uniQure Releases Findings in Hemophilia B Gene Therapy Program

The following is an excerpt from a press release from uniQure. Read the full press release here.

uniQure, a leading gene therapy company advancing transformative therapies for patients with severe medical needs, announced the results of a comprehensive investigation into the case of hepatocellular carcinoma (HCC) diagnosed in one patient in the HOPE-B pivotal trial of etranacogene dezaparvovec. The results of the investigation found that it is highly unlikely the HCC was caused by etranacogene dezaparvovec.

Multiple analyses conducted by an independent laboratory and reviewed by leading external 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.

“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, M.D., 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.”

“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,” stated 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.”

“Taken together, the findings from this investigation strongly suggest that etranacogene dezaparvovec did not contribute to this case of HCC,” he added. “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.”

The FDA placed a clinical hold on uniQure’s hemophilia B program following the submission of a safety report in mid-December 2020 of a possibly related serious adverse event associated with a preliminary diagnosis of HCC in one patient in the HOPE-B trial. The patient has multiple risk factors associated with HCC, including a twenty-five-year history of hepatitis C (HCV), history of hepatitis B (HBV), evidence of non-alcoholic fatty liver disease, history of smoking, familial history of cancer and advanced age. Chronic infections with hepatitis B and C have been associated with approximately 80% of HCC cases.¹

The liver lesion was detected during a routine abdominal ultrasound conducted as part of the required study assessments in patients at one-year post dosing. A surgical resection was conducted along with a small biopsy of adjacent liver tissue and analyzed to determine whether etranacogene dezaparvovec was integrated into the tumor and whether the integration caused malignancy. Polymerase chain reaction analysis of the integration sites and whole genome sequencing also were performed.

All patients in uniQure’s hemophilia B gene therapy program, including the 54 patients in HOPE-B, have now had abdominal ultrasounds performed one year after dosing, and each will continue to be monitored by their care teams. No other cases of HCC have been reported in uniQure clinical trials conducted in more than 100 patients in hemophilia B and other indications, with some patients dosed more than 10 years ago.

“Based on the results from this very thorough investigation involving an independent lab and several expert reviews, we believe it is very unlikely that etranacogene dezaparvovec is related to the HCC event in the HOPE-B study,” stated Matt Kapusta, chief executive officer of uniQure. “Patient safety will always be our top priority, and we are prepared to discuss with the FDA the recently submitted analyses and the status of the clinical hold as expeditiously as possible. As stated previously, we do not anticipate any impact to the HOPE-B pivotal study or our regulatory submission timeline as a result of the clinical hold.”

Read the full press release here.