Immunogenicity Outcomes for Val-Rox Reported From Phase 3 GENEr8-1 Study
Among more than 100 patients with hemophilia A, no FVIII-specific responses showed associations with the assessed safety or efficacy parameters.
Brian R. Long, PhD, MS
(Credit: LinkedIn)
Data from the phase 3 open-label trial GENEr8-1 (NCT03370913) suggest that treatment with valoctocogene roxaparvovec (Roctavian; BioMarin) resulted in immune responses that were mainly directed toward the adeno-associated virus-5 (AAV5) capsid, with every participant All seroconverted to AAV5 total binding antibody (TAb) and AAV5 transduction inhibitor (TI) positive by 8 weeks post dose.1 Additionally, these titers were not associated with affects on Factor VIII (FVIII) activity nor alanine aminotransferase (ALT) elevations.
Colloquially known as val-rox, the gene therapy was the first approved for treatment of adults with severe hemophilia A, defined as congenital factor VIII (FVIII) deficiency with FVIII activity of less than 1 IU/dL who do not have antibodies to AAV5 according to an FDA-approved test. The agency gave the go-ahead based on data from GENEr8-1, the labeling of which includes the prospective data from 112 patients in whom 6-month baseline ABR was collected, who reported a mean ABR reduction of 52% (2.6 bleeds per year) through the end of follow-up (median, 3 years) compared with baseline ABR while receiving routine FVIII prophylaxis (5.4 bleeds per year).2
Study author Brian R. Long, PhD, MS, a principal scientist in clinical immunology at BioMarin Pharmaceutical, and colleagues noted that none of the 134 men included in the study developed a FVIII inhibitor response that proved meaningful. “Of the 4 participants who had a single positive FVIII inhibitor response before or after valoctocogene roxaparvovec administration, 1 instance was a confirmed false positive, and the remaining 3 were isolated and transient,” they noted, adding that in the 9% of patients with FVIII TAb-positive results, cases were “transient and had low titers, consistent with previous reports” from populations of both people with hemophilia A and healthy donors that do not progress to become inhibitors.
“These FVIII TAb responses were not associated with ALT elevations or FVIII-specific cellular immune responses. Furthermore, instances of AAV5 TAb, FVIII TAb, AAV5 cellular immune response, and FVIII cellular immune response positivity at baseline were not associated with altered ALT levels or meaningfully reduced FVIII activity through the data cutoff date,” Long and colleagues wrote.
This analysis included data from the 3-year cutoff of the study, which provided a mean follow-up of 172.8 weeks (SD, 26.61). The most common adverse event (AE) was elevated ALT levels—defined as 1.5 times the baseline or above the upper limit of normal (ULN)—was reported by 90.3% of the cohort through the third year. The median time to this elevation occurred at 8.1 weeks. None of the ALT elevations that emerged post year 2 were managed with immunosuppressants.
Long et al noted that 85.1% (n = 114) of study participants experienced an elevation in ALT in the first year, but incidence declined in years 2 and 3 to 29.9% (n = 40) and 23.7% (n = 31) participants, respectively. Those elevations that started after week 52 were not deemed to eb linked to unanticipated drops in FVIII activity, and so treatment with corticosteroids was not considered beneficial.
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The investigators noted that “the prevailing hypothesis over nearly 2 decades of clinical studies utilizing AAV vector gene therapies, principally for hemophilia B, is that a capsid-specific cellular immune response (or cytotoxic T cell response) emerges following dose administration that infiltrates the liver parenchyma and attacks transduced hepatocytes presenting capsid-derived protein antigens,” but that in several instances, only poor or no association of ALT elevations and/or loss of expression have been observed in detecting capsid-specific cellular immunity. “This brings into question whether a cytotoxic T cell response is the primary cause of the ALT elevations that were observed following systemic administration in nearly every clinical study or whether sampling the peripheral blood mononuclear cell population accurately reflects effector cells that may be present in the liver. Regardless, there is an emerging consensus that the use of oral glucocorticoids in response to ALT elevations is reasonable to moderate immune-mediated toxicities and protect against the possible loss of transgene expression.”
In this assessment, Long and colleagues’ findings suggest that early instances of liver inflammation—3 to 6 months post-dose—may hold relation to adaptive immune responses for some individuals, which would warrant corticosteroid treatment, but that later ALT elevations—6 months or later post-dose—may be mediated by other, poorly defined mechanisms. In these cases, they note, “benefits of corticosteroid treatment for these secondary ALT elevations should be considered carefully.”
In recent weeks, BioMarin publicized that it plans to scale back efforts with val-rox, focusing on distributing the gene therapy in the United States, Germany, and Italy—the 3 countries where it has been approved for use by relevant regulatory authorities, and is reimbursed.3 Additionally, with a sufficient supply on hand, the company plans to pause manufacturing for the time being, as well as any plans to enroll new patients in clinical trials for the gene therapy. In accordance with those plans, BioMarin is aiming to cut annual costs for val-rox down to $60 million starting at beginning of 2025, which it anticipates will allow it to become profitable by the end of next year.
Alexander Hardy, MBA, the president and chief executive officer of BioMarin, said in a statement3 in early August 2024 that, "We continue to believe that Roctavian is an important option for people with severe hemophilia A, offering the potential for years of bleed control after a single, 1-time treatment. By rightsizing our resourcing, we are creating a path for Roctavian to contribute to our profitability while still providing full support to patients. We are deeply grateful to the hemophilia community and to the patients and healthcare providers who participated in our clinical trials, and we will continue to provide support, as well as to meet our regulatory commitments for ongoing monitoring."
