Clinical evidence for utilization of the A3 adenosine receptor as a target to treat rheumatoid arthritis: data from a phase II clinical trial.
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.


CONCLUSIONS
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.
Silverman
Michael H
MH
Can-Fite BioPharma Ltd, Petach Tikva, Israel.
Strand
Vibeke
V
Markovits
Doron
D
Nahir
Menachem
M
Reitblat
Tatiana
T
Molad
Yair
Y
Rosner
Itzhak
I
Rozenbaum
Michael
M
Mader
Reuven
R
Adawi
Muhamad
M
Caspi
Dan
D
Tishler
Moshe
M
Langevitz
Pnina
P
Rubinow
Alan
A
Friedman
Joshua
J
Green
Lesly
L
Tanay
Amir
A
Ochaion
Avivit
A
Cohen
Shira
S
Kerns
William D
WD
Cohn
Ilan
I
Fishman-Furman
Sari
S
Farbstein
Motti
M
Yehuda
Sara Bar
SB
Fishman
Pnina
P
D000241:Adenosine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D058909:Adenosine A3 Receptor Agonists; D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D043684:Receptor, Adenosine A3 / Q000187:drug effects*; D012720:Severity of Illness Index; D016896:Treatment Outcome
D058909:Adenosine A3 Receptor Agonists; C478920:CF101; D043684:Receptor, Adenosine A3; D000241:Adenosine