The recently published review by Baeten et al. outlines the scientific and translational evidence supporting the role of cyclin dependent kinase (CDK) 4/6 in rheumatoid arthritis (RA) pathology, and it discusses how this stromal (synovial fibroblast) target provides the basis for a drug class with a novel non-immunosuppressive mechanism of action that could change the current immunosuppressive treatment paradigm in RA. The early clinical trial (phase 1b) of the next generation CDK4/6 inhibitor, ELV001, showed the rapid clinical improvement, and ELV001 was well tolerated with no clinically meaningful safety signals. This warrants further clinical evaluation of ELV001 in a larger group of patients with active RA, and the phase 2 study with ELV001 (START SYNERGY) is currently in progress.

This commentary article on the published review by Baeten et al. describes additional perspectives, in particular, what is the next step in the clinical development of CDK4/6 inhibition for RA, as well as where CDK4/6 inhibition could be positioned in the RA treatment algorithm. A novel combination strategy that pairs systemic immunosuppression (current therapeutic options) with a synovial-targeted non-immunosuppressive anti-rheumatic therapy (with ELV001) is expected to leverage orthogonal mechanisms of action, and this approach would represent a distinct therapeutic paradigm for RA.

Rheumatoid arthritis, Fibroblast-like synoviocyte, Cyclin dependent kinase, Non-immunosuppressive mechanism of action, ELV001