima, Department of Pediatrics, Nara Medical University, 840 Shijo-cho Kashihara, Nara 634-8522, Japan; e-mail: mshima@naramed-u.ac.jp. Acknowledgements AcknowledgmentsThe authors thank all the patients and their family members, Hoyu Takahashi at Niigata Prefectural Kamo Hospital, investigators and staff at participating medical institutions, Chiai Nagae at the Department of Pediatrics and Kunihisa Miyakawa at the Department of Radiology, St Marianna University School of Medicine, and project team members at Chugai Pharmaceutical Co., Ltd, especially Naoki Fukazawa, Shingo Maisawa, and Mariko Hoshiba.Editorial assistance for this manuscript was provided by Corin Wing, Envision Scientific Solutions, and funded by Chugai Pharmaceutical Co., Ltd. Failed to load PDF: StripeM-Inner Paper sources Abstract screening pilot Abstract screening results Extraction pilot Extraction results Research report * * * Modify setup