In the race to develop the first gene therapy for hemophilia B, uniQure faced a major roadblock late last year when the FDA put a clinical hold on its HOPE-B trial after a trial patient developed hepatocellular carcinoma (HCC). After an inquiry, the company is saying that it is highly unlikely that the HCC is caused by their gene therapy drug.
uniQure is developing a gene therapy for hemophilia B patients that uses AAV vectors to deliver the blood clotting factor IX producing gene. When delivering the gene in the cell, there is a slight chance that the viral DNA also integrates into the human genome. This can be particularly harmful if the viral DNA integrates into a region, which is prone to cancer. Although it has been reported that AAV vectors integrate into the genomic DNA with very low frequency, there is still a chance that it may and cause cancer.
When uniQure presented the data of this one patient with cancer, the FDA put a clinical hold and asked the company to investigate whether its a treatment-related effect. After a thorough investigation, the uniQure states that this is not the case. Following are the conclusions from the investigation.
- Multiple analyses conducted by an independent laboratory and reviewed by leading experts in the field show that AAV vector integration in the patient’s sample was extremely rare and accounted for 0.027% of the cells in the sample. Moreover, none of the integration happened at the site linked to the development of cancer.
- When the genome of the tumor cells was sequenced, it had multiple mutations characteristic of HCC, which were independent of vector integration. Large abnormalities on chromosomes 1 and 8 that are commonly associated with HCC were found in the tumor, along with mutation of the TP53 gene and several oncogenic genes.
- Gene expression analysis of the tumor suggested that the patient’s cells were precancerous. Meaning that the patient had such genetic changes that might have transformed the normal cells into cancerous cells in the future.
“This investigation has employed several complementary genomic approaches to evaluate the involvement of the AAV vector in the development of the liver cell cancer in this patient,” stated David Lillicrap, M.D., FRCPC, Professor of the Department of Pathology and Molecular Medicine, Queen’s University, Kingston, Canada.
uniQure reported last year that the patient in question had a history of hepatitis B and C, evidence of nonalcoholic fatty liver disease, and other risk factors that were associated with cancer. Generating further evidence that those factors are the likely cause of cancer positions uniQure to push its plans of getting its therapy to the market quickly.
“We have now shared these data with the FDA and are prepared to have further communications regarding the status of the clinical hold in the second quarter of 2021. We also expect to submit the data for presentation at an upcoming industry conference yet to be determined,” stated Ricardo Dolmetsch, President of Research and Development at uniQure.
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