uniQure Investigation Clears Hemophilia B Gene Therapy of Causing Liver Cancer

Gene Therapy

uniQure announced findings from a comprehensive investigation into a case of hepatocellular carcinoma (HCC) diagnosed in one patient in the HOPE-B pivotal trial of etranacogene dezaparvovec—the conclusion was it was highly unlikely the HCC was caused by the gene therapy.

Etranacogene dezaparvovec is being evaluated for hemophilia B. The therapy consists of an AAV5 viral vector carrying a gene cassette with the Padua variant of Factor IX.

An investigation was conducted by an independent laboratory and reviewed by leading external experts in the field. These data showed the AAV vector that had integrated into the patient’s tissue samples was extremely rare, making up only 0.027% of the cells in the sample. They were evenly distributed apparently randomly across the patient’s genome, with no evidence of clonal expansion or any dominant integration event.

Whole genome sequencing of the tumor also confirmed that the patient had several genetic mutations often associated with HCC and are not linked with the integration of the gene therapy vector. Also, an analysis of the tumor gene expression as well as adjacent tissue indicated a precancerous state in the liver that is consistent with risk factors that predispose the patient to HCC.

“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,” said David Lillicrap, 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.”

In December 2020, the U.S. Food and Drug Administration (FDA) placed a clinical hold on the company’s program after the patient was diagnosed with HCC during a routine one-year follow-up. It was confirmed by surgical resection and biopsy with additional analysis to decide if the drug had integrated into the tumor and if the integration caused the cancer. The patient was at high risk for liver cancer with a long history of hepatitis C, hepatitis B, non-alcoholic fatty liver disease and advanced age. Chronic infections with hepatitis B and C are associated with about 80% of HCC cases.

“The external lab analyzed more than 220,000 cells from the tissue sample and identified 60 cells with random integration events that have no known association with the development of HCC,” said Ricardo Dolmetsch, president of research and development at uniQure. “Moreover, whole genome sequencing of the tumor showed that this patient had large abnormalities on chromosomes 1 and 8 that are commonly associated with HCC, as well as mutation of TP53 and several other potentially oncogenic genes.”

He went on to say, “Taken together, the findings from this investigation strongly suggest that etranacogene dezaparvovec did not contribute to this case of HCC. We have now shared these data with the FDA and are prepared to have further communications regarding the status of the clinical hold in the second quarter of 2021. We also expect to submit the data for presentation at an upcoming industry conference yet to be determined.”

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