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Background: Valoctocogene roxaparvovec transfers a human factor (F)VIII coding sequence into hepatocytes of people with severe hemophilia A to provide bleeding protection., Objectives: To present 3-year efficacy and safety in the multicenter, open-label, single-arm, phase 3 GENEr8-1 trial., Methods: GENEr8-1 enrolled 134 adult males with severe hemophilia A who were receiving FVIII prophylaxis. Efficacy endpoints included annualized bleeding rate, annualized FVIII utilization, FVIII activity (chromogenic substrate assay; imputed as 1 IU/dL at baseline and 0 IU/dL after discontinuation), and the Haemophilia-Specific Quality of Life Questionnaire for Adults. Safety was assessed by adverse events (AEs)., Results: At week 156, 131 of 134 participants remained in the study; overall, 17 of 134 resumed prophylaxis. Mean annualized bleeding rate for treated bleeds decreased from 4.8 (SD, 6.5) bleeds/y at baseline to 0.8 (SD, 2.3; P < .0001) bleeds/y after prophylaxis (prophylaxis cessation to last follow-up) and 0.97 (SD, 3.48) bleeds/y during year 3. Annualized FVIII utilization decreased 96.8% from baseline after prophylaxis and 94.2% during year 3. At week 156, mean and median FVIII activity were 18.4 (SD, 30.8) and 8.3 IU/dL, respectively. FVIII activity decrease was lower between years 2 and 3 than between years 1 and 2. At the end of year 3, clinically meaningful improvements in the Haemophilia-Specific Quality of Life Questionnaire for Adults Total Score were observed (mean change from baseline, 6.6; 95% CI, 4.24-8.87; P < .0001). Mild alanine aminotransferase elevations remained the most common AE during year 3 (23.7% of participants). A serious AE of B-cell acute lymphoblastic leukemia was considered unrelated to treatment., Conclusion: Hemostatic efficacy was maintained, and safety remained unchanged from previous years., Competing Interests: Declaration of competing interests M.C.O. has participated in advisory boards for Bayer, BioMarin Pharmaceutical Inc, Pfizer, Sanofi, and Takeda and received honoraria from BioMarin Pharmaceutical Inc, Biotest, Novo Nordisk, Pfizer, Roche, Takeda, and Sanofi. P.R. has received grant/travel support from CSL Behring, Sobi, and Takeda and advisory honoraria from Idogen, Pfizer, Sigilon, and Sobi. E.S. has received travel grants from CSL Behring and Novo Nordisk. D.V.Q. has served on advisory boards and speakers bureaus or as a consultant for Bayer, BioMarin Pharmaceutical Inc, Genentech, Novo Nordisk, Octapharma, Sanofi, Takeda, and uniQure. A.D.L. has served as an investigator for BioMarin Pharmaceutical Inc and Pfizer. S.W.P. has served as a consultant for ApcinteX, Bayer, BioMarin Pharmaceutical Inc, CSL Behring, Equilibra Bioscience, GeneVentiv, HEMA Biologics, LFB, Novo Nordisk, Pfizer, Regeneron, Roche, Sanofi, Siemens, Spark, Takeda, and uniQure. G.L. has received honoraria for participating in educational events from Alexion, LEO Pharma, Novartis, Novo Nordisk, Sanofi, Sobi, and Takeda and consulting fees from UCB. G.K. has received grant funding from Genentech and Pfizer and served on advisory boards or as a consultant for Bayer, BioMarin Pharmaceutical Inc, Genentech, Novo Nordisk, Sanofi, Sobi, Spark, and Takeda. M.T.R. has served as an investigator for Bayer and BioMarin Pharmaceutical Inc and served on advisory boards or speakers bureaus for Bayer, CSL Behring, Genentech, HEMA Biologics, Novo Nordisk, Sanofi, and Takeda. M.W. has served as a consultant for Bayer, BioMarin Pharmaceutical Inc, Bioverativ, Catalyst, CSL Behring, Genentech, HEMA Biologics, and Novo Nordisk. A.v.D. has received research funding from Pfizer and Sanofi, is a cofounder and board member of Hematherix Inc, and served as a consultant for ASC Therapeutics, BioMarin Pharmaceutical Inc, CSL Behring, Genentech, Regeneron, Sanofi, Takeda, and uniQure. R.K. 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. S.S. has received speaking, educational, or travel honoraria from CSL Behring, Pfizer, Roche, Sobi, and Takeda. H.C. has served as a consultant for BioMarin Pharmaceutical Inc, Novo Nordisk, Roche, and Sobi. A.L.D has received research funding from BioMarin Pharmaceutical Inc, Novo Nordisk, Sanofi, and Takeda; served as a consultant for CSL Behring, Roche, and uniQure; and is a board member of the National Hemophilia Foundation and World Federation of Hemophilia USA. J.O. has received research funding from Bayer, Biotest, CSL Behring, Octapharma, Pfizer, Swedish Orphan Biovitrum, and Takeda and consultancy, speakers bureau, honoraria, scientific advisory board, and travel expenses from Bayer, Biogen Idec, BioMarin Pharmaceutical Inc, Biotest, Chugai, CSL Behring, Freeline, Grifols, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Spark Therapeutics, Swedish Orphan Biovitrum, and Takeda. F.P. has served as a consultant for BioMarin Pharmaceutical Inc, Grifols, Roche, Sanofi, Sobi, and Takeda. C.M.M. has received research funding from CSL Behring, Grifols, and Takeda and has served as a speaker or consultant for CSL Behring, LFB Pharma, Novo Nordisk, Octapharma, Takeda, and Sobi. D.O., H.Y., E.D.-A., and T.M.R. are employees and shareholders of BioMarin Pharmaceutical Inc. J.Mahlangu has received research funding from BioMarin Pharmaceutical Inc, Catalyst, Roche, Novo Nordisk, Pfizer, Sandoz, Sanofi, and Spark Therapeutics. B.M., J. Mason, and S.-C.C. have no conflicts to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: A prospective, non-interventional study (270-902) followed 294 adults with severe hemophilia A (SHA) receiving prophylactic factor VIII (FVIII). From these participants, 112 rolled over into a single-arm, multicenter, phase 3 trial (GENEr8-1; NCT03370913) that evaluated efficacy and safety of valoctocogene roxaparvovec, a gene therapy that provides endogenous FVIII in individuals with SHA. Participants from 270-902 who did not roll over provide an opportunity for a contemporaneous external control. Therefore, the comparative effectiveness of valoctocogene roxaparvovec vs FVIII prophylaxis was evaluated using propensity scoring (PS)., Methods: This post hoc analysis compared 112 participants from GENEr8-1 (treated cohort) to 73 participants in 270-902 who did not enroll in GENEr8-1 (control cohort). The primary analysis used standardized mortality ratio weighting to re-weight baseline characteristics of the control cohort to better match the treated cohort. Mean annualized bleeding rates (ABR) for treated and all bleeds were compared between cohorts along with the proportion of participants with zero bleeds (treated and all bleeds). Sensitivity and scenario analyses were also conducted., Results: PS adjustments reduced differences in baseline characteristics between cohorts. Mean treated (4.40 vs 0.85; P < 0.001) and all (5.01 vs 1.54; P < 0.001) ABR were significantly lower, and the proportions of participants with zero treated bleeds (82.1% vs 32.9%; P < 0.001) and all bleeds (58.0% vs 28.5%; P < 0.001) were significantly higher in GENEr8-1., Conclusions: PS-adjusted analyses were consistent with prior intra-individual comparisons. Compared with participants receiving prophylactic FVIII, the participants receiving valoctocogene roxaparvovec experienced lower ABR, and a higher proportion had zero bleeds., Trail Registration: ClinicalTrials.gov identifier, NCT03370913., (© 2024. The Author(s).)

Background: Chronic joint pain is a significant and widespread symptom in people with haemophilia (PWH). Despite medical advancements, effective pain management remains challenging., Aim: This study presents an innovative approach that integrates remote physical exercises, pain neuroscience education, and coping strategies to address chronic pain in PWH., Methods: The remote intervention consisted of sixteen 5-min videos encompassing physical exercises for chronic pain management and pain education strategies. These videos formed an 8-week remote intervention program. Clinical and physical assessments were conducted before and after the intervention., Results: A total of thirty-one PWHs, with a median age of 34 years (ranging from 16 to 59 years), completed the remote intervention. The study revealed significant improvements in pain intensity, disability, and physical performance among PWH with chronic pain. Enhanced functional capacity was evident in the Timed Up and Go and Single Leg Stance tests, accompanied by improved scores on the Functional Independence Score in Haemophilia (FISH). Although lacking a control group, our findings are consistent with other successful exercise and pain education programs., Conclusions: This innovative intervention holds promise for managing chronic pain in PWH, underscoring patient empowerment, education, and collaboration. Notably, our study stands out by uniquely combining pain education and coping strategies, bolstering evidence for effective pain management., (© 2024 John Wiley & Sons Ltd.)

Introduction: After decades of stumbling clinical development, the first gene therapies for haemophilia A and B have been commercialized and have normalized factor (F)VIII and factor (F)IX levels in some individuals in the long term. Several other clinical programs testing adeno-associated viral (AAV) vector gene therapy are at various stages of clinical testing., Discussion: Multiyear follow-up in phase 1/2 and 3 studies showed long-term and sometimes curative but widely variable and unpredictable efficacy. Liver toxicities, mostly low-grade, occur in the 1st year in at least some individuals in all haemophilia A and B trials and are poorly understood. Wide variability and unpredictability of outcome and slow decline of FVIII levels are a major disadvantage because immune responses to AAV vectors preclude repeat dosing, which otherwise could improve suboptimal or restore declining expression, while overexpression may predispose to thrombosis. Long-term safety outcomes will need lifelong monitoring because AAV vectors infused at high doses integrate into chromosomes at rates that raise questions about potential oncogenicity and necessitate vigilance. Alternative gene transfer systems employing gene editing and/or non-viral vectors are under development and promise to overcome some limitations of the current state of the art for both haemophilia A and B., Conclusions: AAV gene therapies for haemophilia have now become new treatment options but not universal cures. AAV is a powerful but imperfect gene transfer platform. Biobetter FVIII transgenes may help solve some problems plaguing gene therapy for haemophilia A. Addressing variability and unpredictability of efficacy, and delivery of gene therapy to ineligible patient subgroups may require different gene transfer systems, most of which are not ready for clinical translation yet but bring innovations needed to overcome the current limitations of gene therapy., (© 2024 John Wiley & Sons Ltd.)

Background: Severe hemophilia A (HA) negatively impacts health-related quality of life (HRQOL)., Objectives: We aimed to analyze HRQOL in adult men with severe HA without inhibitors after valoctocogene roxaparvovec gene transfer in the phase 3 trial GENEr8-1., Methods: Participant-reported outcomes were the hemophilia-specific quality of life questionnaire for adults (Haemo-QOL-A), the EQ-5D-5L instrument, the Hemophilia Activities List (HAL), and the Work Productivity and Activity Impairment Questionnaire: Hemophilia Specific (WPAI+CIQ:HS). Participants completed the questionnaires at baseline and through 104 weeks postinfusion with 6 × 10 13 vg/kg of valoctocogene roxaparvovec. Scores were analyzed per participant characteristics and outcomes., Results: For 132 HIV-negative participants, mean change from baseline in Haemo-QOL-A Total Score met the anchor-based clinically important difference (CID: 5.5) by week 12; the mean (SD) increase was 7.0 (12.6) at week 104. At week 104, improvement in Consequences of Bleeding, Treatment Concern, Worry, and Role Functioning domain scores exceeded the CID (6). EQ-5D-5L Utility Index scores improved above the CID at week 52, but not at week 104. EQ-5D-5L visual analog scale and HAL scores increased from baseline to week 104. Participants reported less activity and work impairment at week 104 than baseline. Participants with problem joints had lower mean baseline Haemo-QOL-A Total and domain scores than those without them, but improved over 104 weeks, except for 11 participants with ≥3 problem joints. Participants with 0 bleeds during the baseline prophylaxis period reported Haemo-QOL-A score improvements above the CID, including in the Consequences of Bleeding domain., Conclusion: Valoctocogene roxaparvovec provided clinically meaningful HRQOL improvement for men with severe HA., Competing Interests: Declaration of competing interests B.O.M. reports consulting fees from BioMarin Pharmaceutical Inc and Freeline. A.L.D. reports research funding from Sanofi, Takeda, Freeline, BioMarin Pharmaceutical Inc, and the American Thrombosis and Hemostasis Network; consulting fees from BioMarin Pharmaceutical Inc, Genentech/Roche, Kedrion, CSL Behring, and uniQure; and service on the board of the World Federation of Hemophilia USA. A.D.L. reports consulting or advisory panel fees from BioMarin Pharmaceutical Inc, Dova, CSL Behring, Merck, Catalyst, and HEME Biologics; and participation as a clinical trial investigator in trials sponsored by BioMarin Pharmaceutical Inc, Sangamo, and Pfizer. F.P. reports honoraria as a speaker for educational symposia by Grifols, Sanofi, and Takeda and as an advisory member for Sanofi and Roche. M.C.O. reports consulting fees from Bayer, BioMarin Pharmaceutical Inc, Novo Nordisk, Pfizer, Roche, Sanofi, and Takeda; research grants from Pfizer, Roche, and Takeda; service as a clinical trial investigator for BioMarin Pharmaceutical Inc, Novo Nordisk, Pfizer, Roche, Sanofi, and Takeda; speaker honoraria from Bayer, BioMarin Pharmaceutical Inc, Novo Nordisk, Roche, and Takeda; travel support from Novo Nordisk, Roche, and Takeda; and participation in grant reviewing for Grifols. J.M. reports consulting fees from Baxalta, CSL Behring, Catalyst Biosciences, Freeline, LFB, Novo Nordisk, and Spark; research grants from and service as a clinical trial investigator for BioMarin Pharmaceutical Inc, CSL Behring, Novo Nordisk, Pfizer, Sobi, Roche, Novartis, Sanofi, and Unique; and speaker fees from Novo Nordisk, Pfizer, Sanofi, Sobi, Shire, Roche, Takeda, the International Society on Thrombosis and Haemostasis, and the World Federation of Hemophilia. K.P. reports consulting fees and research grants from Sobi, Octapharma, Novo Nordisk, and Pfizer; and served as a clinical trial investigator for uniQure, BioMarin Pharmaceutical Inc, and Roche. J-D.W. reports consulting fees from Bayer, Novo Nordisk, Pfizer, Chugai, Sanofi, Takeda, and Sobi; speaker fees from Bayer, CSL Behring, Novo Nordisk, Pfizer, Chugai, Sanofi, and Takeda; and service as a clinical trial investigator for Bayer, BioMarin Pharmaceutical Inc, Novo Nordisk, Pfizer, Roche/Chugai, and Sanofi. G.L. has received honoraria for participating in educational events from Novartis, LEO, Sobi, Alexion, Takeda, Novo Nordisk, and Sanofi; and consulting fees from UCB. A.G. reports honoraria for service on advisory boards from BioMarin Pharmaceutical Inc, Genentech, Pfizer, Bayer, ATHN, Novo Nordisk, uniQure, and Sanofi Genzyme; and travel grants from BioMarin Pharmaceutical Inc. E.C. reports consulting fees from Genentech, BioMarin Pharmaceutical Inc, Novo Nordisk, Takeda, Sanofi, HEMA Biologics, and CSL Behring; and speaker fees from Genentech. D.P. reports a travel grant from Pfizer. H.C. reports consulting fees from Bayer, BioMarin Pharmaceutical Inc, Roche, and Sobi; served as a clinical trial investigator for BioMarin Pharmaceutical Inc, Bioverativ, CSL Behring, LFB, Octapharma, Roche, Pfizer, Sobi, and Takeda; reports speaker fees from BioMarin Pharmaceutical Inc, Pfizer, Roche, and Sobi; and reports travel grants from BioMarin Pharmaceutical Inc, CSL Behring, Octapharma, Roche, and Sobi. M.F.L.F. reports participation in advisory boards and receiving speaking fees from Shire/Takeda, Amgen, CSL Behring, Novo Nordisk, Bayer, LFB, Pfizer, and Sobi. E.M. reports consulting fees and travel support from BioMarin Pharmaceutical Inc and served as a clinical trial investigator for BioMarin Pharmaceutical Inc. M.W.S. reports consulting fees from Bayer, BioMarin Pharmaceutical Inc, Pfizer (DMC), Roche/Genentech, Sanofi, Spark (DMC), and Takeda; and research grants from BioMarin Pharmaceutical Inc, Freeline, Roche, Takeda, and uniQure. R.Klamroth reports consulting fees from Bayer, Biotest, BioMarin Pharmaceutical Inc, Novo Nordisk, Octapharma, Pfizer, Roche/Chugai, Sanofi, Takeda/Shire, and Sobi; research grants from Bayer and LEO; speaker fees from Bayer, Biotest, BioMarin Pharmaceutical Inc, CSL Behring, Daiichi Sankyo, LEO, Novo Nordisk, Octapharma, Pfizer, Roche/Chugai, Sanofi, Takeda/Shire, and Sobi; travel support from Bayer, Biotest, BioMarin Pharmaceutical Inc, CSL Behring, Daiichi Sankyo, LEO, Novo Nordisk, Octapharma, Pfizer, Roche/Chugai, Sanofi, Takeda/Shire, and Sobi; and service as a clinical trial investigator for Bayer, BioMarin Pharmaceutical Inc, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche/Chugai, Sanofi, Takeda/Shire, Sobi, and uniQure. S.W.P. reports consulting fees from Apcintex, ASC Therapeutics, Bayer, BioMarin Pharmaceutical Inc, CSL Behring, HEMA Biologics, Freeline, Novo Nordisk, Pfizer, Roche/Genentech, Sanofi, Spark Therapeutics, Takeda, and uniQure; and service as a clinical trial investigator for BioMarin Pharmaceutical Inc, Freeline, Genentech/Roche, Sanofi, and uniQure. J.Q. is a former employee of BioMarin Pharmaceutical and may hold stock. H.Y., T.M.R., and W.Y.W. are employees and stockholders of BioMarin Pharmaceutical Inc. C.W.T., H.T., R.Kazmi, and T-L.K. have no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

The therapeutic landscape for people living with hemophilia A (PwHA) has changed dramatically in recent years, but many clinical challenges remain, including the development of inhibitory antibodies directed against factor VIII (FVIII) that occur in approximately 30% of people with severe hemophilia A. Emicizumab, an FVIII mimetic bispecific monoclonal antibody, provides safe and effective bleeding prophylaxis for many PwHA, but clinicians still explore therapeutic strategies that result in immunologic tolerance to FVIII to enable effective treatment with FVIII for problematic bleeding events. This immune tolerance induction (ITI) to FVIII is typically accomplished through repeated long-term exposure to FVIII using a variety of protocols. Meanwhile, gene therapy has recently emerged as a novel ITI option that provides an intrinsic, consistent source of FVIII. As gene therapy and other therapies now expand therapeutic options for PwHA, we review the persistent unmet medical needs with respect to FVIII inhibitors and effective ITI in PwHA, the immunology of FVIII tolerization, the latest research on tolerization strategies, and the role of liver-directed gene therapy to mediate FVIII ITI., Competing Interests: Declaration of competing interests In addition to BioMarin funding for manuscript preparation, the authors report the following competing interests: L.A.V. reports no additional competing interests; M.C.O. reports grants or contracts from BioMarin, Novo Nordisk, Pfizer, Roche, Sanofi, and Takeda; consulting fees from Pfizer; payment or honoraria from BioMarin, Bayer, Novo Nordisk, Roche, and Takeda; support for attending meetings or travel from Roche and Takeda; participation in a Data Safety Monitory Board (DSMB) or advisory board with BioMarin, Bayer, Novo Nordisk, Roche, Sanofi, and Takeda; unpaid council membership with Novo Nordisk Haemophilia Foundation; and paid grants review for Grifols; R.W.H. reports grants from the National Institutes of Health, Luye Pharma, and Spark Therapeutics; royalties or licenses from Takeda; consulting fees from Regeneron and Prevail Therapeutics (Eli Lilly); payment or honoraria from BioMarin and Pfizer; ownership of US patent no. 8063022; and role as Editor-in-Chief of Molecular Therapy; N.S.K. reports consulting fees from BioMarin and CSL Behring; a leadership role with International Society on Thrombosis and Haemostasis; and service as chair of the grants review panel for Novo Nordisk; A.M.P. reports consulting fees from BioMarin; M.V.R. reports grants or contracts from BioMarin, Sanofi, Spark, Takeda, and the National Heart, Lung, and Blood Institute; payment or honoraria from BioMarin, Hemab, Takeda, and the Institute for Economic Review; a leadership role with the Foundation for Women and Girls with Bleeding Disorders; and receipt of study drug from Takeda; B.J.S.-J. reports grants or contracts from Pfizer and Spark; royalties or licenses from Cabaletta; consulting fees from Genentech and Bayer; payment or honoraria from Pfizer; participation in a DSMB or advisory board with GeneVentiv and Amarna; and stock or stock options from GeneVentiv and Amarna; D.L. reports grants or contracts from Bayer, CSL Behring, Sanofi, and Takeda; consulting fees from BioMarin, CSL Behring, Sanofi, and Takeda; and participation in a DSMB or advisory board with Spark., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Long-term efficacy and safety of the extended half-life recombinant factor IX Fc fusion protein (rFIXFc) has been established among previously treated patients with severe hemophilia B in 2 phase 3 trials (B-LONG [#NCT01027364] and Kids B-LONG [#NCT01440946]) and a long-term extension study (B-YOND [#NCT01425723]). In this study, we report post hoc analyses of pooled longitudinal data for up to 6.5 years for rFIXFc prophylaxis. In the B-LONG study, subjects ≥12 years received weekly dose-adjusted prophylaxis (WP; starting dose, 50 IU/kg), individualized interval-adjusted prophylaxis (IP; initially, 100 IU/kg every 10 days), or on-demand dosing. In the Kids B-LONG study, subjects <12 years received 50 to 60 IU/kg every 7 days, adjusted as needed. In the B-YOND study, subjects received WP (20-100 IU/kg every 7 days), IP (100 IU/kg every 8-16 days), modified prophylaxis, or on-demand dosing; switching between treatment groups was permitted. A total of 123 subjects from B-LONG and 30 from Kids B-LONG study were included, of whom 93 and 27, respectively, enrolled in the B-YOND study. The median cumulative duration of treatment was 3.63 years (range, 0.003-6.48 years) in B-LONG/B-YOND and 2.88 years (range, 0.30-4.80 years) in Kids B-LONG/B-YOND group. Annualized bleed rates (ABRs) remained low, annualized factor consumption remained stable, and adherence remained high throughout treatment. Low ABRs were also maintained in subjects with dosing intervals ≥14 days or with target joints at baseline. Complete resolution of evaluable target joints and no recurrence in 90.2% of baseline target joints during follow-up were observed. rFIXFc prophylaxis was associated with sustained clinical benefits, including long-term bleed prevention and target joint resolution, for severe hemophilia B., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Valoctocogene roxaparvovec delivers a B-domain-deleted factor VIII coding sequence with an adeno-associated virus vector to prevent bleeding in persons with severe hemophilia A. The findings of a phase 3 study of the efficacy and safety of valoctocogene roxaparvovec therapy evaluated after 52 weeks in men with severe hemophilia A have been published previously., Methods: We conducted an open-label, single-group, multicenter, phase 3 trial in which 134 men with severe hemophilia A who were receiving factor VIII prophylaxis received a single infusion of 6×10 13 vector genomes of valoctocogene roxaparvovec per kilogram of body weight. The primary end point was the change from baseline in the annualized rate of treated bleeding events at week 104 after receipt of the infusion. The pharmacokinetics of valoctocogene roxaparvovec were modeled to estimate the bleeding risk relative to the activity of transgene-derived factor VIII., Results: At week 104, a total of 132 participants, including 112 with data that were prospectively collected at baseline, remained in the study. The mean annualized treated bleeding rate decreased by 84.5% from baseline (P<0.001) among the participants. From week 76 onward, the trajectory of the transgene-derived factor VIII activity showed first-order elimination kinetics; the model-estimated typical half-life of the transgene-derived factor VIII production system was 123 weeks (95% confidence interval, 84 to 232). The risk of joint bleeding was estimated among the trial participants; at a transgene-derived factor VIII level of 5 IU per deciliter measured with chromogenic assay, we expected that participants would have 1.0 episode of joint bleeding per year. At 2 years postinfusion, no new safety signals had emerged and no new serious adverse events related to treatment had occurred., Conclusions: The study data show the durability of factor VIII activity and bleeding reduction and the safety profile of valoctocogene roxaparvovec at least 2 years after the gene transfer. Models of the risk of joint bleeding suggest that the relationship between transgene-derived factor VIII activity and bleeding episodes is similar to that reported with the use of epidemiologic data for persons with mild-to-moderate hemophilia A. (Funded by BioMarin Pharmaceutical; GENEr8-1 ClinicalTrials.gov number, NCT03370913.)., (Copyright © 2023 Massachusetts Medical Society.)

Hemophilia A (factor VIII [FVIII] deficiency) and hemophilia B (factor IX [FIX] deficiency) are the X-linked recessive bleeding disorders that clinically manifest with recurrent bleeding, predominantly into muscles and joints. In its severe presentation, when factor activity is less than 1% of normal, hemophilia presents with spontaneous musculoskeletal bleeds and may progress to debilitating chronic arthropathy. Management of hemophilia has changed profoundly in the past decades. From on-demand to prophylactic factor concentrate replacement, the treatment goal shifted from controlling bleeds to preventing bleeds and improving quality of life. In this new scenario, gene therapy has arisen as a paradigm-changing therapeutic option, a one-time treatment with the potential to achieve sustained coagulation FVIII or FIX expression even within the normal range. This review discusses the critical impact of adeno-associated virus (AAV) gene transfer in hemophilia care, including the recent clinical outcomes, changes in disease perceptions, and its treatment burden. We also discuss the challenging scenario of the AAV-directed immune response in the clinical setting and potential strategies to improve the long-lasting efficacy of hemophilia gene therapy efficacy.

PUPs A-LONG evaluated the safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in previously untreated patients (PUPs) with hemophilia A. This open-label, phase 3 study enrolled male PUPs (<6 years) with severe hemophilia A to receive rFVIIIFc. The primary endpoint was the occurrence of inhibitor development. Secondary endpoints included annualized bleed rate (ABR). Of 103 subjects receiving ≥1 dose of rFVIIIFc, 80 (78%) were aged <1 year at the study start, 20 (19%) had a family history of inhibitors, and 82 (80%) had high-risk F8 mutations. Twenty subjects began on prophylaxis, while 81 began an on-demand regimen (69 later switched to prophylaxis). Eighty-seven (81%) subjects completed the study. Inhibitor incidence was 31.1% (95% confidence interval [CI], 21.8% to 41.7%) in subjects with ≥10 exposure days (or inhibitor); high-titer inhibitor incidence was 15.6% (95% CI, 8.8% to 24.7%). The median (range) time to high-titer inhibitor development was 9 (4-14) exposure days. Twenty-eight (27%) subjects experienced 32 rFVIIIFc treatment-related adverse events; most were inhibitor development. There was 1 nontreatment-related death due to intracranial hemorrhage (onset before the first rFVIIIFc dose). The overall median (interquartile range [IQR]) ABR was 1.49 (0.00-4.40) for subjects on variable prophylaxis dosing regimens. In this study of rFVIIIFc in pediatric PUPs with severe hemophilia A, overall inhibitor development was within the expected range, although high-titer inhibitor development was on the low end of the range reported in the literature. rFVIIIFc was well-tolerated and effective for prophylaxis and treatment of bleeds. This trial is registered at www.clinicaltrials.gov (NCT02234323)., (© 2022 by The American Society of Hematology.)

Hemophilia, von Willebrand disease (VWD), and thrombotic thrombocytopenic purpura (TTP) are rare diseases affecting normal hemostasis. Although they differ in their pathogenesis and clinical manifestation, if left undiagnosed and untreated, all these conditions can result in severe long-term consequences and can be potentially life-threatening. This article summarizes a poster series funded by Takeda and presented virtually at the 29th annual congress of the International Society on Thrombosis and Haemostasis (ISTH) in 2021: Data from real-world evidence highlight the importance of joint health and personalized prophylaxis to prevent bleeding for patients with hemophilia, the need to further raise disease awareness in support of timely diagnosis and access to treatment in general practice settings for patients with VWD, and describe the clinical burden for patients with TTP and the importance to advance treatment options for these patients.

Introduction: Gene therapy is emerging as a potential cure for haemophilia. Gene therapy is a one-time treatment that can elevate factor levels for many years and minimize or eliminate the need for clotting factor concentrate (CFC) replacement therapy. However, there is a paucity of reports on gene therapy efforts in countries outside of North America or Europe, especially in low-and-middle-income countries (LMIC). All indications are that gene therapy will be one of standard care treatments for haemophilia in the future. Still, it may not be accessible to many countries due to various barriers and challenges. At the same time, each country may formulate solutions that may be used globally., Aim: To summarize the approaches taken to establish haemophilia gene therapy in Japan, China, India, South Africa, and Brazil, and to describe the US-initiated multi-LMIC haemophilia gene therapy development program to include Peru, Vietnam, Thailand, Nepal, and Sri Lanka., Methods: A review of related published information or as accessible by each country's author., Results: Different starting conditions, differing input and level of support from the multitude of stakeholders, and strong leadership have led to various approaches for facilitating research and developing needed infrastructure and regulatory and financing models. Gene therapy programs are at various stages of development and include both adeno-associated viral and lentiviral vectors., Conclusion: Global partnerships and collaboration, exchange of knowledge and experience, and alignment of processes across borders will promote further progress towards global access to gene therapy for haemophilia., (© 2022 John Wiley & Sons Ltd.)

Adeno-associated virus (AAV)-mediated gene therapy may provide durable protection from bleeding events and reduce treatment burden for people with hemophilia A (HA). However, pre-existing immunity against AAV may limit transduction efficiency and hence treatment success. Global data on the prevalence of AAV serotypes are limited. In this global, prospective, noninterventional study, we determined the prevalence of pre-existing immunity against AAV2, AAV5, AAV6, AAV8, and AAVrh10 among people ≥12 years of age with HA and residual FVIII levels ≤2 IU/dL. Antibodies against each serotype were detected using validated, electrochemiluminescent-based enzyme-linked immunosorbent assays. To evaluate changes in antibody titers over time, 20% of participants were retested at 3 and 6 months. In total, 546 participants with HA were enrolled at 19 sites in 9 countries. Mean (standard deviation) age at enrollment was 36.0 (14.87) years, including 12.5% younger than 18 years, and 20.0% 50 years of age and older. On day 1, global seroprevalence was 58.5% for AAV2, 34.8% for AAV5, 48.7% for AAV6, 45.6% for AAV8, and 46.0% for AAVrh10. Considerable geographic variability was observed in the prevalence of pre-existing antibodies against each serotype, but AAV5 consistently had the lowest seroprevalence across the countries studied. AAV5 seropositivity rates were 51.8% in South Africa ( n  = 56), 46.2% in Russia ( n  = 91), 40% in Italy ( n  = 20), 37.2% in France ( n  = 86), 26.8% in the United States ( n  = 71), 26.9% in Brazil ( n  = 26), 28.1% in Germany ( n  = 89), 29.8% in Japan ( n  = 84), and 5.9% in the United Kingdom ( n  = 17). For all serotypes, seropositivity tended to increase with age. Serostatus and antibody titer were generally stable over the 6-month sampling period. As clinical trials of AAV-mediated gene therapies progress, data on the natural prevalence of antibodies against various AAV serotypes may become increasingly important.

Background: Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) is an adeno-associated virus 5 (AAV5)-based gene-therapy vector containing a coagulation factor VIII complementary DNA driven by a liver-selective promoter. The efficacy and safety of the therapy were previously evaluated in men with severe hemophilia A in a phase 1-2 dose-escalation study., Methods: We conducted an open-label, single-group, multicenter, phase 3 study to evaluate the efficacy and safety of valoctocogene roxaparvovec in men with severe hemophilia A, defined as a factor VIII level of 1 IU per deciliter or lower. Participants who were at least 18 years of age and did not have preexisting anti-AAV5 antibodies or a history of development of factor VIII inhibitors and who had been receiving prophylaxis with factor VIII concentrate received a single infusion of 6×10 13 vector genomes of valoctocogene roxaparvovec per kilogram of body weight. The primary end point was the change from baseline in factor VIII activity (measured with a chromogenic substrate assay) during weeks 49 through 52 after infusion. Secondary end points included the change in annualized factor VIII concentrate use and bleeding rates. Safety was assessed as adverse events and laboratory test results., Results: Overall, 134 participants received an infusion and completed more than 51 weeks of follow-up. Among the 132 human immunodeficiency virus-negative participants, the mean factor VIII activity level at weeks 49 through 52 had increased by 41.9 IU per deciliter (95% confidence interval [CI], 34.1 to 49.7; P<0.001; median change, 22.9 IU per deciliter; interquartile range, 10.9 to 61.3). Among the 112 participants enrolled from a prospective noninterventional study, the mean annualized rates of factor VIII concentrate use and treated bleeding after week 4 had decreased after infusion by 98.6% and 83.8%, respectively (P<0.001 for both comparisons). All the participants had at least one adverse event; 22 of 134 (16.4%) reported serious adverse events. Elevations in alanine aminotransferase levels occurred in 115 of 134 participants (85.8%) and were managed with immune suppressants. The other most common adverse events were headache (38.1%), nausea (37.3%), and elevations in aspartate aminotransferase levels (35.1%). No development of factor VIII inhibitors or thrombosis occurred in any of the participants., Conclusions: In patients with severe hemophilia A, valoctocogene roxaparvovec treatment provided endogenous factor VIII production and significantly reduced bleeding and factor VIII concentrate use relative to factor VIII prophylaxis. (Funded by BioMarin Pharmaceutical; GENEr8-1 ClinicalTrials.gov number, NCT03370913.)., (Copyright © 2022 Massachusetts Medical Society.)

Introduction: Recurrent joint bleeds in haemophilia patients often cause musculoskeletal changes leading to functional capacity impairment., Aim: In this study, we assessed the effects of aquatic activities performed to improve functional capacity in these patients., Methods: The interventional protocol consisted of 24 hydrotherapy sessions during three months, in comparison with 24 swimming sessions. The pre- and post-intervention assessment consisted of Functional Independence Score, haemophilia joint health score (HJHS), Pediatric Haemophilia Activities List (PedHAL), surface electromyography (SEMG) of thigh muscles to assess muscle electric activity, and load cell on extensor and flexor thigh muscles to evaluate muscular strength., Results: Forty-seven haemophilia patients were enrolled in this study, and 32 (23 severe haemophilia A, one moderate haemophilia A and 8 severe haemophilia B), median age 12y (6 to 40y), concluded the aquatic intervention. We observed a statistically significant increase with substantial improvement in functional capacity in the pre- and post-intervention evaluation of hydrotherapy in comparison with the swimming protocol, with HJHS (p = .006 and p = .001 respectively), PedHAL (Sum score) (p = .022 and p = .001) and score FISH (p = .021). The swimming group revealed significant improvements in muscular strength, in all muscles tested (p = .005 and p = .001). SEMG signal amplitude reached significantly higher levels in all muscles evaluated after both interventions except for the vastus medialis (right) in the hydrotherapy group., Conclusion: Our results concluded that both swimming and hydrotherapy were associated with physical improvement in haemophilia patients; however, only hydrotherapy lead to a more significant improvement in functional capacity., (© 2021 John Wiley & Sons Ltd.)

Background: von Willebrand disease (VWD) is a common inherited bleeding disorder. Significant variability exists in management options offered to patients., Objective: These evidence-based guidelines from the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the National Hemophilia Foundation (NHF), and the World Federation of Hemophilia (WFH) are intended to support patients, clinicians, and health care professionals in their decisions about management of VWD., Methods: ASH, ISTH, NHF, and WFH formed a multidisciplinary guideline panel. Three patient representatives were included. The panel was balanced to minimize potential bias from conflicts of interest. The University of Kansas Outcomes and Implementation Research Unit and the McMaster Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline development process, including performing and updating systematic evidence reviews (through November 2019). The panel prioritized clinical questions and outcomes according to their importance to clinicians and patients. The panel used the GRADE approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment., Results: The panel agreed on 12 recommendations and outlined future research priorities., Conclusions: These guidelines make key recommendations regarding prophylaxis for frequent recurrent bleeding, desmopressin trials to determine therapy, use of antiplatelet agents and anticoagulant therapy, target VWF and factor VIII activity levels for major surgery, strategies to reduce bleeding during minor surgery or invasive procedures, management options for heavy menstrual bleeding, management of VWD in the context of neuraxial anesthesia during labor and delivery, and management in the postpartum setting., (© 2021 by The American Society of Hematology.)

Hemophilia is a monogenic disease with robust clinicolaboratory correlations of severity. These attributes coupled with the availability of experimental animal models have made it an attractive model for gene therapy. The road from animal models to human clinical studies has heralded significant successes, but major issues concerning a previous immunity against adeno-associated virus and transgene optimization remain to be fully resolved. Despite significant advances in gene therapy application, many questions remain pertaining to its use in specific populations such as those with factor inhibitors, those with underlying liver disease, and pediatric patients. Here, the authors provide an update on viral vector and transgene improvements, review the results of recently published gene therapy clinical trials for hemophilia, and discuss the main challenges facing investigators in the field., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Fanhdi/Alphanate is a plasma derived factor VIII concentrate used for treating hemophilia A, for which there has not been any dedicated model describing its pharmacokinetics (PK). A population PK model was developed using data extracted from the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) project. WAPPS-Hemo provided individual PK profiles for hemophilia patients using sparse observations as provided in routine clinical care by hemophilia centers. Plasma factor activity measurements and covariate data from hemophilia A patients on Fanhdi/Alphanate were extracted from the WAPPS-Hemo database. A population PK model was developed using NONMEM and evaluated for suitability for Bayesian forecasting using prediction-corrected visual predictive check (pcVPC), cross validation, limited sampling analysis and external evaluation against a population PK model developed on rich sampling data. Plasma factor activity measurements from 92 patients from 12 centers were used to derive the model. The PK was best described by a 2-compartment model including between subject variability on clearance and central volume, fat free mass as a covariate on clearance, central and peripheral volumes, and age as covariate on clearance. Evaluations showed that the developed population PK model could predict the PK parameters of new individuals based on limited sampling analysis and cross and external evaluations with acceptable precision and bias. This study shows the feasibility of using real-world data for the development of a population PK model. Evaluation and comparison of the model for Bayesian forecasting resulted in similar results as a model developed using rich sampling data.

Introduction: The international Haemophilia Experiences, Results and Opportunities (HERO) study assessed the psychosocial aspects of life for people with haemophilia (PWH) and their caregivers in several countries. Brazil was not included in this initiative., Aim and Methods: An observational, multicentre, cross-sectional study was performed involving PWH (moderate-to-severe haemophilia) and their caregivers, from November 2014 to July 2015. The primary objective was to quantify the extent of the primary psychosocial factors affecting PWH in their everyday life. Descriptive statistics and comparisons between Brazilian and global respondents are presented., Results: A total of 100 adult male PWH and 100 caregivers (responding on behalf of their oldest affected child aged <18 years) completed the survey. Sixty-eight per cent of the PWH had haemophilia A without inhibitors. Chronic pain and hepatitis C were the most common conditions related to haemophilia. On the EQ-5D assessment, 64% of PWH reported extreme/moderate pain. Treatment for depression or anxiety was reported by 18% of PWH and by 29% of caregivers. There was a lower employment rate for PWH in Brazil, compared to the countries included in the original HERO survey (51% vs 60%); 71% of PWH stated that haemophilia has a negative impact on their work. Over the previous 5 years, 58% of PWH and 68% of caregivers did not have difficulties in obtaining the concentrated factor for treatment., Conclusions: Our study presents an overview of the psychosocial aspects of life with haemophilia in Brazil, providing a basis for health policy decisions and may further improve comprehensive care for PWH., (© 2019 John Wiley & Sons Ltd.)

Introduction: Turoctocog alfa is a recombinant factor VIII (FVIII) molecule, approved for treatment and prophylaxis of bleeding in patients with haemophilia A. In the guardian 1 (adolescents/adults) and guardian 3 (children) phase 3 trials, turoctocog alfa demonstrated a favourable efficacy and safety profile. Guardian 1 or 3 completers could enrol in the guardian 2 extension. Final guardian 2 results are reported here., Aim: Investigate long-term safety and efficacy of turoctocog alfa administered for prophylaxis and treatment of bleeds., Methods: In this phase 3b open-label trial, previously treated males of all ages with severe haemophilia A received prophylaxis regimens of turoctocog alfa or on-demand treatment of bleeds. The primary safety endpoint was frequency of FVIII inhibitor development. Efficacy endpoints included annualized bleeding rate (ABR) during prophylaxis, haemostatic response in treatment of bleeds and number of injections required to treat bleeds., Results: Overall, 213 patients were dosed with turoctocog alfa; 207 patients received prophylaxis; 19 received on-demand treatment. No FVIII inhibitors (≥0.6 BU) were reported. For all patients on prophylaxis, overall median ABR was 1.37 bleeds/y; success rate for treatment of bleeds was 90.2%; and 88.2% of bleeds were controlled with 1-2 injections of turoctocog alfa. For the on-demand regimen, overall median ABR was 30.44 bleeds/y; success rate for treatment of bleeds was 96.7%; and 94.9% of bleeds were controlled with 1-2 injections of turoctocog alfa., Conclusion: Extended use of turoctocog alfa is safe and effective for prevention and treatment of bleeding episodes in previously treated patients with haemophilia A across all ages., (© 2018 The Authors. Haemophilia Published by John Wiley & Sons Ltd.)

Introduction: The study is the first application of the Principles of Haemophilia Care for Europe (PHCE) in other regions of the world, specifically in Latin America., Objective: To identify strengths in the care of haemophilia, and the aspects that should be improved., Methods: The information was obtained through a questionnaire designed according to the PHCE and answered by specialists in mid-2016. The countries included were as follows: Argentina, Brazil, Chile, Colombia, Costa Rica, El Salvador, Mexico, Panama, Dominican Republic and Venezuela., Results: In most countries, there is a central organization for haemophilia care supported by local groups. The existence of a national registry of people with haemophilia (PWH) was verified in eight countries. Centres of integrated care are located in large cities. In the majority of countries, there was no evidence of the participation of multiple actors in the decision-making. The supply of factor concentrates presents constraints, although it is reported as adequate in half of the countries. In most countries, home treatment is available under special conditions. In most countries, there are restrictions on the use of prophylaxis. The coordination of specialized and emergency services depends on each centre. Unrestricted treatment of inhibitors is performed in most countries. In all countries, there are human resources training programmes; however, clinical and health services researches are not widely developed., Conclusion: The study identifies the initial situation of principles of care, as well as the alternatives that must be implemented to achieve improvements in the quality of life of PWH in the region., (© 2018 John Wiley & Sons Ltd.)

Turoctocog alfa is an approved B-domain truncated recombinant factor VIII concentrate for adults and children with haemophilia A. Clinical data for turoctocog alfa have been reported from the guardian(™) 1, guardian(™) 2 and guardian(™) 3 phase III trials. guardian(™) 1 and guardian(™) 3 phase III trials enrolled 150 adolescents/adults (≥ 12 yr), and 63 children (<12 yr), respectively, with previously treated severe haemophilia A and no history of inhibitors; 188 of these patients continued into the ongoing guardian(™) 2 extension trial. In the three trials, patients have received prophylaxis with turoctocog alfa three times weekly or every second day, with breakthrough bleeds resolved to an expected postinjection level of ≥ 0.50 IU/mL. No safety concerns have arisen, and no patients have developed confirmed inhibitors (primary endpoint). Indeed, no confirmed inhibitors have been detected in >200 patients treated for a cumulative total of >54,000 exposure days in the phase III trials. Pooled efficacy data show a favourable long-term effect of turoctocog alfa on annualised bleeding rate and a success rate for haemostatic response of 86%; 90% of bleeds were resolved with 1-2 doses. This article reviews the clinical development of turoctocog alfa with reference to the guardian(™) clinical programme, describing results obtained to date and ongoing trials., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Nijmegen-Bethesda assay is the gold standard to assess inhibitory antibodies against factor (F) VIII. This method has some limitations, including high coefficient of variation and possible interference of residual endogenous or exogenous factor VIII. Heat-treatment of samples at 56 °C for 30 min could be a strategy to improve the sensitivity of this test. The aim of this study was to compare inhibitor quantification in hemophilia patients with and without inhibitor performed in previously heated and non-heated samples. A total of 109 analyses from 46 patients with severe hemophilia A were performed. Patients were divided into three groups: 20 patients with no history of inhibitor, recently and not recently exposed to FVIII (group I), 21 patients with history of inhibitor not exposed to FVIII (group II), and 5 patients (68 samples) undergoing an immune tolerance induction (ITI) protocol (group III). For patients with no history of inhibitor, heat-treatment did not modify the results (p=0.24). However, differences in inhibitor levels between heated and non-heated samples were observed in patients with history of inhibitor (group II, p<0.05) and in patients in ITI (group III, p<0.001). In 11 samples, inhibitor quantification shifted from negative to positive. Additionally, a longitudinal evaluation of each ITI patient showed similar trend line for the results of heated and non-heated samples. In this study, we demonstrated that heating samples increase sensitivity of Nijmegen-Bethesda assay, with no shift from negative to positive results in patients with no history of inhibitor. Furthermore, this procedure has an important role to patients undergoing an ITI protocol., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The availability of recombinant activated factor VII (rFVIIa, eptacog alfa activated) has greatly advanced the care of patients with haemophilia A or B who have developed inhibitors against the infused replacement factor. Recombinant FVIIa is licensed for the on-demand treatment of bleeding episodes and the prevention of bleeding in surgery or invasive procedures in patients with congenital haemophilia with inhibitors. This article attempts to review in detail the extensive evidence of rFVIIa in congenital haemophilia patients with inhibitors. Patients with acute bleeding episodes are best treated on demand at home, to achieve the short- and long-term benefits of rapid bleed control. Key prospective studies have shown that rFVIIa achieves consistently high efficacy rates in the management of acute (including joint) bleeds in inhibitor patients in the home treatment setting. Substantial post-approval data from key registries also support the on-demand efficacy profile of rFVIIa established by the prospective clinical trials. The availability of rFVIIa has allowed major surgery to become a reality for inhibitor patients. Studies in key surgery, including orthopaedic procedures, have found that rFVIIa provides consistently high efficacy rates. Importantly, the wealth of data does not raise any unexpected safety concerns surrounding rFVIIa use; this is likely because rFVIIa is a recombinant product with a localised mechanism of action at the site of vascular injury. In summary, rFVIIa is established as an effective and well-tolerated first-line treatment for on-demand bleeding control and bleed prevention during minor and major (including elective orthopaedic) surgery in inhibitor patients. Use of rFVIIa has been a major step towards narrowing the gap in outcomes between inhibitor patients and non-inhibitor patients., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Ex vivo gene therapy strategies avoid systemic delivery of viruses thereby mitigating the risk of vector-associated immunogenicity. Previously, we delivered autologous factor VIII (FVIII)-expressing blood outgrowth endothelial cells (BOECs) to hemophilia A mice and showed that these cells remained sequestered within the implanted matrix and provided therapeutic levels of FVIII. Prior to translating this strategy into the canine (c) model of hemophilia A, we increased cFVIII transgene expression by at least 100-fold with the use of the elongation factor 1 alpha (EF1α) promoter and a strong endothelial enhancer element. BOECs isolated from hemophilia A dogs transduced with this lentiviral vector express levels of cFVIII ranging between 1.0 and 1.5 U/mL per 10(6) cells over 24 hours. Autologous BOECs have been implanted into the omentum of 2 normal and 3 hemophilia A dogs. These implanted cells formed new vessels in the omentum. All 3 hemophilia A dogs treated with FVIII-expressing autologous BOECs developed anti-FVIII immunoglobulin G2 antibodies, but in only 2 of the dogs were these antibodies inhibitory. FVIII antigen levels >40% in the absence of FVIII coagulant function were detected in the circulation for up to a year after a single gene therapy treatment, indicating prolonged cellular viability and synthesis of FVIII., (© 2014 by The American Society of Hematology.)

Patients with hemophilia are considered low risk for thromboembolic complications. However, in the presence of risk factors for thrombosis, such as surgical procedures, and intensive replacement therapy this complication has been reported. Major orthopedic surgeries are often required in patients with hemophilia, due to the presence of hemophiliac arthropathy. In individuals that do not have hemophilia, orthopedic surgeries are particularly well recognized as high risk for venous thromboembolism, and the use of thromboprophylaxis for this condition is recommended. However, for hemophilia patients the use of venous thrombosis prophylaxis during major surgeries, including orthopedic procedures remains controversial. For the majority of the patients the use of gradated compression stockings and early mobilization can be sufficient to prevent venous thromboembolism. The use of anticoagulant prophylaxis should be considered just for patients with relevant additional risk factor for thrombosis. However, for hemophilia patients with inhibitor, pharmacologic thromboprophylaxis is not recommended. For patients with von Willebrand disease receiving factor concentrates replacement therapy undergoing surgical procedures, the FVIII plasma levels should be monitored and thromboprophylaxis should be considered if any other thrombosis risk factor is present. It is important for the future to establish risk assessment tools that can help to determine the most effective and safe practice to prevent venous thrombosis in patients with hemophilia and other bleeding disorders who undergo surgical procedures., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Projects are underway in many developing countries to try to improve the provision of treatment and access to care for people with haemophilia (PWH), as long-term prophylactic treatment, which improves quality of life for PWH, is still restricted to developed countries. In most developing countries, therapy is limited to on-demand treatment or even no replacement treatment at all. Combined with limited healthcare resources, this lack of treatment can lead to a vicious circle of lack of care, disability, unemployment and lack of access to health insurance for haemophilia patients. In China, the establishment of the Haemophilia Treatment Centre Collaborative Network of China (HTCCNC), in conjunction with the World Federation of Hemophilia, has improved haemophilia care and the identification of PWH. In Brazil, on-demand treatment has improved the health of PWH but does not prevent musculoskeletal (MSK) complications, the major cause of deterioration in quality of life for PWH. The Novo Nordisk Haemophilia Foundation BR2 project was therefore designed to improve quality of life of PWH through improvements in their physical, mental and social wellbeing. This paper will briefly review these projects and describe the current status of haemophilia care in these countries. While there is still a long way to go before optimal care becomes a reality for all PWH in developing countries, significant progress has been made, and knowledge of the impact and outcomes of these projects can inform best practice worldwide., (© 2012 Blackwell Publishing Ltd.)

The objective to use gene therapy to provide sustained, therapeutic levels of factor VIII (FVIII) for hemophilia A is compromised by the emergence of inhibitory antibodies that prevent FVIII from performing its essential function as a cofactor for factor IX (FIX). FVIII appears to be more immunogenic than FIX and an immune response is associated more frequently with FVIII than FIX gene therapy strategies. We have evaluated a modified lentiviral delivery strategy that facilitates liver-restricted transgene expression and prevents off-target expression in hematopoietic cells by incorporating microRNA (miRNA) target sequences. In contrast to outcomes using this strategy to deliver FIX, this modified delivery strategy was in and of itself insufficient to prevent an anti-FVIII immune response in treated hemophilia A mice. However, pseudotyping the lentivirus with the GP64 envelope glycoprotein, in conjunction with a liver-restricted promoter and a miRNA-regulated FVIII transgene resulted in sustained, therapeutic levels of FVIII. These modifications to the lentiviral delivery system effectively restricted FVIII transgene expression to the liver. Plasma levels of FVIII could be increased to around 9% that of normal levels when macrophages were depleted prior to treating the hemophilia A mice with the modified lentiviral FVIII delivery system.

Inhibitory antibodies to factor VIII (FVIII) are a major complication in the treatment of hemophilia A, affecting approximately 20% to 30% of patients. Current treatment for inhibitors is based on long-term, daily injections of large amounts of FVIII protein. Liver-directed gene therapy has been used to induce antigen-specific tolerance, but there are no data in hemophilic animals with pre-existing inhibitors. To determine whether sustained endogenous expression of FVIII could eradicate inhibitors, we injected adeno-associated viral vectors encoding canine FVIII (cFVIII) in 2 strains of inhibitor hemophilia A dogs. In 3 dogs, a transient increase in inhibitor titers (up to 7 Bethesda Units [BU]) at 2 weeks was followed by continuous decline to complete disappearance within 4-5 weeks. Subsequently, an increase in cFVIII levels (1.5%-8%), a shortening of clotting times, and a reduction (> 90%) of bleeding episodes were observed. Immune tolerance was confirmed by lack of antibody formation after repeated challenges with cFVIII protein and normal protein half-life. A fourth dog exhibited a strong early anamnestic response (216 BU), with slow decline to 0.8 BU and cFVIII antigen detection by 18 months after vector delivery. These data suggest that liver gene therapy has the potential to eradicate inhibitors and could improve the outcomes of hemophilia A patients.

In today's developing world, how do we define a "developing country"? What level of effort and resources is invested in diagnosis, patient care, and research in those countries that we define to be developing? In particular, what is the situation with respect to molecular genetic testing in these countries? How much has been achieved to date, and what are the challenges to further achievements? This article describes the current status, challenges, and future hopes with respect to molecular genetic testing in hemostasis and thrombosis from the perspective of experts from three countries: Brazil, Colombia, and Iran. These individuals have lived and practiced genetic testing in their countries and have also had the experience to work and/or interact with the developed world to enable an appreciation of the difference.

The Committee of Latin America on the Therapeutics of Inhibitor Groups (CLOTTING) is composed of a number of hemophilia specialists from Latin America. The group aims to encourage the adoption of a good standard of care for Latin American patients with hemophilia. The occurrence of inhibitors in patients with hemophilia poses clinical challenges, and it is estimated that between 1000 and 3000 patients in Latin America are affected by hemophilia with inhibitors. There is an urgent need to establish a regional consensus and clinical guidelines for the diagnosis and treatment of these patients. We present an extensive review based on best current clinical practice and published literature, as seen from a Latin American perspective, taking into account the variable nature of hemophilia care available in the various countries in this Region.

Purpose: Periodontal disease in patients with hemorrhagic disorders may lead to severe bleeding during dental treatment. This study evaluated the clinical impact of oral health indexes in hemophilic patients undergoing tooth extraction., Patients and Methods: Thirty-one hemophilic patients underwent teeth extractions using autologous fibrin glue and an oral antifibrinolytic drug (epsilon-aminocaproic acid). Oral health indexes (plaque, PI; gingival, GI; and decay-missing-filling-teeth, DMFT index) were evaluated before tooth extraction., Results: Postsurgical bleeding episodes were observed in 6 hemophilic patients (1 severe, 3 moderate, and 2 mild type). The PI and GI index in the bleeding group were 1.8 and 1.7, respectively, and 1.8 for both of the non-bleeding groups (PI, P = .8; GI, P = .56). The global DMFT index was 18 in the bleeding group and 19.6 in the non-bleeding group (P = .67)., Conclusion: The status of oral health did not interfere with bleeding caused by dental extraction of hemophilic patients.

We have previously shown that a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic levels of F.IX in dogs with severe hemophilia B. We carried out a phase 1/2 dose-escalation clinical study to extend this approach to humans with severe hemophilia B. rAAV-2 vector expressing human F.IX was infused through the hepatic artery into seven subjects. The data show that: (i) vector infusion at doses up to 2 x 10(12) vg/kg was not associated with acute or long-lasting toxicity; (ii) therapeutic levels of F.IX were achieved at the highest dose tested; (iii) duration of expression at therapeutic levels was limited to a period of approximately 8 weeks; (iv) a gradual decline in F.IX was accompanied by a transient asymptomatic elevation of liver transaminases that resolved without treatment. Further studies suggested that destruction of transduced hepatocytes by cell-mediated immunity targeting antigens of the AAV capsid caused both the decline in F.IX and the transient transaminitis. We conclude that rAAV-2 vectors can transduce human hepatocytes in vivo to result in therapeutically relevant levels of F.IX, but that future studies in humans may require immunomodulation to achieve long-term expression.