Efanesoctocog Alfa Prophylaxis for Patients with Severe Hemophilia A.

BACKGROUND: Efanesoctocog alfa provides high sustained factor VIII activity by overcoming the von Willebrand factor-imposed half-life ceiling. The efficacy, safety, and pharmacokinetics of efanesoctocog alfa for prophylaxis and treatment of bleeding episodes in previously treated patients with severe hemophilia A are unclear. METHODS: We conducted a phase 3 study involving patients 12 years of age or older with severe hemophilia A. In group A, patients received once-weekly prophylaxis with efanesoctocog alfa (50 IU per kilogram of body weight) for 52 weeks. In group B, patients received on-demand treatment with efanesoctocog alfa for 26 weeks, followed by once-weekly prophylaxis with efanesoctocog alfa for 26 weeks. The primary end point was the mean annualized bleeding rate in group A; the key secondary end point was an intrapatient comparison of the annualized bleeding rate during prophylaxis in group A with the rate during prestudy factor VIII prophylaxis. Additional end points included treatment of bleeding episodes, safety, pharmacokinetics, and changes in physical health, pain, and joint health. RESULTS: In group A (133 patients), the median annualized bleeding rate was 0 (interquartile range, 0 to 1.04), and the estimated mean annualized bleeding rate was 0.71 (95% confidence interval [CI], 0.52 to 0.97). The mean annualized bleeding rate decreased from 2.96 (95% CI, 2.00 to 4.37) to 0.69 (95% CI, 0.43 to 1.11), a finding that showed superiority over prestudy factor VIII prophylaxis (P<0.001). A total of 26 patients were enrolled in group B. In the overall population, nearly all bleeding episodes (97%) resolved with one injection of efanesoctocog alfa. Weekly prophylaxis with efanesoctocog alfa provided mean factor VIII activity of more than 40 IU per deciliter for the majority of the week and of 15 IU per deciliter at day 7. Prophylaxis with efanesoctocog alfa for 52 weeks (group A) improved physical health (P<0.001), pain intensity (P = 0.03), and joint health (P = 0.01). In the overall study population, efanesoctocog alfa had an acceptable side-effect profile, and the development of inhibitors to factor VIII was not detected. CONCLUSIONS: In patients with severe hemophilia A, once-weekly efanesoctocog alfa provided superior bleeding prevention to prestudy prophylaxis, normal to near-normal factor VIII activity, and improvements in physical health, pain, and joint health. (Funded by Sanofi and Sobi; XTEND-1 ClinicalTrials.gov number, NCT04161495.).

Immune tolerance against infused FVIII in hemophilia A is mediated by PD-L1+ Tregs.

A major complication of hemophilia A therapy is the development of alloantibodies (inhibitors) that neutralize intravenously administered coagulation factor VIII (FVIII). Immune tolerance induction therapy (ITI) by repetitive FVIII injection can eradicate inhibitors, and thereby reduce morbidity and treatment costs. However, ITI success is difficult to predict and the underlying immunological mechanisms are unknown. Here, we demonstrated that immune tolerance against FVIII under nonhemophilic conditions was maintained by programmed death (PD) ligand 1-expressing (PD-L1-expressing) regulatory T cells (Tregs) that ligated PD-1 on FVIII-specific B cells, causing them to undergo apoptosis. FVIII-deficient mice injected with FVIII lacked such Tregs and developed inhibitors. Using an ITI mouse model, we found that repetitive FVIII injection induced FVIII-specific PD-L1+ Tregs and reengaged removal of inhibitor-forming B cells. We also demonstrated the existence of FVIII-specific Tregs in humans and showed that such Tregs upregulated PD-L1 in patients with hemophilia after successful ITI. Simultaneously, FVIII-specific B cells upregulated PD-1 and became killable by Tregs. In summary, we showed that PD-1-mediated B cell tolerance against FVIII operated in healthy individuals and in patients with hemophilia A without inhibitors, and that ITI reengaged this mechanism. These findings may impact monitoring of ITI success and treatment of patients with hemophilia A.

Plasma-derived FVIII/VWF complex shows higher protection against inhibitors than isolated FVIII after infusion in haemophilic patients: A translational study.

INTRODUCTION: Presence of von Willebrand factor (VWF) in FVIII concentrates offers protection against neutralizing inhibitors in haemophilia A (HA). Whether this protection is more evident in plasma-derived (pd) FVIII/VWF or recombinant (r) FVIII concentrates remains controversial. AIM: We investigated the protection exerted by VWF against FVIII inhibitors in an in vivo mouse model of HA exposed to pdFVIII/VWF or to various rFVIII concentrates. METHODS: Haemophilia A mice received the different FVIII concentrates after administration of vehicle or an inhibitory IgG purified from a commercial pool of HA plasma with inhibitors and FVIII:C recoveries were measured. Furthermore, using a novel clinically oriented ex vivo approach, Bethesda inhibitory activities (BU) of a commercial pool of HA plasma with inhibitors were assessed using normal plasma, or plasma from severe HA patients, without inhibitors, after treatment with the same concentrates. RESULTS: in vivo studies showed that pdFVIII/VWF offers markedly higher protection against inhibitors when compared with any of the FVIII products without VWF. More importantly, in the ex vivo studies, plasma from patients treated with pdFVIII/VWF showed higher protection against inhibitors (P values ranging .05-.001) in comparison with that observed in plasma from patients who received FVIII products without VWF, regardless of the type of product evaluated. CONCLUSION: Data indicate that FVIII+VWF complexes assembled in the circulation after rFVIII infusion are not equivalent to the naturally formed complex in pdFVIII/VWF. Therefore, rFVIII infused into HA patients with inhibitors would be less protected by VWF than the FVIII in pdFVIII/VWF concentrates.

Effectiveness of long-term prophylaxis using pdFVIII/VWF concentrate in patients with inherited von Willebrand disease.

BACKGROUND: Patients with symptomatic von Willebrand disease (VWD) should be offered long-term prophylaxis (LTP) to prevent recurrent bleedings. Our objective was to evaluate the effectiveness and safety of Voncento®, a plasma-derived FVIII/VWF concentrate (ratio 1:2.4), administrated in LTP. METHODS: We included patients from the OPALE study (May 2016 to April 2021), a French multicenter observational study following patients with inherited VWD, who received a Voncento® LTP during the study period. RESULTS: Among the 130 OPALE-study patients, 23 patients (12 women) received a LTP and were therefore included. The median (range) age was 16 (1-85) years; 16 patients were type 3, 1 was type 2A, 6 were type 2B. Before inclusion, 19 (83%) were under LTP and 4 (17%) received on-demand (OD) treatment. The indications for initiating prophylaxis in the overall population were joint bleeding (43%), ear, nose, and throat (ENT) bleeding including epistaxis or oral bleeding (39%), and recurrent muscle hematoma (22%). The medians (ranges) dose of Voncento® per infusion, frequency, and weekly dose were 45 (33-109) IU/kg, 2 infusions per week, and 96 (44-222) IU/kg/week, respectively. The median (range) annualized bleeding rate (ABR) was 0.8, 0.7 (0-3.5), and 0 (0-2.3) for type 2A, 2B, 3 patients, respectively. There was no difference regarding to the dose, frequency of infusion, or in terms of ABR in 9/19 patients who replaced previous concentrates with Voncento®. During the study period, no adverse event was reported. CONCLUSION: These results suggest that Voncento® is effective to prevent recurrent bleedings in patients symptomatic VWD.

Évaluation de AfstylaMC (rFVIII): Hémophilie de type A / Afstyla™ (rFVIII) Evaluation: Hemophilia Type A

MANDAT: À la demande du fabricant CSL Behring Canada Inc., l'Institut national d'excellence en santé et en services sociaux (INESSS) a procédé à l'évaluation du produit du système du sang AfstylaMC (lonoctocog alfa), un facteur VIII (FVIII) de coagulation humain recombinant qui s'administre par voie intraveineuse. Au Canada, lonoctocog alfa est indiqué pour la prophylaxie de routine, la maîtrise et la prévention des épisodes hémorragiques ainsi que pour la maîtrise et la prévention des saignements dans un contexte périopératoire chez les adultes et les enfants atteints d'hémophilie A (déficit congénital en facteur VIII). Les indications visées pour cette réévaluation sont identiques à celle reconnue par Santé Canada. Les neuf FVIII suivants sont présentement inscrits sur la Liste des produits du système du sang du Québec et ont servi de comparateurs. Parmi ceux-ci se trouvent six produits à action standard : AdvateMC, HelixateMC, KovaltryMC, NuwiqMC, XynthaMC (inclus Xyntha SolofuseMC) et ZonovateMC (à action standard) ainsi que trois produits à longue action : AdynovateMC, EloctateMC et EsperoctMC. DÉMARCHE D'ÉVALUATION: Une revue des données issues de la littérature et de celles fournies par le fabricant a été réalisée afin de documenter l'efficacité, l'innocuité et l'efficience de lonoctocog alfa. Des données contextuelles et expérientielles issues de la consultation d'experts et de patients sont également présentées. Élaboration par l'INESSS d'une analyse d'efficience et d'impact budgétaire. BESOIN DE SANT: L'hémophilie A, causée par une défaillance du FVIII, se manifeste par des temps de coagulation plus longs que la normale. Dans les cas sévères, le déficit en FVIII mène à des épisodes de saignement fréquents aux articulations, appelés hémarthroses, et aux tissus mous en absence de traumatisme. La prophylaxie à l'aide de FVIII recombinant constitue le traitement privilégié. Celle-ci consiste en plusieurs injections intraveineuses hebdomadaires pour remplacer le FVIII manquant. Malgré une bonne prise en charge de l'hémophilie A au Québec, certaines lacunes liées aux traitements actuels demeurent. Outre le souhait d'un traitement curatif permanent, les besoins suivants ont été identifiés par les experts rencontrés : une meilleure prévention contre le développement d'inhibiteurs (anticorps neutralisants contre le FVIII), la prévention d'arthropathies hémophiliques et des douleurs chroniques, des traitements offrant une protection hémostatique supérieure qui perdure plus longtemps et l'atténuation des contraintes liées aux injections intraveineuses répétées. RÉSULTATS: Efficacité: Lonoctocog alfa est considéré comme un FVIII à action standard. Lonoctocog alfa apparait au moins aussi efficace que ses comparateurs pour prévenir les saignements, lorsqu'utilisé en prophylaxie. Lonoctocog alfa apparait aussi efficace que ses comparateurs pour traiter les saignements perthérapeutiques. Dans les études répertoriées, lonoctocog alfa démontre une efficacité hémostatique bonne ou excellente lors de chirurgies. Innocuité: Le profil d'innocuité de lonoctocog alfa est jugé acceptable. Qualité de vie: Aucune donnée sur l'impact de lonoctocog alfa sur la qualité de vie n'a été présentée. Perspective de l'expert: À la lumière des données disponibles, l'expert consulté est d'avis que l'efficacité de la prophylaxie de lonoctocog alfa est comparable à celle des comparateurs, soient tous les FVIII inscrits à la Liste. Selon l'expert, le profil d'innocuité de lonoctocog alfa est comparable aux autres options disponibles pour la population ciblée.

Clinical Efficacy and Safety of Fanhdi®, a Plasma-Derived VWF/Factor VIII Concentrate, in von Willebrand Disease in Spain: A Retrospective Study.

OBJECTIVE: To evaluate the efficacy and safety of a plasma-derived factor VIII concentrate containing von Willebrand Factor (pdVWF/FVIII) in standard clinical practice in von Willebrand Disease (VWD) patients. METHODS: A retrospective, multicentric, observational study of VWD patients treated with Fanhdi®, a pdVWF/FVIII concentrate, from January 2011 to December 2017 was conducted at 14 centers in Spain. Efficacy and safety were evaluated for acute bleeding episodes, for prevention of bleeding in surgeries, and for secondary long-term prophylaxis. RESULTS: Seventy-two eligible patients, type 1, 2, 3 VWD (25%/38.9%/36.1%) were treated for spontaneous and traumatic bleeding (140 episodes, n = 41 patients), to prevent surgical bleeding (69 episodes, n = 43 patients); and for secondary long-term prophylaxis (18 programs, n = 13 patients). Replacement therapy with pdVWF/FVIII showed an excellent to good clinical efficacy in 96.7% of the bleeding episodes, 100% during surgical procedures and 100% during prophylaxis. No adverse events (AEs), nor serious AEs related to the product were observed. CONCLUSIONS: Fanhdi® was effective, safe and well tolerated in the management of bleeding episodes, the prevention of bleeding during surgeries, and for secondary long-term prophylaxis in VWD patients.

In Vitro Comparison of Recombinant and Plasma-Derived von Willebrand Factor Concentrate for Treatment of Acquired von Willebrand Syndrome in Adult Extracorporeal Membrane Oxygenation Patients.

BACKGROUND: Coagulopathic bleeding is common during adult extracorporeal membrane oxygenation (ECMO), and acquired von Willebrand syndrome is a contributing factor. We compared ECMO patient blood samples that were treated in vitro with recombinant von Willebrand Factor concentrate and plasma-derived von Willebrand Factor concentrate. Our hypothesis was that recombinant von Willebrand Factor (vWF) would have greater efficacy in increasing vWF function. Secondarily, we hypothesized that recombinant vWF would have less impact on thrombin generation. METHODS: Thirty ECMO patients and 10 cardiac surgical controls were enrolled in the study. ECMO patient blood samples were treated in vitro with low- and high-dose recombinant vWFs and low- and high-dose plasma-derived vWFs. Whole blood ristocetin-induced platelet aggregation (RIPA), plasma ristocetin cofactor activity (RCo), and thrombin generation were compared between ECMO patient blood samples and control blood samples and between vWF-treated ECMO patient blood samples and nontreated samples. RESULTS: ECMO patient blood samples had severely reduced median RIPA compared to control samples 2 ohms (1-12 [25th-75th percentile]) vs 20 ohms (11-42) (P < .001). Treatment of ECMO patient blood samples with high-dose recombinant vWF significantly increased median RIPA to 10 ohms (2-15) (P < .001), while low-dose recombinant vWF and low- and high-dose plasma-derived vWFs did not significantly increase RIPA; 6 ohms (3-14), 4 ohms (1-13), and 6 ohms (2-10), respectively (P = .25, >.99, and >.99). Treatment with high-dose recombinant vWF and low- and high-dose plasma-derived vWFs significantly increased median plasma RCo to 4.7 international units (IU)/mL (3.7-5.9), 3.3 IU/mL (2.7-4.8), and 3.9 IU/mL (3.4-5.3), respectively, compared to controls 1.8 IU/mL (1.5-2.3) (all P < .001). Treatment with low- and high-dose plasma-derived vWFs significantly increased mean endogenous thrombin potential (6270.2 ± 2038.7 and 6313.1 ± 1913.3) compared to nontreated samples (5856.7 ± 1924.6) (P = .04 and .006), whereas treatment with low- and high-dose recombinant vWFs had no significant effect on mean endogenous thrombin potential (5776.1 ± 2087.3 and 5856.2 ± 1946.4) (P > .99 for both comparisons). CONCLUSIONS: In vitro treatment of ECMO patient blood samples with high-dose recombinant vWF was superior to low-dose recombinant vWF and plasma-derived vWF in terms of improving RIPA. In addition, recombinant vWF treatment did not increase endogenous thrombin potential, which may reduce overall thrombotic risk if it used to treat acquired von Willebrand syndrome in ECMO patients.

Early cryoprecipitate transfusion versus standard care in severe postpartum haemorrhage: a pilot cluster-randomised trial.

There is a lack of evidence evaluating cryoprecipitate transfusion in severe postpartum haemorrhage. We performed a pilot cluster-randomised controlled trial to evaluate the feasibility of a trial on early cryoprecipitate delivery in severe postpartum haemorrhage. Pregnant women (>24 weeks gestation), actively bleeding within 24 h of delivery and who required at least one unit of red blood cells were eligible. Women declining transfusion in advance or with inherited clotting deficiencies were not eligible. Four UK hospitals were randomly allocated to deliver either the intervention (administration of two pools of cryoprecipitate within 90 min of first red blood cell unit requested plus standard care), or the control group treatment (standard care, where cryoprecipitate is administered later or not at all). The primary outcome was the proportion of women who received early cryoprecipitate (intervention) vs. standard care (control). Secondary outcomes included consent rates, acceptability of the intervention, safety outcomes and preliminary clinical outcome data to inform a definitive trial. Between March 2019 and January 2020, 199 participants were recruited; 19 refused consent, leaving 180 for analysis (110 in the intervention and 70 in the control group). Adherence to assigned treatment was 32% (95%CI 23-41%) in the intervention group vs. 81% (95%CI 70-90%) in the control group. The proportion of women receiving cryoprecipitate at any time-point was higher in the intervention (60%) vs. control (31%) groups; the former had fewer red blood cell transfusions at 24 h (mean difference -0.6 units, 95%CI -1.2 to 0); overall surgical procedures (odds ratio 0.6, 95%CI 0.3-1.1); and intensive care admissions (odds ratio 0.4, 95%CI 0.1-1.1). There was no increase in serious adverse or thrombotic events in the intervention group. Staff interviews showed that lack of awareness and uncertainty about study responsibilities contributed to lower adherence in the intervention group. We conclude that a full-scale trial may be feasible, provided that protocol revisions are put in place to establish clear lines of communication for ordering early cryoprecipitate in order to improve adherence. Preliminary clinical outcomes associated with cryoprecipitate administration are encouraging and merit further investigation.

How do we optimally utilize factor concentrates in persons with hemophilia?

The current mainstay of therapy for hemophilia is to replace the deficient clotting factor with the intravenous administration of exogenous clotting factor concentrates. Prophylaxis factor replacement therapy is now considered the standard of care in both pediatric and adult patients with hemophilia with a severe phenotype to protect musculoskeletal health and improve quality of life. Heterogeneity in bleeding presentation among patients with hemophilia due to genetic, environmental, and treatment-related factors has been well described. Accordingly, the World Federation of Hemophilia recommends an individualized prophylaxis regimen that considers the factors mentioned above to meet the clinical needs of the patient, which can vary over time. This review focuses on the practical points of choosing the type of factor concentrate, dose, and interval while evaluating appropriate target trough factor levels and bleeding triggers such as level of physical activity and joint status. We also discuss the use of a pharmacokinetics assessment and its incorporation in the clinic for a tailored approach toward individualized management. Overall, adopting an individualized prophylaxis regimen leads to an optimal utilization of factor concentrates with maximum efficacy and minimum waste.

Alfadamoctocogue pegol para profilaxia secundária em pacientes com Hemofilia A, a partir de 12 anos, previamente tratados e sem inibidor / Alfadamoctocogue pegol for secondary prophylaxis in patients with Hemophilia A, from 12 years, previously treated and sem inhibitor

INTRODUÇÃO: A hemofilia A é uma doença hereditária ligada ao cromossomo X, caracterizada pela deficiência ou anormalidade da atividade coagulante do fator VIII e representa a maioria dos casos de coagulopatias hereditárias, com aproximadamente 10.123 casos no país em 2016. A manifestação clínica mais frequente da doença é a hemorragia musculoesquelética, principalmente os sangramentos intra articulares (hemartroses) que afetam especialmente as articulações do joelho, tornozelo, cotovelo, ombro e coxofemoral. Hemartroses de repetição em uma mesma articulação podem levar à degeneração articular progressiva com perda funcional e, nos casos graves, os sangramentos ocorrem frequentemente sem causa aparente. O tratamento dos pacientes com hemofilia A requer a infusão intravenosa do fator de coagulação deficiente (FVIII), sendo feito sob demanda (tratamento do episódio hemorrágico) ou de forma profilática para manter os seus níveis séricos adequados, prevenindo os episódios hemorrágicos. O Programa de Coagulopatias do Ministério da Saúde disponibiliza o FVIII recombinante com meia-vida padrão para o uso em profilaxia. A tecnologia proposta consiste em um FVIII recombinante com meia-vida estendida. Os produtos com meia-vida estendida foram desenvolvidos mais recentemente com o objetivo de disponibilizar um tempo maior de FVIII na circulação sanguínea, proporcionando um intervalo maior entre as infusões e melhor proteção contra sangramentos. TECNOLOGIA: Alfadamoctocogue pegol. PERGUNTA: O uso de alfadamoctocogue pegol para profilaxia secundária em pacientes com hemofilia A, a partir de 12 anos, previamente tratados (e sem inibidores) é mais seguro, eficaz e custo-efetivo do que o tratamento padrão no SUS? EVIDÊNCIAS CLÍNICAS: O único estudo comparativo apresentado, ainda que com qualidade de evidência baixa, não demonstrou diferença estatisticamente significativa no principal desfecho, taxa anualizada de sangramento, entre a tecnologia proposta e a tecnologia disponibilizada no SUS. Dentre outros potenciais benefícios relacionados a menor frequência de infusão do alfadamoctocogue pegol, apenas um estudo avaliou isoladamente a satisfação dos pacientes com a tecnologia proposta, sem comparação à tecnologia padrão. Na ausência de evidências científicas demonstrando superioridade da tecnologia proposta, o demandante realizou um painel Delphi, com especialistas na área de hemofilia A que atuam no SUS em diferentes regiões do Brasil, que sugeriu que os pacientes mais beneficiados com o uso do alfadamoctocogue pegol seriam aqueles com perfil sangrador, farmacocinética desfavorável, baixa adesão ao tratamento e com alta atividade diária. AVALIAÇÃO ECONÔMICA: Um estudo de custo-minimização foi construído baseado na premissa do estudo de Batt, 2019 de que ambas as tecnologias possuem a mesma eficácia. Foram construídos cenários para início do tratamento em diferentes faixas etárias (12 e 30 anos) e cenários para diferentes utilizações de UIs dos medicamentos (cenário base e proposto). No horizonte da vida toda, os resultados para os pacientes iniciando com 12 anos de idade foi uma economia por paciente de R$ 1.342.233,18 e R$ 3.625.885,71 para os cenários base e proposto respectivamente. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: Os resultados da análise de custo-efetividade foram utilizados para a construção da análise de impacto orçamentário. Dados do Perfil de Coagulopatias de 2016, do IBGE e do Painel Delphi foram utilizados para estimar o número de pacientes elegíveis ao tratamento. Estimou-se que de 30% a 40% dos pacientes teriam um perfil sangrador e seriam elegíveis a substituição pela formulação de liberação estendida (alfadamoctocogue pegol). Esses valores foram utilizados no market share proposto. Ao final de 5 anos, estimou-se uma economia de R$323.024.411,22. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foram detectadas quatro tecnologias potenciais para o tratamento de pacientes com hemofilia a partir de 12 anos de idade. O Mim-8, um anticorpo IgG4 mimético do fator 8 de coagulação, que tem como alvos os fatores IX e X de coagulação, o fitusiran, um RNA silenciador (siRNA), direcionado ao RNA mensageiro (RNAm) codificador de antitrombina, e os anticorpos monoclonais IgG4 concizumabe e marstacimab, inibidores do inibidor da via do fator tissular (TFPI). Além dos potenciais medicamentos descritos, com mecanismos de ação diferentes dos fatores de coagulação, estão em fase 3 clínica os fatores VIII recombinantes FRSW-107, SCT-800 e efanesoctocog alfa (BIVV001). Além desses, foram registrados, em outros países, os fatores VIII recombinantes damoctocog alfa pegol (Japão, 2019); lonoctocog alfa (EUA, 2016) e turoctocog alfa pegol (Alemanha e Suíça, 2019). O alfadamoctocogue é protegido pela patente PI 0517795-2, depositada no Instituto Nacional da Propriedade Intelectual (INPI) em 14/11/2005, com validade até 31/03/30 (45). CONSIDERAÇÕES FINAIS: Não houve estudos de comparação direta que mostrasse que a intervenção é superior ou possui a mesma efetividade do comparador. Apenas um estudo de comparação indireta demonstrou não haver significância estatística entre as alternativas. A avaliação de custo-minimização e o impacto orçamentário mostraram resultados que representaram economia para o SUS com a incorporação da nova tecnologia. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Diante do exposto, a Conitec, em sua 5ª reunião extraordinária, realizada no dia 12 de maio de 2021, deliberou que a matéria fosse disponibilizada em consulta pública com recomendação preliminar de todos os membros do plenário desfavorável à incorporação do alfadamoctocogue pegol para o tratamento de hemofilia A em profilaxia secundária para pacientes a partir de 12 anos de idade no SUS. Os membros do plenário concordaram que, apesar da comodidade posológica, diante da impossibilidade de desconto nos impostos, o impacto orçamentário que antes produziria uma economia, se torna um gasto próximo a 200 milhões de reais ao final de 5 anos. A matéria foi disponibilizada em consulta pública. CONSULTA PÚBLICA: Foram recebidas 3.387 contribuições, sendo 434 pelo formulário para contribuições técnico-científicas e 2.953 pelo formulário para contribuições sobre experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. Das 434 contribuições de cunho técnico-científico recebidas, 66 foram analisadas, já que as demais não apresentaram informação alguma (em branco) ou argumentação técnica sobre as evidências. No total, 117 concordaram com a recomendação inicial da Conitec, 9 não concordaram e não discordaram e 308 discordaram. Das 117 que concordaram, 44 apresentaram algum comentário sobre essa opinião e todos eles discordavam da decisão da Conitec. Das 2.952 contribuições recebidas sobre experiência com a tecnologia ou opinião sobre o tema, 339 foram analisadas, já que as demais não apresentaram informação alguma (em branco). No total, 559 concordaram com a recomendação inicial da Conitec, 62 não concordaram e não discordaram e 2.331 discordaram. Os assuntos abordados pelos participantes que discordaram da recomendação preliminar foram majoritariamente relacionados ao acesso e a possibilidade de mais uma opção terapêutica, os ganhos em qualidade de vida e a comodidade posológica que a tecnologia traz aos pacientes. RECOMENDAÇÃO FINAL DA CONITEC: Pelo exposto, o Plenário da Conitec, em sua 101ª Reunião Ordinária, no dia primeiro de setembro de 2021, recomendou, por maioria simples, a incorporação de alfadamoctocogue pegol para a profilaxia secundária em pacientes com Hemofilia A, a partir de 12 anos, previamente tratados e sem inibidor no SUS, conforme Protocolo estabelecido pelo Ministério da Saúde. Considerou-se como justificativa para a decisão a maior vantagem posológica e a economia demonstrada ao SUS. Por fim, foi assinado o Registro de Deliberação nº 664/2021. DECISÃO: Incorporar o alfadamoctocogue pegol para profilaxia secundária em pacientes com Hemofilia A, no âmbito do Sistema Único de Saúde ­ SUS, conforme a Portaria nº 11, publicada no Diário Oficial da União nº 31, seção 1, página 71, em 14 de fevereiro de 2022.

Severe haemophilia A in a preterm girl with Turner syndrome: case report - a diagnostic and therapeutic challenge for a paediatrician (Part 2).

BACKGROUND: Haemophilia A is an X-linked genetic condition which manifests itself mainly in male children in the first 2 years of life, during gross motor skill development. This disorder is rare in females. The clinical manifestation of severe haemophilia in preterm infants poses a great challenge to the therapeutic team. As extreme prematurity is linked to an increased risk of central nervous system or gastrointestinal bleeding, a well-informed and balanced treatment from the first days of life is crucial to prevent long-term damage. Haemophilia is most commonly caused by inheriting defective genes, and can also be linked to skewed X inactivation and Turner syndrome. The coincidental occurrence of haemophilia A and Turner syndrome is extremely rare, with only isolated cases described to date. Hence, a multidisciplinary approach is needed. CASE PRESENTATION: The authors report on a preterm girl (gestational age 28 weeks) diagnosed with haemophilia and Turner syndrome. The first manifestation of haemophilia was prolonged bleeding from injection sites on the second day of life. Indeterminate aPTT and factor VIII level < 1% confirmed the diagnosis of haemophilia A. Dysmorphic features which did not match the typical clinical picture of haemophilia, the female sex, and a negative paternal family history led to the diagnosis of Turner syndrome. While in hospital, the girl received multiple doses of recombinant factor VIII in response to prolonged bleedings from the injection sites and from a nodule on the girl's head, and before and after retinal laser photocoagulation. No central nervous system or abdominal cavity bleeding was observed. The substitutive therapy was complicated by the development of factor VIII inhibitor (anti-factor VIII (FVIII) antibodies). Treatment was continued with recombinant factor VIIa. This article aims at demonstrating the complexity of the diagnostics and treatment of a preterm child with two genetic disorders. CONCLUSIONS: Haemophilia should always be considered in the differential diagnosis of prolonged bleeding, even in patients with a negative family history. In the case of coinciding atypical phenotypic features, further diagnostics for another genetic disease are recommended. Infant care should follow current care standards, while considering certain individual features.

Pro-Con Debate: Fibrinogen Concentrate or Cryoprecipitate for Treatment of Acquired Hypofibrinogenemia in Cardiac Surgical Patients.

Cryoprecipitate has been the gold standard for treating acquired hypofibrinogenemia in cardiac surgery for nearly 50 years. More recently, fibrinogen concentrate has been used off-label in the United States and is the standard in European countries and Canada to treat the acquired hypofibrinogenemia during cardiac surgery. Fibrinogen concentrate has multiple potential advantages including rapid reconstitution, greater dose predictability, viral inactivation during processing, and reduced transfusion-related adverse events. However, because fibrinogen concentrate lacks the other components contained in the cryoprecipitate, it may not be the "ideal" product for replacing fibrinogen in all cardiac surgical patients, particularly those with longer cardiopulmonary bypass duration. In this Pro-Con commentary article, we discuss the advantages and disadvantages of using fibrinogen concentrate and cryoprecipitate to treat acquired hypofibrinogenemia in cardiac surgical patients.

First observation of inhibitor development against efmoroctocog alfa in France.

In patients with severe haemophilia receiving clotting factor concentrates, the risk of immunisation against their usual treatment is still patent and feared. New haemophilia drug treatments with an extended half-life have become available over the past few years. The risk of inhibitor development to these new treatments is unclear. We report the case of a 51-year-old man with severe haemophilia A, who was previously treated with no history of inhibitor development. Soon after a switch in his treatment to efmoroctocog alfa he developed an inhibitor against this recombinant Fc fusion extended half-life FVIII (rFc-FVIII) product. The patient was on an on-demand treatment regimen and was treated for mucosal bleeding. The inhibitor was characterised as type I, with classical epitope mapping. The spontaneous evolution of this inhibitor was favourable, but an anamnestic response led to a switch in his treatment to emicizumab.

Gene therapy may not be as expensive as people think: challenges in assessing the value of single and short-term therapies.

At an upfront price of $2.125 million, the one-time gene therapy onasemnogene abeparvovec for spinal muscular atrophy, a rare neuromuscular disorder that is usually fatal by 2 years of age if untreated, has been called the "most expensive drug ever." This flawed characterization raises important methodological and policy issues regarding valuation of high-cost treatments. We reviewed several other high-cost therapies-with a particular focus on hemophilia A treatment-studied by the nonprofit Institute for Clinical and Economic Review (ICER). In ICER's summary report of 2 treatments for managing hemophilia A, published in this month's JMCP issue, the estimated $15-$18 million lifetime cost of factor VIII is characterized as "far too high," representing "a failure of competition [that] … builds a platform for pricing of treatments … that will only exacerbate these problems." Current literature indicates several factors underlying high factor VIII treatment cost (eg, historical pattern of innovation and lack of market competition) that may also drive the pricing dynamics of advanced therapies for other rare diseases. When a treatment's price is driven high (or "distorted"), an economic principle known as "theory of the second best" suggests that market price becomes a poor estimate of social opportunity cost, and adjustments should be made for such distortions. In any case, a high-cost standard of care creates an opportunity for new technology to generate cost savings, providing an inducement for market entry. Recognizing that this potentially creates a tendency to produce price distortions for new treatments, ICER has attempted to apply some ad hoc adjustments. However, challenges remain in creating a "level playing field" across different disease-modifying or potentially curative innovations (eg, one-time therapy vs ongoing or lifelong treatment with repeated doses). While additional policy work is needed to address this dilemma, it would clearly be misleading to assume that gene therapies are inherently expensive. Rigorous economic evaluation of novel therapies requires careful comparison of lifetime cost and benefits vs standard of care, including adjustments for pricing distortions. Fortunately, economic theory suggests that we could adjust to this circumstance by using the social opportunity costs of interventions based on an appropriate variable cost-effectiveness threshold that would be higher for rare severe diseases. DISCLOSURES: The research reported in this Viewpoints article was funded by Novartis Gene Therapies, Inc. Garrison and Jiao were paid by Novartis Gene Therapies, Inc., to conduct this research. Garrison has also received consulting fees from BioMarin, Inc, and UniQure. Dabbous is a full-time employee of Novartis Gene Therapies, Inc., and holds Novartis stock and stock options.

Health care resource utilization and costs among adult patients with hemophilia A on factor VIII prophylaxis: an administrative claims analysis.

BACKGROUND: Standard of care for bleed prevention in patients with severe congenital hemophilia A is continuous prophylaxis with factor VIII (FVIII), typically administered intravenously 2-3 times per week in the home setting. Nonfactor prophylaxis and gene therapy are emerging novel prophylaxis strategies for hemophilia A, and it is important to compare their health economics with that of FVIII prophylaxis. Current data on resource utilization and costs in the adult hemophilia A prophylaxis population are limited, and a structured approach to analyze annual costs in these patients using administrative claims data has not been previously reported. OBJECTIVE: To assess health care resource utilization and costs of continuous FVIII prophylaxis in commercially insured adults with hemophilia A without inhibitors. METHODS: Administrative claims records from beneficiaries covered by major selfinsured companies in the United States from January 1999 through March 2017 (OptumHealth Care Solutions) were queried, and records for adult patients (aged 18-64 years) diagnosed with hemophilia A who received FVIII were extracted. Three criteria were defined to distinguish patients most likely to be managed with continuous FVIII prophylaxis from those on episodic treatment based on the frequency and timing of FVIII claims over a 12-month period of continuous enrollment: (1) having ≥ 4 FVIII claims, (2) having ≥ 6 FVIII claims, or (3) having no gaps > 60 days between FVIII claims. Patients with evidence of bypassing agent use were excluded. Health care resource utilization and costs were assessed for all patients with any FVIII use and for patients defined as being managed with continuous FVIII prophylaxis based on each criterion. RESULTS: The analysis included 189 patients with a diagnosis code for hemophilia A (ICD 9-CM code 286.0; ICD-10-CM code D66) from January 1999 through March 2017 who had at least 12 months of continuous enrollment and at least 1 noninpatient/nonemergency department claim for FVIII concentrate (any type) during their last 12 months of continuous enrollment (overall cohort). Within the overall cohort, 118, 94, and 61 patients met the criteria for FVIII prophylaxis based on the first, second, and third definitions, respectively. Per patient mean (SD) total health care costs for the overall cohort was $287,055 (306,933). For patients meeting criteria 1 through 3, per patient costs ranged from $407,752 (321,036) to $551,645 (302,841). FVIII concentrate accounted for over 90% of costs, with mean (SD) annual FVIII costs of $264,777 (292,423) in the overall cohort and $384,197 (303,826), $433,029 (313,711), and $531,098 (297,142) among patients meeting the respective definitions for prophylaxis. CONCLUSIONS: This analysis highlights the substantial economic burden associated with managing adults with hemophilia A on FVIII prophylaxis, where per patient mean total annual health care costs ranged from $407,752 to $551,645. Over 90% of such costs were attributable to FVIII concentrate dispensed. DISCLOSURES: This study was funded by BioMarin Pharmaceutical, which was involved in protocol development, analysis plan development, data interpretation, manuscript preparation, and publication decisions. All authors contributed to protocol development, analysis plan development, data interpretation, and manuscript development. All authors maintained control over the final content. Sammon, Solari, Kim, and Hinds are employees and shareholders of BioMarin Pharmaceutical. Cook, Sheikh, and Chawla are employees of Analysis Group, a consulting company that was contracted by BioMarin Pharmaceutical to conduct this study and develop the manuscript. Croteau has received professional fees from BioMarin Pharmaceutical, Bayer, CSL Behring, Genentech, and Pfizer. Thornberg has received professional fees from BioMarin Pharmaceutical, Genentech, Novo Nordisk, Sanofi, and Spark Therapeutics, as well as research funding from Novo Nordisk and Sanofi.

von Willebrand disease: what does the future hold?

von Willebrand disease (VWD) is characterized by its heterogeneous clinical manifestation, which complicates its diagnosis and management. The clinical management of VWD has remained essentially unchanged over the last 30 years or so, using von Willebrand factor (VWF) concentrates, desmopressin, and anti-fibrinolytic agents as main tools to control bleeding. This is in contrast to hemophilia A, for which a continuous innovative path has led to novel treatment modalities. Despite current VWD management being considered effective, quality-of-life studies consistently reveal a higher than anticipated burden of VWD on patients, which is particularly true for women. Apparently, despite our perceived notion of current therapeutic efficiency, there is space for innovation with the goal of reaching superior efficacy. Developing innovative treatments for VWD is complex, especially given the heterogeneity of the disease and the multifunctional nature of VWF. In this perspective article, we describe several potential strategies that could provide the basis for future VWD treatments. These include genetic approaches, such as gene therapy using dual-vector adenoassociated virus and transcriptional silencing of mutant alleles. Furthermore, protein-based approaches to increase factor FVIII levels in VWD-type 3 or 2N patients are discussed. Finally, antibody-based options to interfere with VWF degradation (for congenital VWD-type 2A or acquired von Willebrand syndrome-type 2A) or increase endogenous VWF levels (for VWD-type 1) are presented. By highlighting these potential strategies, we hope to initiate an innovative path, which ultimately would allow us to better serve VWD patients and their specific needs.

Population Pharmacokinetic Analysis of Recombinant Factor VIII Fc Fusion Protein in Subjects With Severe Hemophilia A: Expanded to Include Pediatric Subjects.

Recombinant factor VIII Fc fusion protein (rFVIIIFc) has been indicated for adults and children with hemophilia A. The objective of this article was to build a population pharmacokinetic (PK) model using adult and pediatric data sets and explore relevant dosing scenarios across all ages. The activity-time profiles of rFVIIIFc from 3 clinical studies (all trials registered at https://www.clinicaltrials.gov: NCT01027377, NCT01181128, and NCT01458106) were characterized, and covariates that determine variability of rFVIIIFc PK in children and adults were identified and implemented. Data sets were pooled to estimate population PK parameters. Simulations were conducted to generate activity-time profiles at steady state (SS). The proportion of subjects maintaining SS trough >1 and >3 IU/dL and time >10 IU/dL were estimated. The rFVIIIFc model was a two-compartment model that identified weight and von Willebrand factor as significant covariates. Model-predicted SS peaks and troughs of rFVIIIFc activity-time profiles confirmed the necessity of modifying dosing in pediatric subjects. The model also predicted that the average subject in the adult and adolescent group dosed with 40 IU/kg every 2 days maintained factor VIII activity >10 IU/dL for the entire duration. Children aged <6 years and aged 6 to <12 years receiving this dose maintained factor VIII activity of >10 IU/dL for nearly two-thirds and three-quarters of their time, respectively. In conclusion, these population PK analyses characterize activity-time profiles for rFVIIIFc among pediatric and adult subjects. The model was used for simulation of clinically relevant dosing scenarios, which can provide better protection and better clinical outcomes.

Hepatitis E virus: Efficacy of pasteurization of plasma-derived VWF/FVIII concentrate determined by pig bioassay.

BACKGROUND: Hepatitis E virus (HEV) is the leading cause of acute hepatitis throughout the world. Increasing blood component transfusion-associated HEV infections highlight the need for reliable virus inactivation procedures for plasma derivatives from pooled plasma donations. STUDY DESIGN AND METHODS: An animal infection study was conducted to evaluate the efficiency of HEV inactivation by pasteurization during the manufacturing process of the von Willebrand Factor/Factor VIII (VWF/FVIII) concentrate Haemate P/Humate-P (CSL Behring, Marburg, Germany). For this purpose, groups of pigs were inoculated with stabilized VWF/FVIII intermediate spiked with HEV-positive liver homogenate and exposed to increasing incubation times of 0, 3, 6, and 10 h at 60°C. Animals were evaluated for virus replication over 27 days and in a subsequent trial over 92 days. RESULTS: Virus replication was detected in animals up to the 6-h pasteurization group. In contrast, pasteurization for 10 h did not reveal virus detection when the observation period was 27 days. In an additional experiment using the 10-h pasteurized material, two individuals started virus excretion and seroconverted when the observation period was extended to 92 days. Based on the total infection rate (2 of 12) of the animals inoculated with the sample pasteurized for 10 h, a virus reduction factor of at least 4.7 log10 is calculated. CONCLUSION: This study demonstrates that pasteurization at 60°C for 10 h of an HEV-positive plasma derivative leads to the effective reduction of infectivity, resulting in a VWF/FVIII product with an appropriate margin of safety for HEV.

Safety evaluation of emicizumab prophylaxis in individuals with haemophilia A.

INTRODUCTION: Emicizumab is a bispecific-humanized monoclonal antibody that improves hemostasis by bridging activated factor IX and factor X to substitute for the function of missing activated FVIII. It is an alternative to prophylaxis with factor VIII replacement and is associated with improved outcomes in individuals with hemophilia A with and without inhibitors. AREAS COVERED: Emicizumab is efficacious in reducing bleeding events when compared to on-demand treatment and factor-based prophylaxis. Except for the few thrombotic microangiopathy and thrombotic event cases mainly seen in the HAVEN 1 trial, emicizumab has an overall excellent safety profile with minimal side effects. EXPERT OPINION: Knowledge gaps include the efficacy and safety of emicizumab in younger age groups and those with mild or moderate hemophilia A. Future directions for research include exploring the risk of inhibitor recurrence in patients with a history of high titer inhibitor who have been successfully tolerized, who switch from factor prophylaxis to emicizumab, as well as conducting 'real world studies' to evaluate the patient's perception of emicizumab in regard to ease and tolerability in order to optimize individualized treatment plans.