Death Prompts FDA to Suspend Arthritis Gene Therapy Trial

ROCKVILLE, Md., July 27 -- The death of a patient in an arthritis gene-therapy trial has led to suspension of the study pending a precautionary investigation, the FDA announced.
The agency said it had put the phase I/II trial of tgAAC94 for treatment of active inflammatory arthritis on hold, allowing no further treatment or enrollment of new patients, until it ascertains the cause of the patient's illness and subsequent death.
The trial is sponsored by Targeted Genetics of Seattle, which was using a recombinant adeno-associated virus (AAV) to deliver a tumor-necrosis factor-receptor gene. The company informed the FDA of the patient's death on Tuesday.
More than 100 patients enrolled in the trial have been treated without known serious events, the FDA said. Moreover, the FDA said it was not aware of similar adverse events occurring in other gene therapy trials either with this specific product or with those that use other genes in AAV vectors.
However, as a precaution, the agency is further reviewing all ongoing trials involving any use of AAV.
The FDA said it was not known whether the death was caused by the treated but said that the patient became ill after a second injection of the gene therapy. The age of the patient was not given.
Patients enrolled in the trial had the product injected into affected joints with the intent of inhibiting a key mediator inflammation.
Targeted Genetics said it was cooperating in the investigation and would provide the FDA with ongoing results from various tests and all other information it is compiling that may help determine the cause of this patient's death.
Targeted Genetics said participants already enrolled in the study will continue to be followed and monitored. Since the trial began in October 2005, 127 patients have received an initial dose of active drug or placebo, and 74 of the 127 have been assigned to a second dose of active drug.
The company characterized tgAAC94 an investigational therapy utilizing an AAV vector to deliver the gene encoding a soluble form of the receptor for TNF-alpha (TNFR: Fc).
In March 2006, said the company, it received approval from the FDA to amend its protocol for the tgAAC94 clinical trial to include a higher dose group and increase the number of patients.
In all, the company said, 127 adults have been randomized into three dose levels to receive a single intra-articular injection of either tgAAC94 or placebo into the knee, ankle, wrist, metacarpophalangeal or elbow, followed by an open-label injection of tgAAC94 after 12 to 30 weeks, depending on when arthritis symptoms in the target joint meet criteria for re-injection.
The patient's death is yet another blow to the development of gene therapy.
In 1999, gene therapy suffered a major setback with the death of 18-year-old Jesse Gelsinger, who was participating in a gene therapy trial at the University of Pennsylvania for ornithine transcarboxylase deficiency. He died of multiple organ failures four days after starting the treatment. His death was believed to have been triggered by a severe immune response to the adenovirus carrier.
Then in January 2003, the FDA placed a temporary halt on all gene therapy trials using retroviral vectors in blood stem cells. The agency took this action after it learned that a second child treated in a French gene therapy trial had developed a leukemia-like condition. Both this child and another who had developed a similar condition in August 2002 had been successfully treated by gene therapy for X-linked severe combined immunodeficiency.