Daré Bioscience, Inc. announced topline data from its Phase 1/2 clinical study of DARE-VVA1, a novel intravaginal proprietary formulation of tamoxifen being developed for the treatment of moderate to severe vulvar and vaginal atrophy. The randomized, double-blind, placebo-controlled study was designed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of DARE-VVA1 in postmenopausal participants with moderate to severe VVA. The topline data from the study demonstrated safety and tolerability of DARE-VVA1, as well as improvement in the vaginal cytology parameters and the bothersome vaginal symptoms associated with VVA.

DARE-VVA1 has the potential to be the first therapeutic specifically approved for the treatment of VVA in U.S. patients with HR+ breast cancer. There are currently no FDA-approved products labeled for VVA treatment in HR+ breast cancer patients. Globally, breast cancer is the most frequently diagnosed cancer type, accounting for over two million cases each year.

Approximately 4 million U.S. women have a history of invasive breast cancer, and of all breast cancer diagnoses in U.S. women, it is estimated that more than 68% are HR+. VVA prevalence in postmenopausal breast cancer survivors is estimated at 42% to 70%. DARE-VVA1 Phase 1/2 Clinical Trial Study Design: The Phase 1/2 study evaluated different doses of DARE-VVA1, a tamoxifen vaginal insert, in 17 postmenopausal women with VVA.

The study was a randomized, multi-center, double-blind, parallel-arm, placebo-controlled, dose-ranging study that evaluated the safety, tolerability, plasma pharmacokinetics (PK) and pharmacodynamics (PD) of DARE-VVA1. Eligible participants were randomly allocated to one of five treatment groups (approximately 4 participants per group) that evaluated four dose levels (1 mg, 5 mg, 10 mg, and 20 mg) and a placebo. Following a screening visit, DARE-VVA1 was self-administered intravaginally once a day for the first two weeks, and then twice a week for the following six weeks for a total treatment period of 56 days.

In each treatment group, participants had serial blood sampling for PK analysis and underwent safety evaluations and preliminary assessments of effectiveness. Following the completion of the treatment period, participants attended a safety follow-up visit. The primary endpoints of the study evaluated the safety and tolerability of DARE-VVA1 by vaginal administration and determined the plasma PK of DARE-VVA1 after intravaginal application.

Secondary endpoints evaluated preliminary efficacy and PD of DARE-VVA1 in terms of most bothersome vaginal symptom and changes in vaginal cytology and pH. The study was conducted by the company's wholly owned subsidiary in Australia. Topline Results of the Phase 1/2 Clinical Trial: The age of the 17 postmenopausal women with VVA who participated in the study ranged from 49 to 68 years (average age: 60.9).

Fourteen women completed the study. The primary outcomes of this first-in-woman study were safety and plasma PK. Intravaginal administration of DARE-VVA1 was well tolerated and all treatment emergent adverse events were mild or moderate and equally distributed between participants randomized to study drug treatment versus placebo.

Concentration of tamoxifen in plasma samples collected over the course of the study did not exceed 10 ng/mL, even in participants in the highest dose group (20 mg), which is 1/10th of the average steady-state concentration of tamoxifen seen with daily dosing of orally administered tamoxifen citrate tablets (20 mg and 10 mg tamoxifen) for three months (average steady-state plasma concentrations of over 100 ng/mL). Secondary outcomes of the study were preliminary efficacy and PD of DARE-VVA1 in terms of most bothersome vaginal symptom and changes in vaginal cytology and pH. Participants who received study drug treatment (at 1 mg, 5 mg, 10 mg or 20 mg doses) had improvements in the assessments and symptoms associated with VVA – specifically, they had decreases in vaginal pH, increases in the percentage of vaginal superficial cells, significant (p=0.04) decreases in the percentage of vaginal parabasal cells (despite the small sample size), and reduction in their self-assessed most bothersome vaginal symptom reported (either vaginal dryness or pain with intercourse).

Regarding the most bothersome vaginal symptom reported, of the participants randomized to receive study drug treatment, 39% (5/13) reported that vaginal dryness and 62% (8/13) reported that pain with intercourse (dyspareunia) was their most bothersome vaginal symptom at baseline. At the end of the treatment period, among the participants randomized to receive study drug treatment who reported vaginal dryness as their most bothersome symptom at baseline (n=5) (moderate or severe), all those who completed the study reported that vaginal dryness was either absent (n=1) or mild (n=3). Among the participants randomized to receive study drug treatment who reported dyspareunia as their most bothersome symptom at baseline (n=8) (moderate or severe), at the end of the treatment period, four reported no longer experiencing dyspareunia, one reported mild dyspareunia, two had no change in this symptom, and one did not complete the study.

Of the four participants randomized to the placebo group, two reported vaginal dryness and two reported dyspareunia as their most bothersome symptom at baseline. At the end of the treatment period, the participants randomized to the placebo group who reported vaginal dryness as their most bothersome symptom at baseline (n=2) (moderate or severe), reported that vaginal dryness was either absent (n=1) or mild (n=1), and among the participants randomized to the placebo group who reported dyspareunia as their most bothersome symptom at baseline (n=2), one reported no longer experiencing dyspareunia and one did not complete the study. Daré plans to submit data from the Phase 1/2 clinical study of DARE-VVA1 for publication in a peer-reviewed publication.

Following clinical development, Daré intends to leverage the existing safety and efficacy data on the active ingredient in DARE-VVA1, tamoxifen, to utilize the U.S. Food and Drug Administration's (FDA) 505(b)(2) pathway to obtain marketing approval of DARE-VVA1 in the U.S.