Home

Current Issue

Archives

Guidelines for Authors

Classified Ads

Links

Subscriptions

Subscriber Registration

Guidelines for Website Users

JRheum Update Service

Contact Info

WALTER P. MAKSYMOWYCH, GIAN S. JHANGRI, LAUNA ASPESLET, MARK D. ABEL, DANIEL J. TREPANIER, SELVARAJ NAICKER, DERRICK G. FREITAG, BOBBI-LYNN COOPER, ROBERT T. FOSTER, and RANDALL W. YATSCOFF

ABSTRACT.

Objective. To examine the efficacy and toxicity of ISA_TX247, a novel calcineurin inhibitor, in comparison to cyclosporine (cyclosporin A, CSA) and placebo in established collagen induced arthritis. ISA_TX247 has up to 3-fold greater potency than CSA in an in vitro whole blood calcineurin inhibition assay and in in vivo solid organ and cell transplantation models. Phase I clinical trials show no discernible nephrotoxicity.

Methods. Type II collagen immunized DBA/Lac J mice with established arthritis were randomized to treatment with ISA_TX247 (125/250/500 µg/mouse), CSA (250/500 µg/mouse), or drug vehicle, by daily intraperitoneal injection for 10 days from the onset of clinical arthritis.

Results. A significant dose dependent reduction in clinical severity was observed in ISA_TX247 treated but not in CSA treated animals 10 days after the onset of established arthritis, and when examined by area under the curve analysis during the treatment period. Significant improvement in paw swelling (p < 0.001), synovial histology (p < 0.001), and articular cartilage damage scores (p = 0.002) was also noted in ISA_TX247 treated animals, even in the 125 µg dose group (p = 0.03 for paw swelling and synovial histology). By comparison, CSA had no significant effect on either synovial inflammation or articular cartilage damage. ISA_TX247 (500 µg dose group) was the only treatment to significantly decrease the development of proximal interphalangeal joint erosions (p < 0.05). A significant reduction in Type II collagen antibody titer was noted in ISA_TX247 animals in both 250 µg (p = 0.02) and 500 µg (p = 0.004) dosage groups, but only in the 500 µg group for CSA (p = 0.004). Treatment was well tolerated, with no significant toxicity in ISA_TX247 groups.

Conclusion. ISA_TX247 demonstrates efficacy and safety in the treatment of established collagen induced arthritis. Together with its improved potency and nephrotoxicity profile in comparison to CSA, this agent warrants further clinical investigation in autoimmune disease. Phase II studies in rheumatoid arthritis have been initiated. (J Rheumatol 2002;29:1646-52)

Key Indexing Terms:

COLLAGEN ARTHRITIS
CALCINEURIN INHIBITOR
CYCLOSPORINE

Supported by Isotechnika Corporation. Dr. Maksymowych is a Scholar of the Alberta Heritage Foundation for Medical Research.

W.P. Maksymowych, FRCPC, Associate Professor, Department of Medicine; G.S. Jhangri, MSc, Assistant Professor, Department of Public Health Sciences; B-L. Cooper, Laboratory Technician, University of Alberta; L. Aspeslet, PhD; M.D. Abel, PhD; D.J. Trepanier, PhD; S. Naicker, PhD; D.G. Freitag, PhD; R.T. Foster, PhD; R.W. Yatscoff PhD, Isotechnika Corporation.

Address reprint requests to Dr. W.P. Maksymowych, 562 Heritage Medical Research Building, University of Alberta, Edmonton, Alberta T6G 2S2. E-mail: walter.maksymowych@ualberta.ca

Submitted August 9, 2001; revision accepted January 11, 2002.