HOPE-B Trial Update: Gene Therapy Candidate AMT-061 Meeting Goals

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by Patricia Inacio PhD |

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After 18 months, the investigational gene therapy AMT-061 (etranacogene dezaparvovec) continued to prevent bleeds in men with moderate-to-severe hemophilia B, according to top-line data from the Phase 3 HOPE-B clinical trial.

The trial has met its pre-specified primary goal, with control of all bleeds by 18 months not being inferior to the bleed control seen during the trial’s six-month lead-in period.

The study also has reached a secondary goal, with AMT-061 being statistically superior at reducing annualized bleeding rate (ABR) compared with the start of the trial (baseline), at which point patients were being treated with standard prophylaxis, or preventive treatment.

“We are very pleased with these top-line results from what is the largest and first pivotal trial of a gene therapy for patients with hemophilia B,” Ricardo Dolmetsch, PhD, president of research and development at uniQure, the therapy’s developer, said in a press release.

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“The HOPE-B data not only achieved the pre-specified primary endpoint of non-inferiority in annualized bleeding rate following 12 months or more of stable FIX expression, but also the secondary endpoint of superiority in reduction of annualized bleeding, while continuing to demonstrate durability and stability in FIX levels and other benefits to this point in the study,” Dolmetsch added.

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

The one-time therapy is expected to increase the levels of FIX — the defective or missing clotting protein in hemophilia B — and help control bleeds for long periods of time, possibly several years.

AMT-061 was developed originally by uniQure. In May, the therapy’s commercialization and licensing rights were acquired by CSL Behring. Earlier this month, uniQure successfully completed manufacturing operations to ensure commercial access to the therapy. Also, uniQure remains responsible for completing the HOPE-B trial (NCT03569891), which is expected to finish in March 2025.

The HOPE-B study is evaluating AMT-061’s five-year safety and effectiveness in 54 men (mean age 41.5 years), with moderate-to-severe hemophilia B. All but one have completed at least 18 months of follow-up.

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

Previous one-year data from HOPE-B showed the therapy was safe and able to significantly increase FIX activity, while strongly reducing bleeds and the need for preventive treatment.

New top-line data announced by the companies now showed the ABR for all bleeds at 18 months was 1.51 — much lower than the 4.19 seen during the study’s lead-in period. Similarly, ABR for investigator-adjudicated FIX-treated bleeds was 0.83 compared with lead-in ABR of 3.65.

This was accompanied by a stable and durable increase in FIX activity levels, which reached a mean of 36.9% of normal by month 18, relative to the 39% observed six months after treatment.

AMT-061 was generally well-tolerated, with more than 80% of adverse side effects being considered mild.

One 77-year-old patient died at 65 weeks post-infusion (about 1.2 years) due to urosepsis — a generalized infection caused by a bacterial infection of the urinary tract — and cardiogenic shock happens when the heart is no longer able to pump enough blood to meet the body’s demands. This, however, was deemed unrelated to the gene therapy, according to the trial’s investigators and uniQure.

Also, one patient developed hepatocellular carcinoma (HCC), a type of liver cancer, which molecular analysis also found to be unrelated to the gene therapy. No inhibitors to FIX were reported.

“These encouraging results illustrate the potential that gene therapy has to be a long-term treatment option for patients living with hemophilia B and we look forward to sharing more detailed data with the medical community in the near future,” said Brahm Goldstein, MD, vice president of research and development of hematology at CSL Behring.

CSL Behring plans to seek approval of AMT-061 in the U.S. and the European Union by June 2022.

“This milestone advances our efforts towards expected regulatory submissions in first half of 2022,” Goldstein added.

“On behalf of uniQure, we extend our heartfelt gratitude to all the HOPE-B clinical trial patients and their families, as well as the trial investigators,” said uniQure‘s Dolmetsch.

“We now look forward to collaborating with CSL Behring on completing the regulatory submissions that we hope will advance etranacogene dezaparvovec one step closer to reaching hemophilia B patients around the world,” he added.