Targeted Genetics Corp (SEATTLE, Washington), a clinical-stage biotechnology company, announced that interim data from its phase I/II trial of tgAAC94 for inflammatory arthritis suggest that the investigational therapy showed improvement in patient-reported outcome measures. The company also announced that final molecular test results from a fatal serious adverse event (SAE), which led to a clinical trial hold in July 2007, support initial observations that no amplification of viral vector occurred in the patient's body as a result of the investigational therapy and that only trace amounts of vector DNA were detected in tissues outside the treated joint.

The ongoing phase I/II study is designed to assess the safety and efficacy of different doses of tgAAC94 administered directly to affected joints of subjects with inflammatory arthritis. Interim data from 66 phase II subjects who were given a self-administered patient questionnaire to determine improvements in joint symptoms and pain management indicated that 40% of the tgAAC94-injected group reported improvement in joint symptoms, function, and pain, compared to19% of the placebo-injected group. These respective groups also reported a 30% decrease in injected joint global symptoms on visual-analog scale (VAS), 32% versus 19% reported a 30% improvement in injected joint function on VAS, and 12% versus 6% reported two-point decrease in injected joint pain on VAS.

On July 24, 2007, the US FDA stopped the trial as a precautionary measure after the occurrence of an SAE in one subject, who subsequently died due to disseminated histoplasmosis and a severe retroperitoneal hematoma. Initial molecular tests conducted on tissues obtained from the patient's body had indicated there was no replication of vector and only trace amounts of vector DNA in tissues outside the joint. Now, results from final molecular tests conducted in remaining tissues provide additional supportive data indicating that tgAAC94 did not contribute to the patient's death. As announced by the company, the fact pattern surrounding the fatal SAE is as follows: a) vector DNA was detected in the injected joint as expected; b) other medications the subject was taking (adalimumab, methotrexate, and prednisone) are known to be immunosuppressive and a risk factor for histoplasma infection; c) there was no increase in TNF-α binding protein above what was expected based on the subject's ongoing background adalimumab therapy; and d) there was no detectable receptor for TNF-α protein (TNFR:Fc) in serum tested from 16 other subjects who were not on antiTNF-α therapy.

Subjects already enrolled in the study will continue to be followed and monitored. Since the trial began in October 2005, 127 subjects have received an initial intra-articular injection of either tgAAC94 or placebo into the knee, ankle, wrist, metacarpophalangeal, or elbow; 74 of whom have received a second dose of the agent. The company previously reported interim aggregate data on the primary and secondary endpoints from the first 61 subjects in the dose escalation portion (cohorts 1 to 3) of the phase I/II clinical trial of tgAAC94. At week 12 after treatment with the agent, 13%, 14%, and 33% of subjects receiving low, mid, and high dose tgAAC94, respectively, achieved a two-point reduction in swelling versus none in the placebo group. A trend in reduction of swelling in tgAAC94-injected joints versus placebo was also observed in subjects with or without concurrent use of systemic TNF antagonist. The company hopes to resume the trial.

tgAAC94 is being developed 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. The agent utilizes recombinant adeno-associated virus technology vector to deliver the gene encoding a soluble form of TNFR:Fc, an inhibitor of receptor for TNF-α. 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 while avoiding the potential for systemic side effects.