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Targeting the rheumatoid arthritis synovial fibroblast via cyclin dependent kinase inhibition: An early phase trial

Stefan Siebert1, Arthur G Pratt2, Deborah D Stocken3

  • 1Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow.

Medicine
|June 27, 2020
PubMed
Abstract

Insights

This study investigates seliciclib, a novel therapy targeting fibroblast proliferation, as an add-on treatment for rheumatoid arthritis. Preliminary results will assess its safety and efficacy when combined with existing biologic therapies.

Area of Science:

  • Rheumatology
  • Pharmacology
  • Oncology

Background:

  • Rheumatoid arthritis (RA) treatments, including targeted biologic therapies, show limited efficacy, with 10-20% of patients achieving remission.
  • Current RA therapies do not target synovial fibroblasts, which are key drivers of synovitis.
  • Seliciclib, a cyclin-dependent kinase inhibitor, effectively suppresses fibroblast proliferation and has shown promise in preclinical arthritis models.

Purpose of the Study:

  • To evaluate the safety and toxicity of seliciclib when used as an adjunctive therapy with biologic treatments in rheumatoid arthritis patients.
  • To assess the preliminary efficacy of seliciclib in combination with biologic therapies for moderate to severe rheumatoid arthritis.
  • To inform the potential of seliciclib as a novel treatment strategy for rheumatoid arthritis.

Main Methods:

  • The TRAFIC trial is a multi-center, rolling phase Ib/IIa study assessing seliciclib's safety, tolerability, and efficacy in RA patients on biologic therapy.
  • Phase Ib determined the maximum tolerated dose and safety of seliciclib over 4 weeks using a Bayesian continual reassessment method.
  • Phase IIa, a single-arm trial, evaluated seliciclib's efficacy using a composite endpoint of clinical, histological, and MRI scores after 12 weeks.

Main Results:

  • The study is designed to determine the maximum tolerated dose and safety profile of seliciclib in RA patients.
  • Preliminary efficacy will be assessed based on a composite endpoint including clinical, histological, and MRI outcomes.
  • Secondary outcomes include adverse events, pharmacokinetics, pharmacodynamics, autoantibodies, and fatigue levels.

Conclusions:

  • Seliciclib represents a novel therapeutic approach targeting synovial fibroblasts in rheumatoid arthritis.
  • This trial will provide crucial data on the safety and potential efficacy of seliciclib as an adjunctive therapy.
  • Findings will guide future development of seliciclib for rheumatoid arthritis treatment.

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