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

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

Marisa holds an MS in Cellular and Molecular Pathology from the University of Pittsburgh, where she studied novel genetic drivers of ovarian cancer. She specializes in cancer biology, immunology, and genetics. Marisa began working with BioNews in 2018, and has written about science and health for SelfHacked and the Genetics Society of America. She also writes/composes musicals and coaches the University of Pittsburgh fencing club.
Total Posts: 46

José holds a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.

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Marisa holds an MS in Cellular and Molecular Pathology from the University of Pittsburgh, where she studied novel genetic drivers of ovarian cancer. She specializes in cancer biology, immunology, and genetics. Marisa began working with BioNews in 2018, and has written about science and health for SelfHacked and the Genetics Society of America. She also writes/composes musicals and coaches the University of Pittsburgh fencing club.
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