Efficacy, pharmacodynamics, and safety of VX‐702, a novel p38 MAPK inhibitor, in rheumatoid arthritis: Results of two randomized, double‐blind, placebo‐controlled clinical studies

Abstract

Objective. To assess the efficacy and safety of VX-702, a p38 MAPK inhibitor, in patients with active, moderate-to-severe rheumatoid arthritis (RA).Methods. Two 12-week, double-blind, placebocontrolled studies of VX-702 were conducted in patients with active, moderate-to-severe RA. In the VeRA study, 313 patients received placebo or 2 daily doses of VX-702. In Study 304, 117 patients received placebo, daily VX-702, or twice weekly VX-702 in addition to concomitant methotrexate (MTX). Study end points included the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (an ACR20 response), ACR50 and ACR70 responses, changes in the serum levels of biomarkers of inflammation, and safety assessments.Results. The numerically superior ACR20 response rates among patients receiving VX-702 compared with those receiving placebo in both studies did not reach pairwise statistical significance at the highest doses in either study. At week 12 in the VeRA study, ACR20 response rates were 40%, 36%, and 28% among patients receiving 10 mg of VX-702, 5 mg of VX-702, and placebo, respectively. In Study 304, the response rates were 40%, 44%, and 22% for patients receiving 10 mg VX-702 daily plus MTX, 10 mg VX-702 twice weekly plus MTX, and placebo, respectively. Reductions in the levels of C-reactive protein, soluble tumor necrosis factor receptor p55, and serum amyloid A were observed as early as week 1 in both studies, but these levels rapidly returned to baseline values by week 4. The overall frequency of adverse events was similar between the VX-702 and placebo groups. In the VeRA study, serious infections were more frequent in the VX-702 groups compared with the placebo group (2.4% versus 0%) but not in Study 304 (2.6% versus 4.9%).Conclusion. The modest clinical efficacy plus the transient suppression of biomarkers of inflammation observed in this study suggest that p38 MAPK inhibition may not provide meaningful, sustained suppression of the chronic inflammation seen in RA.

Lack of the T cell–specific alternative p38 activation pathway reduces autoimmunity and inflammation

“…38,39 The positive role of p38 in the production of inflammatory cytokines has been a rationale for the use of p38 inhibitors to alleviate chronic inflammation. However, despite some positive results, 40 global inhibition of p38 activity is associated with side effects, such as infection and gastrointestinal disturbances, [41][42][43] possibly because of the ubiquitous expression of p38 and its large variety of functions. 44,45 Our data provide direct genetic evidence that T-cell p38 activated in response to TCR signaling contributes to inflammatory autoimmune responses.…”

Single doses of p38 MAP kinase inhibitors or prednisolone affect CRP and IL-6 in patients with active Rheumatoid Arthritis (RA)

“…It is now evident that clinical studies with p38 MAPK inhibitors have generally been disappointing in RA. Recently, RA data for pamapimod (Roche) [10] and VX-702 (Vertex) [11] have failed to show efficacy in RA patients. There is a growing body of evidence that some initial activity in RA patients may be observed but that for reasons unknown this effect may not be sustained [12].…”

Silencing the Expression of Ras Family GTPase Homologues Decreases Inflammation and Joint Destruction in Experimental Arthritis

“…This is observed in recent clinical trials involving the treatment of RA patients with inhibitors of p38 MAPK, which have reported a disappointing lack of clinical efficacy. 34,35 One possible contributing factor to this may be that while the compounds used in these trials targeted primarily p38␣, ongoing fundamental studies have demonstrated prominent activation of not only p38␣ in RA synovial tissue, but p38␦ as well. 36 Ras proteins represent a newly emerging set of targets in the treatment of chronic inflammatory diseases, playing a central role in coupling the ligation of antigen, cytokine, growth factor, and TNF family receptors to cellular responses of gene regulation, proliferation and survival.…”