Targeting synovial fibroblast proliferation in rheumatoid arthritis (TRAFIC): an open-label, dose-finding, phase 1b trial

Abstract

Background Current rheumatoid arthritis therapies target immune inflammation and are subject to ceiling effects. Seliciclib is an orally available cyclin-dependent kinase inhibitor that suppresses proliferation of synovial fibroblastscells not yet targeted in rheumatoid arthritis. Part 1 of this phase 1b/2a trial aimed to establish the maximum tolerated dose of seliciclib in patients with active rheumatoid arthritis despite ongoing treatment with TNF inhibitors, and to evaluate safety and pharmacokinetics. Methods Phase 1b of the TRAFIC study was a non-randomised, open-label, dose-finding trial done in rheumatology departments in five UK National Health Service hospitals. Eligible patients (aged ≥18 years) fulfilled the 1987 American College of Rheumatology (ACR) or the 2010 ACR-European League Against Rheumatism classification criteria for rheumatoid arthritis and had moderate to severe disease activity (a Disease Activity Score for 28 joints [DAS28] of ≥3•2) despite stable treatment with anti-TNF therapy for at least 3 months before enrolment. Participants were recruited sequentially to a maximum of seven cohorts of three participants each, designated to receive seliciclib 200 mg, 400 mg, 600 mg, 800 mg, or 1000 mg administered in 200 mg oral capsules. Sequential cohorts received doses determined by a restricted, one-stage Bayesian continual reassessment model, which determined the maximum tolerated dose (the primary outcome) based on a target dose-limiting toxicity rate of 35%. Seliciclib maximum concentration (C max) and area under the plasma concentration time curve 0-6 h (AUC 0-6) were measured. This study is registered with ISRCTN, ISRCTN36667085.

Synovial fibroblasts as potential drug targets in rheumatoid arthritis, where do we stand and where shall we go?

“…RA-FLS show a strong tendency to proliferate and in the affected RA synovium, some populations of FLS have been shown to expand 10 37. Seliciclib (R-roscovitine), a cyclin-dependent kinase inhibitor blocking cell proliferation and partially acting on FLS has been found to be safe in a phase 1b clinical trial in TNF-inhibitor-refractory RA patients, giving way to further studies 38. In line with the importance of JAK-STAT signalling in arthritic FLS functions (see below), the pan-JAK inhibitor peficitinib has been shown to modulate synovial fibroblast proliferation in a concentration close to the in vivo well-tolerated values 39…”

Highlights of Strategies Targeting Fibroblasts for Novel Therapies for Rheumatoid Arthritis

“…In a KBxN serum transfer arthritis model, injection of seliciclib significantly reduced the severity of arthritis ( 77 ) although the therapeutic effect of seliciclib was not directly attributed to inhibition of fibroblasts. Based on these findings, a phase Ib clinical trial was conducted in 15 RA patients who display active disease despite treatment with TNFi either as monotherapy or in combination with other disease modifying anti-rheumatic drugs (DMARD) ( 78 ). The trial was designed to assess safety of seliciclib in treating RA patients.…”

Critical Role of Synovial Tissue–Resident Macrophage and Fibroblast Subsets in the Persistence of Joint Inflammation

“…One approach has been to target specific fibroblast cell behavior directly such as proliferation or hypertrophy/organization. A recent multicenter study termed TRAFIC (targeting synovial fibroblast proliferation in rheumatoid arthritis) conducted a phase 1b/2a clinical trial to determine the tolerated dose of seliciclib (152) [a cyclin-dependent kinase (CDK) inhibitor which induces expression of p21 and suppresses expression of the pro-survival protein BCL-2] (153)(154)(155)(156). Although the study deemed seliciclib as safe to continue forward into phase 2 trials, little is known about its therapeutic efficacy in RA currently.…”