A novel estrogen receptor beta-agonist, ERB-041, may offer a new treatment modality in rheumatoid arthritis (RA), Crohn's disease, endometriosis, and potentially other autoimmune inflammatory diseases, according to preclinical and Phase I data presented at the American College of Rheumatology 2005 Innovative Therapies in Autoimmune Disease Meeting in Washington, DC.

In a study presented by Heather Harris, PhD, principal research scientist of the Women's Health Research Institute at Wyeth Research in Collegeville, Pennsylvania, ERB-041 was found to be safe and well tolerated, with no change in endocrine parameters over the 14-day trial period. An ongoing study in Crohn's patients is designed to determine how the drug affects levels of fecal and serum biomarkers of inflammation, including C-reactive protein, haptoglobin, and lactoferrin. Phase II studies of the compound are planned in RA and endometriosis. "I have a positive feeling about taking the compound into the clinic," Dr. Harris tells CIAOMed.

New findings may emphasize why RA remits during pregnancy

"We serendipitously found the anti-inflammatory effect of these types of compounds in animal models early on, shortly after we decided they had no utility as menopausal therapeutics. But that was not entirely surprising because we know that estrogens can have anti-inflammatory effects," Dr. Harris notes. For example, she points out, older studies have shown that RA remits in 70% of women during pregnancy. Also, peak incidence occurs after menopause and in patients enrolled in clinical trials of aromatase inhibitors, which interfere with the production of estrogen, have shown an increase in arthritis.

"ERB-041 will not be a pan-anti-inflammatory agent, [as] the biology of this compound is narrow, but its effect is striking where it works," she adds. "These compounds will not be good for every inflammatory condition, [but] may be very important for RA, where they not only act as an anti-inflammatory agent that improves signs and symptoms, but may potentially have disease-modifying effects."

Although ERB-041 is not a classic estrogenic agonist, stresses Dr. Harris, "it is not the dominant estrogen receptor in the uterus or the breast," she tells CIAOMed. "It was completely negative in all models of classic estrogen activity. It didn't stimulate the uterus or mammary glands, inhibit ovulation, or slow bone loss induced by ovariectomy."

According to Dr. Harris' presentation, promising results have been seen in three in vivo rodent models of arthritis and endometriosis. In the HLA-B27 transgenic and adjuvant-induced rat models of arthritis, ERB-041 ameliorates joint inflammation and reduces joint scores. ERB-041 also led to regression of lesions in a nude mouse model of endometriosis.

"While endometriosis is not a classic autoimmune disease, defects in the immune system likely contribute to its establishment," she says. "Paradoxically, in this situation, ERB-041 seems to have an immunostimulatory effect that enhances the peritoneal immune surveillance cells' ability to recognize implanted tissue as foreign," Dr. Harris notes, adding that "we have a long way to go on deciphering the mechanism of this compound beyond estrogen receptor beta." 

"It is a possible explanation for why patients with RA do better during pregnancy and tend to relapse after pregnancy, as well as develop inflammation after stopping birth control pills," Fred D. Finkelman, MD, director of the division of immunology at the University of Cincinnati College of Medicine in Ohio, tells CIAOMed.

Calling the presentation "extremely interesting," Dr. Finkelman adds that the data suggest that ERB-041 "does not have typical estrogen replacement effects on the reproductive system, but does have anti-inflammatory effects that are very different from corticosteroids." Moreover, he points out that there are no indications of infectious or immunosuppressive side effects.

Reference:

Harris H. Estrogen Receptor beta: A New Target for Anti-inflammatory Therapy? American College of Rheumatology 2005 Innovative Therapies in Autoimmune Disease Meeting, Washington, DC, March 4-6, 2005.