Gene therapy and investigational approaches for hemophilia

INTRODUCTION — 

Hemophilia A (factor VIII [factor 8] deficiency) and hemophilia B (factor IX [factor 9] deficiency) are X-linked hereditary coagulation factor deficiencies that result in lifelong bleeding disorders. However, optimal management is complex, and available therapies carry a number of costs and burdens.

Hemophilia A and B are attractive candidates for gene therapy. They are both monogenic disorders that can be adequately treated by raising factor levels. The deficient factor can be produced and delivered to the circulation by various cell types. Unlike immunodeficiency syndromes, hematopoietic stem cell transplant is not required. (See "Overview of gene therapy, gene editing, and gene silencing", section on 'Inherited single gene disorders'.)

Some gene therapies have been approved for hemophilia A and B, and others are under investigation. Other therapies being investigated include specific therapies directed at the missing factor and general hemostatic approaches. This topic discusses gene therapy and investigational approaches under development.

Separate topic reviews discuss:

●Function of factors VIII and IX – (See "Biology and normal function of factor VIII and factor IX".)

●Hemophilia diagnosis – (See "Clinical manifestations and diagnosis of hemophilia A and B".)

●Prophylactic therapy and minor bleeding – (See "Hemophilia A and B: Routine management including prophylaxis".)

●Treatment of bleeding and surgery – (See "Acute treatment of bleeding and surgery in hemophilia A and B".)

OVERVIEW OF STRATEGIES TO REDUCE BLEEDING RISK — 

There are two main strategies to reduce bleeding risk, each of which has several potential approaches in development that are discussed in the following sections (figure 1).

●Enhancing factor activity

•Gene therapy to replace the deficient factor – (See 'Gene therapy' below.)

•Cellular therapy to transplant transduced cells capable of producing the deficient factor – (See 'Cellular therapy' below.)

•Modifications to factor proteins such as half-life extension or subcutaneous administration – (See 'Improvements to factor products' below.)

•Substitutes for the deficient factor such as bispecific monoclonal antibodies – (See 'Substitutes for clotting factors' below.)

●Decreasing natural anticoagulants

•Function-blocking monoclonal antibodies or small molecules – (See 'Reducing natural anticoagulants' below.)

•Engineered versions of natural inhibitors – (See 'Blocking activated protein C' below.)

GENE THERAPY — 

Gene therapy is appealing because infusion of the gene therapy construct (or treated cells) can provide the deficient factor. Efforts to establish gene therapy approaches for hemophilia are underway in various countries around the world [1].

Some gene therapy constructs have been approved by the US Food and Drug Administration (FDA). However, as stated in a 2021 review, aspects of this approach remain to be optimized and studied for longer durations, and clinician familiarity with the principles and logistics of gene therapy remains to be systematically addressed [2]. (See 'General gene therapy principles' below.)

Gene editing, which uses enzymes to alter the individual's native deoxyribonucleic acid (DNA) sequence rather than introducing a new copy of the gene, is under study for possible use in hemophilia [3-5]. (See "Overview of gene therapy, gene editing, and gene silencing", section on 'Gene editing'.)

General gene therapy principles — Gene therapy is both easy to understand and remarkably complex. A guide is available with figures and a glossary to help clinicians discuss gene therapy with their patients [6].

General information is provided by professional organizations such as:

●World Federation of Hemophilia (WFH; https://wfh.org/)

●National Bleeding Disorders Foundation (previously called National Hemophilia Foundation (https://www.bleeding.org/bleeding-disorders-a-z/treatment/future-therapies/frequently-asked-questions)

●International Society on Thrombosis and Haemostasis (ISTH; https://genetherapy.isth.org/)

Access to clinical trials — Information and resources for enrolling in hemophilia gene therapy trials may be accessed by consulting:

●Websites including clinicaltrials.gov (https://clinicaltrials.gov/search?term=gene%20therapy&cond=Hemophilia&viewType=Table)

●A local Hemophilia Treatment Center or Centre of Excellence

•United States – https://dbdgateway.cdc.gov/HTCDirSearch.aspx

•United Kingdom – https://www.ukhcdo.org/home-2/haemophilia-centre-list/haemophiliacentresa-c/

Methodology — Gene therapy introduces exogenous DNA into cells that can be used to produce a deficient protein. In monogenic disorders such as hemophilia, this may involve a wild-type factor gene or a modified gene with enhanced properties such as greater activity or longer half-life. (See "Biology and normal function of factor VIII and factor IX", section on 'Naturally-occurring gain-of-function variants'.)

●Target cell – Because the factor circulates in the bloodstream, the DNA can be transduced into cells with access to the circulation. Hepatocytes are considered an appropriate target cell for transduction because the liver is the site of synthesis of most clotting factors, including endogenous factor IX. Endogenous factor VIII is produced by liver sinusoidal endothelial cells (LSECs). In gene therapy approaches, constructs for both F8 and F9 are transduced into hepatocytes.

Transduction into hematopoietic cells has also been studied. (See 'Hemophilia A gene therapies under investigation' below.)

●Target factor level – Hemophilia is amenable to gene therapy because factor levels do not need to be raised to the normal range. Production of even a small amount of the missing factor (to raise the factor level from a baseline of 0 percent up to a level of 5 percent) is sufficient to convert the disease from one of frequent potentially life-threatening bleeding into a mild phenotype that no longer requires routine factor prophylaxis. Raising the factor level above 30 to 40 percent may obviate the need for additional hemostatic product administration.

●Vector – A variety of technologies may be used to introduce the F8 or F9 gene, either using ex vivo genetic modification followed by implantation of the modified cells, or direct injection of a vector carrying a construct that includes the normal gene into the patient [7-11].

Adeno-associated viruses (AAV) have become widely used vectors for gene therapy because they generally do not integrate into the nuclear genome and typically are replication-deficient, reducing the risk of insertional mutagenesis. Although random integration events are possible due to high AAV viral load administered, the long-term risk of insertional mutagenesis is likely low. Patient participation in registries for long-term data collection is of utmost importance. Another issue with AAV vectors is that some individuals have immunity to specific serotypes of adenoviruses and AAV due to natural infection; preexisting neutralizing antibodies to these vectors can reduce efficacy of gene therapy, as demonstrated in some trials. (See "Overview of gene therapy, gene editing, and gene silencing", section on 'Types of vectors'.)

●Eligibility – Preliminary gene therapy trials have included males with severe factor deficiency (factor activity <1 to 2 percent). Other individuals with bleeding phenotypes may be included in the future.

Individuals with factor inhibitors were excluded from early gene therapy trials due to concerns about reduced efficacy. Subsequent trials have been expanded to include these individuals. (See "Inhibitors in hemophilia: Mechanisms, prevalence, diagnosis, and eradication".)

Some individuals with severe liver disease or active viral hepatitis have been excluded from clinical trials due to concerns about hepatotoxicity. (See 'Potential concerns' below.)

Children have been excluded from trials due to concerns about informed consent and the likelihood that normal liver growth with proliferation of liver cells would dilute an episomal vector, reducing efficacy over time. There is also a prevailing caution about gene modification in younger children until overwhelming evidence of safety has been demonstrated in adults, adolescents, and older children. (See 'Potential concerns' below.)

●Administration – Gene therapy constructs are typically administered intravenously and home to the target cells (often hepatocytes) to which the vector has tropism.

The dose is typically expressed as number of vector genomes per kg of patient weight (vg/kg) [2].

This can be done as an outpatient procedure with close follow-up for development of adverse effects, including short-term infusion-related reactions and longer-term transaminase elevations. Due to the complexity of the treatment plan, interpretation of laboratory assays, and requirement of close short and long-term follow-up, gene therapy should be administered at an HTC/Hemophilia center of excellence with experience in gene therapy. Efficacy measures including factor levels and bleeding events are monitored longitudinally. (See 'Clinical experience with gene therapy' below.)

The goal of gene therapy is restoration of factor level. Although the goal is restoration of a normal factor level, even conversion from a severe to a mild bleeding phenotype may result in significant symptomatic improvement. (See "Clinical manifestations and diagnosis of hemophilia A and B", section on 'Definitions'.)

Potential concerns — Several concerns have been raised based on reduced efficacy and/or adverse effects observed in clinical trials or in preclinical models [2,12]:

●Eligibility – Some individuals may not be eligible for gene therapy due to preexisting immunity to the vector, preexisting antibodies (inhibitors) to the factor, or underlying liver disease.

●Duration of effect – The longest period of follow-up for any hemophilia gene therapy construct is <10 years, with the longest available follow-up data for factor IX deficiency. Thus, the durability of response has not been definitively established for any gene therapy product. Declining factor VIII levels over time have been observed; durability of expression is under study. (See 'Hemophilia A approved gene therapy' below.)

●Children – If episomal therapies are used in children, ongoing proliferation of liver cells may dilute the number of viral genomes, possibly reducing factor levels.

●Variable expression – Variable expression in different individuals remains unexplained, particularly with factor VIII.

●Long-term complications – Several years of data on toxicity are reassuring, yet longer-term data remain to be collected; the importance of participating in national and global registries should be emphasized

●Hepatotoxicity – Several studies have demonstrated increased transaminases or decreased factor levels; glucocorticoids have been used to reduce the presumed viral vector inflammatory response that can lead to vector loss. Elevated alanine aminotransferase (ALT) levels 1.5- to 2-fold above the upper limit of normal has been reported in all hemophilia gene therapy studies, occurs at 7 to 14 days post-infusion, and is more common in hemophilia A than in hemophilia B [13]. Most patients are asymptomatic, but ALT increases may be associated with reduction in or loss of transgene expression.

●Integration and oncogenesis – Certain vectors (such as those based on retroviruses) carry a theoretical risk of insertional mutagenesis that may cause malignancy. The risk of late genotoxicity with AAV-based therapies is felt to be reduced because these vectors do not integrate as readily into the nuclear genome [14]. However, even non-integrating vectors such as AAV can integrate into the nuclear genome in small amounts. The clinical significance and risk of malignancy in the long-term is unknown [15,16]. Nonetheless, because the number of vector particles used to insert the transgene into the target cell for transcription (as high as 0.6 x 10⁶ in one therapeutic strategy), even a very low rate of insertion could result in many target cells with insertional events [7].

One individual who received the hemophilia B gene therapy construct etranacogene dezaparvovec developed hepatocellular carcinoma; a subsequent detailed investigation concluded that the predisposing factor was not the gene therapy vector, based on no demonstration of proximal insertion of the AAV machinery near a known enhancer or promoter of clonality [17-19]. (See 'Hemophilia B approved gene therapies' below.)

●Immunity to the vector – Certain vectors may elicit a host immune response to viral proteins made by the vector, which could potentially complicate repeat dosing. Possible approaches to facilitating re-transduction are under investigation.

●Transmission to other individuals – Patients should be counseled to consider using male barrier contraception for a minimum of six months after receiving AAV-mediated gene therapy treatment and should be prohibited from donating blood, organs, tissues, or cells after receiving AAV-mediated gene therapy [20].

Gene therapy vectors are shed for a period of time, potentially exposing other individuals. Preclinical studies and early experience suggest that vector shedding can occur transiently in semen [21-26].

Patients who have received a gene therapy construct are counseled to use male barrier contraception. Family planning should be discussed prior to gene therapy so plans can be made. In gene therapy clinical trials, participants were required to use barrier contraceptive measures to eliminate the risk of reproductive transmission until clearance of vector shedding [5,6].

•Vector DNA clearance was assessed using a qPCR assay, which does not measure infectious risk [27,28].

•Vector clearance from semen occurred between 12 and 78 weeks.

Clinical experience with gene therapy — Early gene therapy trials have focused on adults (males) with factor activity <1 to 2 percent who have not developed inhibitors [2,5].

Hemophilia A approved gene therapy — The F8 gene can be modified to remove the B-domain; this is the construct used in recombinant factor VIII replacement products. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Recombinant human factor VIII'.)

The B-domain deleted F8 gene is smaller (F8 is a very large gene that barely fits [or cannot fit] in the adeno-associated viruses [AAV] vectors).

●Valoctocogene roxaparvovec – The first gene therapy construct for hemophilia A to be approved in the European Union was valoctocogene roxaparvovec (approved as Roctavian) in 2022 [29]. This therapy was approved by the US FDA in June 2023 [30].

This construct uses a codon-optimized adeno-associated virus serotype 5 (AAV5) vector containing a gene for B-domain deleted human factor VIII (AAV5-hFVIII-SQ) [31]. The AAV5 vector (and the AAV virus on which it is based) is a non-integrating hepatotrophic vector that remains mostly episomal, although a very small amount integrates into the nuclear genome. (See "Overview of gene therapy, gene editing, and gene silencing", section on 'Integrating versus nonintegrating vectors'.)

The approval is for adults with severe hemophilia A without an inhibitor and with no antibodies to AAV5. The dose is 6 × 10¹³ vector genomes per kilogram (vg/kg), administered as a single intravenous infusion. Other aspects of administration (monitoring of factor VIII and liver function, and indications for glucocorticoids) are described in the product label [29]. Factor VIII activity is expected to rapidly increase over the first six months and then to decline (at first rapidly and then more gradually) but to maintain effective levels, as described in the studies below.

Efficacy and safety of this construct was reported in a 2022 study involving 134 males with severe hemophilia A (baseline factor VIII activity ≤1 percent) who were followed for ≥1 year after receiving the therapy at a dose of 6 x 10¹³ vg/kg intravenously [32]. Individuals who were positive for anti-AAV5 capsid antibodies were not eligible to participate in the trial.

•Efficacy – There were clinically meaningful improvements in bleeding rates due to sustained increases in factor VIII activity [32]. The mean annualized bleeding rate decreased from 4.8 with prior prophylaxis to 0.8 after the gene therapy, and the mean annualized number of factor VIII infusions decreased from 136 to 2. Factor VIII activity levels (assayed by chromogenic substrate) remained increased above baseline through the end of the year (mean, 43 units/dL). Factor VIII activity >40 units/dL was seen in 50 participants (38 percent) and <5 units/dL in 16 participants (12 percent).

Extension studies have shown the safety and durability of the therapy for up to seven years [33-35].

•Safety – Adverse events in the initial and extension studies were common and mostly mild [32,33]. The most common was an increase in alanine aminotransferase (ALT in 86 to 89 percent); these elevations were mostly treated with glucocorticoids (in >80 percent); some were treated with tacrolimus (18 percent) or mycophenolate (10 percent). Serious adverse events related to the study drug were seen in 4 percent (mostly hypersensitivity reactions, including one anaphylaxis), all in the first year of therapy. Glucocorticoid-related adverse events were common. There were no deaths, thromboses, or inhibitor development.

Hemophilia A gene therapies under investigation — The following constructs are under investigation:

●SPK-8011 – This construct uses an AAV-LK3 vector with a liver-specific promoter and a codon-optimized, B-domain deleted F8 gene. In a series of 18 individuals with severe hemophilia A treated in various dose cohorts (from 5 x 10¹¹ vg/kg to 2 x 10¹² vg/kg) observed for a median of three years, 16 had preserved factor VIII expression [22]. Two individuals, both in the highest dose cohort, lost factor VIII expression due to an immune response to the AAV capsid, despite immunosuppression.

•Efficacy – Peak factor levels occurred at 6 to 12 weeks after infusion. For the entire cohort, the annualized bleeding rate decreased from a median of 8.5 events per year before infusion to 0.3 events per year after infusion, a 92 percent reduction. Factor infusions decreased from a median of 58 per year to 0.6 per year. In 15 individuals who were followed for >1 year, factor activity levels were stable at 11±7 percent. Factor activity levels remained stable in 12 individuals who were followed for >2 years.

•Safety – Therapy was well-tolerated, with an infusion reaction in one participant 12 hours after receiving the construct and transaminase elevations in seven. Four participants had adverse effects related to glucocorticoids used to reduce liver toxicity.

●Giroctogcogene fitelparvovec – Giroctocogene fitelparvovec (formerly SB-525) uses an AAV-serotype 6-based vector containing the B-domain deleted F8 gene. In a series of 11 individuals treated with escalating doses of this construct, the mean factor VIII activity at the highest dose level was 43 percent at week 52 and 25 percent at week 104 [25]. There was one reaction with fever and hypotension six hours after infusion that resolved within 24 hours, and some patients had transaminase elevations that responded to glucocorticoids.

●Other constructs – Several other gene therapy constructs for hemophilia A are in various stages of development [5,12]. Some of these have used a retroviral vector or a non-viral, plasmid-based system [21,36]. These have been effective in raising factor VIII activity levels and have generally been well-tolerated, although vector shedding remains possible [21]. (See 'Potential concerns' above.)

Other target cells for transduction – A lentiviral construct that is used to transduce autologous hematopoietic stem cells in the laboratory has also been developed (CD68-LV-ET3); the cells are then returned to the patient as an autologous hematopoietic stem cell transplant rather than being administered intravenously to the patient [37]. The annualized bleeding rate in five individuals treated with this therapy was zero at a cumulative follow up of 81 months, and the median factor VIII level at 28 days after transplantation was 5.2 percent (range, 3 to 8.7 percent). Myeloablative conditioning caused severe cytopenias in all five individuals.

A variant in the F8 gene that increases expression levels was identified in 2021 and has not yet been incorporated into gene therapy constructs. (See "Biology and normal function of factor VIII and factor IX", section on 'Factor VIII Padua'.)

Hemophilia B approved gene therapies — The F9 Padua variant (F9 p.R338L) contains a naturally occurring missense mutation in the F9 gene that increases its activity approximately 4 to 40-fold; this construct has been used in most of the factor IX gene therapy trials. It is appealing because it provides enhanced factor IX activity. Individuals are generally excluded from clinical trials if they have factor IX inhibitors or neutralizing antibodies against the viral vector used to deliver the gene therapy construct. (See "Biology and normal function of factor VIII and factor IX", section on 'Factor IX Padua'.)

●Etranacogene dezaparvovec – Etranacogene dezaparvovec (Hemgenix, formerly AMT-061) is an AAV5 vector containing F9 Padua with a liver-specific promoter. It was approved by the FDA in November 2022 for adults with hemophilia B using factor IX prophylaxis or those with a history of life-threatening bleeding or repeated serious bleeding [38]. In 2024, the National Institute of Health and Care Excellence (NICE) in the United Kingdom recommended this therapy be made available as a treatment option through the National Health Service (NHS) for adults with moderately severe or severe hemophilia B, and after an arrangement with the manufacturer, NHS has agreed to provide it while more data are collected over a five-year period [39].

•Dosing – It is given as a single intravenous dose of 2 x 10¹³ vg/kg.

•Supporting evidence:

-Efficacy – An initial study at a dose of 2 x 10¹³ vg/kg in three males with severe hemophilia B demonstrated reduced bleeding (no bleeds during the study period) and increased factor IX activity levels (mean factor IX activity of 31 percent at six weeks and 47 percent at 26 weeks) [40]. A previous study with an earlier construct (codon-optimized factor IX in the same AAV5 vector) in 10 men with hemophilia B was similarly effective [41].

The HOPE-B study, which followed 53 participants for 18 months, reported reduction in annualized bleeding rate (ABR) from 4.19 to 1.51, with reduced use of factor IX concentrate by a mean of 248,825 units per year per participant in the post-treatment period [42]. Factor IX therapy could be discontinued in 96 percent of participants [43].

Transduction was effective even in individuals with preexisting immunity to the AAV vector up to a titer of 678 (in 21 of 54 patients). Treatment did not produce a response in one patient with an AAV5 neutralizing antibody titer of 3212.

Factor IX activity measured with the chromogenic assay was lower than when measured with the activated partial thromboplastin time (aPTT)-based assay, reported at 16.5±8.8 versus 39±18.7 percent at six months. Expression appears to be stable at three years after treatment [44].

-Safety – Elevations in alanine transaminase (ALT more than two times baseline or above the upper limit of normal) were seen in 11 of 54 (20 percent); most elevations were mild to moderate. In the Hope-B protocol, glucocorticoids were initiated when the alanine aminotransferase (ALT) was twice the patient's baseline and/or above upper limit of normal. Glucocorticoids were used in 9 of the 11 patients, with a mean duration of 80 days. Infusion-related adverse events were seen in 13 percent.

One patient in the HOPE-B study discontinued treatment after a hypersensitivity reaction with the initial drug infusion; he received approximately 10 percent of the full dose and did not have a response to treatment.

One individual developed liver cancer; a detailed analysis concluded that the predisposing factor was not the gene therapy vector, as discussed above [17-19]. (See 'Potential concerns' above.)

One patient died of cardiogenic shock that was considered not to be treatment related.

●Fidanacogene elaparvovec – Fidanacogene elaparvovec (formerly SPK-9001) is an AAV vector containing F9 Padua. It was approved by the FDA in April 2024 (as Beqvez) for adults with moderate to severe hemophilia B using factor IX prophylaxis or with a history of life-threatening or serious bleeding and do not have neutralizing antibodies to the specific serotype of AAV [45]. Production was discontinued in early 2025 based on a business decision [46].

•Dosing – Dosing was as a single intravenous dose of vector at a low dose (5 x 10¹¹ vg/kg) to minimize host antiviral immunity.

•Supporting evidence:

-Efficacy – This therapy was evaluated in the BENEGENE-2 study, involving 45 patients with hemophilia B and factor IX activity <2 percent, using a single intravenous dose of 5×10¹¹ vg/kg [47]. Additional follow-up demonstrated sustained expression:

Of the 44 participants in the initial study with at least 15 months of follow-up, annualized bleeding rate decreased from 4.42 to 1.28 and the mean factor IX activity was 27 percent.

In a study that followed 14 individuals for 3 to 6 years, the mean annualized bleeding rate was <1, and 10 participants had no treated bleeding episodes [48]. The mean factor IX activity during years 4 to 6 ranged from 7 to 44 percent.

-Safety – Elevations in ALT (more than 1.5 times baseline), decreased factor IX activity, or both led to use of glucocorticoids in 28 participants (62 percent) in BENEGENE-2 [47]. In the study with 3 to 6 years follow up, there were no serious treatment-related adverse events [48]. Three participants received glucocorticoids for elevated liver enzymes during the first year; none required glucocorticoids after the first year.

There were no infusion-related serious adverse events, thromboses, or factor IX inhibitors.

Hemophilia B investigational gene therapies — The following are under investigation:

●Verbrinacogene setparvovec – Verbrinacogene setparvovec (formerly FLT180a) is a synthetic AAV vector (AAVS3, designed for increased liver transduction) containing F9 Padua. A dose-finding study in 10 males with hemophilia B and baseline factor IX activity <2 percent reported a decrease in mean annualized bleeding rate from 2.93 per year (range, 0 to 7.33) to 0.71 per year (range, 0 to 1.7) [49]. Only one person resumed factor IX replacement therapy; the other nine had factor IX activity of 28 to 279 percent. Adverse effects were as expected including transaminase elevations and side effects of immunosuppressive therapies (prednisolone, with or without tacrolimus). Thrombosis occurred in one individual with high factor IX activity.

●Other constructs – Earlier studies showed efficacy of other constructs such as an AAV8 vector expressing a codon-optimized F9 gene that produced dose-dependent increases in factor IX levels in 10 individuals (range, 1 to 6 percent, versus pre-study levels of <1 percent) [50,51]. A follow-up study demonstrated that these increases persisted over a median of 3.2 years. Annualized bleeding rates decreased from 16 to 2, and four of seven patients were able to discontinue factor IX prophylaxis. Transient, asymptomatic elevations in alanine aminotransferase levels with corresponding reductions in factor IX activity and increased numbers of AAV8-reactive T lymphocytes were seen in four individuals, suggesting a loss of transduced hepatocytes. These reactions responded to administration of a short course of prednisolone. There were no other major adverse events or factor IX inhibitors [40].

CELLULAR THERAPY — 

Cellular therapy involves introducing intact cells into the patient rather than manipulation of coagulation factor genes. Autologous cells may be treated with a gene therapy construct outside the body and then re-introduced. Foreign cells may be enclosed in immuno-protective devices before implantation to prevent rejection.

●A plasmid-based system was used to transfect autologous dermal fibroblasts with the gene for factor VIII and these cells were injected into the omentum [36]. Administration of autologous bone marrow cells transduced outside the body with a lentiviral vector is also under investigation. This strategy will likely require some degree of myeloablation before reintroduction of the ex-vivo modified hematopoietic cells into the individual. This may, in turn, raise concerns about clonal hematopoiesis, based on observations in individuals with sickle cell disease. (See "Curative therapies in sickle cell disease including hematopoietic stem cell transplantation and gene therapy", section on 'Concern about myeloid malignancy in gene therapy studies'.)

●In a mouse model of hemophilia A, transplantation of liver sinusoidal endothelial cells from non-hemophilic donor animals resulted in increased factor levels and correction of the bleeding phenotype [52].

●A polymer-encapsulated human cell system to express factor VIII (SIG-001) was under development but is no longer being pursued due to development of a factor VIII inhibitor in one recipient [53-55].

IMPROVEMENTS TO FACTOR PRODUCTS

Half-life extension — Several modified factor products are available with extended half-life. The major benefit is an extended interval between doses, which reduces the risks and burdens of intravenous access. Examples include recombinant fusion to the immunoglobulin Fc region or albumin, or PEGylation. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Extended half-life factor VIII' and "Hemophilia A and B: Routine management including prophylaxis", section on 'Longer-lasting recombinant factor IX'.)

For factor VIII, a main determinant that limits half-life extension is the requirement of binding to von Willebrand factor (VWF) for stabilization. A recombinant factor VIII fusion to VWF (efanesoctocog alfa [Altuviiio]) circumvents this dependence, leading to a significant prolongation of half-life that allows once-weekly administration. (See "Biology and normal function of factor VIII and factor IX", section on 'Binding to von Willebrand factor' and "Pathophysiology of von Willebrand disease", section on 'VWF functions' and "Hemophilia A and B: Routine management including prophylaxis", section on 'Efanesoctocog alfa (factor VIII-VWF fusion)'.)

Subcutaneous administration — No subcutaneous factor products are clinically available (emicizumab is given subcutaneously but is not a factor product). Subcutaneous administration would potentially eliminate the need for intravenous access or central venous catheter placement for administration of routine prophylaxis. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Emicizumab for hemophilia A'.)

SUBSTITUTES FOR CLOTTING FACTORS

Bispecific humanized monoclonal antibodies — Emicizumab is a bispecific humanized monoclonal antibody used for prophylaxis in hemophilia A. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Emicizumab for hemophilia A'.)

Mim8 is another bispecific antibody under development that also mimics the role of factor VIIIa in bringing together factor IXa and factor X, restoring tenase function. Like emicizumab, it can be administered subcutaneously in individuals with hemophilia A, both with and without inhibitors [56]. In hemophilia A plasma and whole blood, Mim8 normalized thrombin generation and clot formation, with potencies 13 and 18 times higher than a sequence-identical analog of emicizumab.

REDUCING NATURAL ANTICOAGULANTS — 

Some individuals with hemophilia who also carry a prothrombotic gene variant such as factor V Leiden (FVL) or antithrombin (AT) deficiency have been reported to have less frequent or milder bleeding. (See "Clinical manifestations and diagnosis of hemophilia A and B", section on 'Disease severity'.)

These observations have led to the development of approaches that target endogenous anticoagulant proteins, in effect "rebalancing" the equilibrium between procoagulant and anticoagulant factors.

Since they increase thrombin generation generally rather than by correcting a specific factor deficiency, these therapies have the potential to reduce bleeding regardless of the deficient procoagulant.

Tissue factor pathway inhibitor (TFPI) is a natural inhibitor of coagulation that prevents unchecked amplification of the clotting cascade. It acts in two ways, both inhibiting factor Xa and preventing generation of factor Xa by the extrinsic pathway (tissue factor and factor VIIa). (See "Overview of hemostasis", section on 'Control mechanisms and termination of clotting' and "Overview of hemostasis", section on 'Tissue factor pathway inhibitor'.)

Factor VIII and IX deficiencies reduce thrombin generation via the intrinsic pathway. Monoclonal antibodies against TFPI have the potential to improve hemostasis by allowing generation of higher local concentrations of factor Xa and thrombin by the extrinsic and common pathways.

Two anti-TFPI monoclonal antibodies were approved for hemophilia A or B in 2024. Details of which patients they were approved for (those with inhibitors or without inhibitors) are discussed separately. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Products that can be used for hemophilia A or B'.)

Another monoclonal antibody, befovacimab, was not pursued because three individuals in an early study developed central nervous system thromboses (one venous and two arterial) [57].

An anti-TFPI RNA aptamer was not pursued due to high bleeding rates at the highest dose level [57,58].

Reducing AT — AT is a natural anticoagulant that inhibits thrombin (factor IIa), factor Xa, and other serine proteases in the coagulation cascade such as factor IXa. Reduced AT activity can lead to a prothrombotic state. (See "Antithrombin deficiency", section on 'Pathophysiology' and "Overview of hemostasis", section on 'Antithrombin, heparin, and heparan'.)

Fitusiran is an antisense therapy that reduces AT activity; it was approved by the US Food and Drug Administration in March 2025. Use is discussed separately. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Fitusiran (AT antisense)'.)

Blocking activated protein C — Activated protein C (aPC) is a natural inhibitor of coagulation that proteolyzes factors such as activated factor V (factor Va).

Factor V Leiden (FVL) is a variant of factor V (a point mutation) that is resistant to aPC. (See "Factor V Leiden and activated protein C resistance", section on 'Physiology'.)

Modified SERPINs — Natural inhibitors of aPC exist, including protein C inhibitor (PCI) and alpha-1 antitrypsin (AAT); these are referred to as serine protease inhibitors (SERPINs). aPC also has roles in inflammatory signaling; there have been concerns that disruption of aPC function could have effects beyond the coagulation cascade. (See "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency", section on 'AAT genetics'.)

To circumvent the other roles of aPC, modified versions of natural SERPINs have been created that specifically block aPC activity in the coagulation cascade without disrupting other pathways, and these are under investigation as possible therapies for hemophilia. As an example, SerpinPC was an investigational SERPIN engineered to inhibit aPC; despite reported safety and tolerability, the manufacturer discontinued clinical development in November 2024 [59].

Monoclonal antibody that blocks aPC — SR604 is a monoclonal antibody directed against aPC that blocks the binding of aPC to factor Va and prevents the natural anticoagulant function of aPC but does not interfere with endothelial barrier and anti-inflammatory functions. In a mouse model of hemophilia, SR604 reduced bleeding and shortened clotting times without causing thrombosis [60].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hemophilia A and B".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Hemophilia (The Basics)")

SUMMARY

●Need for new therapies – Despite numerous factor products and other prophylactic therapies, optimal management of hemophilia is complex, and available therapies carry a number of costs and burdens. Some gene therapies have been approved, and others are under development (figure 1), along with other approaches to increase factor activity or to reduce natural anticoagulants. (See 'Introduction' above and 'Overview of strategies to reduce bleeding risk' above.)

●Increasing factor activity

•Gene therapy – Gene therapy introduces exogenous DNA into cells to produce the missing factor. Hepatocytes are considered an ideal target cell for clotting factor genes. Some individuals may not be eligible for gene therapy due to preexisting immunity to the vector, preexisting antibodies (inhibitors) to the factor, underlying liver disease, or age (liver still growing in young children). Durability of factor expression after gene therapy appears to be more of a challenge for factor VIII than for factor IX; long-term follow-up is needed to assure safety and efficacy. Data for specific constructs are presented above. (See 'Gene therapy' above and 'Hemophilia A approved gene therapy' above and 'Hemophilia B approved gene therapies' above.)

•Cellular therapy – Autologous cells treated outside the body with gene therapy or foreign cells can be used to produce the deficient factor. These approaches are in early stages of development. (See 'Cellular therapy' above.)

•Factor half-life extension – Various approaches to extending factor half-life are in development. Recombinant longer half-life products are already in use for hemophilia A and B. (See 'Half-life extension' above and "Hemophilia A and B: Routine management including prophylaxis", section on 'Extended half-life factor VIII' and "Hemophilia A and B: Routine management including prophylaxis", section on 'Longer-lasting recombinant factor IX'.)

•Factor alternatives – Bifunctional monoclonal antibodies (mAbs) that replace the function of the deficient factor are in development. Emicizumab is one such product that is already approved and in wide use for hemophilia A. (See 'Substitutes for clotting factors' above and "Hemophilia A and B: Routine management including prophylaxis", section on 'Emicizumab for hemophilia A'.)

●Reducing natural anticoagulants

•Anti-TFPI – mAbs against tissue factor pathway inhibitor (TFPI) allow generation of higher local concentrations of factor Xa and thrombin by the extrinsic and common pathways; two products were approved in 2024. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Products that can be used for hemophilia A or B'.)

•Reducing antithrombin – Fitusiran is an antisense oligonucleotide (ASO) against antithrombin (AT, encoded by SERPINC1) that prevents proteolysis of thrombin that was approved in March 2025 and is discussed separately. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Fitusiran (AT antisense)'.)

•Blocking aPC – Modified versions of natural serine protease inhibitors (SERPINs) that specifically block activated protein C (aPC) without disrupting other pathways are under investigation. A monoclonal antibody directed against aPC is also being studied. (See 'Blocking activated protein C' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges W Keith Hoots, MD, and Lawrence LK Leung, MD, who contributed to earlier versions of this topic review.