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THU0064 The A3 Adenosine Receptor (A3AR): Therapeutic Target and Predictive Biological Marker in Rheumatoid Arthritis
  1. S. Cohen,
  2. Z. Harpaz,
  3. M. Farbstein,
  4. S. Fishman,
  5. F. Barer,
  6. P. Fishman
  1. Can-Fite Biopharma Ltd, Petah Tikva, Israel

Abstract

Background The Gi protein associated A3 adenosine receptor (A3AR), is over- expressed in inflammatory cells and this high expression is also reflected in the peripheral blood mononuclear cells (PBMCs) of patients with autoimmune inflammatory diseases. CF101, a selective agonist with high affinity to the A3AR, is known to induce robust anti-inflammatory effect in experimental animal models of adjuvant, collagen and tropomyosin induced arthritis. The effect is mediated via de-regulation of the NF-kB and the Wnt signal transduction pathways resulting in apoptosis of inflammatory cells.

Objectives To evaluate A3AR as a therapeutic target and biological predictive marker in rheumatoid arthritis patients' response to CF101.

Methods CF101 administered twice daily to patients with active RA for 12 weeks. A3AR expression levels were measured at baseline.

Results CF101 was found to be safe and well tolerated in all preclinical, Phase I and Phase II human clinical studies. CF101 showed significant anti-rheumatic effect in 2 phase II studies as a standalone drug and a direct significant correlation was found between receptor expression at baseline and patients' response to the drug. In a phase II study, patients were included to the trial based on the expression levels of the A3AR mRNA in the PBMCs (A3AR ≥1.5). CF101 results in ACR20 was 48.6%, statistically significantly higher than that of the placebo group (25.0%) at week 12 (P=0.0352) and also showed superiority in ACR50 and ACR70 values vs. placebo

Conclusions The A3AR is a promising therapeutic target in rheumatoid arthritis and can be used also as a biological marker to predict patients' response to CF101. This is a unique type of a personalized medicine approach which may pave the way for a safe and efficacious treatment for this patient population.

References

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  2. Madi L, Cohn S, Ochaion A, Bar-Yehuda S, Barer F, et al. (2007) Over-expression of A3 Adenosine Receptor in PBMNC of Rheumatoid Arthritis Patients: Involvement of NF-kB in mediating Receptor Level. J. Rheumatology. 34:20-26.

  3. van Troostenburg AR, Clark EV, Carey WDH, Warrington SJ, Kerns WD, Cohn I, Silverman MH, Bar-Yehuda S, Fong KLL, Fishman P. (2004) Tolerability, pharmacokinetics, and concentration-dependent hemodynamic effects of oral CF101, an A3 adenosine receptor agonist, in healthy young men. Int J Clin Pharmacol Ther. 42: 534-542.

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  5. Ochaion A, Bar-Yehuda S, Cohen S, Barer F, Patoka R, et al. (2009) Fishman. The anti-inflammatory target A3 adenosine receptor is over-expressed in rheumatoid arthritis, psoriasis and Crohn's disease. Cellular Immunology 258:115–122

Disclosure of Interest S. Cohen Shareholder of: Can-Fite Biopharma Ltd, Employee of: Can-Fite Biopharma Ltd, Z. Harpaz Shareholder of: Can-Fite Biopharma Ltd, Employee of: Can-Fite Biopharma Ltd, M. Farbstein Shareholder of: Can-Fite Biopharma Ltd, Employee of: Can-Fite Biopharma Ltd, S. Fishman Shareholder of: Can-Fite Biopharma Ltd, Employee of: Can-Fite Biopharma Ltd, F. Barer Shareholder of: Can-Fite Biopharma Ltd, Employee of: Can-Fite Biopharma Ltd, P. Fishman Shareholder of: Can-Fite Biopharma Ltd, Employee of: Can-Fite Biopharma Ltd

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