Recent Advances in Extended Half-Life Products, Nonfactor Replacement Therapies, and Gene Therpy for the Treatment of Hemophilia.

Transition considerations for extended half-life factor products.

The clinical symptoms of rare bleeding disorders (RBDs) range from mucosal to life-threatening haemorrhages or functionally restricting haemorrhages. Congenital coagulation factor (F) deficiencies, VII, FX, FXIII, fibrinogen deficiencies and dysfibrinogenaemias, represent 3‒5% of all inherited coagulation factor deficiencies. Due to this low prevalence and the variability of bleeding manifestations, the clinical features of these RBDs are not well characterised. For this reason we conducted a retrospective multicentre national survey using patient records to characterize clinical bleeding manifestations in patients with congenital isolated/combined coagulation factor deficiencies or with congenital abnormalities of fibrinogen. Fifteen departments (11 haematology and four paediatric departments) across Algeria took part in the study, and data from 234 patients were analyzed. The majority of patients (n=164; 70.1%) had isolated congenital coagulation factor deficiencies, the most common of which was FVII deficiency (n=101; 43.2%). Only 221 patients (9.0%) had combined congenital coagulation deficiencies, the most common of which was FVIII/V deficiency (n=13; 5.6%). Congenital fibrinogen abnormalities were reported in 49 patients (20.9%). Overall, there were 327 bleeding episodes in 163 patients. The majority of bleeding episodes (n=195, 59.6%) were in patients with an isolated factor deficiency, the highest incidence of which was recorded for FVII deficient patients (95 bleeds; mean 1.7 bleeds/patient). Our results support existing descriptions in the literature and may help to target resourcing and plan treatment strategies for those patients at most risk of bleeding.

Expectations and Concerns Towards New Extended Half-Life (EHL) Products - Results of Surveys Among Haemophilia Patients from the Dach Region

Real World Use of Extended Half-Life Products and the Impact on Bleeding Events and Joint Health in the United States

: Rare bleeding disorders usually begin in childhood and manifest as varying degrees of bleeding, which can be life-threatening in severe cases. With the development of gene editing technology, it is expected that hereditary coagulation factor disorders will someday be fundamentally cured by gene therapy. On account of their rarity, comprehension of these diseases is essential for the application of new treatment strategies. We have compiled the features of some newly discovered mutations of prothrombin, factor VII, and factor X in recent years. In addition, this review introduces the advances and obstacles in gene therapy.

Hemophilia, an X-linked monogenic disorder, arises from mutations in the F8 or F9 genes, which encode clotting factor VIII (FVIII) or clotting factor IX (FIX), respectively. As a prominent hereditary coagulation disorder, hemophilia is clinically manifested by spontaneous hemorrhagic episodes. Severe cases may progress to complications such as stroke and arthropathy, significantly compromising patients’ quality of life. Hemophilia has a monogenic nature, coupled with quantifiable therapeutic endpoints and predictable treatment outcomes. These characteristics render it an ideal candidate for gene therapy studies. Currently, Food and Drug Administration (FDA)-approved gene therapies utilize recombinant adeno-associated virus (AAV) vectors to deliver functional transgene cassettes to hepatocytes. These therapies offer distinct advantages: a single intravenous administration achieves sustained FVIII and FIX activity levels, providing robust hemostatic control while markedly enhancing patients’ quality of life. However, several challenges remain, including immunogenicity, thrombotic risks, potential gene integration, and prohibitive costs. Future endeavors should prioritize expanding patient eligibility and integrating precision gene-editing technologies to mitigate these limitations. In this review, we provide a comprehensive overview of recent advances and emerging strategies in hemophilia gene therapy, with a particular focus on clinical translation and technological innovation. Ongoing research in this field remains pivotal to overcome existing barriers, enhance treatment accessibility, and ultimately realize curative potential for patients with hemophilia.

Bleeding disorders with low plasma activity of more than one coagulation factor have been described in several conditions. Multiple coagulation factor deficiency (MCFD) commonly represents as part of acquired conditions. The most well-known acquired causes are liver disease and disseminated intravascular coagulation (DIC) in which impaired synthesis or excessive consumption of coagulation factors occurs, respectively. Dilution states such as massive transfusion and cardiopulmonary bypass are also considered as conditions which lead to MCFD. Congenital deficiencies of more than one coagulation factor rarely have been also described. Such disorders can be rare autosomal bleeding disorder with extremely low incidence. Congenital MCFD may arise from coinheritance of isolated factor defects or may be a result of a single genetic defect. The latter which comprises most of cases is generally caused by defect of a single gene that is implicated in the process or production/activation of multiple factors. The best examples include combined FV and FVIII deficiency (F5F8D) and vitamin K-dependent coagulation factors (VKDCF) deficiency, which have been thoroughly characterized. Isolated combined coagulation factor deficiencies are extremely rare disorders and restricted to isolated case reports.

Hemophilia A/B are caused by deficiency or lack of coagulation factors VIII (FVIII) or factor IX (FIX), respectively, in plasma. A person with hemophilia develops bleeding in the joints and muscles at an early age, which, if left untreated, leads to early arthropathy. Preventive treatment can be achieved by regular (prophylactic) administration of FVIII/FIX. In 1958, this was implemented on a small scale in Sweden with FVIII in patients with severe hemophilia A, and in those with hemophilia B in 1972 when FIX became available. However, there were problems with human immunodeficiency virus and hepatitis infection from contaminated blood products. In the 1990s, recombinant FVIII and FIX concentrates were introduced. The major remaining problems then were the development of inhibitors, and the need for a venous route for the injections in very young children. High-titer inhibitors were treated by immune tolerance induction according to a modified model of the original Bonn high-dose protocol. A central venous line, i.e., Port-A-Cath, has enabled early prophylaxis in many children with poor venous access and has enabled the early start of home treatment with adequate injection frequency. Scoring systems for X-rays, magnetic resonance imaging, and function of joints were developed early in Sweden and have been widely disseminated worldwide, partly with modifications. Extended half-life products with half-life increased three to five times have been developed, which can provide superior bleed protection when dosed once-weekly and can maintain therapeutic trough levels when administered less frequently. The ultimate prophylaxis therapy in the future may be gene therapy.

Hemophilia is characterized by a deficiency in coagulation factors VIII or IX. The general standard of care for severe hemophilia is frequent intravenous recombinant or plasma-derived factor replacement to prevent bleeding. While this treatment is effective in preventing bleeding, frequent infusions are burdensome for patients. Nonadherence to the therapeutic regimen leaves people with hemophilia at risk for spontaneous and traumatic bleeds into joints as well as life-threatening bleeds such as intracranial hemorrhage. The chronicity of the disorder often leads to the formation of target joints, causing long-term pain and impairing mobility. As a monogenic disorder with well-understood genetics, hemophilia is an ideal disorder for implementing innovations in gene therapies. Indeed, recent approvals of two gene therapy products have the potential to shift the hemophilia treatment paradigm. Valoctocogene roxaparvovec and etranacogene dezaparvovec-drlb are gene therapies for hemophilia A and B, respectively. These therapies, given as a single intravenous infusion, may improve patients’ quality of life, decreasing treatment burden and resulting in factor expression that virtually eliminates the need for factor replacement. Since both treatments involve viral vectors targeted to the liver, short- and long-term safety and efficacy monitoring involves monitoring liver enzymes to track liver health. Long-term monitoring of efficacy, durability of gene expression, and safety are ongoing. Gene therapy presents a promising new therapeutic option for patients with hemophilia and warrants continued innovation and investigation.

Rett syndrome (RTT) is a devastating X-linked neurodevelopmental disorder, primarily affecting females, caused by mutations in the MECP2 gene. After a brief period of normal development, affected children experience rapid regression, losing motor and communication skills. Core features include microcephaly, seizures, stereotypic hand movements, and breathing abnormalities. While rooted in neurological dysfunction, growing evidence reveals RTT's widespread impact extends beyond the brain, implicating MECP2 in multisystem disruption. This review provides a comprehensive overview of RTT's genetic and neuropathological basis and highlights the significant advances in gene therapy to restore MECP2 function. Notably, adeno-associated virus (AAV)-based approaches have shown promise in preclinical models by improving survival and motor function in RTT mouse models. Recent advancements in AAV vector design have optimized targeted delivery to neurons and enhanced the regulation of MECP2 expression to prevent overexpression-related toxicity. Additionally, nanoparticle-based delivery systems are being explored as non-viral alternatives, offering the potential for improved targeting and safety. These advancements in gene therapy hold promise for RTT, bringing the possibility of effective targeted treatments closer to clinical application. As research continues to unravel RTT's complex pathophysiology, emerging therapies may offer new hope for improving patient outcomes and quality of life.

Hemophilia is a rare X-linked congenital bleeding disorder due to a deficiency of factor VIII (hemophilia A [HA]) or factor IX (hemophilia B [HB]). Replacement and nonreplacement treatments are available but have limitations. Gene therapy (GT) provides an effective, long-term, single-dose treatment option, now approaching clinical practice. This study aimed to understand patient perspectives on GT for HA and HB in Italy using a qualitative questionnaire distributed through Italian patient associations, addressing patient views on daily life, treatments, unmet needs, quality of life (QoL), and GT for hemophilia. In total, 141 participants had HA, and 14 had HB (severe 78.6%). Daily life was most affected by pain and/or joint function limitations (57.5% of participants), high infusion frequency (42.5%), management of breakthrough bleeding episodes (40.3%), and anxiety/fear of severe or sudden bleeding (38.8%). Despite current treatments, about half of the participants experienced three or more annual bleeding episodes. Most participants knew of GT (87.2%) and expected improvements in QoL (60.5%), reduced frequency of current treatments (53.5%), and a permanent cure (49.1%); 46.4% were unaware of its once-off dosage and 46.4% were not concerned about the costs they anticipated to be associated with GT. Although several fears were reported, 25.0% of participants were willing to undergo GT with the support of a multidisciplinary team. This survey provided valuable insight into patient perspectives on hemophilia and GT in Italy. Overall, relevant proportions of patients still experience limitations affecting their daily life. Most were positive about GT and anticipated improvements in their clinical outcomes and QoL.

Deficiencies in coagulation factors I (FI), FII, FV, combined FV and FVIII (CF5F8) and vitamin K-dependent coagulation factors FVII, FX, FXI, and FXIII have been referred to as rare bleeding disorders (RBDs), rare coagulation factor deficiencies (RCFDs), or recessively inherited coagulation disorders. Fibrinogen was most likely the first member of this group to be identified, with reports of its discovery spanning from 1859 to 1966. If not, then the first coagulation factor to be identified was prothrombin in 1894, and the last coagulation factor to be found was FX in 1956, about 60 years later. The first patient to be diagnosed with an RBD was a 9-year-old boy with afibrinogenemia in 1920 and the vitamin K-dependent coagulation factors deficiency was the most recent RBD in this group to be identified in a 3-month-old child in 1966. The initial therapeutic option for nearly all patients with RBDs was whole blood transfusion; this was replaced in 1941 by fresh frozen plasma (FFP), and then in later years by cryoprecipitate and coagulation factor concentrates. Fibrinogen concentrate was the first coagulation factor concentrate produced in 1956. Coagulation factor concentrate is now available for FI, FVII, FX, FXI, and FXIII; however, FFP and/or platelet transfusion are the only treatments available for FV deficiency. The only recombinant concentrates available for RBDs are for FVII and FXIII, which date from 1988 and the 2000s, respectively. Even though the clinical presentations, diagnosis, and management of lesser-known bleeding disorders have improved significantly in recent decades, more studies are needed to reveal the hidden aspects of these disorders in order to overcome diagnostic and therapeutic challenges and ultimately improve the quality of life for those who are affected.

Keeping up with the Cartashians - Classical Hematology Drug Approvals over Past 5 Years

Haemophilia A and haemophilia B are congenital X-linked bleeding disorders caused by deficiency of coagulation factor VIII (FVIII) and IX (FIX), respectively. The preferred treatment option for patients with haemophilia is replacement therapy. For patients with severe disease, prophylactic replacement of coagulation factor is the treatment of choice; this has been shown to reduce arthropathy significantly, reduce the frequency of bleeds and improve patients' quality of life. Prophylaxis with standard recombinant factor requires regular intravenous infusion at least two (FIX) to three (FVIII) times a week. Recombinant FVIII and FIX products with an extended half-life are in development, or have been recently licensed. With reported mean half-life extensions of 1.5-1.8 times that of standard products for FVIII and 3-5 times that of standard products for FIX, these products have the potential to address many of the unmet needs of patients currently treated with standard factor concentrates. For example, they may encourage patients to switch from on-demand treatment to prophylaxis and improve the quality of life of patients receiving prophylaxis. Indeed, extended half-life products have the potential to reduce the burden of frequent intravenous injections, reducing the need for central venous lines in children, promote adherence, improve outcomes, potentially allow for more active lifestyles and, depending on the dosing regimen, increase factor trough levels. Members of the Zürich Haemophilia Forum convened for their 19th meeting to discuss the practicalities of incorporating new treatments into the management of people with haemophilia. This review of extended half-life products considers their introduction in haemophilia treatment, including the appropriate dose and schedule of infusions, laboratory monitoring, patient selection, safety considerations, and the economic aspects of care.

Deficiencies of coagulation factors VIII and IX and von Willebrand factor constitute the majority of inherited bleeding disorders, while deficiencies of fibrinogen; prothrombin; factors V, VII, X, XI, and XIII; and PAI-1 constitute rare bleeding disorders (RBDs). Inherited deficiencies of inhibitors of fibrinolysis are extremely rare bleeding disorders and are included under the “miscellaneous” category. The clinical spectrum of bleeding symptoms in these disorders ranges from mucocutaneous bleeding to musculoskeletal bleeding. Rarely, these disorders are asymptomatic and present only after hemostatic challenge such as surgical procedures or trauma. Availability of clotting factor concentrates and adjuvant therapies, such as desmopressin (DDAVP) and antifibrinolytics, as well as comprehensive care within specialized hemophilia treatment centers (HTCs), has transformed patient outcomes and quality of life. Modifications to the recombinant factor proteins have prolonged the half-life of these factors, hence reducing the number of doses and increasing the residual trough levels in patients on prophylaxis. Newer therapies for patients with hemophilia A and B include alternative substitution and hemostatic rebalancing therapies and gene therapy. This chapter provides an overview of the clinical presentation, diagnostic testing, and principles of management for patients with inherited bleeding disorders.