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

Daniëlle M. Gerlag, Sally Hollis, Mark Layton, Jiří Vencovský, Z. Szekanecz, Martin Braddock, Paul P. Tak

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Objective To investigate both the preclinical effects of blocking the chemokine receptor CCR5 and the clinical effects of this approach on the signs and symptoms of rheumatoid arthritis (RA) in patients with active disease. Methods Preclinical evaluations of AZD5672, a small-molecule antagonist of CCR5, were performed, including studies of ligand binding and chemotaxis. The pharmacokinetics of AZD5672 were assessed in both single-and multiple-dose studies in healthy volunteers. 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), matched placebo, or open-label etanercept (50 mg subcutaneously, once weekly). The primary end point was the proportion of patients achieving a 20% improvement response on the American College of Rheumatology improvement criteria (ACR20) at week 12. Secondary end points included the ACR20 over time, as well as 50% (ACR50) and 70% (ACR70) improvement responses, changes in individual components of the ACR improvement criteria, and disease activity measured with the Disease Activity Score based on the 28-joint count. Results AZD5672 was a highly potent and selective antagonist of CCR5, displaying nonproportional steady-state pharmacokinetics while inhibiting internalization of CCR5 in an ex vivo macrophage inflammatory protein 1β stimulation assay in which AZD5672 was evaluated over the 20-150-mg dose range. In the phase IIb study testing this dose range in patients with RA (n = 371 patients randomized to received treatment), AZD5672 was generally well tolerated, with no unexpected adverse events. There was no statistically significant difference in the proportion of patients achieving an ACR20 response at week 12 between those receiving any dose of AZD5672 and those receiving placebo; etanercept was significantly more efficacious than AZD5672 and placebo. Conclusion Despite a clear rationale for targeting CCR5, this clinical study showed that AZD5672, administered orally, did not have any clinical benefit, suggesting that CCR5 antagonism alone is unlikely to be a viable therapeutic strategy in RA.

Original languageEnglish
Pages (from-to)3154-3160
Number of pages7
JournalArthritis and Rheumatism
Volume62
Issue number11
DOIs
Publication statusPublished - Nov 2010

Fingerprint

Methotrexate
Rheumatoid Arthritis
Placebos
Pharmacokinetics
Macrophage Inflammatory Proteins
N-(1-(3-(3,5-difluorophenyl)-3-(4-methanesulfonylphenyl)propyl)piperidin-4-yl)-N-ethyl-2-(4-methanesulfonylphenyl)acetamide
Chemokine Receptors
Chemotaxis
Signs and Symptoms
Healthy Volunteers
Therapeutics
Joints
Ligands

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology
  • Pharmacology (medical)

Cite this

Preclinical and clinical investigation of a CCR5 antagonist, AZD5672, in patients with rheumatoid arthritis receiving methotrexate. / Gerlag, Daniëlle M.; Hollis, Sally; Layton, Mark; Vencovský, Jiří; Szekanecz, Z.; Braddock, Martin; Tak, Paul P.

In: Arthritis and Rheumatism, Vol. 62, No. 11, 11.2010, p. 3154-3160.

Research output: Contribution to journalArticle

Gerlag, Daniëlle M. ; Hollis, Sally ; Layton, Mark ; Vencovský, Jiří ; Szekanecz, Z. ; Braddock, Martin ; Tak, Paul P. / Preclinical and clinical investigation of a CCR5 antagonist, AZD5672, in patients with rheumatoid arthritis receiving methotrexate. In: Arthritis and Rheumatism. 2010 ; Vol. 62, No. 11. pp. 3154-3160.
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abstract = "Objective To investigate both the preclinical effects of blocking the chemokine receptor CCR5 and the clinical effects of this approach on the signs and symptoms of rheumatoid arthritis (RA) in patients with active disease. Methods Preclinical evaluations of AZD5672, a small-molecule antagonist of CCR5, were performed, including studies of ligand binding and chemotaxis. The pharmacokinetics of AZD5672 were assessed in both single-and multiple-dose studies in healthy volunteers. 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), matched placebo, or open-label etanercept (50 mg subcutaneously, once weekly). The primary end point was the proportion of patients achieving a 20{\%} improvement response on the American College of Rheumatology improvement criteria (ACR20) at week 12. Secondary end points included the ACR20 over time, as well as 50{\%} (ACR50) and 70{\%} (ACR70) improvement responses, changes in individual components of the ACR improvement criteria, and disease activity measured with the Disease Activity Score based on the 28-joint count. Results AZD5672 was a highly potent and selective antagonist of CCR5, displaying nonproportional steady-state pharmacokinetics while inhibiting internalization of CCR5 in an ex vivo macrophage inflammatory protein 1β stimulation assay in which AZD5672 was evaluated over the 20-150-mg dose range. In the phase IIb study testing this dose range in patients with RA (n = 371 patients randomized to received treatment), AZD5672 was generally well tolerated, with no unexpected adverse events. There was no statistically significant difference in the proportion of patients achieving an ACR20 response at week 12 between those receiving any dose of AZD5672 and those receiving placebo; etanercept was significantly more efficacious than AZD5672 and placebo. Conclusion Despite a clear rationale for targeting CCR5, this clinical study showed that AZD5672, administered orally, did not have any clinical benefit, suggesting that CCR5 antagonism alone is unlikely to be a viable therapeutic strategy in RA.",
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AU - Vencovský, Jiří

AU - Szekanecz, Z.

AU - Braddock, Martin

AU - Tak, Paul P.

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AB - Objective To investigate both the preclinical effects of blocking the chemokine receptor CCR5 and the clinical effects of this approach on the signs and symptoms of rheumatoid arthritis (RA) in patients with active disease. Methods Preclinical evaluations of AZD5672, a small-molecule antagonist of CCR5, were performed, including studies of ligand binding and chemotaxis. The pharmacokinetics of AZD5672 were assessed in both single-and multiple-dose studies in healthy volunteers. 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), matched placebo, or open-label etanercept (50 mg subcutaneously, once weekly). The primary end point was the proportion of patients achieving a 20% improvement response on the American College of Rheumatology improvement criteria (ACR20) at week 12. Secondary end points included the ACR20 over time, as well as 50% (ACR50) and 70% (ACR70) improvement responses, changes in individual components of the ACR improvement criteria, and disease activity measured with the Disease Activity Score based on the 28-joint count. Results AZD5672 was a highly potent and selective antagonist of CCR5, displaying nonproportional steady-state pharmacokinetics while inhibiting internalization of CCR5 in an ex vivo macrophage inflammatory protein 1β stimulation assay in which AZD5672 was evaluated over the 20-150-mg dose range. In the phase IIb study testing this dose range in patients with RA (n = 371 patients randomized to received treatment), AZD5672 was generally well tolerated, with no unexpected adverse events. There was no statistically significant difference in the proportion of patients achieving an ACR20 response at week 12 between those receiving any dose of AZD5672 and those receiving placebo; etanercept was significantly more efficacious than AZD5672 and placebo. Conclusion Despite a clear rationale for targeting CCR5, this clinical study showed that AZD5672, administered orally, did not have any clinical benefit, suggesting that CCR5 antagonism alone is unlikely to be a viable therapeutic strategy in RA.

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