uniQure Announces Findings from HCC Case Investigation in HOPE-B Trial for Gene Therapy

The focus of the HOPE-B trial is etranacogene dezaparvovec, uniQure’s investigational gene therapy candidate for individuals with severe and moderately severe hemophilia B.

uniQure recently announced the results of a comprehensive investigation into a case of hepatocellular carcinoma (HCC) diagnosed in one patient participating in the phase III HOPE-B pivotal trial of etranacogene dezaparvovec, the company’s investigational gene therapy candidate for individuals with severe and moderately severe hemophilia B.

In December 2020 uniQure announced that the U.S. Food and Drug Administration (FDA) put a clinical hold on the trial in response to the submission of a safety report relating to a possible serious adverse event associated with a preliminary diagnosis of HCC, a common form of liver cancer. The liver is the organ targeted for delivery of etranacogene dezaparvovec which consists of adeno-associated virus serotype 5 (AAV5), which has been demonstrated to be safe and well-tolerated, acting as a delivery vector carrying a gene cassette with the Padua variant of factor IX (FIX). AAV5 is a variant of the type of the adeno-associated virus (AAVs) vectors that are being investigated in multiple gene therapy trials.

A company press release laid out the main findings of the investigation:Multiple analyses conducted by an independent laboratory and reviewed by leading experts in the field show that AAV vector integration in the patient’s tissue sample was “extremely rare” and accounted for 0.027% of the cells in the sample. The integration events were distributed randomly across the genome, and there was no evidence of clonal expansion or any dominant integration event. Additionally, whole genome sequencing of the tumor confirmed that the patient had several genetic mutations that are characteristic of HCC and are independent of vector integration. Finally, gene expression analysis of the tumor and adjacent tissue suggested a precancerous state in the liver consistent with several risk factors that predispose this patient to HCC. The findings suggest that it is “highly unlikely” that the HCC was associated with etranacogene dezaparvovec.

“This investigation has employed several complementary genomic approaches to evaluate the involvement of the AAV vector in the development of the liver cell cancer in this patient,” stated David Lillicrap, MD, FRCPC, Professor of the Department of Pathology and Molecular Medicine, Queen’s University, Kingston, Canada. “The investigations that have been performed have shown no evidence to suggest that the AAV vector delivered in the HOPE-B study has played a pathogenic role in the hepatocellular cancer that has now been diagnosed in the patient.”

uniQure also reports that all patients in their hemophilia B gene therapy program, including the 54 participants in HOPE-B, have had abdominal ultrasounds performed one year after dosing, and that each of them will continue to be monitored by their healthcare provider teams. The company also reiterates that no other cases of HCC have been reported in uniQure clinical trials, which have been conducted in more than 100 patients in hemophilia B and other indications. Some of these patients were dosed more than 10 years ago.

Source: uniQure press release dated March 26, 2021