Menerba^® for the Treatment of Vasomotor Symptoms (Hot Flashes) Associated with Menopause

Background
Today, there are approximately 40 million American women transitioning through menopause. At least two thirds of these women will experience vasomotor symptoms, including hot flashes, night sweats, and associated insomnia.

Historically, postmenopausal hormone therapies containing estrogens were an effective treatment for vasomotor symptoms. Hormone therapy (HT) was generally regarded as one of the best pharmacological interventions for treating menopausal symptoms and preventing osteoporosis in postmenopausal women. However, the Women’s Health Initiative randomized trials found that the risks of HT, including breast cancer, stroke, venous thromboembolic events, cardiovascular disease and dementia, exceeded the benefits. These findings led the FDA to issue seven black box warnings for all estrogen-containing hormone therapies. These warnings have made physicians more reluctant to prescribe HT and women more disinclined to use HT, resulting in a dramatic drop in the number of women taking HT for treatment of menopausal symptoms. This represents an unmet medical need where safer alternative treatments to the currently available hormone therapies for menopausal symptoms are of utmost importance.

Menerba’s Mechanism of Action
Menerba, designed to treat vasomotor symptoms (hot flashes) associated with menopause, is a novel selective estrogen receptor beta (ERβ) agonist. Unlike currently available non-selective estrogens contained in hormone therapies, Menerba does not activate the estrogen receptor alpha (ERα), known to be implicated in both breast and uterine cancer formation. Although Menerba is a selective estrogen-receptor modulator (SERM), our drug is distinct from the other FDA-approved SERMs, such as tamoxifen and raloxifene, since these drugs have mixed agonist/antagonist activity and are NOT selective in transcriptional regulation to one of the two known estrogen receptor subtypes. Menerba has distinct chemical structural differences from steroidal estrogens in HT and SERMs resulting in receptor subtype selectivity, thereby, conferring different pharmacological and toxicity profiles. Based on our studies conducted to date, there is clinical evidence that Menerba is effective for the treatment of vasomotor symptoms associated with menopause. Our studies also demonstrate that Menerba will not increase the risks for either breast or uterus cancer. Moreover, due to the absence of ERβ in hepatic cells, we believe Menerba will not result in an increased risk for venous thromboembolic events, a known side effect associated with the currently available HTs and SERMs.

Phase 1 Clinical Results
In a Phase 1 clinical trial of Menerba, conducted at the University of California, San Francisco, the drug was found to be safe, well tolerated and taken with high compliance. There was also statistically significant evidence of efficacy in the Phase 1 study.

Phase 2 Clinical Results
The Phase 2 clinical trial was designed to evaluate the safety and efficacy of 2 doses of Menerba versus placebo and was conducted under the direction of key opinion leader, Dr. Deborah Grady, at the University of California, San Francisco. The trial was a randomized, double-blinded, placebo-controlled study that enrolled 217 healthy postmenopausal women at 6 clinical sites in the U.S. who reported at least 50 moderate to severe hot flashes per week. Participants were randomized to receive Menerba 5 g/day, Menerba 10 g/day or identical placebo for 12 weeks.

The trial was completed by 98% of participants and 91% took at least 75% of assigned doses of study medication during the duration of the study. After 12 weeks of treatment, there was a statistically significant decrease in the frequency of all hot flashes in the higher dose of Menerba when compared to placebo. There was also a very clear dose response trend in multiple efficacy analyses, and statistical modeling indicated that higher doses of Menerba will lead to even greater reductions in the frequency of hot flashes. This trial provided evidence that treatment with Menerba reduced the frequency of hot flashes in healthy postmenopausal women and the drug was very well tolerated without any significant side effects.

The median reduction in the number of all hot flashes per week from baseline to 12 weeks of treatment was as follows: 68 to 41 in the placebo group, 63 to 32 in the Menerba low dose group and 67 to 31 in the Menerba high dose group. The difference in the median reduction in hot flashes per week after 12 weeks of treatment in the Menerba high dose group compared to placebo was statistically significant (p=0.04). Compared to placebo, women in the Menerba 10 g/day group were 2.3-fold more likely to have at least a 50% reduction in all hot flushes at 12 weeks of treatment (OR 2.3, p=0.03). Also of very important clinical significance, Menerba reduced the number of times women were woken up from sleep due to hot flashes, also known as “night awakenings” or “night sweats”. The median percent reduction in night time awakenings from hot flashes for women randomized to the higher dose of Menerba was 67%, and this reduction was statistically superior compared to placebo (p=0.05).

Menerba was very well tolerated and the only statistically significant side effect was loose stools (12% on Menerba versus 3% on placebo; p=0.03), which was most likely due to the presence of soluble fiber in Menerba. For future studies, manufacturing improvements have been implemented to reduce the fiber content in order to minimize this one side effect.

Safety analyses showed no cases of endometrial hyperplasia or uterine cancer during the trial and there were no differences in incidents of vaginal bleeding between the placebo group and the two cohorts treated with Menerba. Likewise, there was no increase in estradiol levels which further supports no untoward effect on either breast or uterine tissues that would lead to an increased risk for female cancers. There was no increase in blood pressure with treatment and there was a statistically significant decrease in both weight and body mass index (BMI) on the higher dose of Menerba compared to placebo.

Phase 3 Clinical Trial Design

To learn more about Menerba, visit http://www.menerba.com

About Dr. Wulf H. Utian, the Clinical Trial Principle Investigator

Dr. Wulf H. Utian is a key opinion leader in the field of gynecological endocrinology, having studied the metabolic and psychosocial aspects of estrogen and menopause for over 30 years. Dr. Utian is currently President of Rapid Medical Research, Inc. and Founder and Executive Director of The North American Menopause Society (NAMS). Dr. Utian is also the Arthur H. Bill Professor Emeritus of Reproductive Biology and Obstetrics and Gynecology, Case Western Reserve University.

Dr. Utian is a member of numerous professional societies, both in the United States and abroad, and serves on a number of national and international committees, including the Board of Trustees of The North American Menopause Society and the Medical Health Advisory Board of the Society for Women's Health Research. He is Chairman of the Council of Affiliated Menopause Societies (CAMS), the policy-making organ of the International Menopause Society.

Over the course of his career, Dr. Utian has written over 190 papers related to the reproductive system in women and has authored five books on menopause and its effects on women. He is editor of both Menopause: The Journal of The North American Menopause Society and Menopause Management. He has served as an advisor to the Office of Technology Assessment (U.S. Federal Government) on menopause and testified before Congress on women's health issues. He is the Honorary Past President of the International Menopause Society and the Honorary Founding President of The North American Menopause Society. He serves on the editorial review boards of multiple professional publications.