Clinical Hold - Hemophilia B

uniQure's hemophilia B program has been placed on clinical hold by the U.S. FDA

In December 2020 we announced that our hemophilia B gene therapy program, including the pivotal, Phase III HOPE-B study, has been placed on clinical hold by the U.S. Food and Drug Administration (FDA). Patient dosing is complete in each of uniQure’s three hemophilia B gene therapy studies, and there is no plan to enroll or treat additional patients.

The clinical hold was initiated following the submission of a safety report in mid-December relating to a possibly related serious adverse event associated with a preliminary diagnosis of hepatocellular carcinoma (HCC), a form of liver cancer, in one patient in the HOPE-B trial that was treated with etranacogene dezaparvovec (AMT-061). The patient has multiple risk factors associated with HCC, including a twenty-five-year history of hepatitis C (HCV), hepatitis B virus (HBV), evidence of non-alcoholic fatty liver disease and advanced age. Chronic infections with hepatitis B and C have been associated with approximately 80% of HCC cases.

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. 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.

All patients in our hemophilia B gene therapy program, including the 54 patients in HOPE-B, will continue to be monitored by their care teams while we gather additional information as rapidly as possible.  

 

Below are answers to several questions that patients may have following this announcement:

Is this issue specific to AMT-061?
It is important to note that at this time we do not know if this event is related etranacogene dezaparvovec, and we will be conducting a rigorous investigation to collect more information.

Over the last 20 years, uniQure has administered its gene therapies to more than 100 patients, including 67 patients with hemophilia B, with up to 10 years of safety follow-up and no reports of HCC prior to this event. We are also not aware of any other reported cases of HCC in other AAV gene therapy studies.

We are taking this matter very seriously, and our clinical and medical teams have already prepared a detailed investigational plan. With respect to the findings from this investigation, we pledge to be transparent with our stakeholders, most importantly the patient communities who we serve. 

How long will the analyses take, and will you share the results?
We are currently assessing the time-lines but we expect to get these results over the next few months.  We will share the results of our investigations in a timely manner with regulators and with the medical and scientific community when possible.

What measures do you take in the study to prevent/monitor for this risk?
Patients in the HOPE-B study receive abdominal ultrasounds annually and tests for alpha fetoprotein levels every six months. These tests are recommended by the AASLD for patients at high risk of HCC [Marrero Hepatology 2018].

Do you expect to make any changes to patient follow-up procedures?
Under the current HOPE-B protocol, all patients are monitored for serum alpha-fetoprotein every 6 months, which is a marker of potential liver malignancies, and receive annual abdominal ultrasounds. This routine screening identified the tumor in the present case early when it was still small enough for surgical resection. These procedures will be continued while we conduct our investigation. Patients will continue to be monitored for a minimum of 5 years, to assess markers of liver health, including serum alpha-fetoprotein, which is a marker of potential liver malignancies, and annual abdominal ultrasounds (uniQure, 2018).

How are you monitoring safety of AAV-based gene therapy for AMT-060 and etranacogene dezaparvovec?
Participants in the phase 3 trial of etranacogene dezaparvovec received a liver ultrasound at screening to identify liver fibrosis and steatosis prior to treatment. Patients will continue to be monitored for a minimum of 5 years, to assess markers of liver health, including serum alpha-fetoprotein, which is a marker of potential liver malignancies, and annual abdominal ultrasounds (uniQure, 2018). As of October 2020, there have been no reports of treatment-related malignancies in 10 patients from the AMT-060 phase I/II trial or 3 patients in the Phase IIb trial, which included up to 5 years and 2 years of follow-up, respectively (Leebeek et al., 2020; von Drygalski et al., 2020). Over half of the patients in the two studies had a history of or current hepatitis C. No other events of liver malignancy have been reported in patients in the HOPE-B study, including additional patients with history of hepatitis C and/or B infection. 

 

If you are a healthcare professional outside of the U.S. interested in more information on uniQure’s clinical trials, please visit our Clinical Trial Information page or contact us at MedInfo@uniqure.com.

 

> ClinicalTrials.gov: HOPE-B Trial of AMT-061 in Severe or Moderately Severe Hemophilia B Patients