Symington, Emily, Rangarajan, Savita, Lester, Will, Madan, Bella, Pierce, Glenn F., Raheja, Priyanka, Robinson, Tara M., Osmond, Dane, Russell, Chris B., Vettermann, Christian, Agarwal, Suresh K., Li, Mingjin, Wong, Wing Yen and Laffan, Michael (2024) Long-term safety and efficacy outcomes of valoctocogene roxaparvovec gene transfer up to six years post-treatment. Haemophilia. (In Press)
Abstract
Introduction: valoctocogene roxaparvovec uses an adeno-associated virus serotype 5 (AAV5) vector to transfer a factor VIII (FVIII) coding sequence to individuals with severe haemophilia A, providing bleeding protection.
Aim: To assess safety and efficacy of valoctocogene roxaparvovec 5‒6 years post-treatment.
Methods: in a phase 1/2 trial, adult male participants with severe haemophilia A (FVIII ≤1 IU/dL) without FVIII inhibitors or anti-AAV5 antibodies received valoctocogene roxaparvovec and were followed for 6 (6x1013 vg/kg; n = 7) and 5 (4x1013 vg/kg; n = 6) years. Safety, including investigation of potential associations between a malignancy and gene therapy, and efficacy are reported.
Results: no new treatment-related safety signals emerged. During year 6, a participant in the 6x1013 vg/kg cohort was diagnosed with grade 2 parotid gland acinar cell carcinoma; definitive treatment was uncomplicated parotidectomy with lymph node dissection. Target enrichment sequencing of tumour and adjacent healthy tissue revealed low vector integration (8.25x10−5 per diploid cell). Integrations were not elevated in tumour samples, no insertions appeared to drive tumorigenesis, and no clonal expansion of integration-containing cells occurred. During all follow-ups, >90% decreases from baseline in annualised treated bleeds and FVIII infusion rates were maintained. At the end of years 6 and 5, mean FVIII activity (chromogenic assay) was 9.8 IU/dL (median, 5.6 IU/dL) and 7.6 IU/dL (median, 7.1 IU/dL) for the 6x1013 and 4x1013 vg/kg cohorts, respectively, representing proportionally smaller year-over-year declines than earlier timepoints.
Conclusions: valoctocogene roxaparvovec safety and efficacy profiles remain largely unchanged; genomic investigations showed no association with a parotid tumour.
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