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- Title
Long‐term safety and efficacy outcomes of valoctocogene roxaparvovec gene transfer up to 6 years post‐treatment.
- Authors
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; Laffan, Michael
- 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 (6 × 1013 vg/kg; n = 7) and 5 (4 × 1013 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 6 × 1013 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 (8.25 × 10−5 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 6 × 1013 and 4 × 1013 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.
- Subjects
GENETIC transformation; TREATMENT effectiveness; BLOOD coagulation factor VIII antibodies; LYMPHADENECTOMY; BLOOD coagulation factor VIII
- Publication
Haemophilia, 2024, Vol 30, Issue 2, p320
- ISSN
1351-8216
- Publication type
Article
- DOI
10.1111/hae.14936