Safety, tolerability, and clinical outcomes after intraarticular injection of a recombinant adeno-associated vector containing a tumor necrosis factor antagonist gene: Results of a phase 1/2 study

Philip J. Mease, Nathan Wei, Edward J. Fudman, Alan J. Kivitz, Joy Schechtman, Robert G. Trapp, Kathryn F. Hobbs, Maria Greenwald, Antony Hou, Stephen A. Bookbinder, Galen E. Graham, Craig W. Wiesenhutter, Larry Willis, Eric M. Ruderman, Joseph Z. Forstot, Michael J. Maricic, Kathryn H. Dao, Charles H. Pritchard, Darrell N. Fiske, Francis X. BurchH. Malin Prupas, Pervin Anklesaria, Alison E. Heald

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

Objective. To assess safety and clinical outcomes in patients with inflammatory arthritis after intraarticular (IA) injection of rAAV2-TNFR:Fc, a recombinant adeno-associated viral vector containing the human tumor necrosis factor (TNF) receptor-immunoglobulin (IgG1) Fc fusion (TNFR:Fc) gene. Methods. In this phase 1/2 randomized study, adults with persistent moderate or severe inflammation in a target joint, being treated with or without systemic anti-TNF therapy, received a single IA injection of either rAAV2-TNFR:Fc (1 × 1011, 1 × 1012, or 1 × 1013 DNase-resistant particles/ml joint volume) or placebo, followed by open-label rAAV2-TNFR:Fc 12-30 weeks later, depending on when the target joint met predetermined criteria for reinjection. Results. 127 subjects received the first injection of blinded study drug; 95 subjects received open-label rAAV2-TNFR:Fc. Administration site reactions, consisting of transient mild to moderate increases in tenderness and swelling of the injected joint, occurred after 23/191 (12%) rAAV2-TNFR:Fc injections and were dose-dependent. Rates of other adverse events were not dose-dependent. Notable serious adverse events (SAE) included culture-negative septic arthritis in a subject receiving leflunomide and fatal disseminated histoplasmosis considered unrelated to rAAV2-TNFR:Fc in a subject receiving adalimumab. In the phase 2 portion of the study, a 30% decrease in target joint global visual analog scale was observed in 21/50 (42%) rAAV2-TNFR:Fc subjects and 3/16 (19%) placebo subjects 12 weeks after first injection (p = 0.14). Conclusion. IA rAAV2-TNFR:Fc resulted in administration site reactions after 12% of injections. A fatal SAE, disseminated histoplasmosis, was considered not related to study agent. Patient-reported outcome measures of clinical response showed greater improvement in treated patients than placebo patients. The Journal of Rheumatology

Original languageEnglish (US)
Pages (from-to)692-703
Number of pages12
JournalJournal of Rheumatology
Volume37
Issue number4
DOIs
StatePublished - Apr 1 2010
Externally publishedYes

Keywords

  • Biological therapy
  • Clinical trials
  • Psoriatic arthritis
  • Rheumatoid arthritis
  • Tumor necrosis factor inhibitors

ASJC Scopus subject areas

  • Rheumatology
  • Immunology and Allergy
  • Immunology

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    Mease, P. J., Wei, N., Fudman, E. J., Kivitz, A. J., Schechtman, J., Trapp, R. G., Hobbs, K. F., Greenwald, M., Hou, A., Bookbinder, S. A., Graham, G. E., Wiesenhutter, C. W., Willis, L., Ruderman, E. M., Forstot, J. Z., Maricic, M. J., Dao, K. H., Pritchard, C. H., Fiske, D. N., ... Heald, A. E. (2010). Safety, tolerability, and clinical outcomes after intraarticular injection of a recombinant adeno-associated vector containing a tumor necrosis factor antagonist gene: Results of a phase 1/2 study. Journal of Rheumatology, 37(4), 692-703. https://doi.org/10.3899/jrheum.090817