PHILADELPHIA, Pennsylvania—A recombinant glycoprotein for rheumatoid arthritis (RA) given as a nasal spray in the hope of inducing mucosal immune tolerance was safe in phase II studies reported at the American College of Rheumatology but did not produce clinical improvement different from placebo. Robert Landewe, MD, and colleagues reported a proof-of-concept trial of an intranasal spray formulation of recombinant human cartilage glycoprotein-39 (HC gp-39, or Org 39141) online in Annals of the Rheumatic Diseases.

The 13-week, phase II, multicenter, double-blind, placebo-controlled, parallel group dose-finding trial randomized 297 RA patients to receive either intranasal applications of placebo or HC gp-39 in doses of 30, 150, 300 or 600 micrograms, once per week. The primary efficacy variable was the DAS28. Subjects were either DMARD-naive or went through a DMARD wash-out period before enrollment.

The goal of the study was to re-establish immunological tolerance and to ameliorate RA disease activity. The only therapy based on mucosal tolerance to reach Phase III testing is an oral therapy with bovine collagen type II.

“Autoantigen-specific immunotherapy by means of mucosal tolerance induction via the intranasal route is an attractive therapeutic option for the treatment of autoimmune diseases, including rheumatoid arthritis RA. HC gp-39 has been identified as a potential key autoantigen in RA. Based on animal studies, intranasal administration of the autoantigen is hypothesized to induce immunological tolerance in RA patients and to ameliorate disease activity,” Dr. Landewe said.

The researchers reported that DAS28 scores decreased similarly for all treatment groups - including placebo - “indicating lack of efficacy of intranasal HC gp-39 therapy in the current setting.” Safety variables were similar for all study groups.

“With the use of the chosen treatment protocol (dose levels and frequency of dosing), intranasal treatment with Org 39141 was safe but did not result in clinical improvement different from that seen in placebo-treated patients,” the investigators concluded. Extensive explorative analyses did not identify any subgroups for which the treatment was more effective than placebo.

Org 39141 was originally developed by NV Organon, now owned by Schering-Plough. HC gp-39 epitopes are recognized by peripheral blood mononuclear cells of RA patients, and the HC gp-39 protein has been detected in RA synovial tissue.

Dr. Landewe explained that the approach tested in this study “builds on mucosal tolerance induction and on establishing bystander suppression” but that, “the present study, exploring mucosal tolerance induction using intranasal administration of Org 39141, did not demonstrate efficacy.”

Reference

1. Landewe RBM, Houbiers JGA, van den Bosch FE, et al. Intranasal administration of recombinant human cartilage glycoprotein-39 as a treatment for rheumatoid arthritis: A Phase II, multicenter, double-blind, randomized, placebo-controlled, parallel group dose-finding trial. Ann Rheum Dis 2009; [epub ahead of print 23 September 2009] doi:10.1136/ard.2009.117234.