Tags

Type your tag names separated by a space and hit enter

MLN3897 plus methotrexate in patients with rheumatoid arthritis: safety, efficacy, pharmacokinetics, and pharmacodynamics of an oral CCR1 antagonist in a phase IIa, double-blind, placebo-controlled, randomized, proof-of-concept study.
Arthritis Rheum. 2009 Dec; 60(12):3572-81.AR

Abstract

OBJECTIVE

To assess the efficacy, safety, pharmacokinetics, and pharmacodynamics of the CC chemokine receptor CCR1 antagonist MLN3897 in patients with rheumatoid arthritis (RA) receiving methotrexate (MTX).

METHODS

In this phase IIa, proof-of-concept study, patients meeting the American College of Rheumatology (ACR) criteria for RA who had been taking MTX for >or=6 months with evidence of active disease were randomly assigned to receive either 10 mg oral MLN3897 or matching placebo once daily for 12 weeks (days 1-83) while continuing to receive MTX once a week. Clinical assessments, safety monitoring, and sampling for pharmacokinetic and pharmacodynamic analyses were performed throughout the study. The primary efficacy end point was the difference in the percentage of patients meeting the ACR 20% improvement criteria (achieving an ACR20 response) on day 84 in the MLN3897-treated group compared with that in the placebo-treated group.

RESULTS

MLN3897 was well tolerated, with no evidence of systemic immunosuppression. In the intent-to-treat population, there was no significant difference in day 84 ACR20 response rates between MLN3897-treated patients and placebo-treated patients (35% versus 33%, respectively; P=0.72). Results were similar for the per-protocol population. Pharmacokinetic analyses demonstrated no interactions between MLN3897 and MTX. MLN3897 was associated with a high degree of CCR1 occupancy (>or=90% on days 28, 56, and 84 in 82% of patients, by macrophage inflammatory protein 1alpha internalization assay).

CONCLUSION

MLN3897 at a concentration of 10 mg once daily had no discernible activity in patients with RA who were also receiving MTX. The results suggest that CCR1 antagonism is unlikely to be a viable strategy for the treatment of RA when used in isolation at the receptor occupancy levels reached in this study.

Authors+Show Affiliations

Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial, Phase II
Journal Article
Randomized Controlled Trial

Language

eng

PubMed ID

19950299

Citation

Vergunst, Clarissa E., et al. "MLN3897 Plus Methotrexate in Patients With Rheumatoid Arthritis: Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of an Oral CCR1 Antagonist in a Phase IIa, Double-blind, Placebo-controlled, Randomized, Proof-of-concept Study." Arthritis and Rheumatism, vol. 60, no. 12, 2009, pp. 3572-81.
Vergunst CE, Gerlag DM, von Moltke L, et al. MLN3897 plus methotrexate in patients with rheumatoid arthritis: safety, efficacy, pharmacokinetics, and pharmacodynamics of an oral CCR1 antagonist in a phase IIa, double-blind, placebo-controlled, randomized, proof-of-concept study. Arthritis Rheum. 2009;60(12):3572-81.
Vergunst, C. E., Gerlag, D. M., von Moltke, L., Karol, M., Wyant, T., Chi, X., Matzkin, E., Leach, T., & Tak, P. P. (2009). MLN3897 plus methotrexate in patients with rheumatoid arthritis: safety, efficacy, pharmacokinetics, and pharmacodynamics of an oral CCR1 antagonist in a phase IIa, double-blind, placebo-controlled, randomized, proof-of-concept study. Arthritis and Rheumatism, 60(12), 3572-81. https://doi.org/10.1002/art.24978
Vergunst CE, et al. MLN3897 Plus Methotrexate in Patients With Rheumatoid Arthritis: Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of an Oral CCR1 Antagonist in a Phase IIa, Double-blind, Placebo-controlled, Randomized, Proof-of-concept Study. Arthritis Rheum. 2009;60(12):3572-81. PubMed PMID: 19950299.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - MLN3897 plus methotrexate in patients with rheumatoid arthritis: safety, efficacy, pharmacokinetics, and pharmacodynamics of an oral CCR1 antagonist in a phase IIa, double-blind, placebo-controlled, randomized, proof-of-concept study. AU - Vergunst,Clarissa E, AU - Gerlag,Danielle M, AU - von Moltke,Lisa, AU - Karol,Michael, AU - Wyant,Tim, AU - Chi,Xuedong, AU - Matzkin,Ellen, AU - Leach,Timothy, AU - Tak,Paul P, PY - 2009/12/2/entrez PY - 2009/12/2/pubmed PY - 2010/2/19/medline SP - 3572 EP - 81 JF - Arthritis and rheumatism JO - Arthritis Rheum VL - 60 IS - 12 N2 - OBJECTIVE: To assess the efficacy, safety, pharmacokinetics, and pharmacodynamics of the CC chemokine receptor CCR1 antagonist MLN3897 in patients with rheumatoid arthritis (RA) receiving methotrexate (MTX). METHODS: In this phase IIa, proof-of-concept study, patients meeting the American College of Rheumatology (ACR) criteria for RA who had been taking MTX for >or=6 months with evidence of active disease were randomly assigned to receive either 10 mg oral MLN3897 or matching placebo once daily for 12 weeks (days 1-83) while continuing to receive MTX once a week. Clinical assessments, safety monitoring, and sampling for pharmacokinetic and pharmacodynamic analyses were performed throughout the study. The primary efficacy end point was the difference in the percentage of patients meeting the ACR 20% improvement criteria (achieving an ACR20 response) on day 84 in the MLN3897-treated group compared with that in the placebo-treated group. RESULTS: MLN3897 was well tolerated, with no evidence of systemic immunosuppression. In the intent-to-treat population, there was no significant difference in day 84 ACR20 response rates between MLN3897-treated patients and placebo-treated patients (35% versus 33%, respectively; P=0.72). Results were similar for the per-protocol population. Pharmacokinetic analyses demonstrated no interactions between MLN3897 and MTX. MLN3897 was associated with a high degree of CCR1 occupancy (>or=90% on days 28, 56, and 84 in 82% of patients, by macrophage inflammatory protein 1alpha internalization assay). CONCLUSION: MLN3897 at a concentration of 10 mg once daily had no discernible activity in patients with RA who were also receiving MTX. The results suggest that CCR1 antagonism is unlikely to be a viable strategy for the treatment of RA when used in isolation at the receptor occupancy levels reached in this study. SN - 0004-3591 UR - https://www.unboundmedicine.com/medline/citation/19950299/MLN3897_plus_methotrexate_in_patients_with_rheumatoid_arthritis:_safety_efficacy_pharmacokinetics_and_pharmacodynamics_of_an_oral_CCR1_antagonist_in_a_phase_IIa_double_blind_placebo_controlled_randomized_proof_of_concept_study_ L2 - https://doi.org/10.1002/art.24978 DB - PRIME DP - Unbound Medicine ER -