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

Robert BM Landewé ¹, Jos G A Houbiers ², Filip E Van den Bosch ³, Joanna in 't Hout ², Patrick CPM Verschueren ⁴, Jan H Meijerink ², Frank H J van den Hoogen ⁵, Bedrich A Masek ⁶, George AW Bruyn ⁷, Jacques MGW Wouters ⁸, Alexandre E Voskuyl ⁹, Jacob M van Laar ¹⁰, Johannes J W Bijlsma ¹¹, Desiree MFM van der Heijde ¹², Ferdinand C Breedveld ¹⁰, Leo B A van de Putte ¹³, André M M Miltenburg ^2* and Filip De Keyser ³

¹ University of Maastricht, Netherlands
² Schering-Plough, Netherlands
³ University Hospital Gent, Belgium
⁴ University Hospitals Leuven, Belgium
⁵ Sint Maartens Clinic Nijmegen, Netherlands
⁶ VieCuri Medical Center Noord-Limburg, Netherlands
⁷ Medical Center Leeuwarden South, Netherlands
⁸ St Franciscus Hospital, Netherlands
⁹ VU University Medical Center, Netherlands
¹⁰ Leiden University Medical Centre, Netherlands
¹¹ University Medical Center Utrecht, Netherlands
¹² University Hospital Maastricht, Netherlands
¹³ University Medical Center Nijmegen, Netherlands

^* To whom correspondence should be addressed. E-mail: a.miltenburg{at}spcorp.com.

Accepted 17 September 2009

Abstract

Objective: 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). Human Cartilage glycoprotein-39 (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. In a Phase I/IIA clinical trial in RA patients, intranasal application of HC gp-39 was safe and well tolerated. The current paper describes the first large clinical study investigating the efficacy of intranasally administered fully human, recombinant HC gp-39 (Org 39141).

Methods: In a 13-wk multicenter, double-blind, randomized, placebo-controlled, parallel group, dose-finding, Proof-of-Concept trial, patients with RA (DMARD naïve or following wash-out of DMARD therapy) were randomized 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.

Results: During the treatment period the DAS28 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.

Conclusion: It was concluded that, 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.