Background:We report efficacy and select safety outcomes of current factor prophylaxis of adults with moderately severe to severe hemophilia A (HA) or hemophilia B (HB) in a large, prospective, noninvestigational product study. Objectives:This study established prospective efficacy data on factor (F)VIII/FIX prophylaxis in the usual care setting. Methods:This prospective, open-label, noninvestigational product, multicenter study (BENEGENE-1) included HA and HB cohorts. Participants remained on their current factor replacement therapy. The primary end point was annualized bleeding rate. Secondary end points included annualized infusion rate of FVIII/FIX replacement therapy. Safety data were also collected. Results:In total, 241 individuals with HA and 333 with HB were screened, and 101 and 111, respectively, were enrolled in this study. The most common reason for screen failure was adeno-associated virus neutralizing antibody positivity, accounting for 82.1% and 92.3% of screen failures in the HA and HB cohorts, respectively. The corresponding overall mean (SD; range) follow-up duration was 310.8 (209.2; 14-948) and 498.6 (293.4; 117-1269) days. Mean (SD) total annualized bleeding rate and annualized infusion rate were 6.1 (10.6) and 127.1 (51.8) for participants with HA and 4.5 (9.4) and 62.8 (33.3) for participants with HB, respectively. No new safety concerns were identified with FVIII/FIX replacement therapy. Conclusion:This study provides a robust, prospective, informative dataset on bleeding rates in participants receiving factor replacement therapy over a mean follow-up of ∼1 year. Although FVIII/FIX prophylaxis was generally well tolerated, bleeding rate data illustrate the limitations of current standard-of-care factor prophylaxis.

Background: Inversions involving intron 22 (Inv22) of the F8 gene are detected in approximately 45% of all severe hemophilia A (HA) patients. Digital droplet polymerase chain reaction using milepost assays and multiplex ligation-dependent probe amplification (MLPA) allows robust diagnosis of inversions, copy number variations, and more complex rearrangements in F8. Objectives: A total of 350 HA patients and 280 of their mothers from the Hemophilia Inhibitor Genetics Study cohort were analyzed to identify additional F8 mutations. Methods: Digital droplet polymerase chain reaction and MLPA were used to investigate archival samples. Results: Of 350 patients analyzed, 13 were found to harbor previously unidentified mutations: 3 with inversions (Inv22 type 1) and 10 with large deletions. In addition, 7 patients had complex rearrangements with duplications, in addition to Inv22 type 1. Of 138 mothers of patients with inversions, 7 were noncarriers. Five of these were found to have the same duplications as those detected in their 7 sons, indicating that most, if not all, noncarrier mothers have other rearrangements in the F8 region. MLPA showed that these duplications had breakpoints in intron 22, with either duplication of the first part of the gene (exons 1-22) or the last part of the gene (exons 23-26). Conclusion: Mutation detection in F8 can be improved by dedicated analysis for inversions and duplications/deletions using milepost assays. Noncarrier mothers of HA patients with Inv22 often have other rearrangements.

Hemophilia A and B are rare, X-linked bleeding disorders characterized by deficiencies in coagulation factor VIII (FVIII) and factor IX (FIX), respectively. Numerous advances have helped to reduce disease burden. However, hemophilia B is not as well studied as hemophilia A, likely reflecting its lower prevalence. Clinical management of hemophilia B has often relied on inference and extrapolation from hemophilia A. Despite being part of the same tenase complex, as enzyme (FIX) and cofactor (FVIII) when activated, with the main task being to activate factor X in the intrinsic pathway, the FIX and FVIII proteins display several molecular differences. These have the potential to impact the clinical phenotype of hemophilia, affect monitoring, and influence treatment options. Consequently, hemophilia B presents several outstanding challenges, requiring a greater degree of understanding and/or attention across a range of areas. Some of these challenges relate to the FIX molecule, with more knowledge needed in relation to: the biological/clinical impact of underlying genetic changes; hemostatic implications of the extravascular distribution of FIX; and FIX clearance. Other challenges relate to clinical management: determining the best ways to monitor the true biological activity of FIX; clarifying the relationship between FIX plasma levels and clinical outcomes when treating patients; inhibitors; affected girls and women; and appreciating the value of novel treatment approaches, while considering possible breakthrough bleeds, thrombosis, and monitoring. In addition, concerted effort is required to address global disparities, which can particularly affect hemophilia B. Identifying such challenges may help to facilitate research that will further existing knowledge, with better understanding being crucial for achieving health equity between hemophilia A and B.

Introduction Despite therapeutic achievements in haemophilia care, there is still the need to monitor and define personal treatment outcomes and document results to achieve the best possible care. Hence, a need for unbiased, timely and comprehensive real-world information exists to support informed shared decision-making regarding treatment and care.Aim To describe a medical device for people living with haemophilia (PLWH) supporting an active involvement to achieve a near to normal life.Methods Florio HAEMO was developed as haemophilia monitoring platform to support PLWH and their care teams in documenting, interpreting and analysing personal reported outcomes. The tool was created partnering closely with PLWH and healthcare professionals to address previously unmet needs compared to existing applications.Results Florio HAEMO was launched in March 2020. Currently, it is available in 25 countries and 24 languages; 1558 PLWH (86% with haemophilia A) are registered users in 121 treatment centres across 20 countries. All users included are on a prophylactic treatment regimen.Conclusion Florio HAEMO allows the collection of contemporaneous data to monitor treatment, like factor level, adherence and consumption as well as monitoring treatment outcomes, including pain, bleeds, wellbeing and levels of physical activity to support self-management, shared decision-making and to enable better care for PLWH. Data collected over time may help to show the impact of individualised prophylaxis and may support the definition of factor levels required for good bleed and joint protection in a real world setting from daily life to physical activities.

ABSTRACT:Concizumab is a novel nonfactor replacement therapy for once-daily subcutaneous prophylactic treatment of hemophilia A/B (HA/HB) with and without inhibitors. Concizumab was superior to on-demand treatment in patients with HA/HB without inhibitors in the prospective, multicenter, open-label phase 3 explorer8 study. Here, longer-term efficacy and safety results from the start of the study up to the 56-week cutoff are presented. Males aged ≥12 years with HA/HB were randomized 1:2 to no prophylaxis (group 1) or concizumab (group 2) or allocated to concizumab (groups 3 and 4). Assessments at the 56-week cutoff included efficacy, pharmacokinetics/pharmacodynamics, and safety. The 56-week cutoff was defined as when all patients in groups 2 to 4 had completed the visit at 56 weeks or permanently discontinued treatment. Of 148 patients in the full analysis set, 21 were randomized to no prophylaxis (group 1: HA, n = 9; HB, n = 12), 42 to concizumab (group 2: HA, n = 18; HB, n = 24), and 85 to the nonrandomized concizumab groups (groups 3 and 4: HA, n = 55; HB, n = 30). After ≥24 weeks of treatment, 17 patients in group 1 switched to concizumab. Low median annualized bleeding rates for treated spontaneous and traumatic bleeding episodes were maintained at the 56-week cutoff in patients receiving concizumab (HA, 1.7 [interquartile range (IQR), 0.0-4.5]; HB, 2.8 [IQR, 0.0-6.4]), consistent with 32-week cutoff results. Concizumab plasma concentration remained stable, with no new safety concerns. Concizumab showed longer-term efficacy in patients with HA/HB at the 56-week cutoff and was considered safe and well tolerated. This trial was registered at www.clinicaltrials.gov as #NCT04082429.

Immune tolerance induction (ITI) to eradicate an immune response against factor VIII (FVIII) has been used in hemophilia A (HA) with various success rates, costs, and treatment burden. The present study aimed to identify markers predictive of ITI success. Data were accrued from 237 patients with severe HA (FVIII level < 1%), history of persistent FVIII inhibitors ≥ 1 BU/mL and having performed ITI. Constitutional and clinical variables associated with ITI outcome were evaluated and multivariable logistic regression models developed. The F8 variant, age at inhibitor detection, and historical peak inhibitor titer were associated with ITI outcome. HLA DRB1*1501 and DQB1*0602 were linked to each other, but not associated with ITI outcome. In a multivariable-adjusted model, large gene deletions, peak titer ≥ 25 BU/mL, and higher age at inhibitor detection were associated with a significantly lower ITI success rate. The discriminatory power of a predictive model was 0.87 (95% confidence interval [CI], 0.85-0.93) with the historical peak titer and 0.69 (95% CI, 0.64-0.80) without. We conclude that the peak inhibitor titer is a key determinant for ITI outcome and additional constitutional markers need to be defined for useful prediction in the clinical setting.

Background: Patients with hemophilia are reported to have a high prevalence of established and potential risk factors for kidney dysfunction and damage. However, comprehensive studies specifically evaluating kidney function in hemophilia, particularly hemophilia B (HB), are limited, with most research focusing on hemophilia A. Objectives: This study aimed to assess markers of glomerular filtration, damage, and tubular function in patients with HB enrolled in the B-Natural study. Methods: Kidney function and damage was evaluated using estimated glomerular filtration rate (eGFR), urine albumin/creatinine ratio, urinary immunoglobulin/creatinine ratio, and protein HC. Correlations with patient characteristics, treatment regimes, and comorbidities were analyzed. Results: The cohort consisted of 209 patients with HB, with 32% having severe, 51% moderate, and 17% mild disease. The median age was 13 years (IQR, 9-22 years; range, 1-73 years). The mean eGFR across the cohort was 107 mL/min/1.73 m2 (range, 13-183 mL/min/1.73 m2). Older age, higher body mass index, a history of kidney disease, diabetes, hypertension, and Asian ethnicity were significantly associated with lower eGFR. Patients with severe HB (factor IX < 1%), and/or a history of inhibitors exhibited a wider range of eGFR values. Only a small proportion of patients showed glomerular damage and tubular dysfunction. Regular prophylactic treatment with factor concentrates had no apparent impact on kidney function or kidney disease markers. Conclusion: Our findings suggest that patients with HB and no inhibitors do not have an increased risk of kidney dysfunction or damage compared to persons without hemophilia. Age and hypertension were the primary risk factors, underscoring the importance of regular follow-ups.

Background: Hemophilia B is a genetic bleeding disorder caused by a deficiency of clotting factor IX, which presents unique challenges in clinical management. Advances in therapeutic strategies for hemophilia B have significantly improved patient outcomes but have also necessitated ongoing education for healthcare professionals. This illustrated review provides an overview of the challenges and opportunities in hemophilia B care, including best practice management, emerging therapies, and remaining research needs. Objectives: To provide a comprehensive visual summary of contemporary perspectives on hemophilia B pathophysiology and management through an illustrated review. Methods: The authors, leveraging their clinical experience and expertise in hemophilia B management, conducted a review of relevant articles in PubMed (Supplementary Methods). Results: The review is divided into illustrated sections that provide an overview of hemophilia B, detailing its clinical manifestations, hemostatic agents, and treatment challenges. It also examines the pharmacokinetic properties of hemophilia B and the importance of individualized treatment approaches. Conclusion: This illustrated review educates healthcare professionals on hemophilia B management in the current treatment landscape, empowering them to further disseminate knowledge to both their colleagues and patients.

INTRODUCTION:Accurate and reproducible measures of factor activity are required to guide clinical decision-making following gene therapy for haemophilia B (HB). Highly significant discrepancies have been observed in measurements of various factor IX (FIX) concentrates that carry molecular modifications to extend their half-life, arguing for the need for careful analysis of new HB treatment modalities with respect to FIX assay performance. AIM:To further characterise variability in FIX activity measured using different one-stage assays (OSAs) and chromogenic assays (CAs) in patients with HB receiving gene therapy utilising the FIX Padua variant and to assess whether assay differences were due to the FIX-Padua variant. METHODS:FIX activity was assessed centrally (OSA and CA) and locally (OSA only) using plasma samples collected from a phase 2b and phase 3 study of etranacogene dezaparvovec and in an in vitro study of wild-type (wt) recombinant human FIX (rhFIX) and rhFIX-Padua. RESULTS:Lower CA than OSA FIX activity for plasma samples from the phase 3 trial was observed (CA:OSA ratio: 0.408 [±0.049]-0.547 [±0.062]). Local OSA:central OSA FIX activity ratios were 0.789 (±0.314)-1.021 (±0.159). Local OSA:central OSA FIX activity ratios across methods and/or reagents were 0.81 (±0.02)-1.28 (±0.04) for rhFIX-wt-spiked samples and 0.67 (±0.02)-1.13 (±0.09) for rhFIX-Padua-spiked samples. CONCLUSION:FIX activity differences between central and local OSAs were modest; similar differences were observed in vitro with rhFIX-wt versus rhFIX-Padua. Commonly available OSAs can be used to monitor patients post-etranacogene dezaparvovec administration; we recommend using the same assay platform throughout the post-treatment period.

Plain Language SummaryWhat is the study about?Hemophilia A is a genetic bleeding disorder that causes bleeding for long periods because of lower than normal levels of factor VIII (FVIII), a protein that is important for blood clotting. FVIII replacement therapy is the typical approach to manage bleeds, but new and improved therapies are becoming widely available. Prophylaxis with the medication emicizumab and gene therapy with valoctocogene roxaparvovec are two such novel treatments approved for use in adults with severe hemophilia A without inhibitors.Two separate clinical trials, HAVEN 3 and GENEr8-1, showed emicizumab and valoctocogene roxaparvovec reduced the frequency of bleeds when switching from FVIII prophylaxis. However, these therapies have not been directly compared in a clinical trial.Given important differences in the overall structure and people who participated in the HAVEN 3 and GENEr8-1 trials, a straightforward comparison of bleeding rates between trials would be inappropriate. Unanchored matching-adjusted indirect comparison (MAIC) is a method used to allow for comparisons across studies that are not exactly the same.What was the objective?This summary shares the results of a MAIC analysis between emicizumab and valoctocogene roxaparvovec using participant data from GENEr8-1 and published data from HAVEN 3. After balancing the baseline characteristics of the participants from each study to be more similar, the proportion of participants with zero bleeds and participants' annualized bleeding rate (ABR) were compared.What are the key takeaways?After valoctocogene roxaparvovec gene therapy, a higher percentage of participants reported zero bleeds, and participants had lower ABRs compared with emicizumab prophylaxis. FVIII prophylaxis (as provided in the GENEr8-1 trial) and emicizumab were also compared, which found less bleeding occurred with emicizumab than with FVIII prophylaxis.What are the main conclusions reported by the researchers?While a single infusion of valoctocogene roxaparvovec provided better protection against bleeds than emicizumab prophylaxis, and emicizumab provided better protection against bleeds compared to FVIII prophylaxis, the limitations of the MAIC analysis as an indirect comparison should be considered when interpreting these results. Overall, these data provide important treatment information for health professionals and individuals with hemophilia A to consider for their treatment goals.This is an abstract of the Plain Language Summary of Publication article.View the full Plain Language Summary PDF of this article to read the full-text AcknowledgementsWe thank all trial participants, investigators, and site staff.Disclosure statementJ Astermark has received research grants from Bayer, CSL Behring, Sobi, and Takeda/Shire and speaker's fees and consultancy from Bayer, BioMarin Pharmaceutical Inc., CSL Behring, Novo Nordisk, Octapharma, Pfizer, Sanofi, Sobi, Spark Therapeutics, Takeda/Shire, and uniQure. TW Buckner has received honoraria for advisory board participation from Bayer, CSL Behring, Novo Nordisk, Pfizer, Spark Therapeutics, Takeda, and Tremeau Pharmaceuticals; has served as a consultant to BioMarin Pharmaceutical Inc., Tremeau Pharmaceuticals, and uniQure; and is on the board of directors for the American Thrombosis and Hemostasis Network. L Frenzel has received research grants from CSL Behring and Pfizer and speaker's fees and consultancy from BioMarin Pharmaceutical Inc., CSL Behring, Novo Nordisk, Pfizer, Roche, and Sobi. AJ Hatswell is an employee of Delta Hat Ltd, which was contracted by BioMarin Pharmaceutical Inc. for input on the study design and execution. D Hinds is an employee and stockholder of BioMarin Pharmaceutical Inc. S Santos is an employee and stockholder of BioMarin UK Ltd. R Klamroth has received grants from Bayer, CSL Behring, and LEO Pharma; consulting fees from Bayer, BioMarin Pharmaceutical Inc., CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche/Chugai, Sanofi, Sobi, and Takeda; and payment of honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bayer, BioMarin Pharmaceutical Inc., Biotest, CSL Behring, Daiichi Sankyo, Grifols, LEO Pharma, Novo Nordisk, Octapharma, Pfizer, Roche/Chugai, Sanofi, Sobi, Shire/Takeda, and uniQure. T Becker serves as a board member of IGH - Interessengemeinschaft Hämophiler e.V. and is on the advisory boards for Bayer, CSL Behring, Novo Nordisk, Octapharma, Roche, Sobi, and Takeda. D York serves as the chair of the board and CEO of the Hemophilia Foundation of New Zealand. The authors have no other competing interests, relevant affiliations, or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Medical writing support was provided by Taryn Bosquez-Berger, PhD, of AlphaBioCom, a Red Nucleus company, and funded by BioMarin Pharmaceutical Inc. Project management support was provided by Gillian Clague, CMPP, of BioMarin Pharmaceutical Inc.Patient reviewers on this PLSP have received honorarium from Expert Review of Hematology for their review work but have no other relevant financial relationships to disclose.Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.FundingThis Plain Language Summary of Publication was funded by BioMarin Pharmaceutical Inc.Supplementary materialSupplemental data for this article can be accessed here

INTRODUCTION:Comorbidities and public health conditions in haemophilia are receiving increasing attention. AIM:To analyse the prevalence of comorbidities and mortality in people with haemophilia (PwH) compared to matched controls in subgroups (factor consumption and sex). METHODS:This study used longitudinal individual-level data (11 years) from national registers in three Nordic countries (Denmark, Finland and Sweden) from the MIND study (NCT03276130) for PwH and matched controls (1:5 on birth year and sex). It compared the prevalence of arthropathy, human immunodeficiency virus (HIV), hepatitis, depression, anxiety, hypertension, ischaemic heart disease, atrial fibrillation, stroke, diabetes, cancer, kidney disease and epilepsy, and mortality. Three severity subgroups for PwH were identified by use of factor concentrates and sex, including female carriers. RESULTS:Data for 2716 PwH (24,921 person-years) were analysed. PwH had increased prevalence of single and multiple comorbidities (p < 0.001), and increased mortality (p < 0.001). Arthropathy was more prevalent in all male PwH subgroups in Nordic countries, and among women including carriers in Sweden (odds ratios: ∼2→12). Arthropathy was a concomitant comorbidity alongside depression, hypertension, cardiovascular conditions, diabetes, hepatitis and HIV. Hypertension was more prevalent for PwH than controls in most subgroups. Hepatitis and HIV had the highest odds ratios among PwH in Denmark and Sweden. CONCLUSION:Arthropathy occurs in combination with a complex of comorbidities. The potential common pathophysiologic denominator should be further explored. Higher prevalence of comorbidities and mortality rates in men and women with haemophilia call for a holistic approach with more ambitious treatment goals for PwH across severities and sexes. TRIAL REGISTRATION:The MIND Study was registered at ClinicalTrials.gov: NCT03276130.

INTRODUCTION:Despite factor (F)VIII prophylaxis, a perceived increased risk of bleeding for some people with severe haemophilia A (PwSHA) exists, limiting physical activity (PA) and restricting quality of life (QoL). AIM:HemiNorth 2 (EudraCT# 2020-003256-32) is an interventional study evaluating the impact of switching from FVIII prophylaxis to emicizumab in PwSHA without FVIII inhibitors who have a need for improved prophylaxis in the Nordic countries. METHODS:Following completion of the HemiNorth non-interventional study (NIS), eligible participants (aged ≥ 12-61 years) were enrolled in HemiNorth 2. The primary endpoint was health-related QoL via the Comprehensive Assessment Tool for Challenges in Hemophilia (CATCH). Secondary endpoints included PA (International Physical Activity Questionnaire-Short Form [IPAQ-SF]), treatment preference (Emicizumab Preference [EmiPref] survey), joint health, model-based annualised bleeding rates (ABRs) and adverse events. RESULTS:Overall, 28 physically active male PwSHA were enrolled. Most baseline CATCH domains were ≤ 25 and remained consistent; mean treatment burden considerably improved from baseline for adults (-17.8) and adolescents (+16.7). IPAQ-SF scores were consistent throughout the study. Overall, 23 of 25 (92.0%) EmiPref respondents preferred emicizumab over FVIII prophylaxis. Model-based ABRs for treated bleeds decreased from 5.9 (95% confidence interval [CI]: 3.8-9.1) to 1.6 (95% CI: 0.9-3.0) from the NIS to HemiNorth 2, and participants with zero treated bleeds increased from 8 (28.6%) to 16 (57.1%). No new safety signals were reported. CONCLUSIONS:Emicizumab improved treatment burden and was preferred by most participants over FVIII prophylaxis. PA levels were consistently high, and bleeding rates improved with emicizumab versus prior FVIII prophylaxis.

Background Etranacogene dezaparvovec, the first gene therapy approved for haemophilia B treatment, was shown be superior to treatment with continuous prophylactic factor IX in terms of bleeding protection 18 months after therapy in a phase 3 trial. We report post -hoc 24 -month efficacy and safety data from this trial to evaluate the longer term effects of etranacogene dezaparvovec in individuals with haemophilia B. Methods The phase 3 HOPE -B trial enrolled males aged 18 years or older with inherited haemophilia B, classified severe (plasma factor IX activity level <1%) or moderately severe (plasma factor IX activity level >= 1% and <= 2%), with severe bleeding phenotype and who were on stable continuous factor IX prophylaxis. Participants were treated with single infusion of etranacogene dezaparvovec (2 x 10 13 genome copies per kg of bodyweight). The primary endpoint, reported previously, was non -inferiority of the annualised bleeding rate (ABR) during the 52 weeks following stable factor IX expression (defined as months 7-18 after treatment) versus an at least 6 -month lead-in period in which participants received their usual continuous factor IX prophylaxis, and is updated here up to month 24. Additional, post -hoc efficacy analyses, including adjusted ABR, factor IX activity, participants within factor IX ranges, and factor IX use, and safety analyses were performed at 24 months after gene therapy. Data were analysed in the full analysis set, which comprised the 54 patients who received at least a partial dose of gene therapy. The trial is ongoing and registered with ClinicalTrials.gov, number NCT03569891. Findings The study began on June 27, 2018, and participants were treated between January, 2019, and March, 2020; date of data cutoff was April 21, 2022. 54 adult males (40 White, two Asian, one Black or African American, 11 other missing) received a single intravenous infusion of etranacogene dezaparvovec and were followed for a median 2651 months (IQR 2454-2799), after a lead-in period of 713 months (651-782). In the updated analysis comparing months 7-24 after gene therapy to the lead-in period, mean adjusted ABR significantly reduced from 418 to (p=00002) for all bleeds and from 365 to 099 (p=00001) for factor IX -treated bleeds. During each 6 -month period after gene therapy, at least 67% of participants experienced no bleeding (36 of 54 during months 0-6 and stable thereafter), compared with 14 (26%) of 54 during the lead-in period. 24 months after gene therapy, 1 (2%) participant had one -stage factor IX activity less than 5%, whereas 18 (33%) had factor IX activity more than 40% (non -haemophilia range), with mean factor IX activity stable and sustained at 367% (SD 190%). 52 (96%) of 54 participants expressed endogenous factor IX, remaining free of factor IX prophylaxis at month 24. No new safety concerns were identified no treatment -related serious adverse events or treatment -related deaths occurred. The most common treatment -related adverse events were an increase in alanine aminotransferase (nine [17%] of 54 patients), headache (eight [15%]), influenza -like illness (seven [13%]), and an increase in aspartate aminotransferase (five [9%]). Interpretation By providing durable disease correction throughout the 24 months after gene therapy, etranacogene dezaparvovec provides a safe and effective therapeutic option for patients with severe or moderately severe haemophilia B.

Over recent decades, management of people with hemophilia (PwH) has been greatly improved by scientific advances that have resulted in a rich and varied therapeutic landscape. Nevertheless, treatment limitations continue to drive innovation, and emerging options have the potential to realize further improvement. We advocate four general principles to optimize benefits from innovation: individualizing the treatment approach, targeting ‘normal,’ making the most of available resources, and considering treatment affordability. Ultimately, all PwH—men and women, of all ages and severities, and worldwide—should have access to treatment that fully prevents bleeding, while allowing personal, social, family, and professional lives of choice. Clearly, we are not there yet, but developing goals/milestones based on the principles we describe may help to achieve this.

Background Concizumab is an anti-tissue factor pathway inhibitor monoclonal antibody in development as a once-daily, subcutaneous prophylaxis for patients with haemophilia A or haemophilia B with or without inhibitors. We aimed to assess the efficacy and safety of concizumab in patients with haemophilia A or B without inhibitors. Here we report the results from the confirmatory analysis cutoff. Methods This prospective, multicentre, open-label, randomised, phase 3a trial (explorer8) was conducted at 69 investigational sites in 31 countries. Eligible patients were male, aged 12 years or older, and had congenital severe haemophilia A or moderate or severe haemophilia B without inhibitors and with documented treatment with clotting factor concentrate in the 24 weeks before screening. The trial was paused because of non-fatal thromboembolic events in three patients (two from this trial [explorer8] and one from a related trial in haemophilia with inhibitors [explorer7; NCT04083781]) and restarted with mitigation measures, including a revised dosing regimen of subcutaneous concizumab at 1 center dot 0 mg/kg loading dose on day 1 and subsequent daily doses of 0 center dot 20 mg/kg from day 2, with options to decrease to 0 center dot 15 mg/kg, stay on 0 center dot 20 mg/kg, or increase to 0 center dot 25 mg/kg on the basis of concizumab plasma concentration measured after 4 weeks on concizumab. Patients recruited after treatment restart were randomly assigned 1:2 using an interactive web response system to receive no prophylaxis and continue on-demand clotting factor (group 1) or concizumab prophylaxis (group 2). The primary endpoints were the number of treated spontaneous and traumatic bleeding episodes for patients with haemophilia A and haemophilia B separately, assessed at the confirmatory analysis cutoff in randomly assigned patients. Analyses were by intention-to-treat. There were two additional groups containing non-randomly-assigned patients: group 3 contained patients who entered the trial before the trial pause and were receiving concizumab in the phase 2 trial (explorer5; NCT03196297), and group 4 contained patients who received previous clotting factor concentrate prophylaxis or on-demand treatment in the non-interventional trial (explorer6; NCT03741881), patients randomly assigned to groups 1 or 2 before the treatment pause, and patients from explorer5 enrolled after the treatment pause. The safety analysis set contained all patients who received concizumab. Superiority of concizumab over no prophylaxis was established if the two-sided 95% CI of the treatment ratio was less than 1 for haemophilia A and for haemophilia B. This trial is registered with ClinicalTrials.gov, NCT04082429, and its extension part is ongoing. Findings Patients were recruited between Nov 13, 2019 and Nov 30, 2021; the cutoff date for the analyses presented was July 12, 2022. 173 patients were screened, of whom 148 (86%) were randomly assigned or allocated to the four groups in the study after trial restart on Sept 30, 2020 (nine with haemophilia A and 12 with haemophilia B in group 1; 18 with haemophilia A and 24 with haemophilia B in group 2; nine with haemophilia A in group 3; and 46 with haemophilia A and 30 with haemophilia B in group 4). The estimated mean annualised bleeding rate ratio for treated spontaneous and traumatic bleeding episodes during concizumab prophylaxis versus no prophylaxis was 0 center dot 14 (95% CI 0 center dot 07-0 center dot 29; p<0 center dot 0001) for patients with haemophilia A and 0 center dot 21 (0 center dot 10-0 center dot 45; p<0 center dot 0001) for patients with haemophilia B. The most frequent adverse events in patients who received concizumab were SARS-CoV-2 infection (19 [13%] of 151 patients), an increase in fibrin D-dimers (12 [8%] patients), and upper respiratory tract infection (ten [7%] patients). There was one fatal adverse event possibly related to treatment (intra-abdominal haemorrhage in a patient from group 4 with haemophilia A with a long-standing history of hypertension). No thromboembolic events were reported between the trial restart and confirmatory analysis cutoff. Interpretation Concizumab was effective in reducing the bleeding rate compared with no prophylaxis and was considered safe in patients with haemophilia A or B without inhibitors. The results of this trial suggest that concizumab has the potential to be one of the first subcutaneous treatment options for patients with haemophilia B without inhibitors. Copyright (c) 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license