Potential First monthly-therapy for both the
vasomotor and the vaginal symptoms of menopause
DARE-HRT1 is an investigational intravaginal ring (IVR) designed to deliver bio-identical 17β-estradiol and bio-identical progesterone continuously over a 28-day period as part of a hormone therapy regimen. The IVR technology used in DARE-HRT1 was developed by Dr. Robert Langer from the Massachusetts Institute of Technology and Dr. William Crowley from Massachusetts General Hospital and Harvard Medical School. Unlike other vaginal ring technologies, our IVR drug delivery technology is designed to release more than one active ingredient via a solid ethylene vinyl acetate polymer matrix without the need for a membrane or reservoir to contain the active drug or to control the release, allowing for sustained drug delivery.
For some women, hormone therapy is a highly effective treatment for the symptoms associated with menopause, such as hot flashes and vaginal dryness, and may also prevent bone loss and fracture. The delivery of hormone therapy over 28 consecutive days with no daily intervention demonstrated in a Phase 1 clinical study supports DARE-HRT1’s potential to be a first-in-category option offering ease-of-use and continuous dosing to women suffering from menopausal symptoms. There are currently no FDA-approved products that continuously deliver hormone therapy with both estradiol and progesterone together over multiple consecutive weeks.
DARE-HRT1 PHASE 1/2 CLINICAL TRIAL
Phase 1/2 Study Design
The randomized, open-label, two-arm, parallel group Phase 1/2 study was designed to evaluate DARE-HRT1’s safety, pharmacokinetics (PK), and preliminary efficacy in improving the vasomotor symptoms (VMS) as well as the vaginal symptoms of menopause in approximately 20 healthy, post-menopausal women (age range 51-65 years, mean 59 years) with intact uteri over approximately three consecutive months of use. The primary objective of the study was to describe the safety, tolerability, and PK of two different dose combinations (estradiol 80 µg/progesterone 4 mg IVR and estradiol 160 µg/progesterone 8 mg IVR) over 12 weeks of use. Secondary objectives of the study were to assess the usability, participant tolerability, and preliminary effectiveness of DARE-HRT1 for both the VMS and vaginal symptoms of menopause.
The study was conducted by the company’s wholly owned subsidiary in Australia.
Topline Results of the Phase 1/2 Clinical Trial
The levels of estradiol released from both the lower and higher dose formulation of DARE-HRT1 evaluated in the study achieved statistically significant improvement in VMS as well as the genitourinary symptoms of menopause, and vaginal pH and maturation index.
Menopausal symptoms, including hot flashes and night sweats, were reduced compared with baseline in both DARE-HRT1 dose groups (p<0.01). Participants also showed significant improvement from baseline in all measures surveyed on The Menopausal Quality of Life Survey (MENQOL), which surveys not only parameters of VMS, but also physical, psychosocial and sexual symptoms (p<0.01 on all domains). With DARE-HRT1 use, vaginal pH significantly decreased compared to baseline (p<0.01) and cytologic tests of the vaginal epithelium (vaginal maturation index) showed significant normalization (all p values <0.01 for increases in superficial cells, increases in intermediate cells and decreases in parabasal cells from baseline) among all participants. The most common genitourinary symptom, vaginal dryness, which was reported by 70% of participants at baseline, showed significant improvement in both DARE-HRT1 groups (p<0.01) and this subset also experienced significant decreases in vaginal pain with DARE-HRT1 use (p<0.01).
The study treatment was well tolerated with the types of most common adverse events consistent with other vaginal products. There were only two early discontinuations due to an adverse event, and no serious adverse events were reported.
DARE-HRT1 had a high level of acceptability in the study, with 100% of subjects reporting that the IVR was comfortable to wear, and there were no reports of the IVR being expelled from the vagina during use. Additionally, over 95% of subjects stated they would be either somewhat or very likely to use the IVR for a women’s health condition or unrelated disease if needed.
The company anticipates that topline PK data from the Phase 1/2 study will be available and reported later in the fourth quarter 2022.
The company plans to submit data from the study for publication in a peer-reviewed publication.
Following clinical development, the company intends to leverage the existing safety and efficacy data on the active ingredients in DARE-HRT1, estradiol and progesterone, to utilize the FDA’s 505(b)(2) pathway to obtain marketing approval of DARE-HRT1 in the U.S.
Read more about the DARE-HRT1 Phase 1/2 clinical study here.
PRIOR DARE-HRT1 PHASE 1 CLINICAL TRIAL
Phase 1 Study Design
The randomized, open-label, three-arm, parallel group Phase 1 study was designed to evaluate the PK of DARE-HRT1 in approximately 30 healthy, post-menopausal women with intact uteri. The primary objective of the study was to describe the PK parameters of two different dose combinations over 28 days. Secondary objectives of the study were to assess the safety and tolerability of DARE-HRT1 and to compare the systemic exposure of estradiol (the active form for therapeutic hormone therapy purposes), estrone, and progesterone of DARE-HRT1 over 28 days against a daily combination of FDA-approved oral estrogen and oral progesterone products evaluated in the Phase 1 study.
The study was conducted by the company’s wholly owned subsidiary in Australia.
Positive Topline Results of Phase 1 Clinical Trial
Data from the study demonstrate that DARE-HRT1 successfully delivered estradiol and the progesterone over the 28-day evaluation period. The baseline-corrected steady state release of estradiol and progesterone from both the lower (IVR1) and higher (IVR2) dose versions of DARE-HRT1 evaluated in the study demonstrated steady state release levels over 28 days as shown in the table below:
Steady State (Standard Deviation)
|DARE-HRT1 IVR1 (n=10)|
|Estradiol||20.6 (16.8) pg/mL|
|Progesterone||1.32 (0.20) ng/mL|
|DARE-HRT1 IVR2 (n=11)|
|Estradiol||32.5 (9.3) pg/mL|
|Progesterone||2.23 (0.61) ng/mL|
The levels of estradiol released from both the lower and higher dose formulation of DARE-HRT1 evaluated in the study achieved or exceeded the levels that were targeted for hormone therapy. Target levels of estradiol for hormone treatment for either the vasomotor symptoms (VMS) or vaginal symptoms of menopause were established by reviewing PK levels published for FDA-approved products for both the treatment of VMS as well as the genitourinary symptoms of menopause. Based on the estradiol PK data in the DARE-HRT1 Phase 1 study, the results support the potential of DARE-HRT1 as an effective hormone therapy for both VMS and vaginal symptoms associated with menopause. The levels of progesterone released from both versions of DARE-HRT1 evaluated in the study met the objectives of releasing progesterone. Progesterone is used in hormone therapy to reduce the impact of estrogen on nontarget sites, such as the endometrium, to prevent estrogen-induced endometrial hyperplasia.1
In addition, the DARE-HRT1 Phase 1 study treatment was well tolerated with the most common adverse events consistent with other vaginal products. There was only one early discontinuation due to an adverse event, which was found to be unrelated to study treatment or participation, and no serious adverse events were reported. The proportion of participants reporting adverse events was similar across all dose groups, the two DARE-HRT1 groups as well as the group receiving a daily combination of FDA-approved oral estrogen and oral progesterone products, with 89% of adverse events mild in severity and all other adverse events (11%) rated as moderate.
DARE-HRT1 had a high level of acceptability in the study, with over 80% of subjects on the lower and higher dose versions of DARE-HRT1 reporting the IVR as comfortable or very comfortable. Additionally, over 80% of subjects in each IVR dose group stated they were either somewhat or very likely to use the IVR for a women’s health condition or disease if needed.
Read more about the results of the DARE-HRT1 Phase 1 clinical study here.
Menopause is defined as the final menstrual period and is typically confirmed after a woman has missed her period for 12 consecutive months. Most women experience menopause between ages 40 and 58.2 An estimated 45 million women in the U.S. are approaching or in menopause, which results in a decrease in estrogen and other hormones.2,3 Hot flashes, vaginal dryness and loss of bone density are frequently associated with menopause. Night sweats (hot flashes that occur during sleep) often cause sleep disturbance, and vaginal atrophy (the drying and thinning of vaginal tissues) can cause a feeling of vaginal tightness during sex along with pain, burning, or soreness.3 Hence, management of menopausal symptoms can impact quality of life, productivity and health. The North American Menopause Society (NAMS) believes that hormone therapy is the most effective treatment for VMS and the genitourinary syndrome of menopause and observes that a non-oral route may offer advantages over oral routes of administration.3
1 Kuhl, H. (2005) Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric, 8:sup1, 3–63. DOI: 10.1080/13697130500148875
2 Menopause 101: A primer for the perimenopausal. NAMS, accessed 15 October 2022. http://www.menopause.org/for-women/menopauseflashes/menopause-symptoms-and-treatments/menopause-101-a-primer-for-the-perimenopausal.
3 NAMS Position Statement. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause: The Journal of The North American Menopause Society Vol. 29, No. 7, pp. 767-794 DOI: 10.1097/GME.0000000000002028. https://www.menopause.org/docs/default-source/professional/nams-2022-hormone-therapy-position-statement.pdf