Clinical Evidence for Utilization of the A₃ Adenosine Receptor as a Target to Treat Rheumatoid Arthritis: Data from a Phase II Clinical Trial

MICHAEL H. SILVERMAN, VIBEKE STRAND, DORON MARKOVITS, MENACHEM NAHIR, TATIANA REITBLAT, YAIR MOLAD, ITZHAK ROSNER, MICHAEL ROZENBAUM, REUVEN MADER, MUHAMAD ADAWI, DAN CASPI, MOSHE TISHLER, PNINA LANGEVITZ, ALAN RUBINOW, JOSHUA FRIEDMAN, LESLY GREEN, AMIR TANAY, AVIVIT OCHAION, SHIRA COHEN, WILLIAM D. KERNS, ILAN COHN, SARI FISHMAN-FURMAN, MOTTI FARBSTEIN, SARA BAR YEHUDA, and PNINA FISHMAN

ABSTRACT.

Objective. Adenosine exerts antiinflammatory effects via activation of the A₃ adenosine receptor (A₃AR), a Gi protein-associated cell-surface receptor, overexpressed in synovial tissue and peripheral blood mononuclear cells (PBMC) in patients with active rheumatoid arthritis (RA). CF101 is a highly specific orally bioavailable A₃AR agonist.

Methods. This was a multicenter study, blinded to dose, designed to assess the clinical activity and safety of CF101 in active RA. Seventy-four patients were randomized to receive 0.1, 1.0, or 4.0 mg CF101 bid for 12 weeks. The primary efficacy endpoint was American College of Rheumatology 20% response (ACR20) at Week 12. A₃AR expression levels were analyzed in PBMC from 18 patients.

Results. Maximal responses were observed with 1.0 mg bid, lower at 0.1 and 4.0 mg bid. At 12 weeks, 55.6%, 33.3%, and 11.5% of the patients receiving 1.0 mg CF101 achieved ACR20%, 50%, and 70% responses, respectively. CF101 was generally well tolerated, with mild headache (4.1%), nausea (2.7%), and rash (2.7%) being the most common treatment-related adverse events. Statistically significant correlations between A₃AR overexpression at baseline and ACR50 and ACR70 responses were observed.

Conclusion. CF101 administered bid for 12 weeks resulted in improvement in signs and symptoms of RA that did not achieve statistical significance, and was safe and well tolerated. The expression level of A₃AR was directly correlated with patient responses to CF101, suggesting its utilization as a biomarker for the pharmacodynamic and therapeutic effects of this novel agent. These findings require confirmation in a double-blind randomized placebo-controlled trial, currently under way. (First Release Nov 15 2007; J Rheumatol 2008;35:41-8)

Key Indexing Terms:

A₃ ADENOSINE RECEPTOR
RHEUMATOID ARTHRITIS
CLINICAL TRIALS

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From Can-Fite BioPharma, Petach Tikva; Rambam Medical Center and Bnei Zion Medical Center, Haifa; The Barzilai Medical Center, Ashkelon; Rabin Medical Center, Beilinson Campus, Petah-Tikva; Ha'Emek Medical Center, Afula; Tel Aviv Sourasky Medical Center, Tel Aviv; Assaf Harofeh Medical Center, Zerifin; The Chaim Sheba Medical Center, Tel-Hashomer; Hadassah Medical Organization, Jerusalem; Kaplan Medical Center, Rechovot; The E. Wolfson Medical Center, Holon, Israel; and Division of Immunology/Rheumatology, Stanford University, Palo Alto, California, USA.

Supported by Can-Fite BioPharma Ltd.

M.H. Silverman, MD; A. Ochaion, MSc; S. Cohen, MSc; W.D. Kerns, DVM; I. Cohn, PhD; S. Fishman-Furman, MSc; M. Farbstein, BSc; S. Bar Yehuda, PhD; P. Fishman, PhD, Can-Fite BioPharma; V. Strand, MD, Division of Immunology/Rheumatology, Stanford University; D. Markovits, MD; M. Nahir, MD, Rambam Medical Center; T. Reitblat, MD, The Barzilai Medical Center; Y. Molad, MD, Rabin Medical Center, Beilinson Campus; I. Rosner, MD; M. Rozenbaum, MD, Bnei Zion Medical Center; R. Mader, MD; M. Adawi, MD, Ha'Emek Medical Center; D. Caspi, MD, Tel Aviv Sourasky Medical Center; M. Tishler, MD, Assaf Harofeh Medical Center; P. Langevitz, MD, The Chaim Sheba Medical Center; A. Rubinow, MD, Hadassah Medical Organization; J. Friedman, MD; L. Green, MD, Kaplan Medical Center; A. Tanay, MD, The E. Wolfson Medical Center.

Address reprint requests to Dr. P. Fishman, Can-Fite BioPharma Ltd., 10 Bareket Street, Petach Tikva 49170, Israel. E-mail: pnina@canfite.co.il

Accepted for publication August 10, 2007.

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