NON-HORMONAL TREATMENT FOR VULVAR AND VAGINAL ATROPHY BEING DEVELOPED SPECIFICALLY FOR PATIENTS WITH HORMONE RECEPTOR-POSITIVE BREAST CANCER*
Vulvar and vaginal atrophy (VVA) is an inflammation and thinning of the vaginal epithelium due to the reduction in levels of circulating estrogen. Typical symptoms include vaginal dryness, itching, burning, and painful intercourse, adversely impacting quality of life. VVA is a common condition in postmenopausal women and women with, or with a history of, hormone receptor-positive (HR+) breast cancer. Many breast cancer survivors experience menopausal symptoms irrespective of age as a direct consequence of their cancer treatment. Breast cancer patients treated with aromatase inhibitors refer to VVA as one of the most unpleasant side effects of treatment.1 Approximately 10 percent of women in the U.S. will develop breast cancer. The prevalence of VVA in postmenopausal breast cancer patients is estimated to be between 42 and 70 percent.
Products containing estrogen are commonly used to treat VVA. However, the use of estrogen-containing products for the treatment of VVA may be contraindicated for HR+ breast cancer patients and survivors because of the concern that estrogen use will promote recurrence of disease.2
DARE-VVA1 is an investigational, proprietary formulation of tamoxifen for intravaginal administration with the potential to be a first-in-category treatment of VVA for women with or at-risk of HR+ breast cancer. We are advancing DARE-VVA1 as a potential non-hormonal treatment alternative for this population.
Tamoxifen is a well-known and well-characterized selective estrogen receptor modulator (SERM) that has been prescribed by oncologists for decades for the treatment of breast cancer. In breast tissue, tamoxifen acts as an estrogen antagonist. In contrast, in other tissues such as vaginal tissues, tamoxifen has been reported to exert an estrogen-like response on vaginal cytology. Studies of tamoxifen conducted over the last 40 years have documented its estrogen-like effects on vaginal epithelium. Localized tamoxifen therapy such as DARE-VVA1 thus has the potential to counter the physiologic changes that lead to VVA without introducing estrogen back into the system. Data from an exploratory study of intravaginally administered tamoxifen published in Clinical and Experimental Obstetrics and Gynecology demonstrated improvements in vaginal pH and vaginal dryness without significant systemic absorption in postmenopausal women with VVA.3
DARE-VVA1 PHASE 1/2 CLINICAL TRIAL
Phase 1/2 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.
Topline Results of the Phase 1/2 Clinical Trial
In the fourth quarter of 2022, we announced positive topline results of the Phase 1/2 study. 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. 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.
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 concentration of over 100 ng/mL).
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.
The topline results of the Phase 1/2 study support ongoing development of DARE-VVA1.
Read more about the DARE-VVA1 Phase 1/2 study here.
1 Biglia N., Bounous V.E., D’Alonzo M., Ottino L., Tuninetti V., et al. Vaginal Atrophy in Breast Cancer Survivors: Attitude and Approaches Among Oncologists. Clin. Breast Cancer, 2017 Dec; 17(8):611-17. DOI: https://doi.org/10.1016/j.clbc.2017.05.008
2 American College of Obstetricians and Gynecologists’ Committee on Gynecologic Practice. The Use of Vaginal Estrogen in Women With a History of Estrogen-Dependent Breast Cancer. Committee Opinion No. 659, March 2016 (Reaffirmed 2020).
3 J. Chollet, L. A. Meyn, F. Mermelstein. Weekly vaginal administration of tamoxifen for three months in postmenopausal women with vulvar and vaginal atrophy: a possible new treatment approach?. Clinical and Experimental Obstetrics & Gynecology, 2019, 46(2): 285-288. DOI: https://doi.org/10.12891/ceog4948.2019
*This page includes forward-looking statements subject to qualifications described in the Terms of Service, including Section 13.4, Forward-Looking Statements; Disclaimer.