uniQure’s Hemophilia B Gene Therapy Program Placed on Hold

The U.S. Food and Drug Administration (FDA) has placed a clinical hold on uniQure’s gene therapy program for hemophilia B, which includes AMT-061 (etranacogene dezaparvovec), due to a possibly related serious adverse event in one patient.

The event concerns a preliminary diagnosis of hepatocellular carcinoma (HCC), a form of liver cancer, during a routine trial assessment at one-year post-treatment during the HOPE-B Phase 3 trial (NCT03569891).

Notably, the patient has multiple risk factors for this type of cancer, including chronic infections with hepatitis C and B viruses — which mainly affect the liver and are linked to about 80% of HCC cases — evidence of non-alcoholic fatty liver disease (in which fat accumulates inside liver cells), and advanced age.

“Patient safety will always be our top priority, and we are working closely with the FDA and our advisors to conduct a thorough investigation into the cause of this event which we expect to be completed in early 2021,” Ricardo Dolmetsch, PhD, uniQure’s president of research and development, said in a press release.

“At this time, we do not have adequate data to determine a possible causal relationship, especially in the context of the other known risk factors,” he added.

Detailed analysis of the patient’s liver lesion, set to be surgically removed this week, will help determine the HCC diagnosis.

The company said it does not anticipate this clinical hold to affect its regulatory submission timeline seeking the approval of AMT-061 for the treatment of hemophilia B.

AMT-061 uses a modified and harmless version of the adeno-associated virus variant 5 to deliver a highly functional copy of the F9 gene, which is mutated in people with hemophilia B and impairs the production of clotting factor IX (FIX).

Given through a single infusion directly into the bloodstream, this highly functional copy is called FIX-Padua.

AMT-061’s five-year safety and effectiveness is currently being evaluated in 57 men: three with severe hemophilia B in a Phase 2b trial (NCT03489291) and 54 with moderate to severe disease in the HOPE-B Phase 3 study.

Previous data from both studies showed that the gene therapy was generally well-tolerated and effectively increased FIX activity, controlled bleedings, and prevented the need for prophylactic (preventive) treatment.

uniQure’s hemophilia B gene therapy program also includes a Phase 1/2 study (NCT02396342) of AMT-060, the company’s first-generation candidate of which AMT-061 is meant to be an improved version. Up to five years of follow-up data from its 10 participants have also shown a favorable safety profile and promising effectiveness.

Dosing and enrollment have been completed in all three uniQure trials.

“All patients in our hemophilia B gene therapy program, including the 54 patients in HOPE-B, will continue to be monitored by their care teams while we gather additional information as rapidly as possible,” said Matt Kapusta, uniQure’s CEO.

According to additional information provided by uniQure, all HOPE-B participants are monitored for the blood levels of alpha-fetoprotein — a marker of potential liver malignancies — every six months, and undergo annual abdominal ultrasounds.

It was one of these ultrasound exams that detected the patient’s potential tumor when it was still small enough to be surgically removed.

No other cases of HCC have been reported among the more than 100 patients who received uniQure’s experimental gene therapies over the past 20 years, including some HOPE-B participants who had a history of hepatitis C and/or B infection.