“None of the available data support a conclusion that the gene therapy agent contributed to the patient's clinical course or death.”—Karen M. Frank, MD, PhD
The committee concluded that the patient's death was primarily due to disseminated histoplasmosis with subsequent bleeding complications and multiorgan failure, not to the active gene therapy agent tgAAC94.“The apparent risk factor was the systemic adalimumab (Humira®) and living in an endemic area,” said lead study author Karen M. Frank, MD, PhD, a pathologist at the University of Chicago Medical center in Illinois. “None of the available data support a conclusion that the gene therapy agent contributed to the patient's clinical course or death.”
When asked if the revelation should be interpreted as a green light for future gene therapy trials, Dr. Frank said each trial should evaluated by the appropriate Institutional Review Boards and other oversight committees, but “I don't think that this case should cause all gene therapy trials to be put on hold.”
AAV Vector Was Used to Transfect Anti-TNF Receptor Gene Into Affected Joints
The 36-year-old patient was enrolled in a phase I/II trial conducted by Targeted Genetics Corp of tgAAC94 for treatment of active inflammatory arthritis. The trial included 127 patients with active inflammatory arthritis who were being treated with injections of the antitumor necrosis factor-α (TNF-α) receptor gene therapy or placebo.
The gene transfer vector was a recombinant AAV, which was injected directly into affected knee, ankles, wrist, metacarpophalangeal or elbow joints. AAV is a naturally occurring virus that has not been associated with any disease in humans, according to Targeted Genetics Corp.
IIlness began after second injection
The patient who died had received concurrent TNF-blockade and other immunosuppressive agents while living in an area where histoplasmosis was endemic. She had tested negative for tuberculosis, HIV infection, hepatitis B, and hepatitis C when screened for the study.
The patient reported fatigue the day of the second injection of the study drug. This was followed by nausea, vomiting fever and chills, diarrhea and abdominal pain. She received antibiotics for the fever. Five days later she went to the emergency room with a high fever where she was discharged after being diagnosed with a “viral syndrome.”
The patient was diagnosed with thrombocytopenia, which worsened, and experienced an episode of hypotension and respiratory distress which necessitated mechanical ventilation.
Ultimately, the patient was sent to the University of Chicago for possible liver transplantation. She died 12 days after her initial hospitalization and 22 days after the second gene-therapy injection. Her death prompted the US FDA to stop the study, but the agency eventually permitted the trial to continue.
Translating RA gene therapy research into practice: Many lessons learned
Trial investigators need to be on the ball when it comes to all trials, particularly gene therapy studies, Dr. Frank said.
“For any trial, make sure all trial physicians have a low threshold to consider potential impact of the gene therapy on an unexpected illness in a study participant, and consult relevant expert’s early,” she said. “Make sure the FDA is notified at appropriate time in such a situation [and] have assays available to distinguish gene therapy agent from other medications.”
Investigators should also create a trial contact number for each trial, she said. This way, “if a patient is out of town visiting relative and becomes suddenly ill requiring trip a to the emergency room, the doctors at that hospital could call the trial contact number and obtain any relevant information.”
Moreover, there should be discussion about what specimens should be collected from any study participant who is admitted to the hospital and how those specimens will be stored and by whom before the trial begins, she said.
“Before the trial begins, [there should also be] a detailed outline of what specimens should be collected if an autopsy is ever performed on a study participant,” she said. “In this case, multiple separate tissue specimens stored in separate containers from each relevant organ would have been useful.”
There should also be pre-determined criteria for administration of study agent to study participants, such as what temperature or other symptoms would cause treatment to be delayed or deferred.
“I think that all scientists and physicians involved in any clinical trial should continue efforts to educate the public about the many issues associated with advances in medicine,” Dr. Frank said. “This case had complicated molecular strategies used to develop a new medicine, and even other physicians would not be familiar with the details.”
Reference
1. Frank KM, Hogarth DK, Miller JL. Investigation of the Cause of Death in a Gene-therapy trial. N Engl J Med. 2009; 361:161-169.
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