By: Paulina Maczko, PharmD Candidate 2027, Sarah El-Rowmeim, PharmD Candidate 2027, and Laura Pham, PharmD Candidate 2025

Valoctocogene roxaparvovec-rvox, sold under the brand name “Roctavian” by BioMarin Pharmaceuticals, was approved by the Food and Drug Administration (FDA) on June 29, 2023. It is a single-dose adeno-associated virus vector-based gene therapy infusion indicated for the treatment of adults with severe hemophilia A without antibodies to adeno-associated virus serotype 5 (AAV5).¹ Roctavian utilizes a modified virus, also known as a vector, and is used to treat hemophilia A. The vector transports a functional form of the Factor VIII gene to hepatic cells. The imported gene allows the production of clotting factors, preventing excessive bleeding.² Roctavian represents a significant breakthrough in treating severe hemophilia A, offering patients a promising option for managing the rare genetic bleeding disorder.

Background on Hemophilia A

Hemophilia A is an inherited bleeding disorder caused by a gene mutation that reduces the production of factor VIII (FVIII). FVIII is a protein responsible for blood clotting and thus, a deficiency in FVIII results in uncontrolled bleeding. A patient without hemophilia A exhibits factor VIII levels of 50% to 150%. Therefore, the severity of the disease is influenced by how much FVIII is produced; for example, patients with moderate hemophilia A have FVIII blood levels of 1% to 5% while those with mild hemophilia A have 6% to up to 49%.³ The majority of patients with hemophilia A have a severe form of the disease with less than 1% of FVIII in the blood, putting them at a much higher risk of experiencing bleeding into vital organs such as the kidneys and brains.⁴ Prior to Roctavian, available treatment options consisted of either endogenous FVIII or emicizumab, a monoclonal antibody that mimics activated FVIII.⁵

Gene Therapy Treatment

The approval of Roctavian presents the first gene therapy treatment available for this disease. This treatment utilizes the virus adeno-associated serotype 5 (AA5V) as a vector to insert the therapeutic gene into the hepatocytes. Thus, allowing the liver cells to produce the absent FVIII protein to permit proper blood clotting.²

In GENEr8-1, an open-label, single-group, multicenter, phase 3 clinical study, Roctavian’s efficacy and safety were evaluated in men at least 18 years of age with severe hemophilia A.⁶ Participants had to be recipients of prophylactic FVIII concentrates for at least 1 year prior to enrollment. Those with pre-existing anti-AAV5 antibodies, liver cirrhosis, substantial liver fibrosis, or who were positive for FVIII inhibitors, were excluded. Diagnosis of human immunodeficiency virus (HIV) was also considered an exclusion criterion after a protocol amendment.⁶ 134 participants received a single infusion and completed more than 51 weeks of follow-up.  Upon analysis of the modified intention-to-treat population (132 participants) which only included HIV-negative patients, there was a significant average increase from the baseline of FVIII activity level was 41.9 IU/dL during weeks 49-52 (95% confidence interval [CI] 34.1 to 49.7; P<0.001). Additionally, following the administration of Roctavian, the mean reduction in the rate of bleeding episodes was 83.8%, which was considered significant and superior to prophylaxis with FVIII concentrates.⁶ All 134 participants had at least one adverse event, with 16.4% experiencing serious adverse reactions. A few examples of serious adverse events that occurred in 2 or more participants include gastroenteritis, an increase in alanine aminotransferase (ALT), rectal hemorrhage, and diarrhea. However, the most common adverse reactions were headache (38.1%), nausea (37.3%), and an increase in aspartate aminotransferase (AST) levels (35.1%). More notably, 85.5% of patients experienced an increase in ALT levels and were treated with immunosuppressants.⁶

Though current treatments for hemophilia A are effective, most involve frequent intravenous injections. Not only this, but the risk of FVIII inhibitor development, a neutralizing immune reaction against FVIII, is especially high in patients with severe hemophilia A being treated with intravenous FVIII. Comparatively, Roctavian is a single treatment that allows the expression of the deficient FVIII for the entire lifetime of the recipient. Furthermore, Roctavian has demonstrated superiority in reducing the rate of bleeds and has shown a significant increase in FVIII levels.⁵

Conclusion

Roctavian represents a promising therapeutic advancement in treating severe hemophilia A, providing patients with a potentially transformative gene therapy option. Clinical trials, such as GENEr8-1, have demonstrated the efficacy and safety of Roctavian, with participants experiencing an increase in FVIII activity levels and a decrease in bleeding. Although adverse reactions were reported, further research and continued monitoring will be crucial in assessing the long-term efficacy and safety profile of Roctavian. In conclusion, although the approval of Roctavian displays the best of medical innovation, there are a variety of factors that will ultimately determine its real-world impact.

References

1. Roctavian. Package insert. BioMarin Pharmaceutical Inc; 2023.
2. How Roctavian Gene Therapy for Hemophilia A Works. BioMarin Pharmaceuticals. Accessed February 23, 2024. https://www.roctavian.com/en-us/how-roctavian-works/
3. Hemophilia A. National Bleeding Disorders Foundation. Accessed February 23, 2024. https://www.hemophilia.org/bleeding-disorders-a-z/types/hemophilia-a
4. FDA Approves First Gene Therapy for Adults with Severe Hemophilia A. Food and Drug Administration. June 29, 2023. Accessed February 23, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-adults-severe-hemophilia
5. Castaman G, Di Minno G, De Cristofaro R, Peyvandi F. The Arrival of Gene Therapy for Patients with Hemophilia A. Int J Mol Sci. 2022;23(18):10228. doi:10.3390/ijms231810228
6. Ozelo MC, Mahlangu J, Pasi KJ, et al. Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A. N Engl J Med. 2022;386(11):1013-1025. doi:10.1056/NEJMoa2113708

Published by Rho Chi Post