The selective estrogen receptor alpha agonist Org 37663 induces estrogenic effects but lacks antirheumatic activity: a phase IIa trial investigating efficacy and safety of Org 37663 in postmenopausal female rheumatoid arthritis patients receiving stable background methotrexate or sulfasalazine.

Abstract

OBJECTIVE:

Multiple lines of evidence suggest that sex hormones may play a role in the pathogenesis or clinical expression of rheumatoid arthritis (RA). Studies on the effects of exogenous estrogens in RA patients have yielded contradictory results. We undertook this study to determine the effects of the selective estrogen receptor alpha (ERalpha) agonist Org 37663 in patients with RA, in terms of both its estrogenic effects and its ability to ameliorate disease activity.

METHODS:

A 10-week, multicenter, randomized, double-blind, placebo-controlled, parallel group, dose-finding, proof-of-concept trial was initiated to obtain data on the efficacy and safety of Org 37663 in postmenopausal female patients with RA who were receiving background treatment with either methotrexate or sulfasalazine. Patients were randomized to receive placebo or Org 37663 at doses of 4 mg/day, 15 mg/day, or 50 mg/week. The primary efficacy variable was the Disease Activity Score in 28 joints (DAS28).

RESULTS:

Org 37663 induced a clear biologic, estrogenic response in several organ systems, including a dose-related increase in levels of sex hormone binding globulin. However, the DAS28 decreased similarly for all treatment groups including placebo, indicating lack of clinical efficacy of Org 37663 in this trial.

CONCLUSION:

The observed lack of clinical benefit in RA patients treated with an ERalpha agonist, in association with a clear biologic response to the study drug, provides evidence that a biologically relevant ERalpha-mediated estrogenic effect is not associated with a clinically relevant effect on RA symptoms and signs.

• Authors: Ronald F van Vollenhoven, Jos G A Houbiers, Frank Buttgereit, Joanna In 't Hout, Maarten Boers, Susanne Leij, Tore K Kvien, Ben A C Dijkmans, Leszek Szczepański, Istvan Szombati, Stanislaw Sierakowski, André M M Miltenburg
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 62 Issue 2 Pg. 351-8 (Feb 2010) ISSN: 0004-3591 [Print] United States
• PMID: 20112368 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antirheumatic Agents
• Estrogen Receptor alpha
• Org 37663
• Placebos
• Steroids
• Sulfasalazine
• Methotrexate

Topics

• Antirheumatic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Arthritis, Rheumatoid (drug therapy)
• Drug Therapy, Combination
• Estrogen Receptor alpha (agonists)
• Female
• Humans
• Medication Adherence
• Methotrexate (administration & dosage)
• Middle Aged
• Placebos
• Postmenopause
• Steroids (administration & dosage, adverse effects, pharmacokinetics)
• Sulfasalazine (administration & dosage)
• Treatment Failure