Long-term safety and efficacy outcomes of valoctocogene roxaparvovec gene transfer up to 6 years post-treatment.
Author
Symington, EmilyRangarajan, 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
Publication date
2024-02-05Subject
Haematology
Metadata
Show full item recordAbstract
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.Citation
Symington E, Rangarajan S, Lester W, Madan B, Pierce GF, Raheja P, Robinson TM, Osmond D, Russell CB, Vettermann C, Agarwal SK, Li M, Wong WY, Laffan M. Long-term safety and efficacy outcomes of valoctocogene roxaparvovec gene transfer up to 6 years post-treatment. Haemophilia. 2024 Mar;30(2):320-330. doi: 10.1111/hae.14936.Type
ArticleAdditional Links
https://pubmed.ncbi.nlm.nih.gov/38317480/PMID
38317480Journal
HaemophiliaPublisher
Wileyae974a485f413a2113503eed53cd6c53
10.1111/hae.14936