Hemophilia

Roctavian (valoctocogene roxaparvovec, AAV5-hFVIII-SQ), called ValRox until May 2020, is an investigational gene therapy under regulatory review for the treatment of severe hemophilia A, defined as a factor VIII level of 1 IU/dL or lower.¹

Hemophilia A is a genetic disease caused by a deficiency of clotting factor VIII. It occurs much more frequently in males. Patients with hemophilia A are susceptible to spontaneous and trauma-induced episodes of bleeding in soft tissues and joints, resulting in an impaired quality of life, possibly life-threatening complications, and early death.

Roctavian, which is being developed by BioMarin, is an adeno-associated virus serotype 5 (AAV5)-based gene therapy vector containing a coagulation factor VIII complementary DNA driven by a liver-selective promoter. It is designed to deliver a working copy of the 6e13 genome in the liver using an engineered viral vector. Upon injection into the blood, the virus delivers the recombinant F8 gene to several tissues, including the liver. However, the factor VIII protein is synthesized only in liver cells because the promoter is liver-specific. The factor VIII protein is then secreted into the bloodstream by the liver.²

Past and Present Roctavian Clinical Trials

A multiyear phase 1/2 dose escalation study (NCT02576795)³ assessed the safety and efficacy of valoctocogene roxaparvovec in 15 adults with severe hemophilia A. Of the 15 enrolled patients, 7 received a high dose (6×10¹³ viral genomes per kilogram) of valoctocogene roxaparvovec. The primary endpoint of a factor VIII activity level of 5 IU/dL or higher at week 16 was noted in all 7 participants. The mean factor VIII activity level in the 7 patients after 1 year was 64 IU/dL, which is within the nonhemophilic range (>40 IU/dL).⁴

The factor VIII levels decreased in all participants during the follow-up years. The mean factor VIII level dropped to 36 IU/dL in the second year, 33 IU/dL in the third year, and 24 IU/dL in the fourth year. The mean annualized bleeding rate (ABR) for treated bleeds in the 7 participants dropped from 16.3 events per year at baseline to a cumulative mean of 0.7 per year after a follow-up of 4 years, representing a 96% reduction.^5,6

An ongoing open-label, single-arm, multicenter phase 3 trial (NCT03370913)⁷ enrolled patients with severe hemophilia A to study the safety and efficacy of valoctocogene roxaparvovec. The participants, who were at least 18 years of age, did not have pre-existing anti-AAV5 antibodies or a history of the development of factor VIII inhibitors, and had been receiving prophylaxis with factor VIII concentrate, received a single intravenous infusion at a dose of 6×10¹³ viral genomes per kilogram. Results showed that valoctocogene roxaparvovec treatment increased the mean factor VIII activity level at weeks 49 through 52 and significantly reduced bleeding and the prophylactic use of factor VIII concentrate.⁸

The most common treatment-related adverse event in the phase 1/2 and phase 3 studies was elevation of the alanine aminotransferase level, a marker of liver inflammation.

Another open-label, single-arm phase 3 study (NCT03392974)⁹ will evaluate the safety and efficacy of valoctocogene roxaparvovec at a dose of 4×10¹³ viral genomes per kilogram in patients with severe hemophilia A who are receiving prophylactic factor VIII infusions. The study will determine the changes in mean factor VIII activity and the number of episodes of bleeding requiring the use of exogenous factor VIII concentrate from week 5 to week 52 after a single infusion. The study is expected to be completed in 2023.

A phase 1/2 study (NCT03520712)¹⁰ is currently recruiting 10 patients with severe hemophilia A who have pre-existing antibodies against AAV5 to evaluate the safety and efficacy of valoctocogene roxaparvovec at a single dose of 6×10¹³ viral genomes per kilogram. This trial aims to assess the efficacy of valoctocogene roxaparvovec in achieving factor VIII activity at or above a level of 5 IU/dL at week 26 and the effect of valoctocogene roxaparvovec on the number of episodes of bleeding and the use of exogenous factor VIII replacement therapy. Participants with liver dysfunction, chronic or active hepatitis B or C, active malignancy, or any immunosuppressive disorder were excluded from the study. The study is expected to be completed in 2027.

References

1. Valoctocogene roxaparvovec for severe hemophilia A. Pipeline. BioMarin.. Accessed May 31, 2022.
2. Agboola F, Rind DM, Walton SM, Herron-Smith S, Quach D, Pearson SD. The effectiveness and value of emicizumab and valoctocogene roxaparvovec for the management of hemophilia A without inhibitors. J Manag Care Spec Pharm. 2021;27(5):667-673. doi:10.18553/jmcp.2021.27.5.667
3. Gene therapy study in severe haemophilia A patients (270-201). ClinicalTrials.gov. October 15, 2015. Updated February 23, 2022. Accessed May 31, 2022.
4. Rangarajan S, Walsh L, Lester W, et al. AAV5-Factor VIII gene transfer in severe hemophilia A. N Engl J Med. 2017;377(26):2519-2530. doi:10.1056/NEJMoa1708483
5. Pasi KJ, Rangarajan S, Mitchell N, et al. Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for hemophilia A. N Engl J Med. 2020;382(1):29-40. doi:10.1056/NEJMoa1908490
6. Pasi KJ, Laffan M, Rangarajan S, et al. Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A. Haemophilia. 2021;27(6):947-956. doi:10.1111/hae.14391
7. Single-arm study to evaluate the efficacy and safety of valoctocogene roxaparvovec in hemophilia A Patients (BMN 270-301). ClinicalTrials.gov. Accessed May 31, 2022.
8. 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
9. Single-Arm study to evaluate the efficacy and safety of valoctocogene roxaparvovec in hemophilia a patients at a dose of 4E13 vg/kg. ClinicalTrials.gov. December 19, 2017. Accessed May 31, 2022.
10. Gene therapy study in severe hemophilia A patients with antibodies against AAV5 (270-203). ClinicalTrials.gov. April 3, 2018. Accessed May 31, 2022.

Reviewed by Debjyoti Talukdar, MD, on 5/31/2022.

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Erum Naqvi, PhD

Erum Naqvi obtained her Ph.D. in Molecular Medicine from Hannover Medical School (Germany) after completing her Masters in Biomedical Science and Bachelors in Microbiology from University of Delhi (India). She has several years of experience as a science writer.