Inhibitor development in haemophilia according to concentrate Four-year results from the European HAemophilia Safety Surveillance (EUHASS) project

Inhibitor development represents the most serious side effect of haemophilia treatment. Any difference in risk of inhibitor formation depending on the product used might be of clinical relevance. It was this study's objective to assess inhibitor development according to clotting factor concentrate in severe haemophilia A and B. The European Haemophilia Safety Surveillance (EUHASS) was set up as a study monitoring adverse events overall and according to concentrate. Since October 2008, inhibitors were reported at least quarterly. Number of treated patients was reported annually, specifying the number of patients completing 50 exposure days (Previously Untreated Patients, PUPs) without inhibitor development. Cumulative incidence, incidence rates and 95 % confidence intervals (CI) were calculated. Data from October 1, 2008 to December 31, 2012 were analysed for 68 centres that validated their data. Inhibitors developed in 108/417 (26 %; CI 22-30 %) PUPs with severe haemophilia A and 5/72 (7 %; CI 2-16%) PUPs with severe haemophilia B. For Previously Treated Patients (PTPs), 26 inhibitors developed in 17,667 treatment years [0.15/100 treatment years; CI 0.10-0.22) for severe haemophilia A and 1/2836 (0.04/100; (CI 0.00-0.20) for severe haemophilia B. Differences between plasma-derived and recombinant concentrates, or among the different recombinant FVIII concentrates were investigated. In conclusion, while confirming the expected rates of inhibitors in PUPs and PTPs, no class or brand related differences were observed

EFFICACY AND SAFETY OF EPTACOG BETA (RECOMBINANT HUMAN FVIIA) ACCORDING TO AGE IN PERSONS WITH HAEMOPHILIA A/B WITH INHIBITORS UNDERGOING SURGICAL PROCEDURES

Introduction: Eptacog beta (CEVENFACTA®) is a new rFVIIa approved by the EMA for the treatment of bleeding events and prevention of bleeding during surgery in persons with haemophilia A/B with inhibitors (PwHABI) aged ≥12 years (y). Methods: PERSEPT 3 was a Phase 3 (NCT02020369) trial of eptacog beta in PwHABI who required surgical procedures. Eptacog beta was administered at an initial dose of 200μg/kg or 75μg/kg for major or minor procedures respectively. This was followed by 75μg/kg for ≥5 (major procedures) or ≥2 (minor procedures) days. Haemostatic efficacy was assessed using a 4-point scale during the intra and postoperative care period (primary efficacy endpoint was determined by the investigator at the study centre 48±4h after the last dose of eptacog beta, based on the totality of the assessments performed on the patient (pt) at each timepoint). This post-hoc analysis compared the efficacy and safety of eptacog beta by age (pts aged \u3c12 vs ≥12y). Results: Twelve pts were included (\u3c12y: n=5, 1 major and 4 minor procedures; ≥12y: n=7, 5 major and 2 minor procedures). The primary endpoint success proportion was 100% (95% CI: 39.8-100) in pts aged \u3c12y (4 successes, 1 missing) and 71.4% (95% CI: 29.0-96.3) in pts aged ≥12y (5 successes; 2 failures). The intraoperative success proportion was 100% (95% CI: 47.8-100) for pts aged \u3c12y (5 successes) and 100% (95% CI: 59.0-100) for pts aged ≥12y (7 successes). The success proportion 24h post-procedure was 100% (95% CI: 47.8-100) for pts aged \u3c12y (5 successes) and 100% (95% CI: 47.8-100) for pts aged ≥12y (5 successes; 2 missing). Two pts discontinued treatment (1 aged \u3c12y withdrew consent; 1 aged ≥12y due to an adverse event (AE): postprocedural hematoma). One pt experienced 2 serious AEs leading to death, both were considered unrelated to the treatment. No allergic or thrombotic events occurred; no neutralising antibodies were detected. Antifibrinolytics were used concomitantly with eptacog beta in 4 patients without any safety concerns. Discussion/Conclusion: This post-hoc subgroup analysis shows that eptacog beta is effective and well-tolerated in perioperative care irrespective of patient age (\u3c12 vs ≥12y), supporting the use of eptacog beta for bleed management (prevention and treatment) in major and minor surgical procedures in all PwHABI

Antithrombotic Treatment in Patients With Hemophilia: an EHA-ISTH-EAHAD-ESO Clinical Practice Guidance

Cardiovascular disease is an emerging medical issue in patients with hemophilia (PWH) and its prevalence is increasing up to 15% in PWH in the United States. Atrial fibrillation, acute and chronic coronary syndromes, venous thromboembolism, and cerebral thrombosis are frequent thrombotic or prothrombotic situations, which require a careful approach to fine-tune the delicate balance between thrombosis and hemostasis in PWH when using both procoagulant and anticoagulant treatments. Generally, PWH could be considered as being naturally anticoagulated when clotting factors are 20 IU/dL in need for any form of antithrombotic therapy, usually treatment without additional clotting factor prophylaxis could be used, but careful monitoring for bleeding is recommended. For antiplatelet treatment, this threshold could be lower with single-antiplatelet agent, but again factor level should be at least 20 IU/dL for dual antiplatelet treatment. In this complex growing scenario, the European Hematology Association in collaboration with the International Society on Thrombosis and Haemostasis, the European Association for Hemophilia and Allied Disorders, the European Stroke Organization, and a representative of the European Society of Cardiology Working Group on Thrombosis has produced this current guidance document to provide clinical practice recommendations for health care providers who care for PWH

The effect of emicizumab prophylaxis on health-related outcomes in persons with haemophilia A with inhibitors: HAVEN 1 Study

Introduction: Persons with haemophilia A (PwHA) with inhibitors to factor VIII often experience decreased health-related outcomes. In HAVEN 1 (NCT02622321), there was a statistically significant reduction in bleeding with emicizumab prophylaxis versus no prophylaxis. Aim: Describe health-related outcomes in PwHA with inhibitors in HAVEN 1. Methods: PwHA with inhibitors aged 6512\ua0years previously on episodic bypassing agents (BPAs) were randomized to emicizumab prophylaxis (Arm A; n\ua0=\ua035) or no prophylaxis (Arm B; n\ua0=\ua018); participants previously on BPA prophylaxis received emicizumab prophylaxis (Arm C; n\ua0=\ua049). Health-related outcomes assessed at baseline and monthly thereafter: Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL), Haemophilia-specific Quality of Life Questionnaire for Children Short Form (Haemo-QoL SF), EuroQol 5-Dimensions 5-Levels (EQ-5D-5L) index utility score (IUS) and visual analogue scale (EQ-VAS) and work/school days. Days hospitalized also recorded. Results: At week 25, differences (ANCOVA) in adjusted mean scores (95% confidence interval) favoured Arm A versus B for Haem-A-QoL \u201cTotal\u201d score (14.0 [5.6, 22.5]; P\ua0=\ua00.002) and \u201cPhysical Health\u201d (21.6 [7.9, 35.2]; P\ua0=\ua00.003); EQ-VAS ( 129.7 [ 1217.6, 121.82]; P\ua0=\ua00.017); and IUS ( 120.16 [ 120.25, 120.07]; P\ua0=\ua00.001); mean scores are comparable in Arms A and C. Throughout the study, a greater proportion of participants on emicizumab prophylaxis than no prophylaxis exceeded questionnaire-specific responder thresholds. Mean proportion of missed work days and number of days hospitalized were lower with emicizumab prophylaxis than no prophylaxis. Conclusions: In PwHA with inhibitors, emicizumab prophylaxis was associated with substantial and meaningful improvements in health-related outcomes

EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks

BACKGROUND AND AIMS: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. APPROACH AND RESULTS: EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization. CONCLUSIONS: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies. (Hepatology 2020;71:1546-1558)

EXPLORE: A prospective, multinational natural history study of patients with acute hepatic porphyria with recurrent attacks

BACKGROUND AND AIMS: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. APPROACH AND RESULTS: EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization. CONCLUSIONS: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies. (Hepatology 2020;71:1546-1558)

EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks

Abstract Acute hepatic porphyria comprises a group of rare, genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months prior to the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a healthcare facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased healthcare utilization. Conclusions: Patients experienced attacks often requiring treatment in a healthcare facility and/or with hemin, as well as chronic symptoms that adversely influence day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies. This article is protected by copyright. All rights reserved.Peer reviewe

Efficacy and safety of a VWF/FVIII concentrate (wilate®) in inherited von Willebrand disease patients undergoing surgical procedures

Introduction: Surgical procedures in von Willebrand disease (VWD) patients may require prophylactic treatment with exogenous von Willebrand factor (VWF) and coagulation factor VIII (FVIII) to prevent excessive bleeding. Wilate\uc2\uaeis a plasma-derived, double virus-inactivated, highly purified, freeze-dried VWF/FVIII concentrate, containing both factors in a physiological activity ratio of 1:1. Aim: To investigate the efficacy and safety of wilate\uc2\uaein maintaining haemostasis in VWD patients undergoing surgical procedures. Methods: This prospective, open-label multinational clinical study documents 28 individuals who underwent 30 surgical procedures managed with wilate\uc2\uae. Twenty-one patients had VWD Type 3, and 21 surgeries were major. Efficacy was assessed intra- and postoperatively by the surgeon and investigator, respectively, and adjudicated by an Independent Data Monitoring Committee, using an objective scale based on blood loss, transfusion requirements and postoperative bleeding and oozing. Treatment success (primary endpoint) was determined using a composite assessment algorithm and was formally assessed. Results: Surgical prophylaxis with wilate\uc2\uaewas successful in 29 of 30 procedures. The overall rate of success was 96.7% (98.75% CI: 0.784, 1.000). All 21 surgeries in patients with VWD Type 3 were managed successfully. There was no accumulation of VWF or FVIII after multiple dosing, and no thromboembolic events or inhibitors to VWF or FVIII were observed. Conclusions: Wilate\uc2\uaedemonstrated effective prevention and treatment of bleeding in inherited VWD patients undergoing surgery, with no clinically significant safety concerns

EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurren

Background and Aims: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. Approach and Results: EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization. Conclusions: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies