Hemophilia B Gene Therapy AMT-061 Prevents Bleeds After 1 Year

After one year, the investigational gene therapy AMT-061 (etranacogene dezaparvovec) continued to safely and effectively increase factor IX (FIX) activity and prevent bleeds in men with moderate to severe hemophilia B, according to new data from the Phase 3 HOPE-B trial.

The men participating in the study did not need preventive treatment, the one-year data showed, raising hope for uniQure, the therapy’s developer, that AMT-061 will have long-term benefit.

The trial findings will be presented at the International Society on Thrombosis and Haemostasis 2021 Virtual Congress, set for July 17–21.

“We continue to be very encouraged by the data generated from the HOPE-B pivotal study,” Ricardo Dolmetsch, PhD, uniQure’s president of research and development, said in a press release.

“The 52-week data show mean FIX activity in the normal range and increase our confidence in the potential durability and long-term benefits of [AMT-061], bringing us one step closer to our goal of delivering this groundbreaking therapy to fulfill an unmet medical need for patients living with hemophilia B,” Dolmetsch said.

AMT-061’s commercialization and licensing rights were acquired in May by CSL Behring. However, uniQure remains responsible for completing the HOPE-B trial (NCT03569891), which is expected to finish in March 2025. The developer also will scale up manufacturing to ensure commercial access to the therapy.

uniQure and CSL Behring expect to file an application seeking AMT-061’s approval by the U.S. Food and Drug Administration (FDA) in early 2022. In a pre-biologics license application meeting, the agency had required one-year follow-up data from the moment all HOPE-B participants achieved steady-state FIX activity.

Since this was attained at six months post-treatment, uniQure will now assess changes in annualized bleeding rates at 1.5 years after AMT-061’s single dose; these data are anticipated by September.

AMT-061 uses a modified and harmless version of the adeno-associated virus variant 5 (AAV5) to deliver FIX-Padua, a highly functional copy of the mutated, disease-causing F9 gene, to patients’ cells. It is administered directly into the bloodstream through a single injection.

As such, the one-time therapy is expected to increase the levels of FIX, the missing blood-clotting protein in hemophilia B patients. Its goal is to prevent and help control bleeds for long periods of time, possibly several years.

The Phase 3 HOPE-B study is evaluating AMT-061’s five-year safety and effectiveness in 54 men (mean age 41.5), with moderate to severe hemophilia B, making it the largest trial of an experimental gene therapy for hemophilia B.

Most participants (70.4%) had bleeds during the trial’s six-month lead-in period, despite prophylaxis, or preventive treatment.

Previous six-month data from HOPE-B showed the therapy was generally well-tolerated and significantly increased FIX activity, while strongly reducing bleeding events and the need for preventive treatment.

Notably, these benefits were seen regardless of pre-existing antibodies against the treatment’s viral carrier, AAV5, suggesting that nearly all hemophilia B patients may benefit from AMT-061.

Newly released results demonstrated sustained and durable effects at one year post dosing, with patients achieving a mean of 41.5% of normal FIX activity levels, relative to the 39% observed at six months.

There continued to be no clinically significant link between FIX activity and pre-existing anti-AAV5 antibodies up to a titer of 678.2 — a range expected to include more than 93% of the general population, according to uniQure. A titer is a measure of how much a sample can be diluted before antibodies can no longer be detected, with higher titers indicating that more dilutions are needed until no antibodies can be detected.

In addition, a single dose of AMT-061 significantly reduced — by 80% or more — the annualized rate of both total and spontaneous bleeds requiring treatment. Total annual bleeding episodes requiring treatment dropped from 3.39 at the study’s start to 0.68 per year, while spontaneous bleeds requiring treatment fell from 1.16 to 0.18 per year.

Notably, all but two patients (96.3%) were able to discontinue routine preventive treatment and remained prophylaxis-free. The two non-responders included a man who only received a partial dose (less than 10%) of the therapy due to an infusion reaction, and another who had exceptionally high levels of anti-AAV5 antibodies.

The use of FIX replacement therapy also declined by 96%.

AMT-061 continued to be generally safe, with no treatment-related serious adverse events and no reported development of antibodies against the delivered FIX. Also, there was no association between safety and pre-existing anti-AAV5 antibodies.