THU0064 The A3 Adenosine Receptor (A3AR): Therapeutic Target and Predictive Biological Marker in Rheumatoid Arthritis
Authors: S. Cohen, Z. Harpaz, M. Farbstein, S. Fishman, F. Barer, P. Fishman
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> The Gi protein associated A<sub>3</sub> adenosine receptor (A<sub>3</sub>AR), 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 A<sub>3</sub>AR, 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. <h3>Objectives</h3> To evaluate A<sub>3</sub>AR as a therapeutic target and biological predictive marker in rheumatoid arthritis patients9 response to CF101. <h3>Methods</h3> CF101 administered twice daily to patients with active RA for 12 weeks. A<sub>3</sub>AR expression levels were measured at baseline. <h3>Results</h3> 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 patients9 response to the drug. In a phase II study, patients were included to the trial based on the expression levels of the A<sub>3</sub>AR mRNA in the PBMCs (A<sub>3</sub>AR ≥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 <h3>Conclusions</h3> The A<sub>3</sub>AR is a promising therapeutic target in rheumatoid arthritis and can be used also as a biological marker to predict patients9 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. <h3>References</h3> Fishman P, Bar-Yehuda S, Madi L, Rath-Wolfson L, Ochaion A, et al. (2006) The PI3K-NF-kB signal transduction pathway is involved in mediating the anti-inflammatory effect of IB-MECA in adjuvant induced arthritis. Arthritis Research &amp; Therapy, 8:R33. 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. 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. Silverman MH, Strand V, Markovits D, Nahir M, Reitblat T, Molad Y, Rosner I, Rozenbaum M, Mader R, Adawi M, Caspi D, Tishler M, Langevitz P, Rubinow A, Friedman J, Green L, Tanay A, Ochaion A, Cohen S, Kerns WD, Cohn I, Fishman-Furman S, Farbstein M, Bar Yehuda S, Fishman P. (2008) Clinical Evidence for Utilization of the A3 Adenosine Receptor as a Target to Treat Rheumatoid Arthritis: Data from a Phase II Clinical Trial. J. Rheumatology. 35:1-7. 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 Crohn9s disease. Cellular Immunology 258:115–122 <h3>Disclosure of Interest</h3> 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