The FDA has lifted the clinical hold on uniQure's Phase 3 trial of etranacogene dezaparvovec (AMT-061), a gene therapy for hemophilia B, after an investigation into a case of hepatocellular carcinoma (HCC) in a patient. The FDA concluded that the cancer was unlikely to be caused by the gene therapy.
The biotech company said the FDA's investigation, conducted with an independent lab, found no evidence that the genetic modification associated with AMT-061 played a role in the tumor's formation. The agency determined the cause was likely a pre-malignant state in the patient's liver, predisposed to HCC due to a history of hepatitis B and C infections.
Resumption of HOPE-B Trial
Dosing in the HOPE-B trial can now resume, and uniQure anticipates reporting top-line results before the end of June. The company previously stated that the clinical hold would not delay its regulatory filing for the one-time therapy, expected before year-end in the US.
Shares in uniQure rose more than 8% after the announcement. The lifting of the hold provides relief for uniQure and other gene therapy developers, as there is always a concern that inserting genes into patient cells could inadvertently activate cancer-causing genes. This has been observed with retroviruses and lentiviruses used in gene therapies in the past, including a French trial involving children with severe combined immunodeficiency (SCID) where four of nine treated patients developed leukemia.
AAV Vector Integration Analysis
AMT-061 uses an adeno-associated virus (AAV) vector to deliver its genetic payload into cells. AAV is considered less likely to integrate into cellular DNA. Biopsies from the tumor and adjacent liver tissue revealed that AAV vector integration in the tissue sample from the liver cancer patient was "extremely rare," accounting for only about 0.027% of the cells, according to uniQure. These AAV integrations appeared random across the genome, with no evidence that any location was more common than others or that an integration had stimulated a cell to divide more often, which could indicate malignancy.
Previous HOPE-B Data
The last readout from HOPE-B at the American Society of Hematology (ASH) meeting last November showed that AMT-061 significantly reduced bleeding episodes and practically eliminated the need for clotting factor IX infusions in patients with severe or moderately severe hemophilia B.
Competitive Landscape
The lifting of the hold allows uniQure to remain competitive with Pfizer, whose fidanacogene elaparvovec candidate is also in late-stage testing for hemophilia B.
