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.

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 x 10(11), 1 x 10(12), or 1 x 10(13) 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.

• Authors: 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 Burch, H Malin Prupas, Pervin Anklesaria, Alison E Heald
• Journal: The Journal of rheumatology (J Rheumatol) Vol. 37 Issue 4 Pg. 692-703 (Apr 2010) ISSN: 0315-162X [Print] Canada
• PMID: 20032102 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial)

Chemical References

• Antirheumatic Agents
• Immunoglobulin G
• Receptors, Tumor Necrosis Factor
• Tumor Necrosis Factor-alpha

Topics

• Adenoviridae
• Adult
• Antirheumatic Agents (adverse effects, immunology)
• Arthritis (immunology, therapy)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Enzyme-Linked Immunosorbent Assay
• Female
• Genetic Therapy (adverse effects)
• Genetic Vectors
• Humans
• Immunity, Cellular
• Immunoglobulin G (adverse effects, genetics, immunology)
• Injections, Intra-Articular
• Male
• Patient Selection
• Receptors, Tumor Necrosis Factor (genetics, immunology, therapeutic use)
• Treatment Outcome
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, genetics)