Ann Rheum Dis. 2013 May; 72(5):741–4This phase2 trial assessed the efficacy of GLPG0259, a first-in-class ATP-competitive inhibitor of MAPKAPK5. The trail involved 31 patients with active RA and an inadequate response MTX. Patients received either 50 mg/day GLPG0259 with MTX or a placebo with MTX (patients randomised 2:1) for 12 weeks with the primary efficacy variable being ACR 20 response at week 12. Analysis showed that 5 patients (26.3%) in the GLPG0259 group and 3 patients (27.3%) in the placebo group achieved ACR 20 at 12 weeks. The secondary efficacy variables of ACR 20 per treatment group and time to ACR50/70 response showed a steady increase in patients achieving ACR 20 in the GLPG0259 group, increasing from 10.5% at weeks 2 and 4, to 21.1% at week 8 and 26.3% by week 12. One patient achieved ACR 50 in the GLPG0259 group and two in placebo group (all at week 8). ACR 50 was not achieved at any other time, and no patients achieved ACR70. The interim analysis of both the primary and secondary efficacy variables showed that an orally administered, once-daily dose of 50mg GLPG0259 is not superior to placebo. Several potential explanations are suggested for the lack of efficacy, including the complexity of the inflammatory pathway, and that the blocking of one kinase may lead to compensatory effects from others, a theory that is supported by a number of failed p38 MAPK studies. The lack of efficacy resulted in the discontinuation of this first trial of small-molecule inhibition of MAPKAPK5.