Targeted Genetics Corp (SEATTLE, Washington), a clinical-stage biotechnology company, reported on the public hearing conducted by the National Institutes of Health (NIH) recombinant DNA advisory committee (RAC), which reviewed the serious adverse event (SAE) reported by Targeted surrounding the death of a patient participating in the company's phase I/II trial of tgAAC94 for inflammatory arthritis. Data suggest it is unlikely the agent contributed to the fatality.

At this point, the data indicate that histoplasmosis played a significant role in the cause of the patient's death. The clinical symptoms experienced from this infection can be highly variable depending on factors including the relative strength of the infected person's immune system. Many of the medications commonly prescribed to patients undergoing treatment for inflammatory arthritis including, according to the company's report, those being taken by the patient are recognized to have immunosuppressant effects.

In addition, initial molecular tests showed there was no replication of vector and only trace amounts of vector DNA in tissues outside the joint. Molecular tests are being conducted in remaining tissues.

The phase I/II study is designed to assess the safety and potential efficacy of different doses of tgAAC94 administered directly to affected joints of subjects with inflammatory arthritis. Subjects already enrolled in the study will continue to be followed and monitored, as specified by the US FDA in the interest of patient safety. Since the trial began in October 2005, 127 adults have been randomized into three dose levels to receive a single intraarticular injection of either tgAAC94 or placebo in 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 reinjection. Of the 127 subjects, 74 have received a second dose of active drug, 55 of whom have received two doses of active drug.

tgAAC94 utilizes the company's recombinant adeno-associated virus (rAAV) technology vector to deliver the gene encoding a soluble form of the receptor for TNF-α (TNFR:Fc), a potent inhibitor of TNF-α. AAV is a naturally occurring virus that has not been associated with any disease in humans. Additionally, tgAAC94 is being developed as a supplemental therapeutic to systemic antiTNF-α protein therapy for patients with inflammatory arthritis who have one or more joints that do not fully respond to systemic protein therapy. Direct injection of the agent into affected joints leads to the localized production of secreted TNFR:Fc within joint cells, reducing the activity of TNF-α and potentially leading to a decrease in the signs and symptoms of inflammatory disease and inhibition of joint destruction.

—A. Techman