FDA Lifts Hold on uniQure’s Gene Therapy AMT-061 for Hemophilia B

The U.S. Food and Drug Administration (FDA) has lifted its clinical hold on uniQure’s gene therapy program for hemophilia B, which includes AMT-061 (etranacogene dezaparvovec), the company announced.

According to uniQure, the FDA found it was “very unlikely” that AMT-061 had contributed to a case of liver cancer in a patient who had received the therapy during the Phase 3 HOPE-B trial (NCT03569891).

The regulatory agency’s decision to release the hold was based on the satisfactory resolution of all issues identified by the FDA related to the diagnosis of hepatocellular carcinoma (HCC), a form of liver cancer, in a HOPE-B trial patient. That diagnosis had led to the program’s clinical hold in December 2020.

“Patient safety is our top priority, and we are grateful to our advisors and the FDA for their help in resolving this clinical hold,” Ricardo Dolmetsch, PhD, president of research and development at uniQure, said in a press release.

A comprehensive investigation conducted by an independent laboratory and reviewed by leading outside experts showed that AMT-061 “is very unlikely to have contributed to the HCC in our patient,” Dolmetsch said.

He added that uniQure expects to announce top-line, one-year data from HOPE-B by mid-year.

AMT-061 uses a modified and harmless version of the adeno-associated virus variant 5, known as AAV5, to deliver FIX-Padua, a highly functional version of the F9 gene, to people with hemophilia B. The F9 gene is mutated in people with the disorder, disrupting the production of a clotting protein called factor IX (FIX). As such, the one-time therapy is expected to increase FIX levels, helping to prevent and control bleeds.

The treatment candidate previously received breakthrough therapy designation in the U.S. and priority medicine designation in Europe, all meant to accelerate its development. If approved, the therapy will be marketed globally by CSL Behring, which entered a commercialization and licensing agreement with uniQure last year.

HOPE-B, which is expected to conclude in March 2025, was designed to assess the five-year safety and effectiveness of a single intravenous (into-the-vein) injection of AMT-061. The trial involves 54 men with moderate to severe hemophilia B.

The HCC case was detected in an abdominal ultrasound during one of the trial’s routine assessments at one year post-treatment. The tumor and surrounding tissue were surgically removed, and then processed for a detailed genetic and molecular analysis.

This analysis showed the integration of the viral DNA into the patient liver cells’ DNA — which could potentially lead to cancer-promoting mutations — was extremely rare and randomly distributed across the genome of affected cells.

Since the viral DNA would have shown up in the same DNA regions in many tumor cells if it had triggered a single liver cell to grow out of control, these findings suggested that none of the viral DNA-containing cells gave rise to identical tumor cells.

In addition, the patient’s tumor cells had genetic mutations commonly associated with HCC and cancer in general, which were independent of viral integration. Moreover, the surrounding tissue was in a pre-cancerous state. Together, all of the factors were found to have likely predisposed the patient to HCC.

The review also found that the patient had several other risk factors for this type of cancer. These included a 25-year history of infection with the hepatitis C and B viruses — which are linked to about 80% of HCC cases — evidence of non-alcoholic fatty liver disease, advanced age, and a history of smoking and cancer in the family.

AMT-061’s clinical program also includes a Phase 2b trial (NCT03489291), which is evaluating the therapy’s long-term safety and effectiveness in three men with severe hemophilia B.

Previous data from both studies showed that the therapy safely and effectively increased FIX activity, controlled bleeds, and eliminated the need for other preventive therapies. Enrollment and dosing have been completed in both trials.

UniQure’s hemophilia B gene therapy program also includes AMT-060, the company’s first-generation gene therapy candidate. AMT-060 was tested in 10 adults with moderate to severe hemophilia B in a now-completed, five-year, Phase 1/2 study (NCT02396342). Those results also showed the therapy had a favorable safety profile and promising effectiveness.

According to uniQure, all patients in these trials have had abdominal ultrasounds one year following treatment, and each individual will continue to be closely monitored.

So far, no other cases of HCC have been reported among the more than 100 patients who have received the company’s experimental gene therapies during the past 10 years. These include some HOPE-B participants who had a history of hepatitis C and/or B infection.