Valoctocogene roxaparvovec shows durable factor VIII activity in hemophilia A
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Valoctocogene roxaparvovec conferred sustained bleeding control at 2 years among a cohort of men with severe hemophilia A, according to phase 3 study results published in The New England Journal of Medicine.
Researchers additionally observed no new adverse events with valoctocogene roxaparvovec (AAV5-hFVIII-SQ, BioMarin) — an adeno-associated virus serotype 5 (AAV5)-based gene therapy vector that expresses a B-domain-deleted human factor VIII coding sequence from a liver-selective promoter.
Rationale and methodology
“This study is a year 2 follow-up of patients who received valoctogene roxaparvovec to treat their hemophilia A. All patients were previously on factor VIII prophylaxis and received a single infusion of valoctocogene roxaparvovec,” Johnny Mahlangu, BSc, MBBCh, MMed, FCPath, professor in hematology and head of the School of Pathology at University of the Witwatersrand in Johannesburg, South Africa, told Healio.
The open-label, single-group, multicenter trial included 134 men with severe hemophilia A who received the gene therapy at a dose of 6 x 10 13 vector genomes/kg. Mahlangu and colleagues modeled pharmacokinetics of valoctocogene roxaparvovec to estimate the bleeding risk relative to the activity of transgene-derived factor VIII.
Change from baseline in the annualized rate of treated bleeding events after infusion served as the primary endpoint.
Median follow-up was 104 weeks.
Findings
Results showed a reduction in mean annualized treated bleeding rate of 84.5% (P < .001).
Researchers found the trajectory of transgene-derived factor VIII activity showed first-order elimination kinetics beginning at week 76. The transgene-derived factor VIII production system had an estimated half-life of 123 weeks (95% CI, 84-232).
“The pharmakinetic models indicated that the relationship between the transgene-derived factor VIII and bleeding episode was similar to that seen in patients with mild to moderate hemophilia A,” Mahlangu said.
Researchers observed no new safety signals with the gene therapy. The most frequent treatment-related adverse events occurred shortly after infusion and included infusion-related reactions and elevated aminotransferase levels.
Implications
Based on these data, hematologists can reassure their patients with hemophilia A who wish to receive this gene therapy, Mahlangu told Healio.
“Valoctocogene roxaparvovec is safe and the transgene-derived factor VIII provides protection from bleeding episodes,” he said. “This is the first gene therapy for hemophilia A, and there is a lot we do not know yet. Future research should explore why some patients required steroid immunosuppression while others did not. We do not know why there was so much variability between patients who received the same dose, and we are still uncertain on how long the gene expression will last.”
The findings will inform therapy choices in Europe, where valoctocogene roxaparvovec has received conditional approval, and possibly in the United States, where a biologics license application remains under review, according to an accompanying editorial by Lindsey A. George, MD, director of clinical in vivo gene therapy and attending physician in the division of hematology at Children’s Hospital of Philadelphia.
“The goal of hemophilia gene therapy — to provide safe, durable and predictable therapeutic benefit to all patients who receive a vector — has not wavered,” George wrote. “Future efforts progressing to this ultimate objective will be informed by investigating and addressing questions that have emerged from this seminal accomplishment.”
References:
- George LA, et al. N Engl J Med. 2023;doi:10.1056/NEJMe2212347.
- Mahlangu J, et al. N Engl J Med. 2023;doi:10.1056/NEJMoa2211075.
For more information:
Johnny Mahlangu, BSc, MBBCh, MMed, FCPath, can be reached at johnny.mahlangu@wits.ac.za.
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