FDA Lifts Clinical Hold on Etranacogene Dezaparvovec for Hemophilia B

Ricardo Dolmetsch, PhD

The FDA has lifted a clinical hold, which was placed on the development of etranacogene dezaparvovec (AMT-061) in late December 2020, after an independent investigation found the AAV5 gene therapy was high unlikely to have caused hepatocellular carcinoma (HCC) in a patient with hemophilia B enrolled in the phase 3 HOPE-B trial.

“Patient safety is our top priority, and we are grateful to our advisors and the FDA for their help in resolving this clinical hold,” Ricardo Dolmetsch, PhD, president of research and development at uniQure, the company developing the gene therapy, said in a statement. “Our comprehensive investigation showed that AMT-061 is very unlikely to have contributed to the HCC in our patient. We look forward to announcing top-line 52-week data from the HOPE-B pivotal trial later this quarter.”

Etranacogene dezaparvovec is an AAV5-based gene therapy, which carries a gene cassette with the Padua variant of factor IX (FIX). Preliminary results from the 54 patients enrolled in the HOPE-B study were presented at the 2020 ASH Annual Meeting in early December 2020. At baseline, the mean age of patients was 41.5 years and 81.5% were deemed to have severe hemophilia B (<1% FIX expression), while the remainder had moderately severe disease (FIX ≥1% and ≤2%).

After 26-weeks of follow up post-etranacogene dezaparvovec treatment, the mean FIX rate reached near normal levels, with a 36% 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 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. The liver samples were analyzed using 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.

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.

In the analysis, 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. Gene expression analyses of the tumor and adjacent tissue also suggested the liver was in a precancerous state, which predisposed the patient to HCC.