Outcomes in children with hemophilia A with inhibitors: Results from a noninterventional study.

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 <12 years with current FVIII inhibitors and high-titer inhibitor history were enrolled. Participants remained on usual treatment; no interventions were applied. Outcomes included ABR, safety, and HRQoL. RESULTS: Twenty-four PwHA aged 2-11 years (median 7.5) were enrolled and monitored for 8.7-44.1 weeks (median 23.4). In the episodic (n = 10) and prophylactic (n = 14) groups, respectively, 121 of 185 (65.4%) and 101 of 186 (54.3%) bleeds were treated using activated prothrombin complex concentrate (aPCC) and/or recombinant activated FVII (rFVIIa). ABRs (95% confidence interval) were 19.4 (13.2-28.4) and 18.5 (14.2-24.0) for treated bleeds, and 32.7 (20.5-52.2) and 33.1 (22.4-48.9) for all bleeds, respectively. Most prophylactic group participants (92.9%) were prescribed aPCC; 50% adhered to their prescribed treatment regimen. Adherence to prophylactic rFVIIa was not assessed. Serious adverse events included hemarthrosis (12.5%) and mouth hemorrhage (12.5%); the most common nonserious adverse event was viral upper respiratory tract infection (12.5%). HRQoL showed functional impairment at baseline; scores remained stable throughout, with little intergroup variation. CONCLUSIONS: ABRs remained high in pediatric PwHA with inhibitors receiving standard treatment. This study demonstrates the need for more effective treatments, with reduced treatment burden, to prevent bleeds, increase prophylaxis adherence, and improve patient outcomes.

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.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: F Hoffmann-La Roche and Chugai Pharmaceutical.

Bleeding and safety outcomes in persons with haemophilia A without inhibitors: Results from a prospective non-interventional study in a real-world setting.

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.