Etranacogene Dezaparvovec Is Highly Unlikely the Cause of HCC in Hemophilia B Study

Ricardo Dolmetsch

An independent investigation has found that etranacogene dezaparvovec (AMT-061) was "highly unlikely" to be the cause of hepatocellular carcinoma (HCC) in a patient with hemophilia B enrolled in the phase 3 HOPE-B trial, according to a statement from uniQure, the company developing the AAV5 gene therapy.

UPDATE: FDA Lifts Clinical Hold on Etranacogene Dezaparvovec for Hemophilia B

In December 2020, the FDA placed a clinical hold on the etranacogene dezaparvovec development program in hemophilia B to examine the preliminary report of HCC. As a next step, uniQure has submitted these findings to the FDA.

“Taken together, the findings from this investigation strongly suggest that etranacogene dezaparvovec did not contribute to this case of HCC,” Ricardo Dolmetsch, president of research and development at uniQure, said in a statement. “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.”

In the analyses of the patient, the AAV vector was integrated in just 0.027% of cells. These events were random across the genome and there was no evidence of widespread proliferation or dominance of the vector. Additional testing found several independent genetic alterations that were associated with the formation of HCC, which were deemed unrelated to the vector.

In addition to these genetic findings, the patient diagnosed with HCC was elderly and had suffered from a 25-year history of hepatitis C virus (HCV) infection, hepatitis B virus (HBV) infection, and evidence of non-alcoholic fatty liver disease. Together, these characteristics are rick factors for the development of HCC in approximately 80% of cases. There have been no other reports of HCC in the uniQure studies.

“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,” Dolmetsch said. “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.”

The liver lesion that resulted in the hold was found during routine abdominal ultrasound, which was required during at 1-year post-infusion of etranacogene dezaparvovec as part of the study. The liver samples were analyzed used polymerase chain reaction and whole genome sequencing. Following discovery of the case in December, all 54 patients in the study underwent abdominal screening. There were no other suspicious findings in HOPE-B or in more than 100 other patients treated with the gene therapy.

“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,” David Lillicrap, MD, FRCPC, professor of the Department of Pathology and Molecular Medicine, Queen’s University, Kingston, Canada, said in a statement. “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.”

Etranacogene dezaparvovec is an AAV5-based gene therapy, which carries a gene cassette with the Padua variant of FIX. Preliminary results from the 54 patients enrolled in the study were presented at the 2020 ASH Annual Meeting. The mean age of patients was 41.5 years and 81.5% were deemed to have severe hemophilia B (<1% factor IX [FIX] expression), while the remainder had moderately severe disease (FIX ≥1% and ≤2%). HBV infection was present in 5.6% of patients and 50% had an HCV infection. There were 123 cumulative bleeds in the 26-week study lead in period, and 29.6% of patients did not have a bleed during this time.

After 26-weeks of follow up post-etranacogene dezaparvovec treatment, the mean FIX rate reached near normal levels, with a 36.01% increase from baseline. There was no need to prophylactic immunosuppression with the therapy and 52 of 53 patients who received the full dose responded. Almost all patients receiving the gene therapy were able to discontinue prophylaxis (98%) and remained off prophylaxis at the time of the analysis. There was no bleeding in the majority (72%) of patients through week 26.

The last patient enrolled on the pivotal HOPE-B study of etranacogene dezaparvovec reached the 52-week follow-up in March 2021. The company plans to present additional data from the study and from the independent investigation in the second quarter of 2021.

“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,” Matt Kapusta, chief executive officer of uniQure, said in a statement. “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.”