OP-0121 – Safety, Local Tolerability and Clinical Response after Intra-Articular Administration of a Recombinant Adeno-Associated Vector Containing a TNF Antagonist Gene in Inflammatory Arthritis.
Mease, Wei, Fudman, Kivitz, Schechtman, Trapp, Hobbs, Anklesaria, Heald. United States. [Sponsor=Targeted Genetics]
Objective:
This aim of this study was to assess the safety, local tolerability and clinical response after intra-articular (IA) administration of an adeno-associated virus vector containing the cDNA for the human TNF receptor-IgG1 (IgG1) Fc fusion (TNFR:Fc) gene (rAAV2-TNFR:Fc). Patients with inflammatory arthritis who had joints that were unresponsive to systemic anti-TNF therapy, or with disease limited to a few joints for whom systemic anti-TNF therapy may not be warranted, were targeted.
Methods:
The phase I study was a dose escalation study; phase I/II study targeted patients who were incomplete responders to anti-TNF therapy. Patients with RA, psoriatic arthritis and ankylosing spondylitis were enrolled who had persistent moderate to severe inflammation in a target joint (TJ). 127 patients were randomized to treatment with a single IA injection of either rAAV2-TNFR:Fc [1x1011, 1x1012 or 1x1013 DNase resistant particles (DRP)/mL joint volume] or placebo, followed by open-label rAAV2-TNFR:Fc based on when the TJ met pre-determined criteria for re-injection.
Results:
10% of patients reported increased tenderness and swelling of the injected joint. Two serious adverse events occurred. One was a culture negative septic arthritis 15 wks after the injection. A second subject developed fatal disseminated histoplasmosis [diagnosed at autopsy] and retroperitoneal hemorrhage after the second injection of rAAV2-TNFR:Fc. This patient was receiving systemic anti-TNF therapy and had had repeated steroid injections in the TJ. The infection appears to have been contracted prior to the 2nd study injection. The rAAV2-TNFR:Fc vector was not found outside the TJ. Furthermore, post-injection TNF levels were not higher than those pre-injection. The independent Data and Safety Monitoring Committee considered this serious adverse event to be unrelated to rAAV2-TNFR:Fc. Clinical response was assessed in 66 subjects in phase 2 using patient reported outcomes [TJ global visual analog scale (VAS), TJ functional VAS, TJ pain] and physical examination [TJ tenderness (scale 0-3), TJ swelling (scale 0-3)]. A 30% decrease in the TJ global VAS was reported by 42% and 19% in the rAAV2-TNFR:Fc and placebo groups, respectively, 12 weeks after the 1st injection. A 2-point decrease in TJ swelling was noted in 16% and 19% of the rAAV2-TNFR:Fc and placebo groups, respectively.
Conclusion:
IA rAAV2-TNFR:Fc appears to be safe and well-tolerated in inflammatory arthritis subjects with and without systemic TNF antagonists. In this study, patient reported outcome measures appear to be more sensitive than physical examination in assessing clinical response.
Editorial Comment:
The above conclusions are those presented by the investigators. It is prudent to withhold enthusiasm until more data are available. It is important to note that there are no standardized, validated methods yet for evaluating response of a single joint to an intervention, so it is premature to imply that the patient reported outcomes are more valid. It is disturbing that a significant difference in a semi-objective measure - joint swelling - was not observed. It will be important also to know how long the TNF receptor continues to be produced after injection in the joint. Classically, elaboration of the protein by these vectors in other experimental systems has been relatively short lived, thus the benefit may not outweigh the risk. As for safety, the conclusion of the Safety Committee regarding the patient with disseminated histoplasmosis is reassuring and should not inhibitor further attempts to study this and similar agents.
