The selective estrogen receptor α 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

• Published in: Arthritis and rheumatism 2010-02, Vol.62 (2), p.351-358
• Main Authors: van Vollenhoven, Ronald F., Houbiers, Jos G. A., Buttgereit, Frank, in 't Hout, Joanna, Boers, Maarten, Leij, Susanne, Kvien, Tore K., Dijkmans, Ben A. C., Szczepański, Leszek, Szombati, Istvan, Sierakowski, Stanislaw, Miltenburg, André M. M.
• Format: Article
• Language: English
• Subjects: Antirheumatic Agents - administration & dosage; Antirheumatic Agents - adverse effects; Antirheumatic Agents - pharmacokinetics; Arthritis, Rheumatoid - drug therapy; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Diseases of the osteoarticular system; Drug Therapy, Combination; Estrogen Receptor alpha - agonists; Female; Humans; Inflammatory joint diseases; Medical sciences; Medication Adherence; Medicin och hälsovetenskap; Methotrexate - administration & dosage; Middle Aged; Pharmacology. Drug treatments; Placebos; Postmenopause; Steroids - administration & dosage; Steroids - adverse effects; Steroids - pharmacokinetics; Sulfasalazine - administration & dosage; Treatment Failure
• ISSN: 0004-3591; 1529-0131
• DOI: 10.1002/art.27196

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 α (ERα) 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 ERα agonist, in association with a clear biologic response to the study drug, provides evidence that a biologically relevant ERα‐mediated estrogenic effect is not associated with a clinically relevant effect on RA symptoms and signs.