Preclinical and clinical investigation of a CCR5 antagonist, AZD5672, in patients with rheumatoid arthritis receiving methotrexate.

Arthritis and rheumatism 2010 Jul 26; In press

Gerlag D DM, Hollis S, Layton M, Vencovsky J, Szekanecz Z, Braddock M, Tak P PP, on behalf of the ESCAPE study investigators

Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

OBJECTIVE.: To investigate the preclinical effects of blocking the chemokine receptor CCR5 and the clinical effects on the signs and symptoms of rheumatoid arthritis (RA) in patients. METHODS.: Preclinical evaluations of the small molecule CCR5 antagonist AZD5672 were performed, including ligand binding and chemotaxis studies. Pharmacokinetics (PK) of AZD5672 were assessed in both single- and multiple-dose studies in healthy volunteers and patients with RA. A randomized, placebo-controlled, Phase IIb study was conducted in patients with active RA receiving methotrexate. Treatment arms were AZD5672 (20, 50, 100 or 150 mg orally once daily), placebo or open-label etanercept (50 mg subcutaneously once weekly). The primary endpoint was the proportion of patients achieving ACR20 at week 12. Secondary endpoints included ACR20, ACR50, ACR70, individual ACR components, ESR and DAS28, over time. RESULTS.: AZD5672 was a highly potent and selective antagonist of CCR5, displaying non-proportional steady-state PK while inhibiting CCR5 internalization in an ex-vivo MIP-1beta stimulation assay over the 20-150 mg dose range investigated in the Phase IIb study. In the Phase IIb study, 371 patients received treatment. AZD5672 was generally well tolerated with no unexpected adverse events.There was no statistically significant difference in the proportion of patients reaching ACR20 at week 12 between any AZD5672 dose and placebo; etanercept was significantly more efficacious than AZD5672 and placebo. CONCLUSION.: Despite a clear rationale for targeting CCR5, this clinical study showed that AZD5672 dosed orally did not have any clinical benefit, suggesting that CCR5 antagonism alone is unlikely to be a viable therapeutic strategy in RA.

Keywords: AZD5672 CCR5 methotrexate arthritis rheumatoid arthritis