Targeted Genetics Corp (SEATTLE, Washington), a clinical-stage biotechnology company, announced that after recent discussions with the US FDA, the phase I/II clinical study of tgAAC94, an investigational therapy for the treatment of inflammatory arthritis, has been placed on clinical hold. A clinical hold is an order issued by the FDA that immediately suspends or imposes restrictions on an ongoing (or proposed) clinical study if the agency determines that the study may pose significant risks for human subjects or is otherwise seriously deficient. The FDA, in a precautionary measure, stopped further administration of tgAAC94 owing to the uncertainty regarding the cause of a serious adverse event (SAE) that occurred in one of the trial subjects. Targeted Genetics must address this issue before the hold order can be removed.

According to the company, there is insufficient information to determine to the cause of the SAE, and therefore the study will remain on clinical hold while additional data is gathered and analyzed. In the interest of patient safety, those already enrolled in the study will continue to be followed and monitored, as specifically permitted by the FDA. Since the trial began in October 2005, 127 subjects have received an initial dose of active drug or placebo, of which 74 subjects have received a second dose of active drug.

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. The therapy utilizes the company's recombinant adeno-associated virus (AAV) technology vector to deliver the gene encoding a soluble form of the receptor for TNF-α (TNFR:Fc). AAV is a naturally occurring virus that has not been associated with any disease in humans; the TNFR:Fc protein is a potent inhibitor of TNF-α, a key mediator of inflammation.

In March 2006, the company 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. A total of 127 adults have been randomized into three dose levels to receive a single intraarticular 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 reinjection.

Interim data reported in June and November 2006 and in June 2007 support the safety and tolerability of single and repeat intraarticular injections of tgAAC94 to affected joints at doses up to 1x10¹³ DNase Resistant Particles per milliliter (DRP/mL) of joint fluid in subjects with and without systemic TNF-α antagonists. This interim data also suggest that treatment with tgAAC94 may lead to improvements in signs and symptoms of arthritis in injected joints.

The company is developing tgAAC94 as a supplemental therapeutic to systemic antiTNF-α protein therapy for use in patients with inflammatory arthritis who have one or more joints that do not fully respond to systemic protein therapy. Direct injection of tgAAC94 into affected joints leads to the localized production of secreted TNFR:Fc within joint cells, reducing the activity of TNF-α within the joint and, potentially, leading to a decrease in the signs and symptoms of inflammatory disease and inhibition of joint destruction.

—A. Techman