Long‐term safety and efficacy outcomes of valoctocogene roxaparvovec gene transfer up to 6 years post‐treatment

• Published in: Haemophilia : the official journal of the World Federation of Hemophilia 2024-03, Vol.30 (2), p.320-330
• Main 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
• Format: Article
• Language: English
• Subjects: acinar cell carcinoma; adeno‐associated virus; Adult; clinical trial; Coagulation factors; Dependovirus; Diploids; Factor VIII - genetics; Gene therapy; haemophilia; Hemophilia; Hemophilia A - complications; Hemorrhage - prevention & control; Hemostatics; Humans; Lymph nodes; Male; Malignancy; Neoplasms - complications; Parotid gland; phase 2; Recombinant Fusion Proteins; Safety; Tumorigenesis
• ISSN: 1351-8216; 1365-2516
• DOI: 10.1111/hae.14936

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.