FDA Removes Clinical Hold on Hemophilia B Gene Therapy Program

Rare Daily Staff

The U.S. Food and Drug Administration has lifted a clinical hold on UniQure’s hemophilia B gene therapy program after the company addressed issues identified by the agency related to a single patient diagnosed with hepatocellular carcinoma in the HOPE-B pivotal trial.

Hemophilia B is a rare bleeding disorder caused by mutations in the F9 gene resulting in insufficient levels of the blood clotting protein factor IX. Symptoms can range from mild to severe depending on the level of factor IX in the blood and can range from prolonged bleeding after injury to frequent spontaneous bleeds into the muscles and joints and organs in severe cases that cause pain and other problems. Bleeding in the brain can lead to death if untreated.

Etranacogene dezaparvovec consists of an AAV5 viral vector carrying a gene cassette with the patent-protected Padua variant of Factor IX (FIX-Padua). UniQure holds multiple issued patents in the United States and Canada broadly covering methods of treating bleeding disorders, including hemophilia B, using AAV gene therapy with the FIX-Padua variant. Etranacogene dezaparvovec has been granted Breakthrough Therapy designation by the U.S. Food and Drug Administration and access to Priority Medicine (PRIME) regulatory initiative by the European Medicines Agency.  

In June 2020, the company and CSL Behring entered into a licensing agreement providing CSL Behring with exclusive global rights to etranacogene dezaparvovec. 

“Our comprehensive investigation showed that AMT-061 (etranacogene dezaparvovec) is very unlikely to have contributed to the hepatocellular carcinoma (HCC) in our patient,” said Ricardo Dolmetsch, president of research and development at UniQure.

The company expects to announce top-line 52-week data from the HOPE-B pivotal trial later this quarter.

In December, the FDA placed UniQure’s hemophilia B program on clinical hold following the diagnosis of HCC in one patient in the HOPE-B trial. The patient had multiple risk factors associated with HCC, including a twenty-five-year history of hepatitis C, history of hepatitis B. Chronic infections with hepatitis B and C have been associated with approximately 80 percent of HCC cases.

Following a surgical resection of both tumor and adjacent liver tissue, 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 percent 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 tumor had 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 that may have predisposed this patient to HCC.

All patients in UniQure’s hemophilia B gene therapy program, including the 54 patients in HOPE-B, have had abdominal ultrasounds performed one year after dosing, and each will continue to be monitored by their care teams. Patients will continue to receive abdominal ultrasounds every six-months. 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.

Photo: Ricardo Dolmetsch, president of research and development at UniQure