Gene Therapy Trial To Resume Despite Patient's Death
It is “unlikely” that a gene-based arthritis treatment caused the death of a patient in a clinical trial, an NIH advisory committee announced Dec. 3.
On Nov. 26, the FDA gave permission for the company, Targeted Genetics, to resume its trial. It involves injecting the DNA viral vector tgACC94 into the joint affected by arthritis to reduce inflammation.
The NIH Recombinant DNA Advisory Committee (RAC) reported that 36-year-old Jolee Mohr's July 2007 death was caused by a systemic fungal infection, disseminated histoplasmosis. Mohr died about three weeks after getting a second injection of the drug into her right knee.
“We looked at every conceivable sample that was available to us and we analyzed all that was thought to be relevant in understanding the clinical course and potential for an investigational agent to be implicated in her death. There's nothing more that can be done at this point,” RAC chairman Howard Federoff, MD, PhD, professor of neurology and executive vice president for health sciences at Georgetown University Medical Center, told Neurology Today.
Dr. Federoff said ideally, the committee would have liked more data, including Mohr's experimental drug levels in blood and the ability to measure T-cell responses to the AVV vector. There was no validated test to measure the experimental drug outside the site of Mohr's injection.
As part of her regular arthritis treatment, Mohr was also taking the drug adalimumab (Humira), a tumor necrosis factor antagonist. But Dr. Federoff said disseminated histoplasmosis is rarely seen in people who have received a systemically administered tumor necrosis factor antagonist. Because the amount of the experimental drug could not be measured in Mohr's blood, it was not possible to definitively rule out that it contributed to her death.
Dr. Federoff said the committee recommended changes to the study: patients who are already enrolled should read and sign the consent forms again; blood should be drawn at different times after administration of the drug with the possibility of measuring the experimental agent when a validated assay is available; researchers should collect peripheral blood monouclear cells for measurement of T-cell responses for evidence of an immunological reaction; people who have a fever or any other sign of a possible infection on the day they are to receive the injection shouldn't receive the drug.
According to the company, since the phase 1/2 trial began in October 2005, more than 127 patients have been enrolled.
Jeffrey Chamberlain, PhD, professor of neurogenetics at the University of Washington School of Medicine in Seattle, and director of the Wellstone Muscular Dystrophy Cooperative Research Center, said that the RAC investigation indicates that the trial protocols were not associated with any serious adverse events. “In an era where tens of thousands of patients die each year from prescription medication mistakes made by hospitals,” he said, “and when new surgeries, such as organ transplantation, are often associated with enormously high mortality rates, it is important to remember that thousands of patients have participated in human clinical gene therapy trials and there is still only one death linked directly to gene therapy.”
Dr. Chamberlain was referring to the case of Jesse Gelsinger, a teenager who died in 1999 after receiving gene therapy for a rare metabolic disorder.