AMT-061 Increases FIX Activity, Reduces Bleeding in Phase 3 Trial, Data Show

AMT-061 (etranacogene dezaparvovec), an investigational gene therapy uniQure is developing to treat hemophilia B, successfully increased factor IX (FIX) activity and controlled bleeding — while markedly reducing the need for other treatments — in the Phase 3 HOPE-B clinical trial, top-line data show.

These findings will be presented at the 62nd Annual Meeting & Exposition of the American Society of Hematology (ASH), to be held virtually Dec. 5-8. The presentation is titled “First data from the Phase 3 HOPE-B Gene Therapy Trial: Efficacy and Safety of Etranacogene Dezaparvovec (AAV5-Padua hFIX variant; AMT-061) in Adults with Severe or Moderate-Severe Hemophilia B Treated Irrespective of Pre-existing AntiCapsid Neutralizing Antibodies.”

Hemophilia B is caused by missing or defective FIX, a clotting protein. AMT-061 uses an AAV5 viral vector to deliver the Padua variant — a version of the F9 gene that has high FIX activity — to patients, thereby allowing their cells to produce functional FIX.

In the HOPE-B trial (NCT03569891), 54 men with severe or moderately severe hemophilia B (mean age 41.5) were given a single dose of the investigational gene therapy by intravenous (into-the-vein) infusion. Most participants (70.4%) had bleeds during the lead-in to the trial, despite preventive treatment.

The trial’s main goal was to determine the effect of AMT-061 treatment on FIX activity after 26 weeks (about six months). At this timepoint, FIX activity had rapidly increased to a mean of 37.2% — a 36% increase relative to the start of the trial — which was sustained over 18 months.

“We are extremely pleased that these top-line pivotal data show that a single administration of etranacogene dezaparvovec gene therapy led to sustained increases of Factor IX (FIX) to functionally-curative levels capable of eliminating the need for regular infusions to control and prevent bleeding episodes,” Ricardo Dolmetsch, PhD, president of research and development at uniQure, said in a press release.

At the study start, 42.6% of participants had antibodies against AAV5 that could neutralize the viral vector. For most of the men, the team found no association between the presence of these antibodies and treatment response — though one participant, who had exceptionally high antibody levels, did not respond to treatment.

“The ability to dose a gene therapy in patients with pre-existing neutralizing antibodies has not been demonstrated for any other gene therapy and illustrates the potentially unique ability of our AAV5 platform to address the needs of a broad set of patients living with hemophilia B and other disorders,” Dolmetsch said.

Apart from the participant with the highest antibody levels, and one other individual who received a partial dose, all of the patients (96.3% in total) were able to discontinue routine preventive treatment. Relatedly, the mean annual FIX use prior to the trial, which was 292,304 units per participant, was reduced by 96% — to 12,622 units — at six months.

Also, 39 patients (72.2%) experienced no bleeds during this period; 21 total bleeds were reported among the remaining 15 men.

The gene therapy was generally well-tolerated; no serious adverse events or on-study deaths were reported. In total, 37 participants (68.5%) reported adverse events, of which 81.5% were mild. The most common treatment-related adverse events were elevated levels of liver enzymes, which occurred in nine men (17%) and were treated with steroids, as well as infusion-related reactions, headaches, and flu-like symptoms, each reported in 13% of participants.

“The safety profile was consistent with early phase AAV5 studies and together these data support a favorable safety and efficacy profile for etranacogene dezaparvovec,” the researchers wrote.

The participants will be monitored for five years to evaluate the long-term safety of etranacogene dezaparvovec, the company noted.

“We believe that etranacogene dezaparvovec has the potential to be a first- and best-in-class gene therapy for patients with hemophilia B,” said Matt Kapusta, uniQure’s CEO. “We are very pleased to have met the 26-week FIX primary endpoint [goal] and to feature these promising data at the upcoming ASH conference.”

“Based on interactions with the FDA [U.S. Food and Drug Administration] and EMA [European Medicines Agency], we plan to incorporate FIX activity and bleeding rates at 52 weeks as additional co-primary endpoints in the study,” Kapusta added. “We look forward to holding our pre-BLA [biologics license application] meeting with the FDA and completing the last patient’s 52-week follow-up visit in the first quarter of 2021.”

Information on registering for the ASH annual meeting can be found here.