1092. Clinical Studies of Intra_Articular Administration of a Recombinant Adeno_Associated Vector Containing a TNF_α Antagonist Gene in Inflammatory Arthritis
Authors: Alison Heald, Greg Pate, Pervin Anklesaria
Journal: Molecular Therapy (2006)

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Although tumor necrosis factor-alpha (TNF-|[alpha]|) antagonists have revolutionized the treatment of inflammatory arthritis, some patients have one or more persistently symptomatic joints despite TNF-|[alpha]||[nbsp]|blockade. Other patients have disease limited to a few joints, which may not warrant use of systemic TNF-|[alpha]| antagonists. Intra-articular (IA) injection of an adeno-associated virus (AAV) vector containing the cDNA for the human tumor necrosis factor-immunoglobulin (IgG1) Fc fusion (TNFR:Fc) gene (tgAAC94) may be a means to provide local high concentrations of soluble TNFR:Fc for an extended period of time without requiring frequent administration. To evaluate the safety of IA administration of tgAAC94 in inflammatory arthritis patients with and without concurrent TNF-|[alpha]| antagonists, the first clinical study of IA tgAAC94 was completed, and a second is underway.

In the first study, 15 subjects not on TNF-|[alpha]| antagonists with persistent moderate or severe inflammation in a target joint due to inflammatory arthritis received a single IA injection of either tgAAC94 at 1x1010 (n=5), 1x1011 (n=6) DNase resistant particles (DRP) per mL joint volume or placebo (n=4). In the second study, 21 adults meeting similar entry criteria, except concurrent TNF-|[alpha]| antagonist use was permitted, were randomized to receive a single IA injection of either tgAAC94 1|[times]|1011 DRP/mL (n|[asymp]|16) or placebo (n|[asymp]|4), followed by an open-label injection of tgAAC94 1|[times]|1011 DRP/ mL after 12 to 36 weeks, depending on when swelling in the target joint meets criteria for re-injection. Similarly, a second cohort of 20 subjects will be randomized to receive tgAAC94 1|[times]|1012 DRP/mL (n|[asymp]|16) or placebo (n|[asymp]|4), followed by an open-label injection 12 to 36 weeks later.

In the first study, 12 females and 2 males with rheumatoid arthritis and 1 male with ankylosing spondylitis received an injection into the knee (n=14) or ankle (n=1) and were followed for 24 weeks. Improvement in a composite tenderness and swelling score was noted in all treatment groups, particularly among subjects who received the higher dose of tgAAC94. IA tgAAC94 was safe and well-tolerated. None of the 50 adverse events reported among 12 of 15 subjects were definitely related to study drug. Two events, nasopharyngitis and sinus congestion, were considered possibly related to study drug. One event, mild knee pruritis, was considered probably related to study drug. One 88-year-old female with RA had four SAEs considered unrelated to study drug: labyrinthitis, myocardial infarction and two episodes of congestive heart failure. In the second study, 21 subjects, 10 of whom were receiving concurrent TNF-|[alpha]| antagonists, received an injection of blinded study drug into the knee (n=12), ankle (n=4), wrist (n=2) or MCPs (n=3). No safety concerns were identified after 8-12 weeks of follow-up. Thus, a single dose of IA tgAAC94 appears to be safe and well- tolerated in subjects with and without concurrent TNF-|[alpha]| antagonist use. Enrollment in the ongoing study will continue and determine the safety of higher and repeat doses of tgAAC94, and to evaluate the effect of treatment and its duration.

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