Amelioration of accelerated collagen induced arthritis by a novel calcineurin inhibitor, ISA(TX)247.
OBJECTIVE
To examine the efficacy and toxicity of ISA(TX)247, a novel calcineurin inhibitor, in comparison to cyclosporine (cyclosporin A, CSA) and placebo in established collagen induced arthritis. ISA(TX)247 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(TX)247 (125/250/500 microg/mouse), CSA (250/500 microg/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(TX)247 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(TX)247 treated animals, even in the 125 pg 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(TX)247 (500 microg 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(TX)247 animals in both 250 microg (p = 0.02) and 500 microg (p = 0.004) dosage groups, but only in the 500 microg group for CSA (p = 0.004). Treatment was well tolerated, with no significant toxicity in ISA(TX)247 groups.


CONCLUSIONS
ISA(TX)247 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.
Maksymowych
Walter P
WP
Department of Medicine, University of Alberta, Edmonton, Canada. walter.maksymowych@ualberta.ca
Jhangri
Gian S
GS
Aspeslet
Launa
L
Abel
Mark D
MD
Trepanier
Daniel J
DJ
Naicker
Selvaraj
S
Freitag
Derrick G
DG
Cooper
Bobbi-Lynn
BL
Foster
Robert T
RT
Yatscoff
Randall W
RW
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D065095:Calcineurin Inhibitors; D002358:Cartilage, Articular / Q000187:drug effects / Q000473:pathology; D024043:Collagen Type II / Q000276:immunology / Q000494:pharmacology; D016572:Cyclosporine / Q000008:administration & dosage / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006614:Hindlimb / Q000187:drug effects / Q000473:pathology; D007274:Injections, Intraperitoneal; D007596:Joints / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D011897:Random Allocation; D016896:Treatment Outcome
D000276:Adjuvants, Immunologic; D018501:Antirheumatic Agents; D065095:Calcineurin Inhibitors; D024043:Collagen Type II; D016572:Cyclosporine