Ophena™ (ospemifene) is a product candidate for the treatment of postmenopausal vaginal atrophy. QuatRx has completed two pivotal Phase III clinical studies 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.

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 four Phase II clinical studies and three Phase III studies. 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. Ophena™ had similar effects on bone turnover to raloxifene in Phase II.

Phase III Clinical Results

QuatRx has held 4 meetings with the FDA to date confirming the Ophena™ development plan under the applicable published FDA Guidance for VVA. QuatRx’s first pivotal U.S. Phase 3 trial included a total of 826 postmenopausal women and successfully met all co-primary endpoints required for approval. Women treated with 60mg Ophena™ showed statistically significant improvements in vaginal dryness and dyspareunia (painful intercourse), as well as statistically significant improvement in the proportion of parabasal and superficial cells in the epithelium of vaginal walls and a decline in vaginal pH levels. In addition, per FDA requirement, a non-hormonal vaginal lubricant was provided to women for prn use and statistical significance was demonstrated above and beyond such use.

In the second U.S. pivotal Phase 3 trial of Ophena™ included two patient cohorts, both of which have now completed. This second Phase 3 study is a randomized, double-blind, placebo-controlled trial of 919 patients with vaginal atrophy conducted at 116 sites in the United States. Patients were stratified into two cohorts based on their most bothersome moderate to severe vaginal atrophy symptom - either vaginal dryness or dyspareunia (sexual pain). The results conclusively demonstrate efficacy in all four co-primary endpoints. These results confirm those seen in the first pivotal Phase 3 trial.

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