FLT180a: A New Gene Therapy Candidate for Severe Hemophilia B

In a small study of patients with severe hemophilia B, the novel adeno-associated virus (AAV) gene therapy FLT180a was associated with increased factor IX (FIX) expression in all treated patients, according to data presented at the International Society on Thrombosis and Hemostasis (ISTH) 2020 Virtual Congress. Pratima Chowdary, MBBS, who presented the findings, noted that 4 of the 10 treated patients had FIX levels within the normal range at 6 months post-infusion.

“Achieving normal FIX levels may mitigate the potential loss of expression over time,” said Dr. Chowdary, who is Director of the Katharine Dormandy Haemophilia & Thrombosis Centre at the Royal Free Hospital in London. The gene therapy also could eliminate the need for FIX replacement therapies.

FLT180a is an experimental gene therapy that uses AAVS3, a synthetic capsid, to deliver a codon optimized F9 gene with a gain-of-function mutation to liver cells. The phase I/II, multicenter B-AMAZE trial is evaluating the safety and effectiveness of 4 single doses of FLT180a in men with moderately severe to severe hemophilia B. Dr. Chowdary explained that B-AMAZE uses an adaptive design in which investigators can increase or decrease the FLT180a dose according to FIX levels.

The planned enrollment is 24 patients. All participants have hemophilia B with FIX levels of ≤2% and were given prophylactic immunosuppression to decrease the risk and severity of transaminitis. The goal of the study was to identify a dose of FLT180a that normalized FIX activity between 50% and 150%.

Dr. Chowdary presented results from 10 patients, who received starting doses of:

  • 5e11 vg/kg (2 patients)
  • 5e12 vg/kg (2 patients)
  • 5e11 vg/kg (2 patients)
  • 75e11 vg/kg (4 patients)

At the lowest dose, patients achieved FIX activity levels within the normal range for mild hemophilia B by week 3 after infusion. These patients had stable FIX levels of approximately 40% up to 2 years after treatment. There was no evidence of transaminitis.

“What we see is the expression increased through 6 months and continues to be stable within the hemophilia B range of just under the 50% mark,” Dr. Chowdary said.

In the second dosing group (1.5e12 vg/kg), FIX expression at week 3 was within the normal range. Around week 6, researchers noted that one patient had elevated ALT and AST on a tapering dose of steroids, but this did not result in a change in FIX level. Another patient experienced mild breakthrough transaminitis at week 4, which responded to tacrolimus and methylprednisolone.

Neither of the patients in the third dosing group (7.5e11 vg/kg) achieved normal FIX levels by week 3, but each had divergent responses through week 52, Dr. Chowdary reported. This was likely related to development of transaminitis in 1 patient, which led to lower FIX levels. FIX appeared to be dose-dependent but not proportional, suggesting a threshold effect, Dr. Chowdary added.

In the highest dosing group (9.75e11 vg/kg), patients received a prophylactic strategy of combined prednisone and tacrolimus to prevent transaminitis during the critical phase. By week 3, all 4 patients achieved normal FIX levels. The combined prophylactic strategy appears to be effective, Dr. Chowdary said, but she noted that the investigators are still determining the optimal duration of immunosuppression.

In terms of safety, the most common drug-related serious adverse event was transient transaminase elevation, which occurred in 4 patients overall. However, continuous monitoring for transaminase elevation is recommended, Dr. Chowdary said. There was no evidence of neutralizing anti-FIX antibodies or infusion reactions.

The study’s findings are limited by the small patient population, but Dr. Chowdary concluded that the data support the development of a phase III trial.

Study authors report relationships with Freeline, the manufacturer of FLT180a.


Chowdary P, et al. A novel adeno associated virus (AAV) gene therapy (FLT180a) achieves normal FIX activity levels in severe hemophilia B (HB) patients (B-AMAZE study). Abstract LB/CO01.1. Presented at ISTH 2020 Virtual Congress, July 13, 2020.