UniQure plans to file etranacogene dezaparvovec with the FDA for hemophilia B in March, pending a positive resolution to a clinical hold placed in December.
UniQure is anticipating a positive resolution to a clinical hold placed in December on etranacogene dezaparvovec (AMT-061), and, once the agent is cleared, it is planning to submit a biologics license application to the FDA for the AAV5 gene therapy for hemophilia B, according to a statement from the company. These milestones are anticipated before the end of March.
UPDATE: FDA Lifts Clinical Hold on Etranacogene Dezaparvovec for Hemophilia B
The FDA placed a clinical hold on the etranacogene dezaparvovec development program in hemophilia B to examine a preliminary report of hepatocellular carcinoma, which occurred in 1 patient treated in the pivotal phase 3 HOPE-B trial. At the time of the hold, there were 54 patients in the HOPE-B study.
“Patient safety will always be our top priority, and we are working closely with the FDA and our advisors to conduct a thorough investigation into the cause of this event which we expect to be completed in early 2021,” Ricardo Dolmetsch, PhD, president of research and development at uniQure, said in a statement when the hold was placed. “We will investigate whether there is a relationship to treatment. At this time, we do not have adequate data to determine a possible causal relationship, especially in the context of the other known risk factors.”
The company indicated that 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, and lead to approximately 80% of cases. There have been no other reports of HCC in the uniQure studies. The last patient enrolled on the pivotal HOPE-B study of etranacogene dezaparvovec will reach the 52-week follow-up in March. The company plans to present these topline data in the second quarter of 2021.
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 most common safety findings were elevated transaminase levels, which required intervention with steroids. Liver enzyme elevations resolved with corticosteroids, which were discontinued by week 26. Additionally, there were infusion-related reactions. Overall, 9 patients (17%) experienced a transaminase increase and 7 had an infusion-related reaction (13%).
“These initial data on etranacogene dezaparvovec are encouraging, because thus far in these patients, severe hemophilia B appears to have been transformed into a functionally curative state following administration of this one-time gene therapy, providing cessation in bleeding for a majority of patients and no need for ongoing, chronic replacement therapy,” principal investigator Steven Pipe, MD, professor of pediatrics and pathology and pediatric medical director of the hemophilia and coagulation disorders program at the University of Michigan, said in a statement when the findings were released.
In June 2020, CSL Behring announced that it would be acquiring exclusive global license right to commercialize etranacogene dezaparvovec for the treatment of hemophilia B, pending standard antitrust clearance from the Federal Trade Commission. Additional information was submitted for the filing in January and companies hope to complete the transaction during the second quarter of 2021.
“I’m very proud of uniQure’s accomplishments, including completing patient dosing in the HOPE-B pivotal trial, presenting positive 26-week data on 54 patients that met the study’s first primary endpoint, and announcing a landmark transaction with CSL Behring for the global commercialization of etranacogene dezaparvovec, which is expected to close in the second quarter of 2021 following the US antitrust review," Matt Kapusta, chief executive officer at uniQure, said in the statement.