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Introduction Severe haemophilia A (HA) has a major impact on health‐related quality of life (HRQoL). Aim Assess the impact of emicizumab on HRQoL in persons with severe HA (PwHA) without factor VIII (FVIII) inhibitors in the phase 3 HAVEN 3 and 4 studies. Methods This pooled analysis examines the HRQoL of PwHA aged ≥ 18 years treated with emicizumab prophylaxis via Haemophilia‐Specific Quality of Life Questionnaire for Adults (Haem‐A‐QoL) and EuroQoL 5‐Dimensions 5‐levels (EQ‐5D‐5L). In particular, changes from baseline in Haem‐A‐QoL ‘Physical Health’ (PH) domain and ‘Total Score’ (TS) are evaluated. Results Among 176 evaluable participants, 96 (55%) had received prior episodic treatment and 80 (45%) prophylaxis; 70% had ≥ 1 target joint and 51% had experienced ≥ 9 bleeds in the previous 24 weeks. Mean Haem‐A‐QoL PH and TS improved after emicizumab initiation. Mean (standard deviation) –12.0 (21.26)‐ and –8.6 (12.57)‐point improvements were observed in PH and TS from baseline to Week 73; Week 73 scores were 27.9 (24.54) and 22.0 (14.38), respectively. Fifty‐four percent of participants reported a clinically meaningful improvement in PH scores (≥ 10 points) by Week 73. Subgroups with poorer HRQoL prior to starting emicizumab (i.e. receiving episodic treatment, ≥ 9 bleeds, target joints) had the greatest improvements in PH scores, and corresponding reductions in missed workdays; change was not detected among those previously taking prophylaxis. No change over time was detected by the EQ‐5D‐5L questionnaire. Conclusions Emicizumab prophylaxis in PwHA without FVIII inhibitors resulted in persistent and meaningful improvements in Haem‐A‐QoL PH and less work disruption than previous treatment.

Many people with hemophilia A (PwHA) undergo surgery in their lifetime, often because of complications of their disease. Emicizumab is the first bispecific monoclonal antibody prophylactic therapy for PwHA, and its efficacy and safety have been previously demonstrated; however, there is a need to build an evidence base on the management of PwHA on emicizumab undergoing surgery. Data from the HAVEN 1-4 phase 3 clinical trials were pooled to provide a summary of all minor and major surgeries in PwHA with or without factor VIII (FVIII) inhibitors who were receiving emicizumab prophylaxis. Overall, 233 surgeries were carried out during the HAVEN 1-4 trials: 215 minor surgeries (including minor dental and joint procedures, central venous access device placement or removal, and endoscopies) in 115 PwHA (64 with FVIII inhibitors) and 18 major surgeries (including arthroplasty and synovectomy) in 18 PwHA (10 with FVIII inhibitors). Perioperative hemostatic support was at the discretion of the treating physician. Overall, the median (interquartile range [IQR]) age was 33.5 (13.0-49.0) years and the median (IQR) emicizumab exposure time before surgery was 278.0 (177.0-431.0) days. Among the 215 minor surgeries, 141 (65.6%) were managed without additional prophylactic factor concentrate, and of those, 121 (85.8%) were not associated with a postoperative bleed. The majority (15 of 18 [83.3%]) of major surgeries were managed with additional prophylactic factor concentrate. Twelve (80.0%) of these 15 surgeries were associated with no intraoperative or postoperative bleeds. The data demonstrate that minor and major surgeries can be performed safely in PwHA receiving emicizumab prophylaxis. These trials are registered at www.clinicaltrials.gov as #NCT02622321, #NCT02795767, #NCT02847637, and #NCT03020160.

Introduction Emicizumab is a humanised, bispecific monoclonal antibody mimicking the cofactor function of activated factor (F)VIII. It is indicated for routine prophylaxis of bleeding episodes in persons with haemophilia A (PwHA) with/without FVIII inhibitors. Aim To evaluate the development of anti-emicizumab antibodies and their impact on pharmacokinetics (PK), pharmacodynamics (PD), efficacy and safety in PwHA. Methods Data from seven completed or ongoing phase 3 studies were pooled. The assessment of the immunogenicity profile of emicizumab included anti-drug antibody (ADA) measurement and the association of ADAs with PK, PD, bleeding events, and adverse events. Results Of 668 PwHA evaluable for immunogenicity analysis, 34 (5.1%) developed ADAs after exposure to emicizumab. ADAs were transient in 14/34 PwHA (41.2%). ADAs were neutralising in vitro in 18/34 PwHA (52.9%) and associated with decreased emicizumab concentration in 4/668 evaluable PwHA (.6%); of those, one (.1%) discontinued emicizumab due to loss of efficacy. ADAs without decreased exposure did not impact emicizumab efficacy. The proportion of PwHA who had injection-site reactions (ISRs) was higher in ADA-positive PwHA (29.4% vs. 20.8%); however, the safety profile was similar between ADA-positive and ADA-negative PwHA, overall. No cases of anaphylaxis or hypersensitivity were reported in ADA-positive participants. Conclusion The immunogenicity risk of emicizumab in phase 3 studies was low. ADAs, including in vitro neutralising ADAs, were not associated with a change in safety profile. Routine surveillance is, therefore, not warranted; however, in cases where a loss and/or waning of efficacy are observed, prompt evaluation by a healthcare provider should be sought.

Introduction: Emicizumab-a subcutaneously administered, bispecific, humanized, monoclonal antibody-promotes effective hemostasis in people with hemophilia A (PwHA). The primary efficacy and safety of emicizumab were reported previously, but long-term data are limited. Here, data from a wide age-range of PwHA with/without factor (F)VIII inhibitors enrolled in the Phase III HAVEN 1 (NCT02622321), HAVEN 2 (NCT02795767), HAVEN 3 (NCT02847637), and HAVEN 4 (NCT03020160) studies are pooled to establish the durable efficacy and safety of emicizumab. Methods: The studies enrolled pediatric and adult PwHA with/without FVIII inhibitors. Participants received emicizumab prophylaxis 1.5 mg/kg weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks. All participants assigned to receive emicizumab (including those assigned to control arms who later switched) are included in this analysis. Participants and/or caregivers recorded outcomes of bleeding events via the Bleed and Medication Questionnaire (BMQ). Data from HAVEN 1-4 were pooled for an aggregate analysis of emicizumab efficacy and safety. Efficacy endpoints include calculated mean annualized bleed rates (ABRs; discrete, consecutive 24-week treatment intervals), model-based ABRs (calculated via negative binomial regression for full study period), percentage of participants with zero and 1-3 treated bleeds, and annualized cumulative dose of coagulation factor (ACD). Safety endpoints include incidence of adverse events (AEs) and AEs of special interest. Results: Overall, 400 PwHA in HAVEN 1, 2, 3 and 4 (n=113, 88, 151, and 48, respectively) are included in the efficacy analysis for a total of 970.3 patient years (cutoff: 15 May 2020). The safety population comprises 399 PwHA who received ≥1 dose of emicizumab (1 PwHA was randomized to receive emicizumab but did not start treatment). The median age at baseline was 28.5 (range 1-77) years. The majority of participants were White (66.8%) or Asian (18.8%); 52.3% had FVIII inhibitors. In the 24 weeks prior to study entry, 60.9% of participants had target joints. The median duration of efficacy period was 120.4 (interquartile range 89.0-164.4) weeks; 85.0% of participants had an efficacy period of ≥74 weeks; 11 participants (2.8%) discontinued study treatment. Across all 4 studies, 90.9-94.8% of the observation period was covered by completed BMQs. Across all studies, the model-based treated bleed ABR was 1.4 (95% confidence interval 1.1-1.7); treated bleed ABRs remained low throughout, and were seen to decrease with successive 24-week treatment intervals (Table 1). During Weeks 121-144 (n=170), 82.4% of participants had zero treated bleeds, and 15.3% of participants had 1-3 treated bleeds. During the same period, 91.8% and 90.0% had zero treated spontaneous/joint bleeds respectively (Figure 1). The proportion of participants with target joints reduced from 60.9% prior to study entry to 4.6% at Weeks 1-24, then ACD of FVIII (Table 2), activated prothrombin complex concentrate (aPCC) and activated recombinant FVII (rFVIIa, Table 3) generally decreased across each 24-week treatment interval. Emicizumab was well tolerated (Table 4), and no participants discontinued due to AEs beyond the five previously described (Oldenburg et al. N Engl J Med 2017; Young et al. Blood 2019; Mahlangu et al. N Engl J Med 2018; Pipe et al. Lancet Haem 2019). At data cut, 1 fatality, 3 thrombotic microangiopathies (TMAs), and 4 thromboembolic events (TEs) have been reported; all but 1 occurred in HAVEN 1. All TMAs and 2 of 4 TEs were associated with concomitant aPCC use. The percentage of participants with ≥1 drug-related AE in Weeks 1-24, 25-48 and 49-72 were 28.8%, 6.8%, and 3.0% respectively; over the same intervals, injection site reactions were observed in 23.3%, 4.8%, and 2.5% of participants. Conclusions: With nearly 3 years of follow-up, emicizumab maintained low bleed rates in PwHA of all ages, with/without FVIII inhibitors. ABRs continued to decrease and the proportion of participants with zero treated bleeds increased with each consecutive 24-week period; the trend was the same for the proportion of participants with zero joint bleeds and almost all target joints resolved. The ACDs of FVIII, aPCC, and rFVIIa decreased with successive treatment intervals. Emicizumab remains well tolerated over long-term follow-up, and no new safety concerns have been identified to date. Disclosures Callaghan: Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biomarin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Speakers Bureau; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Research Funding; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Hema Biologics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alnylum: Current equity holder in publicly-traded company; Spark: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Speakers Bureau; Roche/Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Speakers Bureau; NovoNordisk: Other, Speakers Bureau; Sancillio: Other. Négrier:CSL Behring, Octapharma, Shire/Takeda, Sobi: Research Funding; CSL, F. Hoffmann-La Roche Ltd, Sobi: Other: Travel support; Bayer, Biomarin, CSL Behring, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann-La Roche Ltd, Sanofi, Shire/Takeda, Sobi, Spark: Consultancy. Paz-Priel:Genentech, Inc: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company, Other: All authors received editorial support for this abstract, provided by Scott Battle, PhD, of Health Interactions and funded by F. Hoffmann-La Roche.. Chang:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Chebon:F. Hoffmann-La Roche Ltd: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Lehle:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in private company. Mahlangu:CSL Behring, Catalyst Biosciences, Freeline Therapeutics, Novo Nordisk, F. Hoffmann-La Roche Ltd, Sanofi, Spark and Takeda: Consultancy; South Africa Medical Research Council, Wits Health Consortium, Colleges of Medicine of South Africa: Membership on an entity's Board of Directors or advisory committees; CSL Behring, Catalyst Biosciences, Novo Nordisk, F. Hoffmann-La Roche Ltd, Sanofi, Spark and Takeda: Speakers Bureau; BioMarin, CSL Behring, Freeline Therapeutics, Novo Nordisk, Novartis, Pfizer, Sanofi, F. Hoffmann-La Roche Ltd, uniQure: Research Funding. Young:Bayer, CSL Behring, Freeline, UniQure: Consultancy; Genentech/Roche, Grifols, and Takeda: Research Funding; BioMarin, Freeline, Genentech/Roche, Grifols, Kedrion, Novo Nordisk, Sanofi Genzyme, Spark, Takeda, and UniQure: Honoraria. Kruse-Jarres:Biomarin, Chugai Pharmaceutical Co., CSL Behring, CRISPR Therapeutics, Genentech, Inc.: Consultancy; CSL Behring, Genentech, Inc., Spark: Research Funding; Biomarin, Chugai Pharmaceutical Co., CSL Behring, CRISPR Therapeutics, Genentech, Inc.: Honoraria; F. Hoffmann-La Roche Ltd: Speakers Bureau. Mancuso:Bayer, CSL Behring, Novo Nordisk, Pfizer, F. Hoffmann-La Roche Ltd, Octapharma, Kedrion, Grifols, Sobi, PedNet Foundation: Consultancy; Bayer, CSL Behring, Novo Nordisk, F. Hoffmann-La Roche Ltd, Octapharma, Grifols, Sobi: Speakers Bureau; Bayer, CSL Behring, Novo Nordisk, Pfizer, F. Hoffmann-La Roche Ltd, Octapharma, Kedrion, Grifols, Catalyst, Kedrion, Sobi: Membership on an entity's Board of Directors or advisory committees; Center for Thrombosis and Hemorrhagic Diseases, Humanitas Clinical and Research Center - IRCCS, Rozzano, Milan, Italy: Current Employment. Niggli:F Hoffmann-La Roche Ltd: Current Employment. Kuebler:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Selak Bienz:F. Hoffmann-La Roche Ltd: Current Employment. Shima:Chugai Pharmaceutical Co., F. Hoffmann-La Roche Ltd, BioMarin, Bayer, Sanofi: Membership on an entity's Board of Directors or advisory committees; Chugai Pharmaceutical Co. , Sanofi, Bayer, Sysmex: Speakers Bureau; Patents related to anti-FIXa/FX bispecific antibodies: Patents & Royalties; Chugai Pharmaceutical Co.: Honoraria; Chugai Pharmaceutical Co. , F. Hoffmann-La Roche Ltd, Sanofi, CSL Behring, KM Biologics, Novo Nordisk, Shire/Takeda: Research Funding; Chugai Pharmaceutical Co.: Consultancy. Jimenez-Yuste:F. Hoffman-La Roche Ltd, Novo Nordisk, Takeda, Sobi, Pfizer, Grifols, Octapharma, CSL Behring, Bayer: Honoraria; F. Hoffman-La Roche Ltd, Novo Nordisk, Takeda, Sobi, Pfizer: Consultancy; Grifols, Novo Nordisk, Takeda, Sobi, Pfizer: Research Funding. Schmitt:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Asikanius:Fimea: Current Employment; F Hoffman-La Roche Ltd: Ended employment in the past 24 months; F Hoffmann-La Roche Ltd: Divested equity in a private or publicly-traded company in the past 24 months. Levy:F Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Genentech, Inc.: Ended employment in the past 24 months; Spark Therapeutics: Current Employment; Baxalta US: Patents & Royalties: Royalties from ADAMTS13 patent . Pipe:Medical and Scientific Advisory Council to the National Hemophilia Foundation; Medical Advisory Board to World Federation of Hemophilia: Membership on an entity's Board of Directors or advisory committees; Apcintex, Bayer, BioMarin, Catalyst Biosciences, CSL Behring, HEMA Biologics, Freeline, Novo Nordisk, Pfizer, F. Hoffmann-La Roche Ltd/Genentech, Inc., Sangamo Therapeutics, Sanofi, Takeda, Spark Therapeutics, uniQure: Consultancy; Siemens: Research Funding. Oldenburg:Bayer, BioMarin, Biotest, Chugai Pharmaceuticals Co., CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann-La Roche, Ltd, Spark, Swedish Orphan Biovitrum and Takeda: Speakers Bureau; Bayer, BioMarin, Biotest, Chugai Pharmaceuticals Co., CSL Behring, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann-La Roche. Ltd, Spark, Swedish Orphan Biovitrum and Takeda: Other; Bayer, BioMarin, Biotest, Chugai Pharmaceuticals Co., CSL Behring, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann-La Roche, Ltd, Spark, Swedish Orphan Biovitrum and Takeda: Membership on an entity's Board of Directors or advisory committees; University Clinic Bonn: Current Employment; Bayer, Biotest, CSL Behring, Novo Nordisk, Octapharma, Pfizer and Takeda: Research Funding; Bayer, BioMarin, Biotest, Chugai Pharmaceuticals Co., CSL Behring, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann-La Roche, Ltd, Spark, Swedish Orphan Biovitrum and Takeda: Honoraria.

Objectives: To compare the efficacy of emicizumab prophylaxis with that of factor VIII (FVIII) prophylaxis in patients with hemophilia A without inhibitors using two approaches: network meta-analyses (NMA) and additional sub-group analyses from the HAVEN 3 trial. Methods: The NMA used data from trials identified using a systematic literature review and compared bleed rates in patients receiving emicizumab prophylaxis and patients receiving FVIII prophylaxis using a Bayesian, random effects generalized linear model with log link Poisson likelihood. Additional sub-groups of the HAVEN 3 trial included here were defined as patients whose dose-taking behavior met either European label or World Federation of Hemophilia guidelines. A negative binomial regression model was used to conduct an intra-patient comparison of bleed rates within the sub-groups, during treatment with FVIII prophylaxis before entering HAVEN 3 and treatment with emicizumab prophylaxis during HAVEN 3. Results: Four studies were included in the base-case NMA. Evidence showed that the total treated bleed rate was lower with emicizumab prophylaxis compared with FVIII prophylaxis (rate ratio [RR] = 0.36 [95% credible interval (CrI) = 0.13–0.95]). Similar associations were observed in sensitivity analyses. The additional HAVEN 3 analyses also showed lower rates of treated bleeds with emicizumab prophylaxis than with FVIII prophylaxis (RRs [95% confidence interval (CI)] = 0.380 [0.186–0.790] and 0.472 [0.258–0.866] in two sub-groups). These results confirm the original HAVEN 3 intra-patient comparison findings. Conclusions: Combined findings from NMA and additional sub-group analyses of HAVEN 3 support the superiority of emicizumab prophylaxis over FVIII prophylaxis in patients with hemophilia A without inhibitors.

Introduction Real-world data on health-related outcomes in persons with haemophilia A (PwHA) can provide useful information for improving patient care. The global, non-interventional study (NIS; NCT02476942) prospectively collected high-quality data in PwHA, including those without factor VIII (FVIII) inhibitors treated according to local routine clinical practice. Aim To report health-related quality of life (HRQoL) and health status of adult/adolescent PwHA without FVIII inhibitors. Methods Participants were PwHA without FVIII inhibitors age ≥12 years; they remained on existing episodic treatment or prophylaxis. HRQoL was assessed by Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL) or Haemophilia-Specific Quality of Life Assessment for Children and Adolescents Short Form (Haemo-QoL-SF II). Health status was assessed through EuroQol 5-Dimensions 5-Levels (EQ-5D-5L) index utility score and visual analogue scale (EQ-VAS). Results Ninety-four participants enrolled; median age was 34.0 years (range 12-76). Forty-five received episodic treatment and 49 received prophylaxis for a median time of 27.7 weeks and 30.4 weeks, respectively. Mean (standard deviation) baseline Haem-A-QoL total scores were 40.1 (17.0) for the episodic group and 26.6 (14.6) for the prophylaxis group, indicating impairments in HRQoL, which remained consistent over time. Mean EQ-5D-5L IUS scores were similar between treatment regimens (0.8 episodic; 0.9 prophylaxis) and consistent over time. The mean EQ-VAS scores were similar between treatment regimens, and lower on days when bleeding occurred (79.0 vs 85.0 for episodic treatment; 77.0 vs 82.0 for prophylaxis, respectively). Conclusions Adult and adolescent PwHA without FVIII inhibitors had HRQoL impairments regardless of whether they were treated with episodic or prophylactic standard care with FVIII.

Dear Editor,We thank Jain and Lethagen for the opportunity to clarify some points of interest.As outlined in Mahlangu et al.1, emicizumab prophylaxis has demonstrated a statistically significant an...

Background: Data regarding management of pediatric persons with hemophilia A (PwHA) with factor VIII (FVIII) inhibitors are limited. This prospective noninterventional study (NCT02476942) evaluated annualized bleeding rates (ABRs), safety, and health-related quality of life (HRQoL) in pediatric PwHA with FVIII inhibitors. Procedure: PwHA aged, Was funded by F. Hoffmann-La Roche Ltd.

Analysis of clustered data is often performed using random effects regression models. In such conditional models, a cluster-specific random effect is often introduced into the linear predictor function. Parameter interpretation of the covariate effects is then conditioned on the random effects, leading to a subject-specific interpretation of the regression parameters. Recently, Marginalized Multilevel Models (MMM) and the Bridge distribution models have been proposed as a unified approach, which allows one to capture the within-cluster correlations by specifying random effects while still allowing for marginal parameter interpretation. In this paper, we investigate these two approaches, and the conditional Generalized Linear Mixed Model (GLMM), in the context of right-truncated, interval-censored time-to-event data, further characterized by clustering and additional overdispersion. While these models have been applied in literature to model the mean, here we extend their application to modeling the hazard function for the survival endpoints. The models are applied to analyze data from the HET-CAM

Emicizumab, a subcutaneously administered, humanised, bispecific, monoclonal antibody, is approved to treat people with haemophilia A of all ages with and without coagulation factor VIII (FVIII) inhibitors. HAVEN 4 assessed emicizumab prophylaxis administered as one dose every 4 weeks in adults and adolescents with haemophilia A, regardless of FVIII inhibitor status.In this phase 3, multicentre, open-label, two-stage study, patients aged 12 years and older with severe congenital haemophilia A (1% of normal FVIII activity in blood) or haemophilia A with FVIII inhibitors, undergoing treatment with either FVIII concentrates or bypassing agents were recruited from three sites in Japan and Spain for a run-in cohort, and from 17 sites in Australia, Belgium, Japan, Poland, Spain, and the USA for a subsequent expansion cohort. Participants in the run-in and expansion cohorts were given emicizumab subcutaneously 6 mg/kg every 4 weeks for 24 weeks or more; for patients in the expansion cohort this regimen was preceded by four loading doses of 3 mg/kg once weekly. In the run-in cohort, we assessed pharmacokinetics after single and multiple (every 4 weeks) subcutaneous administration of 6 mg/kg emicizumab and safety. In the expansion cohort, the efficacy endpoint was efficacy of prophylactic emicizumab in maintaining adequate bleed prevention, assessed in all patients who received at least one dose of emicizumab and reported as annualised bleed rates for treated bleeds, all bleeds (treated and untreated), treated spontaneous bleeds, treated joint bleeds, and treated target joint bleeds. Safety was assessed in all participants given emicizumab. This study is registered with ClinicalTrials.gov, number NCT03020160, and is ongoing.Between Jan 30, 2017, and Feb 27, 2017, seven patients were enrolled into the initial run-in cohort, which confirmed the expected pharmacokinetic profile and safety of the regimen based on model-based simulations, providing sufficient evidence for opening of the expansion cohort (n=41), which was recruited and enrolled between May 24, 2017, and June 30, 2017. The annualised rate of treated bleeds was 2·4 (95% CI 1·4-4·3). 23 (56·1%; 95% CI 39·7-71·5) of 41 reported no treated bleeds and 37 (90%; 76·9-97·3) reported zero to three treated bleeds. The annualised bleed rate was 4·5 (95% CI 3·1-6·6) for all bleeds, 0·6 (0·3-1·5), for treated spontaneous bleeds, 1·7 (0·8-3·7) for treated joint bleeds, and 1·0 (0·3-3·3) for treated target joint bleeds. The most frequent treatment-related adverse event was injection-site reaction (nine [22%] of 41 patients). We observed no thrombotic events or development of de-novo antidrug antibodies with neutralising potential or FVIII inhibitors.Emicizumab given once every 4 weeks showed clinically meaningful bleed control while being well tolerated. This regimen could improve patient care by decreasing treatment burden and increasing adherence to effective prophylaxis, potentially decreasing the development of secondary complications for people with haemophilia A.F Hoffmann-La Roche and Chugai Pharmaceutical.

Statistical analysis of count data typically starts with a Poisson regression. However, in many real-life applications, it is observed that the variation in the counts is larger than the mean, and one needs to deal with the problem of overdispersion in the counts. Several factors may contribute to overdispersion: (1) unobserved heterogeneity due to missing covariates, (2) correlation between observations (such as in longitudinal studies), and (3) the occurrence of many zeros (more than expected from the Poisson distribution). In this paper, we discuss a model that allows one to explicitly take each of these factors into consideration. The aim of this paper is twofold: (1) investigate whether we can identify the cause of overdispersion via model selection, and (2) investigate the impact of a misspecification of the model on the power of a covariate. The paper is motivated by a study of the occurrence of drug-induced arrhythmia in beagle dogs based on electrocardiogram recordings, with the objective to evaluate the effect of potential drugs on the heartbeat irregularities. Copyright © 2016 John Wiley & Sons, Ltd.

Introduction Prospectively collected real-world data on bleeds, haemophilia treatment and safety in persons with haemophilia A (PwHA) without factor VIII (FVIII) inhibitors are limited. A global, non-interventional study (NIS; NCT02476942) prospectively collected real-world data in PwHA who were treated per local routine clinical practice. Aim Assess annualized bleeding rate (ABR), haemophilia treatment practices and adverse events (AEs) in adult/adolescent PwHA without inhibitors. Methods Eligible participants aged ≥12 years with severe HA without history of inhibitors prospectively collected bleeding and treatment information. Results Ninety-four participants were enrolled (median [range] age, 34 [12-76] years) and monitored for a median (range) of 29.8 (12.4-47.7) weeks. In the episodic (n = 45) and prophylactic (n = 49) treatment groups, respectively, 872/1066 (81.8%) and 151/189 (79.9%), bleeds were treated; ABRs (95% confidence interval) were 36.1 (30.8-42.3) and 5.0 (3.3-7.5), respectively, for treated bleeds and 43.1 (36.5-50.9) and 6.2 (4.2-9.2), respectively, for all bleeds, and median (interquartile range) ABRs were 31.1 (19.8-51.6) and 1.9 (0.0-8.2), respectively, for treated bleeds and 35.3 (21.7-62.9) and 2.7 (0.0-9.4), respectively, for all bleeds. Half of the participants on FVIII prophylaxis had relatively high adherence to treatment, using 2.9 and 2.1 median doses/wk of standard and extended half-life FVIII, respectively. Serious AEs included gastrointestinal polyp haemorrhage and haemarthrosis; the most common AE was viral upper respiratory tract infection. Conclusion PwHA without inhibitors continue to bleed on prophylaxis, consistent with the literature, and require treatment for breakthrough bleeds. This prospective NIS demonstrates the need for more efficacious haemostatic approaches.

This paper deals with the analysis of data from a HET-CAMVT experiment. From a statistical perspective, such data yield many challenges. First of all, the data are typically time-to-event like data, which are at the same time interval censored and right truncated. In addition, one has to cope with overdispersion as well as clustering. Traditional analysis approaches ignore overdispersion and clustering and summarize the data into a continuous score that can be analysed using simple linear models. In this paper, a novel combined frailty model is developed that simultaneously captures all of the aforementioned statistical challenges posed by the data. Copyright © 2015 John Wiley & Sons, Ltd.

Background Hemophilia A with or without inhibitors to factor VIII (FVIII) has a major impact on the quality of life of people with this condition. This may be exacerbated by the treatment burden associated with current factor treatments that require frequent IV administration to reduce the risk of bleeding. Previous studies have noted that patients favor treatments that have a goal of achieving a "normal life" and avoid negative effects (e.g. infusion-related pain, time-consuming, or high treatment burden) (Cimino et al. Patient Prefer Adherence 2014). Two Phase III studies recently demonstrated the efficacy and safety of subcutaneous emicizumab administered weekly (QW) or every 2 weeks (Q2W) in persons with hemophilia A (PwHA) without inhibitors (HAVEN 3; NCT02847637; Mahlangu et al. N Engl J Med 2018, in press), and every 4 weeks (Q4W) in PwHA with or without inhibitors (HAVEN 4; NCT03020160; Pipe et al. WFH 2018). The studies included questionnaires developed and validated to investigate patients' preference and satisfaction with emicizumab compared with prior treatment. Methods In HAVEN 3, PwHA without inhibitors aged ≥12 years on prior episodic FVIII were randomized 2:2:1 to receive emicizumab QW (Arm A), Q2W (Arm B), or to no prophylaxis control (Arm C). Patients on prior prophylactic FVIII received emicizumab QW (Arm D). In HAVEN 4, PwHA with or without inhibitors aged ≥12 years with prior episodic bypassing agents (BPAs) or prophylactic FVIII received emicizumab Q4W. Patient preference was assessed through the Emicizumab Preference Survey (EmiPref) at Week 17 in both studies when patients had gained sufficient experience with emicizumab, potential bias due to anticipation associated with being in a study subsided, and they could still reliably recall their experience with prior therapy. The survey included three questions: patients were initially asked which they preferred - previous hemophilia treatment, new study treatment, or no preference. Those expressing a preference were then asked to rank the top three reasons for their choice. Finally, patients could provide additional free text related to their experience with emicizumab. Treatment satisfaction was assessed in Arm D of HAVEN 3 using the Satisfaction Questionnaire - Intravenous Subcutaneous Hemophilia Injection (SQ-ISHI). This 16-item questionnaire was to be completed at baseline and then either Week 21 or 25 after initiation of emicizumab. Results EmiPref was completed by 95/134 patients (71%) from Arms A, B, or D in HAVEN 3. Eighty-nine patients (94%) preferred emicizumab to their previous treatment and only 2 (2%) favored their previous treatment. The most frequent reasons selected for preference included a more convenient mode of administration ("frequency of treatments was lower" and "route of administration was easier") and reduced concern of bleeds ("worries about having bleeds were less"), reflecting the superior efficacy demonstrated in this study. In HAVEN 4, all 41 (100%) participants completed the EmiPref survey and all (100%) reported preferring emicizumab to their prior treatment. The most frequent reasons selected for preference were "the frequency of treatments was lower", followed by "the route of administration was easier", and "quality of life, in general, was better". When patients in HAVEN 3 and 4 were examined together, 99% (75/76) of patients who received prior FVIII or BPA prophylaxis favored emicizumab. Of the patients receiving prior episodic treatment, 92% (55/60) preferred emicizumab. Notably, all participants in HAVEN 3 and 4 continue to receive emicizumab beyond the primary analysis, including those who did not report favoring emicizumab, confirming the preference for emicizumab. The results of the SQ-ISHI completed by 50 patients in Arm D of HAVEN 3 at Week 21 indicated that 90% of patients were "much more" or "a lot more satisfied" with their current emicizumab prophylaxis compared with their pre-study treatment. Conclusions Almost all patients in HAVEN 3 and all patients in HAVEN 4 preferred emicizumab to their prior treatment. These results likely reflect the high efficacy and lower treatment burden previously reported. Such strong preference will be important for individuals currently receiving either episodic or prophylactic treatment when considering emicizumab prophylaxis in the future and may be associated with improved adherence, a substantial clinical obstacle with FVIII or BPAs. Disclosures Jimenez-Yuste: Roche: Consultancy, Research Funding; Shire: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Sobi: Consultancy, Research Funding; Octapharma: Consultancy, Research Funding; CSL Behring: Consultancy; Grifols: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; NovoNordisk: Consultancy, Research Funding. Shima:F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees; 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. Paz-Priel:Genentech Inc: Employment. Parnes:Genentech Inc: Research Funding; Biogen Idec: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Shire: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees. Lehle:F. Hoffmann-La Roche: Employment. Giermasz:Bioverative, Biomarin, Genentech, Spark, Opko: Research Funding; Bioverativ, Biomarin, Genentech, Alexion, Bayer: Membership on an entity's Board of Directors or advisory committees. Campinha-Bacote:Genentech Inc: Employment. Niggli:F. Hoffmann-La Roche: Employment. Windyga:Alexion, Baxalta, Bayer, CSL Behring, Ferring Pharmaceuticals, Novo Nordisk, Octapharma, Rigel Pharmaceuticals, Roche, Sanofi, Shire, Siemens, SOBI, Werfen: Membership on an entity's Board of Directors or advisory committees; Alnylam, Baxalta, Bayer, Novo Nordisk, Octapharma, Rigel Pharmaceuticals, Roche, Sanofi, Shire, SOBI: Research Funding. Chebon:F. Hoffmann-La Roche: Employment. Trask:F. Hoffmann-La Roche: Employment; Genentech Inc: Employment. Mahlangu:Alnylam: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy; Bayer: Research Funding; Biogen: Research Funding, Speakers Bureau; Biomarin: Research Funding, Speakers Bureau; Catalyst Biosciences: Consultancy, Research Funding; Chugai: Consultancy; CSL Behring: Consultancy, Research Funding, Speakers Bureau; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; LFB: Consultancy; Roche: Consultancy, Research Funding, Speakers Bureau; Sanofi: Research Funding, Speakers Bureau; Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau; Spark: Consultancy, Research Funding. Pipe:Apcintex: Consultancy; Catalyst Biosciences: Consultancy; Genentech: Consultancy; Spark Therapeutics: Consultancy; Pfizer: Consultancy; CSL Behring: Consultancy; Bioverativ: Consultancy; R2 Diagnostics: Research Funding; HEMA Biologics: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy; Ainylam: Consultancy; Freeline: Consultancy; Bayer: Consultancy; uniQure: Consultancy; Biomarin: Consultancy; Nove Nordisk: Consultancy; Shire: Consultancy, Research Funding; Siemens: Research Funding. Oldenburg:Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Swedish Orphan Biovitrum: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Introduction Emicizumab is a bispecific humanized monoclonal antibody given subcutaneously, which bridges FIXa and FX to restore the function of missing FVIIIa in PwHA. It is approved for routine prophylaxis in PwHA with inhibitors of all ages, and its efficacy and safety in PwHA without inhibitors was recently described (Mahlangu et al. N Engl J Med 2018, in press; Pipe et al. WFH 2018). Anti-drug antibody (ADA) formation is commonly observed with biologics (e.g. monoclonal antibodies). Presence of ADAs may alter the pharmacokinetics (PK) and pharmacodynamics (PD), and can affect efficacy and safety. Therefore, characterization of the rate and clinical significance of anti-emicizumab antibodies is of importance. Four patients (4/18) tested positive for ADAs in the phase I/II study of emicizumab (Shima et al. Blood Adv 2017). We optimized the immunoassay sensitivity and report here the updated analysis of the immunogenicity of emicizumab in four phase III studies: HAVEN 1, 2, 3 and 4. Methods All PwHA enrolled in HAVEN 1 (NCT02622321), HAVEN 2 (NCT02795767), HAVEN 3 (NCT02847637) or HAVEN 4 (NCT03020160) who had at least one ADA measurement after exposure to emicizumab were included in the analysis. Blood samples for detection of anti-emicizumab antibodies were collected at baseline and at regular intervals (initially monthly and later every 12 weeks) during emicizumab treatment or 24 weeks after the last dose for discontinuations. Samples were screened for the presence of ADAs with a sandwich enzyme-linked immunosorbent assay (ELISA) method. Positive samples underwent confirmatory analysis in the presence of unlabeled emicizumab to ensure binding specificity. The assay cut-point for ADA positivity was generated from all study patients' samples before emicizumab exposure (n=398). The confirmatory cut-point was generated from randomly selected baseline samples from these patients (n=100). ADA positivity was assessed according to the recommendations of the American Association of Pharmaceutical Scientists Therapeutic Protein Immunogenicity Focus Group (Shankar at al. AAPS J 2014). In absence of a sensitive neutralizing antibody assay, ADAs associated with consistent decline of emicizumab exposure were considered as having a neutralizing potential; associated loss of PD effect (e.g. decreased FVIII activity, decreased generation of thrombin and prolonged activated partial thromboplastin time) was reviewed as supportive information. The association between ADAs and clinical response or adverse events was also examined. Results Of 398 HAVEN patients included in this analysis, 14 (3.5%) tested positive for ADA (2/111, 4/88, 6/151 and 2/48 in HAVEN 1, 2, 3 and 4, respectively). For 7 patients, ADAs were transient, i.e. detected on a single occasion. Three patients (n=1 HAVEN 1; n=2 HAVEN 2), who tested positive for ADA and displayed decline of PK and reduced PD effect, were classified as having ADAs with neutralizing potential, i.e. 0.75% of the overall population. Of those, 1 patient discontinued emicizumab due to a loss of efficacy and resumed pre-study treatment without complication. The presence of ADAs without neutralizing potential was not associated with decreased efficacy. No cases of anaphylaxis or hypersensitivity were reported in ADA-positive patients. Patients who tested positive for ADA did not have a safety profile that differed from that of the overall population. Specifically, there was no trend towards increased frequency or severity of injection site reactions after patients tested positive for ADAs. Conclusions Emicizumab treatment is associated with a low rate of patients who tested positive for ADA (3.5%), similar to other humanized monoclonal antibodies. ADAs with a neutralizing potential were observed in Disclosures Paz-Priel: Genentech Inc: Employment. Chang:Genentech: Employment, Equity Ownership. Asikanius:Roche: Employment, Equity Ownership. Chebon:F. Hoffmann-La Roche: Employment. Emrich:Roche: Employment, Patents & Royalties. Fernandez:Roche: Employment. Kuebler:Genentech: Employment; Roche: Equity Ownership. Schmitt:F. Hoffmann-La Roche: Employment, Equity Ownership.

Introduction Despite recent efforts to standardize the definition of 'new bleeds' in hemophilia A clinical trials, most notably by Blanchette et al. (J Thromb Haemost 2014), cross-study comparisons of these endpoints are still compromised by different bleed definitions, analysis methodologies and data collection approaches. The emicizumab clinical development program included an observational, non-interventional study (NIS; NCT02476942), in which a bleed and medication questionnaire (BMQ) was used to prospectively collect data on treatment with standard-of-care with factor VIII (FVIII) or bypassing agents (BPA) in adult and adolescent people with hemophilia A (PwHA) with and without inhibitors to FVIII. The study design allowed for an examination of the differences between treated and untreated bleeds, as well as any differences in their incidence between the inhibitor and non-inhibitor populations. Participation in the study was not expected to affect the number of treated and untreated bleeds. Methods The NIS was a global prospective study designed to collect real-world data on PwHA with or without inhibitors treated with current standard-of-care therapy according to routine clinical practice. Eligible participants from the NIS subsequently could enroll in a Phase III trial of emicizumab. Adult and adolescent participants (aged ≥12 years) were prompted to complete the BMQ daily. The BMQ was developed by the sponsor to enable data collection directly by patients. In addition to treatments administered, the BMQ allowed the patient to enter all the bleeds the patient experienced, irrespective of whether they were treated or not. For the purpose of the analysis of primary and secondary endpoints, a bleed was derived from the data using the definitions outlined by Blanchette et al. (J Thromb Haemost 2014) and Oldenburg et al. (N Engl J Med 2017). The efficacy endpoints included treated bleeds, all bleeds, spontaneous bleeds, joint bleeds and target joint bleeds. Results In the inhibitor and non-inhibitor cohorts, 103 and 94 patients were enrolled, with a median efficacy period of 25.4 and 27.7 weeks, respectively. NIS data for treated and untreated bleeds, including bleed types and bleed causes, are displayed in Table 1. Of all bleeds reported in the study, 625 (40.0%) were untreated in patients with inhibitors, and 160 (13.5%) were untreated in patients without inhibitors. Conclusions The NIS was the first study to report large numbers of untreated bleeds in PwHA, particularly in those with inhibitors, where approximately 40% of all bleeds were untreated (Mahlangu et al. ASH 2016; Kruse-Jarres et al. EAHAD 2018). The design of the BMQ allowed participants to capture bleeds and bleed treatment independently and enabled granular information on untreated and treated bleeds to be derived, as opposed to only bleeds where a treatment was administered, as had previously been captured in the majority of clinical studies (Keipert et al. ISTH 2018; Clausen et al. Haemophilia 2014). The reason for the large difference in the proportion of untreated bleeds in the inhibitor population versus the non-inhibitor population is unknown and warrants further investigation, but may be at least partially due to higher confidence in the efficacy of FVIII, less treatment burden, and better drug availability compared with BPAs; this may therefore influence the patient's decision on whether or not to treat. The NIS showed that further efforts to harmonize bleed definitions, analyses methodology and data collection in hemophilia A clinical trials are warranted in order to provide transparency on treated and untreated bleeds, as the latter might have been under-reported in clinical studies to date. Capturing untreated bleeds in future trials could provide useful insights to physicians as, while the long-term sequelae of untreated bleeds are as yet unknown, they are expected to be, at the very least, distressing for patients. Acknowledgments: Editorial assistance under the direction of the authors was provided by Maria Alfaradhi, PhD, of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd. Disclosures Callaghan: Sancilio Pharmaceuticals Company: Employment; Hema Pharmaceuticals: Honoraria; Alnylam Pharmaceuticals: Equity Ownership; Amgen: Employment; Roche/Genentech: Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therepeutics: Employment; Novo Nordisk: Employment, Membership on an entity's Board of Directors or advisory committees; Pfizer: Employment, Honoraria, Research Funding; Bioverativ: Honoraria; Octapharma: Honoraria; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Honoraria; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Asikanius:Roche: Employment, Equity Ownership. Lehle:F. Hoffmann-La Roche: Employment. Oldenburg:Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Swedish Orphan Biovitrum: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mahlangu:Novo Nordisk: Honoraria, Research Funding; Pfizer: Research Funding; Spark: Honoraria; Bayer: Research Funding; Roche: Honoraria, Research Funding; Chugai: Honoraria; CSL Berhing: Honoraria; Alnylam: Research Funding; Shire: Honoraria; CLS: Research Funding. Uguen:F.Hoffmann-LaRoche: Employment. Chebon:F. Hoffmann-La Roche: Employment. Kruse-Jarres:Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jimenez-Yuste:Grifols: Consultancy, Research Funding; Octapharma: Consultancy, Research Funding; NovoNordisk: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sobi: Consultancy, Research Funding; Shire: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; CSL Behring: Consultancy. Shima:F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees; 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. Trask:Roche: Employment, Equity Ownership. Kessler:Genentech: Research Funding; Sangamo: Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biomarin: Research Funding; Dimension Advisory boards: Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Research Funding; DSMB: Membership on an entity's Board of Directors or advisory committees. Levy:Roche: Employment, Equity Ownership. Santagostino:Shire: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Grifols: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

Introduction Emicizumab is a novel, subcutaneously (SC) administered, recombinant, humanized, bispecific monoclonal antibody that is under investigation for the prevention of bleeds in persons with hemophilia A (PwHA). Emicizumab restores the function of activated coagulation FVIII, which is deficient in PwHA, by bridging activated FIX and FX to enable effective hemostasis. Due to its mechanism of action, emicizumab is not expected to induce or be affected by anti-FVIII antibodies (inhibitors) and is thus being assessed in PwHA both with and without inhibitors. Once-weekly emicizumab prophylaxis was shown to substantially reduce bleed rates by 87% in PwHA with inhibitors compared with no prophylaxis in the Phase 3 HAVEN 1 study (Oldenburg et al. NEJM 2017; July 10: epub). An interim analysis of the HAVEN 2 study showed that once-weekly emicizumab also prevented or reduced bleeds in pediatric PwHA with inhibitors ( Methods Eligible patients in the HAVEN 4 study were aged ≥12 years with congenital hemophilia A with or without inhibitors. In the PK run-in phase, patients must have been receiving episodic (on-demand) treatment with FVIII replacement therapy or bypassing agents with documentation of treatment for ≥24 weeks prior to study entry; the on-study regimen is 6 mg/kg Q4W. The regimen being investigated in the subsequent expansion cohort includes a loading dose of 3 mg/kg SC QW for 4 weeks followed by emicizumab 6 mg/kg Q4W for ≥24 weeks. Results At the data cutoff of April 10, 2017, 7 patients with severe hemophilia A had enrolled into the PK run-in cohort - 4 patients without inhibitors and 3 patients with inhibitors, of which 6 patients were aged ≥18 years of age and followed for a minimum of 6 weeks. Individual observed PK profiles were within the 95% prediction interval computed from a population PK model based on clinical data from a 1.5 mg/kg QW regimen (Figure). Emicizumab PK parameters derived after single SC administration of 6 mg/kg emicizumab (Table) were consistent with values observed in previous studies with emicizumab (Uchida et al. Blood 2016; 127 (13):1633-1641). During the observation period (median, 8 weeks), 14 adverse events (AEs) were reported in 5 patients at the time of data cut-off, including 1 Grade 3 serious AE (worsening of hypertension); no AEs were considered related to study drug. No anti-drug antibodies were detected. Also, 6 of 7 patients had no bleeds while receiving Q4W emicizumab; 1 patient experienced 3 spontaneous nose bleeds on Study Days 12, 14 and 21, which did not require treatment. Conclusions Preliminary data from the HAVEN 4 study showed that Q4W dosing of emicizumab at 6 mg/kg exhibited a PK behavior that was consistent with prior predictions, leading to an expected steady-state concentration average similar to the clinically confirmed dosing regimen (i.e., 1.5 mg/kg/QW). The safety and efficacy results from this PK run-in cohort enabled the opening of the HAVEN 4 expansion cohort, and provided promising support for a Q4W emicizumab prophylaxis regimen for the management of hemophilia A. The HAVEN 4 study is fully enrolled (N=48, including the PK run-in cohort patients). Disclosures Jimenez-Yuste: Roche: Consultancy; Novo Nordisk: Consultancy, Honoraria, Research Funding. Shima: Pfizer: Honoraria, Research Funding; Baxalta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Honoraria, Research Funding; Biogen: Consultancy, Honoraria; Kaketsuken: Honoraria; Novo: Honoraria, Research Funding; Bayer: Honoraria, Research Funding. Fukutake: EPS: Research Funding; Cimic: Research Funding; Sekisui Medical: Consultancy, Honoraria, Speakers Bureau; Roche Diagnostics: Honoraria, Speakers Bureau; Bioverative: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbott: Honoraria, Speakers Bureau; Kaketsuken: Honoraria; Japan Blood Products Organization: Honoraria, Research Funding; Pharmaceutical Co., Ltd: Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; LSI Medience: Consultancy; SRL Inc: Consultancy; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxalta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Siemens: Speakers Bureau; CSL Behring: Consultancy, Honoraria, Research Funding; Chuugai: Consultancy, Honoraria, Speakers Bureau; Octapharma AG: Honoraria; Torii Pharmaceutical Co., Ltd: Speakers Bureau. Lehle: F. Hoffmann La Roche: Employment. Chebon: F. Hoffmann-La Roche Ltd: Employment. Retout: F. Hoffmann La Roche: Employment. Portron: F. Hoffmann La Roche: Employment. Levy: Genentech, Inc.: Employment.

Statistical analysis of count data typically starts with a Poisson regression. However, in many real-life applications, it is observed that the variation in the counts is larger than the mean, and one needs to deal with the problem of overdispersion in the counts. Several factors may contribute to overdispersion: (1) unobserved heterogeneity due to missing covariates, (2) correlation between observations (such as in longitudinal studies), and (3) the occurrence of many zeros (more than expected from the Poisson distribution). In this paper, we discuss a model that allows one to explicitly take each of these factors into consideration. The aim of this paper is twofold: (1) investigate whether we can identify the cause of overdispersion via model selection, and (2) investigate the impact of a misspecification of the model on the power of a covariate. The paper is motivated by a study of the occurrence of drug-induced arrhythmia in beagle dogs based on electrocardiogram recordings, with the objective to evaluate the effect of potential drugs on the heartbeat irregularities. Copyright © 2016 John WileySons, Ltd.

This paper deals with the analysis of data from a HET-CAM(VT) experiment. From a statistical perspective, such data yield many challenges. First of all, the data are typically time-to-event like data, which are at the same time interval censored and right truncated. In addition, one has to cope with overdispersion as well as clustering. Traditional analysis approaches ignore overdispersion and clustering and summarize the data into a continuous score that can be analysed using simple linear models. In this paper, a novel combined frailty model is developed that simultaneously captures all of the aforementioned statistical challenges posed by the data.