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.1Approximately 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
The Phase 1/2 study will evaluate different doses of DARE-VVA1, a tamoxifen vaginal insert, in approximately 40 postmenopausal women with VVA, including a cohort of women with a history of breast cancer. The study is a randomized, multi-center, double-blind, parallel-arm, placebo-controlled, dose-ranging study that will evaluate the safety, tolerability, plasma pharmacokinetics (PK) and pharmacodynamics (PD) of DARE-VVA1. Eligible participants will be randomly allocated to one of five treatment groups (approximately 8 participants per group) that will evaluate four dose levels (1mg, 5mg, 10mg, and 20mg) and a placebo. Following a screening visit, DARE-VVA1 will be 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 will have serial blood sampling for PK analysis and undergo safety evaluations and preliminary assessments of effectiveness. Following the completion of the treatment period, participants will attend a safety follow-up visit.
The primary endpoints of the study will evaluate the safety and tolerability of DARE-VVA1 by vaginal administration and determine the plasma PK of DARE-VVA1 after intravaginal application. Secondary endpoints will evaluate preliminary efficacy and PD of DARE-VVA1 in terms of most bothersome symptom and changes in vaginal cytology and pH.
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: 10.12891/ceog4948.2019