- UniQure on Monday said its experimental hemophilia B gene therapy was "highly unlikely" to have caused the liver cancer of a participant in a late-stage study testing the treatment, citing a months-long investigation conducted by the company, an independent laboratory and several outside experts.
- The laboratory analyzed more than 220,000 cells collected from a biopsy of the participant's tumor, which was surgically removed. Only 60 had pieces of DNA from the harmless virus used to deliver functional copies of the target gene into the body, and those "integration events" were distributed randomly throughout the cells' genome, rather than clustered around genes known to be linked to cancer.
- The findings are a major relief for UniQure, which hopes to submit its gene therapy for Food and Drug Administration review after discussing the investigation result with the agency. The news is similarly positive for other gene therapy developers, many of which use the same or similar viruses for their experimental treatments.
UniQure is the furthest company along in developing a gene therapy for hemophilia B, the less common form of the inherited bleeding disorder.
Study results have shown treatment can substantially raise levels of the clotting protein that's missing or defective in people with hemophilia B, leading to the near-elimination of bleeding among trial volunteers and allowing them to stop use of standard drugs.
But UniQure's progress was derailed in mid-December last year, following the diagnosis of liver cancer in one study participant who had received the company's gene therapy in 2019.
While a cancer diagnosis is always a serious safety issue, it's a particular concern in gene therapy research, which has been shadowed by studies conducted decades ago in which early gene therapies led to blood cancer in a handful of patients.
Following the diagnosis, the FDA placed the study on hold while investigators hunted for potential links between UniQure's therapy and the reported case of liver cancer. That review now seems to have absolved the treatment, called etranacogene dezaparvovec or AMT-061, although a complete ruling-out may be more difficult.
Key to the investigation is an analysis of where and how frequently the viral vector UniQure uses for AMT-061 integrated into the genome of cells taken from the patient's tumor. Were the therapy to have caused the cancer, it's likely researchers would have found integration of the viral vector in a high percentage of tumor cells, as well as at places in the genome where mutations or alterations can trigger unchecked cellular growth and, eventually, cancer.
Instead, an independent lab found integration by the vector in only 0.027% of the cells included in the tumor sample. Moreover, there was no "clonal expansion," or proliferation of cells marked by a similar genetic signature including DNA from the viral vector.
Genetic sequencing showed chromosomal abnormalities in the tumor cells that are associated with liver cancer, as well as mutations in a cancer gene known as TP53.
"Taken together, the findings from this investigation strongly suggest that etranacogene dezaparvovec did not contribute to this case of [hepatocellular carcinoma]," said Ricardo Dolmetsch, UniQure's head of R&D, in a statement.
The patient had a 25-year history of hepatitis C and a history of hepatitis B — both risks factors for liver cancer — as well as signs of a fatty liver disease that can sometimes progress to cancer over time.
Researchers conducting the study detected the cancer via a planned abdominal ultrasound one-year post dosing with UniQure's therapy, a step all 54 patients in the study have now undergone. No other cases of hepatocellular carcinoma have been reported from the trial or in past studies of AMT-061 that encompass more than 100 patients with hemophilia B.
UniQure shared its findings with the FDA on March 26 and expects to meet with the agency by June.If the regulator agrees with the company's conclusions, Uniqure could resume its study and move forward with plans to submit AMT-061 for approval.
Shares in UniQure rose by 9% in early morning trading before falling back to trade up 3%. In addition to UniQure, Pfizer and Freeline Therapeutics are in clinical testing with gene therapies for hemophilia B.
In the more common hemophilia A, BioMarin Pharmaceuticals is most advanced, although the FDA last year surprisingly rejected its therapy and requested longer follow-up data.
UniQure's announcement Monday comes several weeks after Bluebird bio, another gene therapy developer, disclosed results from an investigation into two cancer cases reported in a study of its sickle cell disease treatment. Similarly, the company declared its gene therapy "very unlikely" the cause.