Gene Therapy for Hemophilia: Considering Therapeutic Value, Patient Selection

Researchers assert that valoctocogene roxaparvovec and etranacogene dezaparvovec-drlb have the potential to transform the treatment of severe hemophilia, but uncertainties persist regarding immunosuppression, response unpredictability, long-term efficacy, and safety. A recent research review focusing on Phase 3 data highlights the efficacy and safety distinctions between hemophilia A and B and suggests criteria for evaluating patient eligibility for gene therapy.

Hemophilia, a disorder characterized by a deficiency in coagulation factors, is typically treated with frequent intravenous factor replacement to prevent bleeding. However, this treatment can be burdensome for patients, making gene therapies such as valoctocogene roxaparvovec and etranacogene dezaparvovec-drlb appealing alternatives that may improve patients' quality of life by reducing treatment burden and eliminating the need for factor replacement.

In 2022, two gene therapies for hemophilia were approved for clinical use. Valoctocogene roxaparvovec, developed by BioMarin Pharmaceutical Inc, received approval in Europe in August 2022, while etranacogene dezaparvovec-drlb received FDA approval in the USA in November 2022 and European approval in February 2023.

Valoctocogene roxaparvovec is indicated for the treatment of severe hemophilia A in adult patients without FVIII inhibitors and detectable antibodies to AAV5. The approval was based on data from the GENEr8-1 Phase 3 clinical trial, which involved 134 participants. The trial showed a significant increase in mean FVIII activity at year 1 and a substantial decrease in bleeding rates. The gene therapy demonstrated safety and efficacy, but longer-term data is needed to assess gene expression durability and bleeding phenotype.

However, challenges remain for valoctocogene roxaparvovec, including the waning of gene expression over time and the need for prolonged use of immunosuppression with corticosteroids. Future studies are needed to fill gaps and optimize protocols for minimizing side effects. The ongoing GENEr8-3 trial will explore the relationships between ALT elevations, FVIII expression, and the use of glucocorticoids and/or other immunosuppressants. These data will be crucial for improving the therapeutic options for a broader range of hemophilia patients.

Etranacogene Dezaparvovec-drlb, a gene therapy developed by uniQure and CSL Behring, is being studied in the HOPE-B Phase 3 clinical trial for hemophilia B treatment. The trial includes 54 adult males with severe or moderately severe hemophilia B who are on FIX prophylaxis therapy. The trial aims to compare the bleeding rate during months 7-18 after treatment to the lead-in period. The therapy effectively reduces bleeding events and improves quality of life. Safety outcomes include common adverse events like ALT elevation and headache, but there were no major concerns. One participant developed hepatocellular carcinoma unrelated to the gene therapy. 

Etranacogene dezaparvovec-drlb shows promise in treating hemophilia B with positive efficacy and safety outcomes. Comparatively, it provides a more sustained response with less hepatotoxicity than the gene therapy studied in the GENEr8-1 trial for hemophilia A. However, predicting expression levels can be difficult and patients may need to resume prophylactic therapy if there is a lack or loss of response. Considering the risks and benefits is important, as valoctocogene roxaparvovec, the treatment for hemophilia A, has higher risks and requires immune suppression. Maintaining liver health is crucial for all AAV gene therapies. Patients with pre-existing neutralizing antibodies to AAV5 were included in the HOPE-B trial, while they were excluded in the GENEr8-1 trial for hemophilia A. Redosing with current strategies is not possible due to the development of AAV antibodies after treatment.

Gene therapies for hemophilia raise questions about long-term efficacy, note researchers. While single infusions aim for lasting effectiveness, their true duration remains unclear. Variability in therapy durability may stem from diverse AAV vector target cells. Collecting ongoing trial data is vital to optimize patient benefits and engage in gene therapy registries. Safety, especially liver health, is a concern, given potential immunosuppression effects, yet long-term impacts remain uncertain. Transparency regarding risks and uncertainties is crucial for discussions between clinicians and patients.

Determining eligibility for hemophilia gene therapy is pivotal, guided by therapy-specific criteria. These criteria, distinct from trial standards, may change over time. Prospective patients must recognize eligibility limitations, including factors like inhibitor history and AAV5 antibodies. HIV status and immunocompromised cases lack substantial evaluation. Patient characteristics, quality of life, and willingness are vital factors. A three-tier stratification—unlikely, potential, good candidates—considers hemophilia severity, antibodies, inhibitors, health, and patient commitment. Mental health and treatment satisfaction are vital, and gene therapy might not suit all situations, including children and specific health cases. Eligibility and liver health's gene therapy effects remain debated among experts.

Gene therapy has revolutionized hemophilia care, sparking fresh questions and uncertainties. Key ideas and researcher recommendations from the review included: 

• Identifying apt candidates, involving patients in decisions about benefits, risks, and logistics are vital. 
• Empowering patients enhances health advocacy and adherence awareness. 
• Factors influencing decisions encompass regimen history, efficacy, and lifestyle.
• Long-term safety and early adoption are key concerns. 
• A "Hub and Spoke Model" aids monitoring while registries gather data. 
• Limits like joint damage and waning gene expression must be acknowledged. 
• Children's suitability for gene therapy is complex. 
• Evolving gene therapy aims for wider eligibility, robust expression, safety, and child-friendliness.

“We believe gene therapy is a valuable therapeutic option, which will undoubtedly benefit from further investigation,” said researchers. “Going forward, delving into the world of gene therapy has the potential to revolutionize how we think about treating genetic disorders.” 

Reference: 
Thornburg CD, Simmons DH, et all. Evaluating gene therapy as a potential paradigm shift in treating severe hemophilia. BioDrugs. Published July 25, 2023. doi.org/10.1007/s40259-023-00615-4