Budget impact of prophylactic treatment of rVIII-SingleChain in moderate and severe hemophilia A in Italy.

INTRODUCTION: rVIII-SingleChain, a recombinant factor VIII (rFVIII), has demonstrated safety and efficacy in patients with hemophilia A in clinical trials and real-world evidence. This analysis aimed to estimate the potential budget impact of increasing the usage of rVIII-SingleChain for the prophylactic treatment of hemophilia A over 3 years in Italy. METHODS: Patients with moderate and severe hemophilia A receiving prophylaxis were included in the analysis. Epidemiological data were obtained from published literature. Mean product consumption and mean annual bleeding rate for rVIII-SingleChain, rFVIIIFc, octocog alfa and BAY 81-8973 were based on pooled real-world data from Italy, Germany and US. A budget impact model has been developed in order to compare two scenarios: a base-case scenario where current rVIII-SingleChain shares are kept constant over 3 years and an alternative scenario where rVIII-SingleChain shares increase by taking from other rFVIII products. Analysis 1 was based on the current Italian list prices and Analysis 2 considered current regional acquisition prices for both scenarios. RESULTS: Annually, adult patients treated with rVIII-SingleChain prophylaxis are expected to consume 324,589 units per patient, resulting in annual costs of €240,196 per patient. In Analysis 1, comparing the base case (constant market share of 9% rVIII-SingleChain over time) with the alternative scenario (higher rVIII-SingleChain market share and increasing from 15% in the first year to 25% in the third year), the total expenditure for prophylaxis using rFVIII products is expected to decrease by €1.4 million in Year 1, by €3.1 million in Year 2 and by €5.4 million in Year 3. In Analysis 2 based on regional prices, the results remained consistent. DISCUSSION/CONCLUSION: This analysis suggests that increasing utilization of rVIII-SingleChain in hemophilia A patients may lead to cost savings as a result of reduced consumption with uncompromised efficacy in bleed protection.

Why was the study done? Hemophilia A is a rare inherited bleeding disorder. People with severe hemophilia are more likely to bleed compared to people without hemophilia and bleeds can occur spontaneously or in response to trauma. Patients are treated with medication to reduce the chance of bleeding. However, the cost of treating patients with hemophilia can be high and place demands on the healthcare system.What did we do and find?This study looked at the cost of treating people with hemophilia in Italy and used a type of economic analysis (called budget impact modelling) to estimate the effect of increasing the use of a particular medication (rVIII-SingleChain), compared to other medications that are available. Different variations of the model were tested to compare a range of scenarios.The results of this analysis suggested that increasing the use of rVIII-SingleChain may lead to cost-savings for the Italian healthcare system, compared to using the other currently available treatments. This analysis suggests that the use of rVIII-SingleChain enables people with hemophilia A to remain protected from bleeds, whilst using less product compared to other available medications.What is the influence of this study on the wider field?This type of analysis can be useful to healthcare systems, to guide the decision-making process regarding which medications to use or when making decisions related to healthcare policy.

Role of L-Arginine on the Expression of Coagulation Factor VIII Gene.

Objective: To explore the key sites in which L-arginine affects the expression of human coagulation factor VIII gene, and to create new drug targets for the treatment of hemophilia. Methods: A total of 5 human FVIII genes (A1, A2, A3, C1 and C2) with B domain deletion were transfected into human umbilical vein endothelial cells (HUVECs) as promoters. Run-on assay and ELISA analysis were performed to observe the driving effect of each domain gene on chloramphenicol acetyl transferase (CAT) gene transcription and expression, and the effect of L-arginine on each promoter. Results: In co-culture with L-arginine, transcriptional expression of the CAT gene was not detected in the PCAT3-Basic group (negative control without promoters), PA3-CAT3-Enhancer group or PC1-CAT3-Enhancer group. The transcriptional expression of CAT gene in the PCAT3-Control group (positive control with promoters) and PA1-CAT3-Enhancer group was unchanged compared with the non-L-arginine intervention, while the transcriptional expression of CAT gene in the PA2-CAT3-Enhancer group was significantly enhanced. Conclusions: A1 and A2 domain genes had promoter function and could initiate the transcription and expression of CAT gene, but A3, C1 and C2 domain genes could not. Moreover, L-arginine can significantly enhance transcription and expression of human coagulation factor VIII via A2 domain.

The full-length Auxin Response Factor 8 isoform ARF8.1 controls pollen cell wall formation and directly regulates TDF1, AMS and MS188 expression.

Auxin Response Factor 8 plays a key role in late stamen development: its splice variants ARF8.4 and ARF8.2 control stamen elongation and anther dehiscence. Here, we characterized the role of ARF8 isoforms in pollen fertility. By phenotypic and ultrastructural analysis of arf8-7 mutant stamens, we found defects in pollen germination and viability caused by alterations in exine structure and pollen coat deposition. Furthermore, tapetum degeneration, a prerequisite for proper pollen wall formation, is delayed in arf8-7 anthers. In agreement, the genes encoding the transcription factors TDF1, AMS, MS188 and MS1, required for exine and pollen coat formation, and tapetum development, are downregulated in arf8-7 stamens. Consistently, the sporopollenin content is decreased, and the expression of sporopollenin synthesis/transport and pollen coat protein biosynthetic genes, regulated by AMS and MS188, is reduced. Inducible expression of the full-length isoform ARF8.1 in arf8-7 inflorescences complements the pollen (and tapetum) phenotype and restores the expression of the above transcription factors. Chromatin immunoprecipitation-quantitative polymerase chain reaction assay revealed that ARF8.1 directly targets the promoters of TDF1, AMS and MS188. In conclusion, the ARF8.1 isoform controls pollen and tapetum development acting directly on the expression of TDF1, AMS and MS188, which belong to the pollen/tapetum genetic pathway.

The influence of the CYP1A2-163 C>A polymorphism on the hemostatic response to exercise following caffeine supplementation.

BACKGROUND: Prior work from our group suggests that caffeine increases thrombotic potential after acute exercise. The aim of this study was to determine if hemostatic responses to exercise affected by caffeine are influenced by the CYP1A2-163 C>A polymorphism. METHODS: Forty-two healthy men performed two trials in which a graded maximal exercise test was completed one hour after consuming either 6 mg/kg of caffeine or placebo. Subjects were categorized as possessing the C allele (N.=21) or being homozygous for the A allele (N.=21). RESULTS: Factor VIII increased more (265%) during exercise in the caffeinated condition than the placebo condition (178%) (P<0.05). Tissue plasminogen activator (tPA) activity also increased more following caffeine as compared to placebo (increase of 8.70±4.32 IU/mL vs. 6.77±3.79 IU/mL respectively, P<0.05). There was no treatment × genotype or treatment × time × genotype interactions. CONCLUSIONS: Although caffeine increases factor VIII and tPA responses to maximal exercise, these changes are not influenced by the CYP1A2-163 C>A polymorphism.

Eradication of FIX inhibitor in haemophilia B children using low-dose immune tolerance induction with rituximab-based immunosuppressive agent(s) in China.

INTRODUCTION: Development of haemophilia B inhibitors (HBI) results in the ineffectiveness of FIX replacement therapy. Inhibitor eradication by immune tolerance induction (ITI) is therefore necessary. In HBI, ITI even at high FIX dose is less effective and has a higher risk of severe complications. AIM: To characterize clinical features and outcome of ITI on HBI. METHODS: This retrospective study was conducted in Haemophilia Paediatric Comprehensive Care Centre of China. We used low-dose ITI (25-50 FIX IU/kg/three-times-weekly to every-other-day) with domestic prothrombin complex concentrate (PCC), combined with two successive immunosuppressive (IS) regimens. RESULTS: Sixteen HBI children, representing 5.7% of all and 14.4% of our severe registered HB patients, were enroled. Seven cases reported allergic reactions (ARs) proximal to inhibitor development. The historic peak inhibitor titre was median 54.2 (range 4.7-512) BU, and 15 (93.8%) had high-titre inhibitors. Twelve patients adherent to ITI were analysable. Of the nine ITI patients who received rituximab/prednisone (IS Regimen-1), four achieved tolerization in 1.4-43.3 months. Two subsequently relapsed but re-tolerized after a second course of IS Regimen-1. During ITI, the median treated bleed was .39/month (82.7% reduction from before ITI), and the incidence of AR and nephrotic syndrome (NS) complications was each at 22% (2/9). Three ITI patients received modified 'Beutel' protocol (IS Regimen-2) using multiple-IS-drugs, and two had rapid tolerization (.8 and 1.8 months). CONCLUSIONS: Inhibitor eradication could be achieved by low-dose ITI protocol using PCC combined with IS. Larger studies are needed to confirm if ITI with IS Regimen-2 is more effective with less complications.

Management and outcomes of mild hemophiliacs and hemophilia carriers during pregnancy and peripartum period: a hemophilia treatment center experience in the United States.

BACKGROUND: Pregnancy, peripartum management, and outcomes of mild hemophiliacs and hemophilia carriers in the United States are not well established. AIM: To describe the management and outcomes of mild hemophiliacs and hemophilia carriers during assisted conception, pregnancy, peripartum and post-partum period at our hemophilia treatment center (HTC). METHODS: Retrospective review of electronic medical records of pregnant women with mild hemophilia A or B (Factor VIII [FVIII] or Factor IX [FIX] level <0.4 IU/mL) and hemophilia A and B carriers followed at our HTC from January 2008 to October 2020. Demographics, the reason for diagnosis, FVIII and FIX levels at baseline and third trimester, bleeding phenotype and genotype were obtained. Method of conception, factor replacement, iron supplementation, mode of delivery, type of anesthesia, peripartum complications, and offspring outcomes was recorded. RESULTS: There was a total of 18 pregnancies in 12 women (2 with mild hemophilia A, 2 mild hemophilia B, 6 hemophilia A carriers, and 2 hemophilia B carriers). Eleven pregnancies (61%) were conceived naturally and 7 (39%) via in-vitro fertilization (IVF). Eight (44.4%) and 10 (55.6%) pregnancies were vaginal and C-section deliveries, respectively. Neuraxial anesthesia was administered in 17 (94.4%) deliveries without complications. Four pregnancies (22.2%) had bleeding complications, 2 of which were post-partum hemorrhages not requiring transfusion. CONCLUSION: In our case series of pregnant hemophilia carriers and mild hemophiliacs, successful outcomes were achieved with a carefully detailed multidisciplinary-driven approach.

Generation of iPSC line from urine cells of hemophilia A with F8 (p. R814X) mutation.

The lack of coagulation factor VIII in patient with nonsense mutation hemophilia A leads to varying degrees of bleeding symptoms, and long-term use of alternative therapies can produce inhibitors that affect the efficacy. In this study, human induced pluripotent stem cells (iPSCs) of hemophilia A were generated by reprogramming of urine cells. Human urine cells (HUCs) were isolated by collecting patients' mid-stream urine, and cultured to good state in urine medium. Then, the HUCs were transfected with PEP4-EO2S-ET2K and pCEP4-M2L, and iPSCs were obtained in the medium without trophoblast cells and the composition was determined. Finally, alkaline phosphatase staining, karyotype analysis, immunofluorescence staining and teratoma were used to verify that we successfully reprogrammed hemophilia A-specific human induced pluripotent stem cells from patients' urine cells, providing a safe and effective cell model for the study of molecular mechanism and related treatment of hemophilia.

Real-world experience on the tolerability and safety of emicizumab prophylaxis in paediatric patients with severe haemophilia A with and without FVIII inhibitors.

BACKGROUND: Emicizumab is a bispecific monoclonal antibody that bridges activated factor (F) IX and FX, and maintains haemostasis in patients with haemophilia A (PwHA). As a novel agent, many questions remain unanswered about the loss of emicizumab efficacy due to anti-drug antibody (ADA) development, the incidence of inhibitor recurrence in previously tolerized patients, and the risk of de novo inhibitor development. AIM: To present real-world experience regarding tolerability, side effects, and outcomes of adverse events of emicizumab prophylaxis in paediatric PwHA. METHODS: Data on tolerability, compliance, adverse events, and laboratory results of paediatric patients receiving emicizumab prophylaxis, treated at the Haemophilia Comprehensive Care Centre, at Birmingham Children's Hospital between March 2018 and June 2021, were collected. RESULTS: Our results showed that out of 52 patients, four experienced minor adverse events, two developed headaches, one developed abdominal pain and nausea, and one developed injection site reactions. Moreover, four patients experienced major adverse events, including severe headaches, major bleeding events, development of ADAs, and recurrence of inhibitors. Emicizumab prophylaxis was discontinued in three patients (5.7% of the cohort) due to adverse events. In addition, emicizumab was discontinued in one patient because of poor compliance. No adverse events were reported in previously untreated/minimally treated patients, represented by four patients in our cohort. CONCLUSIONS: The real-world experience of emicizumab prophylaxis in our cohort showed that emicizumab was safe and well tolerated in paediatric PwHA with and without inhibitors. Long-term assessment is crucial to monitor major adverse events, recurrence of inhibitors, and development of ADAs.

Nonfactor Therapies: New Approaches to Prophylactic Treatment of Haemophilia.

For several decades, the treatment of haemophilia has relied on factor replacement therapy, which restores haemostasis by replacing the missing coagulation factor. In recent years, novel alternative therapies for the treatment of haemophilia in patients with and without inhibitors have been developed. These emergent therapies promote haemostasis by mimicking coagulation factors or inhibiting natural anticoagulants. They provide a less invasive route of administration (i.e. subcutaneous) and some offer reduced frequency of dosing (i.e. every 2 weeks, monthly) compared with the majority of factor replacement therapies, and thus have the potential to simplify treatment, increase adherence and subsequently improve outcomes for patients. Their introduction has transformed the care of haemophilia patients with inhibitors to factor VIII, with similar expectation for haemophilia B patients with inhibitors. However, these therapies also come with several new challenges including their limitation to prophylactic treatment, the observed increased incidence of thrombosis, or their impact on the natural history of the disease and potential disruption of existing treatment guidelines like the use of immune tolerance induction. Moreover, questions remain regarding the long-term impact of non-replacement therapies on joint health as well as the optimal strategy to manage breakthrough bleeds in patients with inhibitors.

Confirmed long-term safety and efficacy of prophylactic treatment with BAY 94-9027 in severe haemophilia A: final results of the PROTECT VIII extension study.

INTRODUCTION: The phase 2/3 PROTECT VIII main study demonstrated efficacy and safety of BAY 94-9027 (damoctocog alfa pegol; Jivi® ), a B-domain-deleted recombinant factor VIII (FVIII), site-specifically PEGylated to extend its half-life. AIM: To report the final efficacy and safety data for BAY 94-9027 from the PROTECT VIII extension. METHODS: Previously treated males aged 12-65 years with severe haemophilia A (FVIII <1%) who completed the multicentre, open-label PROTECT VIII main study were eligible for the extension. Patients received either on demand or prophylaxis treatments (30-40 IU/kg twice weekly [2 × W], 45-60 IU/kg every 5 days [E5D], or 60 IU/kg every 7 days [E7D]) and could switch to any prophylaxis regimen (variable frequency) as needed. Annualised bleeding rates (ABR), zero bleeds and safety outcomes were included in this final analysis. RESULTS: At extension completion, patients (n = 121) received BAY 94-9027 for a median (range) total time of 3.9 (0.8-7.0) years. Median (Q1; Q3) total ABR was 1.49 (0.36; 4.80) for prophylaxis patients (n = 107), compared with 34.09 (20.3; 36.6) for on-demand patients (n = 14). Median total ABRs for 2 × W (n = 23), E5D (n = 33), E7D (n = 23) and variable frequency (n = 28) groups were 1.57, 1.17, 0.65 and 3.10, respectively. Of prophylaxis patients, 20.6% were bleed-free during the entire extension (median time, 3.2 years) and 50.0% were bleed-free during the last 6 months. No patient developed FVIII inhibitors. No deaths or thrombotic events were reported. CONCLUSIONS: Efficacy and safety of BAY 94-9027 was confirmed, with extension data supporting its use as a long-term treatment option for patients with haemophilia A.

The changing treatment landscape in haemophilia: from standard half-life clotting factor concentrates to gene editing.

Congenital haemophilia A (factor VIII deficiency) and B (factor IX deficiency) are X-linked bleeding disorders. Replacement therapy has been the cornerstone of the management of haemophilia, aiming to reduce the mortality and morbidity of chronic crippling arthropathy. Frequent intravenous injections are burdensome and costly for patients, consequently with poor adherence and restricted access to therapy for many patients worldwide. Bioengineered clotting factors with enhanced pharmacokinetic profiles can reduce the burden of treatment. However, replacement therapy is associated with a risk for inhibitor development that adversely affects bleeding prevention and outcomes. Novel molecules that are subcutaneously delivered provide effective prophylaxis in the presence or absence of inhibitors, either substituting for the procoagulant function of clotting factors (eg, emicizumab) or targeting the natural inhibitors of coagulation (ie, antithrombin, tissue factor pathway inhibitor, or activated protein C). The ultimate goal of haemophilia treatment would be a phenotypical cure achievable with gene therapy, currently under late phase clinical investigation.

Early Phase Clinical Immunogenicity of Valoctocogene Roxaparvovec, an AAV5-Mediated Gene Therapy for Hemophilia A.

Evaluation of immune responses to adeno-associated virus (AAV)-mediated gene therapies prior to and following dose administration plays a key role in determining therapeutic safety and efficacy. This report describes up to 3 years of immunogenicity data following administration of valoctocogene roxaparvovec (BMN 270), an AAV5-mediated gene therapy encoding human B domain-deleted FVIII (hFVIII-SQ) in a phase 1/2 clinical study of adult males with severe hemophilia A. Patients with pre-existing humoral immunity to AAV5 or with a history of FVIII inhibitors were excluded from the trial. Blood plasma and peripheral blood mononuclear cell (PBMC) samples were collected at regular intervals following dose administration for assessment of humoral and cellular immune responses to both the AAV5 vector and transgene-expressed hFVIII-SQ. The predominant immune response elicited by BMN 270 administration was largely limited to the development of antibodies against the AAV5 capsid that were cross-reactive with other common AAV serotypes. No FVIII inhibitor responses were observed within 3 years following dose administration. In a context of prophylactic or on-demand corticosteroid immunosuppression given after vector infusion, AAV5 and hFVIII-SQ peptide-specific cellular immune responses were intermittently detected by an interferon (IFN)-γ and tumor necrosis factor (TNF)-α FluoroSpot assay, but they were not clearly associated with detrimental safety events or changes in efficacy measures.

Recombinant FVIIIFc Versus BAY 94-9027 for Treatment of Patients with Haemophilia A: Comparative Efficacy Using a Matching Adjusted Indirect Comparison.

INTRODUCTION: Prophylaxis with recombinant factor VIII (rFVIII) is the current standard of care for haemophilia A. Several approaches have been used to extend the half-life of rFVIII to improve prophylaxis outcomes. An indirect comparison of pivotal clinical trial data was performed to evaluate the relative efficacy of two extended half-life therapies approved for the prophylactic treatment of haemophilia A: recombinant FVIII-IgG1 Fc domain fusion protein (rFVIIIFc) and pegylated rFVIII (BAY 94-9027). METHODS: Matching-adjusted indirect comparison (MAIC) was conducted to compare the rFVIIIFc individualised prophylaxis arm of the A-LONG phase III clinical trial (n = 117) and the BAY 94-9027 approved dosing regimens of the PROTECT VIII phase II/III study (n = 110). Following matching for baseline characteristics, mean annualised bleeding rate (ABR) and the proportion of patients with zero bleeds were compared for rFVIIIFc and BAY 94-9027. Additional supportive analyses comparing rFVIIIFc individualised prophylaxis and the individual prophylaxis regimens included in the PROTECT VIII group (twice weekly, and every 5 and 7 days [Q5D and Q7D]) were conducted. RESULTS: Mean ABR was lower in the rFVIIIFc individualised prophylaxis group versus the BAY 94-9027 pooled prophylaxis population (3.0 versus 4.9), providing a clinically relevant and statistically significant difference (mean difference [MD] - 1.9; 95% confidence interval [CI] - 3.5 to - 0.4). A statistically significant difference in ABR was also observed for rFVIIIFc compared with BAY 94-9027 Q7D (3.2 versus 6.4; MD - 3.3; 95% CI - 6.4 to - 0.2). The difference in the proportion of patients with zero bleeds between rFVIIIFc (46.5%) and BAY 94-9027 pooled prophylaxis population (38.2%) was not statistically significant (odds ratio 1.4; 95% CI 0.8 to 2.5). CONCLUSIONS: This indirect treatment comparison indicates a statistically significant and clinically relevant difference in ABR favouring individualised prophylaxis with rFVIIIFc versus BAY 94-9027 prophylaxis. The proportion of patients with zero bleeds was numerically greater with rFVIIIFc treatment but did not achieve statistical significance.

Pathological mechanism of joint destruction in haemophilic arthropathy.

Haemophilic arthropathy (HA), caused by intra-articular haemorrhage, is one of the most common complications in patients with haemophilia. Factor replacement therapy provides missing coagulation factors to prevent children with haemophilia from joint bleeding and decreases their risk for HA. However, haemophilia patients in developing countries are still suffering from HA due to insufficient replacement therapy. Symptoms such as pain and activity limitations caused by HA seriously affect the functional abilities and quality of life of patients with HA, causing a high disability rate in the haemophilia cohort. The pathological mechanism of HA is complicated because the whole pathological mainly involves hypertrophic synovitis, osteopenia, cartilage and bone destruction, and these pathological changes occur in parallel and interact with each other. Inflammation plays an important role in the whole complex pathological process, and iron, cytokines, growth factors and other factors are involved. This review summarizes the pathological mechanism of HA to provide background for clinical and basic research.

Monitoramento do horizonte tecnológico: Medicamentos em desenvolvimento para o tratamento da Hemofilia A / Monitoring the technological horizon: Drugs under development for the treatment of Hemophilia A

A DOENÇA: A hemofilia A (HA) é uma doença genética hemorrágica, com herança ligada ao cromossomo X. Uma vez que os homens apresentam apenas um cromossomo X e não há alelo homólogo correspondente no cromossomo Y, a hemofilia A acomete principalmente indivíduos do sexo masculino. Ela é caracterizada pela deficiência ou anormalidade da atividade coagulante do fator VIII. Os pacientes tendem a ter sangramento recorrente de gravidade variável, que ocorre espontânea ou pós-traumaticamente em qualquer órgão ou tecido. A gravidade dos episódios hemorrágicos varia de acordo com a atividade residual coagulante do fator VIII. A maioria envolve sangramento intra-articular e hemartrose, a qual, quando recorrente e tratada de forma inadequada, resulta em dano permanente à cartilagem articular. No Brasil, em 2019, havia 10.821 pessoas diagnosticadas com HA, sendo 98,5% do sexo masculino e 36,6% tendo seu quadro clínico classificado como grave. A prevalência da HA estimada é de, aproximadamente, um caso em cada 10.000 nascimentos do sexo masculino. Dentre as coagulopatias hereditárias no Brasil, a HA é a mais frequente, correspondendo à 38,7% do total (4). No país, entre 1999 e 2016, ocorreram 927 óbitos masculinos relacionados à hemofilia, sendo 45,1% como causa básica e 54,9% como causa associada ao óbito. A principal causa associada foi hemorragia intracraniana, seguida de doenças infecciosas e parasitárias, prevalecendo a doença pelo vírus da imunodeficiência humana (HIV) e a hepatite viral. TRATAMENTO RECOMENDADO: No Brasil, as recomendações a respeito do tratamento da HA estão dispostas na segunda edição do manual de hemofilia, publicado pelo Ministério da Saúde em 2015. Também estão disponíveis o Protocolo de uso de Profilaxia Primária para Hemofilia Grave e o Protocolo de uso de indução de imunotolerância para pacientes com hemofilia A e inibidor. O tratamento da hemofilia inclui prevenção de sangramento e danos nas articulações e gerenciamento imediato de episódios hemorrágicos. O principal pilar é a reposição do fator de coagulação deficiente ­ no caso da HA, a reposição do fator VIII. A profilaxia com concentrados de fator de coagulação é referida como terapia de reposição regular, enquanto a terapia de reposição episódica ou terapia sob demanda caracteriza-se pela administração do fator apenas no momento de um sangramento. Diferentes terapias de coagulação estão disponíveis para o tratamento da hemofilia. Há os derivados de plasma humano (hemoderivados), os quais são submetidos a técnicas de diagnóstico, inativação viral e purificação; ou concentrados recombinantes, desenvolvidos por técnicas de biologia molecular. Dos recombinantes, há fatores de coagulação com meia-vida estendida, que aumentam a segurança hemostática na profilaxia e mantêm os níveis do fator mais elevados. Em eventos hemorrágicos, outros agentes são também recomendados, como o acetato de desmopressina e os antifribinolíticos (ácido tranexâmico e ácido épsilon-aminocaproico). ESTRATÉGIA DE BUSCA: Para identificar os medicamentos em pesquisa clínica para HA, foi consultado o sítio eletrônico ClinicalTrials.gov, em 07 de maio de 2021, empregando os termos "hemophilia" e "haemophilia". Foram considerados medicamentos que estão em fase 3 de pesquisa clínica, com a HA como alvo e sem registro para essa indicação terapêutica no Brasil. Para a pesquisa de resultados publicados dos ensaios clínicos, utilizaram-se os códigos de registro do ClinicalTrials.gov referentes aos estudos identificados na etapa anterior e os nomes de cada um dos medicamentos. Entre 13 e 20 de maio de 2020, foram feitas buscas nas bases de dados MEDLINE (via Pub Med), EMBASE e, também, o Google Acadêmico. De forma complementar, anais de congressos científicos, diretrizes clínicas internacionais e a base de dados CortellisTM foram consultados. Os estados regulatórios das terapias selecionadas foram consultados nos sítios eletrônicos da Agência Nacional de Vigilância Sanitária (Anvisa), European Medicines Agency (EMA) e Food and Drug Administration (FDA). NOVAS TERAPIAS: terapias alternativas (sem reposição de fator) que inibem as vias anticoagulantes: Concizumabe. Fitusiran. Marstacimabe. Terapia gênica. Giroctocogene fitelparvovec. Fatores de coagulação VIII com meia-vida estendida. LIMITAÇÕES: A maioria dos estudos de fase 3 localizados nesse informe ainda está em andamento. Embora alguns deles já possuam resultados publicados, esses estão disponíveis apenas sob forma de resumo ou apresentações em eventos científicos. As conclusões sobre a eficácia e segurança das tecnologias ainda são prematuras. Pacientes com hemofilia têm qualidade de vida reduzida devido, principalmente, a dor e às limitações físicas, com repercussão potencial na educação, no emprego e nos relacionamentos interpessoais (56). Avanços em técnicas de biologia molecular e terapias gênicas vêm mudando o cenário dos tratamentos disponíveis para a hemofilia. As melhorias nos fatores de coagulação de reposição permitem, por exemplo, a redução da frequência da infusão e a melhora da atividade biológica. O desenvolvimento de terapias de reposição sem fator de coagulação começou recentemente a oferecer uma abordagem alternativa de tratamento para pacientes com hemofilia. A terapia gênica oferece o potencial de uma cura vitalícia, uma melhor qualidade de vida e liberdade de várias morbidades relacionadas, embora com efeitos de longo prazo ainda desconhecidos. Os dois anticorpos monoclonais (concizumabe e marstacimabe) e o iRNA (fitusiran) são terapias de administração subcutânea que inibem as vias anticoagulantes, reduzindo ou cessando a necessidade de reposição do fator de coagulação. Estudos de fase 2 e resultados preliminares de estudos de fase 3 vêm demonstrando uma redução da taxa de sangramento anual de pacientes com HA que fizeram uso dessas tecnologias. Em relação à terapia gênica, o valoctocogene roxaparvovec e o giroctocogene fitelparvovec estão em fase 3 de desenvolvimento, e demonstram resultados promissores. Dados de estudos de fase 3 publicados em resumos e apresentações de congresso mostram níveis de atividade de FVIII substanciais e sustentados, reduções em episódios de sangramento autorrelatados, reduções em infusões de reposição de FVIII e perfil de segurança bem tolerado após a terapia com valoctocogene roxaparvovec. Os fatores de coagulação VIII com meia-vida estendida permitem a conveniência da redução na frequência da infusão do fator. No entanto, em geral, essas reduções são modestas. Foi apresentado o efanesoctocog alfa que possui três a quatro vezes a meia-vida relacionada a outros fatores VIII, permitindo a sua administração uma vez por semana. Os dados publicados abordam, em geral, a farmacocinética do medicamento, não permitindo conclusões sobre a sua eficácia e segurança. As tecnologias abordadas nesse informe de MHT estão em estudos de fase 3. Em geral, os resultados publicados são dos estudos de fase 2 ou são resultados preliminares de estudos de fase 3, publicados como resumos de eventos científicos. Em relação aos registros sanitários em outros países, das terapias avaliadas, apenas o Valoctocogene roxaparvovec tem a autorização de comercialização solicitada no EMA. No FDA, a autorização foi solicitada, mas a agência pediu dados suplementares e a empresa ainda não submeteu o pedido novamente (58). Nenhuma outra terapia discutida nesse MHT está registrada no EMA ou no FDA até a data de consulta. O desenvolvimento de novos tratamentos para a HA vem permitindo o maior controle da doença e de seus impactos. Caso tenham o registro aprovado por agências regulatórias e solicitada a incorporação destas tecnologias, análises cuidadosas devem ser feitas quanto ao perfil de eficácia/efetividade comparativa e segurança, além do impacto econômico que poderiam gerar ao sistema de saúde.

A systematic review evaluating the efficacy and factor consumption of long-acting recombinant factor VIII products for the prophylactic treatment of hemophilia A.

AIMS: Long-acting (LA) recombinant FVIII (rFVIII) products with extended dosing intervals have been developed for the treatment of hemophilia A; however, no direct head-to-head trial has been conducted to compare the efficacy of these products. MATERIALS AND METHODS: A systematic literature search was conducted to identify published Phase III clinical trials of prophylactic LA rFVIII treatment in previously treated patients aged ≥12 years, with moderate-to-severe hemophilia A (endogenous FVIII levels ≤2%). Studies that did not meet these criteria, or did not report the included outcomes, were excluded. Bleeding rates and consumption were extracted and summarized; only data for the dosing frequencies indicated in the US product labels (which are similar to those indicated in the European Medicines Agency labels) were included. RESULTS: Five articles met the inclusion criteria; these studies only included patients with severe hemophilia A. Treatment length, reported outcomes and dose (range: 20-65 IU/kg) varied between studies. Median annualized bleeding rate (ABR) (IQR) reported in the relevant studies was 1.14 (0.00-4.30), rVIII-SingleChain 2 or 3 times weekly; 1.6 (0.0-4.7), rFVIIIFc 2 times weekly followed by every 3-5 days; 1.9 (0.0-5.8), BAX855 2 times weekly; 1.18 (0.00-4.25), N8-GP every 4 days; 1.9 (0.0-5.2) and 4.1 (2.0-10.6), BAY 94-9027 2 times weekly for the cohort who experienced >1 or <1 bleed in the study run-in phase, respectively. Median spontaneous ABR was 0.0 across studies reporting relevant data. Reported consumption was comparable among all LA products. LIMITATIONS: The primary limitation of this systematic review was the variation in study design and not all studies reported all desired outcomes, which limited the quantity of data available. CONCLUSIONS: This systematic review identified pivotal trial data for LA rFVIII products. Real-world evidence is needed to understand how these products perform in clinical practice.

Tailoring haemophilia A prophylaxis with BAY 81-8973: A case series.

BAY 81-8973 is an unmodified, full-length third generation recombinant factor VIII (rFVIII) which offers a more favorable pharmacokinetic (PK) profile, compared to its predecessor sucrose-formulated rFVIII (rFVIII-FS). We here report on a retrospective case series of nine patients affected by hemophilia A (HA), with variable disease severity, bleeding phenotype and comorbidities, to underline our clinical practice on prophylaxis with a recently introduced standard hall-life recombinant Factor VIII. The current case series highlights how the current clinical management of hemophilia is able to personalize treatment in several specific conditions like concomitant illnesses with thrombotic risk and allergic reactions.

How I treat gastrointestinal bleeding in congenital and acquired von Willebrand disease.

Gastrointestinal (GI) bleeding is distinctive of severe von Willebrand disease (VWD), generally arising in older patients; in most cases, blood transfusion and hospitalization are required. The presence of arteriovenous malformations is often described when endoscopic examinations are performed. Patients with congenital type 3, 2A, and 2B are those most frequently affected by this symptom, possibly due to the loss of high-molecular-weight multimers of von Willebrand factor (VWF). GI bleeding can also occur in patients affected by acquired von Willebrand syndrome. Endoscopic examination of the GI tract is necessary to exclude ulcers and polyps or cancer as possible causes of GI bleeding. In congenital VWD, prophylaxis with VWF/factor VIII concentrates is generally started after GI-bleeding events, but this therapy is not always successful. Iron supplementation must be prescribed to avoid chronic iron deficiency. Possible rescue therapies (high-dose statins, octreotide, thalidomide, lenalidomide, and tamoxifen) were described in a few case reports and series; however, surgery may be necessary in emergency situations or if medical treatment fails to stop bleeding. In this article, we present several clinical cases that highlight the clinical challenges of these patients and possible strategies for their long-term management.