PARIS, France—Proof-of-principle data reported at the EULAR 2008 meeting suggest that anti-TNF gene might offer an alternative to TNFα inhibitors for treatment of rheumatoid arthritis (RA). Researchers found that a single intra-articular injection of a construct carrying a gene for a tumor necrosis factor (TNF) antagonist was well-tolerated, reduced pain and inflammation, and improved joint function.¹

Intra-articular gene therapy might be an attractive option for RA patients who do not respond to systemic TNF-inhibitors and for patients whose inflammatory arthritis affects only a few joints, according to lead investigator Phillip Mease, MD, and associates.

The researchers used an adeno-associated virus vector containing the cDNA for the human TNF receptor-immunoglobulin Fc fusion (TNFR:Fc) gene rAAV2-TNFR:Fc. “[Intra-articular] rAAV2-TNFR:Fc appears to be safe and well-tolerated in inflammatory arthritis subjects with and without systemic TNF antagonists,” said Dr. Mease, from Seattle Rheumatology Associates at Swedish Medical Center in Washington. The goal of this approach is to provide sustained TNFR:Fc protein into the joint of inflammatory arthritis patients to halt TNF associated with joint inflammation.

Dr. Mease's placebo-controlled phase I-II study included 127 adults with persistent moderate or severe inflammation in a target joint. Patients received a single intra-articular injection of either rAAV2-TNFR:Fc or placebo, followed by open-label rAAV2-TNFR:Fc based on when the target joint met predetermined criteria for re-injection.

About 10% of patients had injection site reactions such as mild-to-moderate tenderness and swelling, erythema, or pruritis. There was one case of culture negative septic arthritis that occurred 15 weeks after injection of rAAV2-TNFR:Fc, and was thought to be related to the study agent. One fatal case of disseminated histoplasmosis and retroperitoneal hemorrhage occurred after second injection of rAAV2-TNFR:Fc in a patient who was also taking systemic anti-TNF therapy. “Histoplasma antigen was not detected in serum specimens from earlier time-points, but was detected just prior to second injection, indicating that the subject had Histoplasma infection prior to second injection,” Dr. Mease reported.

Possible spread of the injected gene beyond its intended target is always a concern in gene therapy trials. Dr. Mease said that the rAAV2-TNFR:Fc vector did not disseminate and amplify in extra-articular tissues, that there was no over-expression of TNFR:Fc protein in tissues, and that injection of vector into joints did not result in any detectable circulating TNFR:Fc. Consequently, the independent Data Monitoring Committee did not consider the histoplasmosis death to be related to rAAV2-TNFR:Fc.

Sixty-six subjects enrolled in the phase II study had clinical response assessed. The outcome measures in the target joint were pain, using a global visual analog scale (VAS), functional VAS, reported pain, and physical examination of tenderness (scale 0-3) and swelling (scale 0-3).

Dr. Mease said that 21 of 50 treated patients and 3 of 16 placebo patients reported a ≥30% decrease in the target joint global VAS at 12 weeks after first injection. At that time, there was also a 2-point decrease in target joint swelling in eight of treated patients and in 3 of 16 placebo recipients.

“In this study, patient reported outcome measures appear to be more sensitive than physical examination in assessing clinical response,” Dr. Mease said.

Reference

1. Mease P,  Wei N, Fudman E, et al. Safety, local tolerability, and clinical response after intra-articular administration of a recombinant adeno-associated vector containing a TNF antagonist gene in inflammatory arthritis. Presented at: EULAR 2008; June 11-14, 2008; Paris, France. Presentation OP-0121.