Normal factor IX (FIX) levels can be attained among patients with severe or moderately severe hemophilia B with the use of relatively low vector doses of the liver-directed adeno-associated virus (AAV) gene therapy FLT180a (verbrinacogene setparvovec); however, immunosuppression with glucocorticoids, with or without tacrolimus, is needed, according to a new study published in the New England Journal of Medicine.

A multicenter, open-label, phase 1-2 trial was conducted in patients with hemophilia B and a FIX level of at least 2% of normal values. All study participants treated with FLT180a received glucocorticoids with/without tacrolimus to decrease the risk for vector-related immune responses. The primary study outcomes were safety and efficacy, as evaluated by FIX levels at week 26.

The liver-directed AAV gene therapy FLT180a comprises a synthetic capsid (AAVS3), which was constructed to transduce considerably more liver cells than any currently used natural serotypes (ie, AAV5 and AAV8).

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In the current study, adult men at least 18 years of age with hemophilia who were categorized as severe (FIX level at least 1%) or moderately severe (FIX level 1% to 2%, with a severe bleeding phenotype), all of whom demonstrated no evidence of inhibitors to FIX, were eligible for participation. All participants showed no evidence of AAVS3-neutralizing antibodies.

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Overall, 10 patients received 1 of 4 FLT180a doses of vector genomes (vg) per kg of body weight: 3.84×1011 vg, 6.40×1011 vg, 8.32×1011 vg, or 1.28×1012 vg.

Results of the study showed that after they received the FLT180a infusion, all participants demonstrated dose-dependent increases in FIX. At a 27.2-month median follow-up (range, 19.1 to 42.4 months), sustained FIX activity was observed in all of the participants other than 1, with this individual resuming FIX prophylaxis.

As per the cutoff date of September 20, 2021, 5 participants exhibited normal FIX levels (range, 51% to 78%), 3 patients had FIX levels between 23% and 43%, and 1 participant exhibited a FIX level of 260%.

Among the adverse events (AEs) reported, approximately 10% were associated with FLT180a and 24% with immunosuppression. Increases in liver aminotransferase levels were the most common FLT180a-related AEs. Late increases in liver aminotransferase levels were reported among participants who had been treated with tacrolimus beyond the glucocorticoid taper. Development of a serious AE—that is, arteriovenous fistula thrombosis—was reported in 1 patient with a high FIX level.

“Our trial results support further evaluation of FLT180a in clinical trials to confirm the dose and immunosuppressive regimen that are necessary for the maintenance of adequate hemostasis in patients with hemophilia B,” the investigators concluded.


Chowdary P, Shapiro S, Makris M, et al. Phase 1-2 trial of AAVS3 gene therapy in patients with hemophilia B. N Engl J Med. 2022;387(3):237-247. doi:10.1056/NEJMoa2119913