Ophena™ (ospemifene) is a product candidate for the treatment of postmenopausal vaginal atrophy. QuatRx has completed a pivotal Phase III clinical study of Ophena™ which met all 4 co-primary efficacy endpoints, consistent with the appropriate FDA guidance.

Ophena™ is differentiated from hormone therapies such as estrogen. Ophena™ is a new SERM (selective estrogen receptor modulator) that selectively binds to estrogen receptors and either stimulates or blocks estrogen's activity in different tissue types. SERMs in development have been shown to mimic estrogen's beneficial action in bone tissue but do not stimulate estrogen's harmful effects in the breast and uterus which increase the risk of cancer.

The therapeutic effects of SERMs depend on their tissue specificity. Raloxifene (marketed as Evista® by Eli Lilly) is the only approved SERM for non-oncological treatment. Raloxifene is effective in treatment of osteoporosis, but it has no effect on vaginal tissue and therefore does not treat vaginal atrophy. Further, according to its product label, raloxifene increases the incidence of hot flashes.

Post-Menopausal Population

In North America, Europe and Japan, it is estimated that there are more than 145 million postmenopausal women, a number that is projected to increase as the median age of the population increases. Postmenopausal women suffer from a number of conditions as a result of a decline in estrogen levels. These conditions include decreased bone density, known as osteoporosis, hot flashes and vaginal atrophy.

Vaginal Atrophy

Up to 40% of postmenopausal women suffer from vaginal atrophy, a chronic condition characterized by vaginal dryness, burning, irritation, itching and vaginal discharge. Dryness and irritation accompanying decreases in vaginal secretions and lubrication can often cause pain and/or bleeding during sexual intercourse. Associated urinary symptoms can include urinary frequency, pain on urination, urinary tract infections and incontinence. In contrast to hot flashes, which eventually disappear, vaginal atrophy persists as women age.

Vaginal atrophy results from a decline in estrogen levels that causes thinning of the vaginal cell lining. This condition leads to fragile vaginal mucous membrane characterized by decreased elasticity, paleness and disappearance of the small folds found in the vaginal wall. Vaginal secretions and blood flow to the vagina decrease, resulting in decreased lubrication. The decline in estrogen levels also leads to an increase in vaginal pH, creating an environment more susceptible to infection.

Clinical Development Program

Ophena™ has completed five Phase I and two Phase II clinical studies in Europe and one pivotal Phase III study in the US. The first Phase II trial was a 12 week randomized, double-blind study of Ophena™ versus raloxifene in 118 postmenopausal women. The second Phase II study was a randomized, double-blind study of Ophena™ versus placebo in 159 postmenopausal women, also for 12 weeks. Ophena™ was well-tolerated and no safety issues were observed in studies to date. The Phase II trials demonstrated that Ophena™ has an estrogen-like effect on vaginal cells. Ophena™ caused statistically significant relative decreases in parabasal cells and increases in superficial cells, as reflected in the vaginal maturation index. Raloxifene did not induce such changes. Ophena™ had similar effects on bone turnover to raloxifene in the first Phase II study.

Phase III Clinical Trial Results

This pivotal Phase III study was designed to evaluate the efficacy of Ophena™ versus placebo over a 12-week treatment period in women with moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause. A total of 826 women were enrolled in the study from 80 centers in the US. The primary endpoints for the Phase III Ophena™ clinical trial were defined as the change from baseline to week 12 in the percentage of parabasal cells in the vaginal maturation index, the percentage of superficial cells in the vaginal maturation index, vaginal pH, and the most bothersome moderate to severe vulvovaginal atrophy symptom, consistent with the appropriate FDA guidance. The study achieved a statistically significant result in each of these co-primary endpoints and Ophena™ was well tolerated. The study investigated two doses of Ophena™ versus placebo, administered once daily, with patients randomized (1:1:1) into a double-blind 12-week treatment period with a four-week follow-up or the opportunity to continue in a long-term safety extension study. All subjects were supplied with a non-hormonal vaginal lubricant to be applied as needed during the 12-week treatment period.

Related Topics

Clinical Portfolio / Ophena™ / Market Opportunity

Additional Reading

Selective estrogen receptor modulators inhibit growth and progression of premalignant lesions in a mouse model of ductal carcinoma in situ. Namba R et al. Breast Cancer Research. 2005. 7:R881-R889
 
Effects of Ospemifene and raloxifene on hormonal status, lipids, genital tract, and tolerability in postmenopausal women. Komi J et al.  Menopause. 2005. 12(2) 202-209

Effects of Ospemifene, a novel SERM, on biochemical markers of bone turnover in healthy postmenopausal women. Komi J et al. Gynecol. Endocrinology. 2004. 18:152-158

Effects of Ospemifene, a novel SERM, on hormones, genital tract, climacteric symptoms, and quality of life in postmenopausal women: a double-blind, randomized trial. Rutanen E-M et al.  Menopause. 2003. 10 (5): 433-439

Effects of Ospemifene, a novel SERM, on vascular markers and function in healthy postmenopausal women. Ylikorkala O et al. Menopause. 2003. 10 (5):440-447
 
Effects of Ospemifene (FC-1271a) on uterine endometrium, vaginal maturation index, and hormonal status in healthy postmenopausal women. Voipio SK et al.  Maturitas. 2002. 43: 207-214

Selective Estrogenic Effects of a Novel Triphenylethylene Compound, FC1271a, on Bone, Cholesterol Level, and Reproductive Tissues in Intact and Ovariectomized Rats. Qu Q et al.  Endocrinology. 2000. 141(2): 809-820