Hemophilia is a rare, X-linked bleeding disorder characterized by deficiency of factor VIII (hemophilia A) or IX (hemophilia B). In severe phenotypes, factor levels are less than 1 percent, and spontaneous bleeding into joints and soft tissue can result in significant morbidity and mortality.1-3 The mainstay of treatment is administration of intravenous factor concentrate, but this is associated with a substantial financial burden as well as an impact on quality of life due to the need for frequent intravenous interventions.4-6 In patients who develop inhibitors to factor VIII and IX, treatment is even more costly, and prophylaxis options are limited.7 Research has been burgeoning in the field of hemophilia to improve outcomes and quality of life for patients, with several new drug approvals in the past decade as well as promising experimental therapies that may drastically alter the treatment landscape.
In the past decade, the U.S. Food and Drug Administration (FDA) approved multiple recombinant factor products with an extended half-life to reduce the frequency of factor infusions. These products use polyethylene glycol (PEG), albumin, or the neonatal Fc receptor to prolong plasma half-life to 18 to 24 hours for factor VIII products and 68 to 102 hours for factor IX products.8-13 Emicizumab, a humanized bispecific antibody that mimics the cofactor activity of activated factor VIII by bridging activated factor IX and factor X, has also revolutionized the treatment of hemophilia A with inhibitors.
More recently, several investigational therapies have shown a substantial reduction in annual bleeding rate (ABR) for patients with severe hemophilia. Efanesoctocog alfa builds on neonatal Fc receptor technology by adding a region of von Willebrand factor and XTEN® polypeptides to prolong half-life and allow for once-weekly prophylactic administration in hemophilia A — a milestone not yet achieved with currently approved extended half-life therapies. In the phase III XTEND-1 study, 133 patients previously receiving prophylactic factor VIII infusions had a median ABR of 0.0 while on once-weekly efanesoctocog alfa.14 A median ABR of 0.0 was also achieved for patients with hemophilia A or B with inhibitors with the use of once-daily subcutaneous concizumab in the Explorer 7 trial.15 Unlike standard therapies for hemophilia, concizumab does not function by replacing factor VIII or IX, but by targeting tissue factor pathway inhibitor — a serine protease inhibitor that normally inhibits factor X and the tissue factor/factor VIIa complex to down-regulate coagulation. Likewise, the investigational agent fitusiran targets novel areas of the coagulation cascade to restore hemostatic balance. Fitusiran is an siRNA that targets antithrombin mRNA to decrease production of antithrombin in the liver. By reducing antithrombin, fitusiran is proposed to increase thrombin generation thereby shifting hemostatic balance toward coagulation. Data from the phase III ATLAS-PPX trial has also shown a median ABR of 0.0 with the use of once-monthly fitusiran prophylaxis for patients with or without inhibitors.16
Perhaps the most groundbreaking treatment under investigation for hemophilia is the use of gene therapy. Unlike standard prophylactic therapies for hemophilia, the promise of gene therapy is that it is a single intervention with long-lasting effects to free patients from the burden of chronic medication administration to prevent bleeding events. Most therapies use a recombinant adenoassociated virus (AAV) vector to deliver the gene for the required clotting factor to the cell nucleus. Wildtype AAV is a nonpathogenic, weakly immunogenic member of the parvovirus family that can deliver a gene cassette up to 5 kb.17 Engineered AAV capsids have been developed with strong hepatocyte tropism to allow for cassette insertion and factor production in the liver.18,19 Because most people are infected with AAV during childhood and may develop neutralizing antibodies, and transduced hepatocytes may trigger T-cell activation resulting in a transient transaminitis and decrease in factor levels, immunosuppressive regimens (e.g., corticosteroids) are administered early during treatment.
Etranacogene dezaparvovec is a promising gene therapy for hemophilia B that uses the highly active Padua variant of factor IX with an AAV5 vector. In the phase III HOPE-B trial, a single infusion of etranacogene dezaparvovec produced a mean increase in factor IX level of 36.9 percent at 18 months postinfusion in 54 men with severe or moderately severe hemophilia B.20 Compared to baseline, the total number of bleeding events decreased by 83 percent, and the number of treated bleeds decreased by 91 percent at 26 weeks, and 96 percent of patients were able to discontinue prophylactic factor infusions.
Despite initial challenges packaging the factor VIII gene, significant progress in gene therapy for hemophilia A has also recently been achieved. Roctavian® (valoctocogene roxaparvovec) is an AAV5-based gene therapy vector produced by BioMarin. In the open-label, single-group, multicenter phase III GENEr8-1 trial, 134 participants received an infusion, and by weeks 49 to 52, mean factor VIII activity had increased by 42.9 IU/dL.21 Among the 112 patients enrolled from a prospective noninterventional study, mean ABR decreased by 83.8 percent and annualized rates of factor VIII concentrate use decreased by 98.6 percent (p<0.001 for both comparisons). No development of factor VIII inhibitors or thrombosis occurred, and the most common adverse event was elevated transaminases. In August 2022, Roctavian was granted conditional authorization in the European Union for adults with severe hemophilia A without a history of factor VIII inhibitors or neutralizing antibodies to AAV5. Due to the potential for hepatic toxicity, Roctavian is currently contraindicated in patients with acute or uncontrolled chronic hepatitis or in patients with known cirrhosis. Following initial rejection by the FDA in June 2020, BioMarin plans to resubmit to the FDA in the near future.
A lentiviral approach to gene therapy has shown promise in mice and nonhuman primates and has recently been introduced to humans in two phase I studies.22 In these studies, hematopoietic stem cells are collected by apheresis and genetically modified to allow for production of factor VIII by progenitor platelets. This approach may decrease immune responses to the therapy due to a significantly lower level of pre-existing lentiviral immunity and may also allow for larger packaging capacity.
After decades of limited treatment options, the influx of new and highly effective therapies will drastically alter the treatment landscape for patients with hemophilia with or without inhibitors. However, the greater challenge now will be determining which patients will benefit from these novel therapies and selecting which therapy is most appropriate for individual patients. While functionally curative options are likely to be FDA approved in the near future, they are associated with unique risks and may not be warranted for all patients with hemophilia.
When approaching the discussion of novel therapies with patients, it is important to first consider the current status of their disease. The primary benefit of gene therapy is a reduction in ABR over time without the need for repeated factor dosing, so in patients with minimal bleeding on a well-tolerated regimen, the risks of gene therapy may outweigh the benefits. While gene therapy might potentially be curative and free patients from the burden of IV prophylaxis, it is not without costs of its own. In clinical trials, the most significant harm of both etranacocgene dezaparvovec and valoctocogene roxaparvovec was liver enzyme elevation requiring prolonged treatment with corticosteroids. For patients who opt to pursue these treatments, special care will need to be taken to ensure adequate liver health including screening for hepatic malignancy and discontinuation of hepatotoxic medications. Additionally, the risk of prolonged corticosteroid use will have to be deemed acceptable prior to starting treatment, which may limit patients with poorly controlled diabetes, glaucoma, or osteoporosis. Other costs associated with these treatments include the need for frequent lab monitoring, abstinence from alcohol for a year, and requirement for barrier contraception until viral vector is cleared from semen. The financial burden of gene therapy is also not negligible, with an estimated cost of approximately $2.5M per dose.23 The greatest risk of gene therapy is the uncertainty of long-term efficacy and effects on the liver. While liver enzyme elevations all resolved with steroid use in the current trials, there has not yet been enough follow-up to guarantee that this treatment will not cause long-term damage to the liver, particularly the risk of hepatocellular carcinoma (HCC). The duration of meaningful levels of factor production following gene therapy also remains to be determined. Patients may be limited to one lifetime exposure to gene therapy due to the production of neutralizing antibodies to the vector, so they may not want to risk their “one shot” at a curative option until the duration of response is better understood.
With this in mind, all decisions regarding the use of gene therapy should be made with patients via a shared decision-making process. People with hemophilia have indicated that their primary consideration regarding gene therapy is the effect on bleeding rate, followed closely by frequency of administration and durability.24 Given the influx of novel therapies with a median ABR of 0.0 and a prolonged half-life, the risks and benefits of gene therapy versus an alternative novel treatment must be carefully considered. Patients have also expressed concern regarding both short- and long-term safety issues associated with gene therapy. As more data are obtained regarding the safety and durability of gene therapy, we are cautiously optimistic that these fears may be alleviated. With the advent of commercially available gene therapy just around the corner, it will be imperative for both providers and patients to gain a high level of understanding and to partake in robust conversations to ensure that the optimal treatment can be pursued. When applied to the appropriate patient population, gene therapy has the potential to radically alter the quality of life for patients with hemophilia and is sure to leave a lasting impact on the approach to heritable diseases for decades to come.
Dr. Corrao and Dr. Malec indicated no relevant conflicts of interest.