Phase 1–2 Trial of AAVS3 Gene Therapy in Patients with Hemophilia B

Authors: Chowdary, P; Shapiro, S; Makris, M; Evans, G; Boyce, S; Talks, K; Dolan, G; Reiss, U; Phillips, M; Riddell, A; Peralta, MR; Quaye, M; Patch, DW; Tuddenham, E; Dane, A; Watissée, M; Long, A; Nathwani, A

Affiliations: Università degli Studi di Milano, Department of Pathophysiology and Transplantation, Milan, Italy ; Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, Milan, Italy ; Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Department of Biomedical Surgical and Dental Sciences, Milan, Italy ; Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Department of Healthcare Professions, Milan, Italy ; Università degli Studi di Milano, Department of Biomedical Sciences for Health, Milan, Italy

Publication: New England Journal of Medicine; 2022; 387. 237–247

Abstract: BACKGROUND: FLT180a (verbrinacogene setparvovec) is a liver-directed adeno-associated virus (AAV) gene therapy that uses a synthetic capsid and a gain-of-function protein to normalize factor IX levels in patients with hemophilia B. METHODS: In this multicenter, open-label, phase 1–2 trial, we assessed the safety and efficacy of varying doses of FLT180a in patients with severe or moderately severe hemophilia B (factor IX level, ≤2% of normal value). All the patients received glucocorticoids with or without tacrolimus for immunosuppression to decrease the risk of vector-related immune responses. After 26 weeks, patients were enrolled in a long-term follow-up study. The primary end points were safety and efficacy, as assessed by factor IX levels at week 26. RESULTS: Ten patients received one of four FLT180a doses of vector genomes (vg) per kilogram of body weight: 3.84×1011 vg, 6.40×1011 vg, 8.32×1011 vg, or 1.28×1012 vg. After receiving the infusion, all the patients had dose-dependent increases in factor IX levels. At a median follow-up of 27.2 months (range, 19.1 to 42.4), sustained factor IX activity was observed in all the patients except one, who resumed factor IX prophylaxis. As of the data-cutoff date (September 20, 2021), five patients had normal factor IX levels (range, 51 to 78%), three patients had levels from 23 to 43%, and one had a level of 260%. Of the reported adverse events, approximately 10% were related to FLT180a and 24% to immunosuppression. Increases in liver aminotransferase levels were the most common FLT180a-related adverse events. Late increases in aminotransferase levels occurred in patients who had received prolonged tacrolimus beyond the glucocorticoid taper. A serious adverse event of arteriovenous fistula thrombosis occurred in the patient with high factor IX levels. CONCLUSIONS: Sustained factor IX levels in the normal range were observed with low doses of FLT180a but necessitated immunosuppression with glucocorticoids with or without tacrolimus. (Funded by Freeline Therapeutics; ClinicalTrials.gov numbers, NCT03369444 and NCT03641703; EudraCT numbers, 2017 -000852-24 and 2017-005080-40.).