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The US Food and Drug Administration has allowed the resumption of clinical trials of an experimental form of gene therapy for inflammatory arthritis. Trials were suspended in July when a patient died after a second injection into the knee joint of the gene based therapy developed by Targeted Genetics Corporation of Seattle, Washington.
Targeted Genetics said in a press release that the FDA had reviewed data on safety concerning all 127 patients in the trial of the treatment, which used tgAAC94, an investigational gene therapy product developed to treat active inflammatory arthritis, as well as data from the patient who died. The investigation found that the drug did not contribute to her death, the company said.
The Recombinant Advisory Committee of the National Institutes of Health (NIH) met on 3 December to consider the patient who died. Voting on the findings was postponed to the next meeting.
At the meeting the NIH’s Office of Biotechnology Activities reported that the patient died from a large retroperitoneal haematoma (3.5 kg at autopsy) and from disseminated histoplasmosis. The source of the bleeding could not be determined, and doctors were unable to control it despite massive transfusions. The report said it was unlikely that an immune reaction had a role in her death. No evidence of contamination of the product was found, and the vector was found only at extremely low levels outside the knee.
“This patient’s unfortunate death was primarily a result of an opportunistic infection, disseminated histoplasmosis with subsequent bleeding complications and multi-organ failure. Her apparent risk factor . . . was her systemic RA [rheumatoid arthritis] therapy, chiefly the TNF [tumour necrosis factor] antagonist adalimumab.”
The patient was identified as Jolee Mohr, 36, of Taylorville, Illinois, who was married and had a 5 year old daughter. She was given the first injection in February and the second on 2 July. She experienced vomiting and fever soon after the second injection. When her symptoms worsened she was admitted to hospital and later transferred to the University of Chicago Hospital, where she died on 24 July.
For her rheumatoid arthritis, which she had had for 15 years, she was taking adalimumab, methotrexate, and prednisone, all of which are immunosuppressive and a risk factor for histoplasma infection, the company said.
The trials used a recombinant, adeno associated virus as a vector. An FDA press release said that the vector delivers the gene for tumour necrosis factor receptor, with the aim of inhibiting a key mediator of inflammation. The vector was injected directly into the joint. Science magazine (2007;317:580) reported that existing drugs for rheumatoid arthritis also inhibit this mediator of inflammation, but they do not always penetrate all joints and need to be injected frequently.
In its press release Targeted Genetics said that final molecular test results had shown that there was no amplification of the viral vector in the patient’s body. The results were presented last month to the American College of Rheumatology.
Although the FDA said it was not aware of similar problems in other gene therapy trials—either those that used the same agent or those that used other genes in the same vector—it was reviewing all ongoing trials that involve any use of the adeno associated virus.
Targeted Genetics said it was revising the trial’s informed consent document for patients to include information about the death. It also said that it “will amend the protocol to encompass suggestions made by the FDA and its independent data safety monitoring board.”
“Over the next several weeks, the company will work with trial sites to obtain institutional review board approval of the amended protocol and revised informed consent and to re-consent the approximately 35 patients who have yet to receive the second injection,” it said.