Our Pipeline:

DARE-HRT1

Potential First Monthly Therapy for the Vasomotor Symptoms of Menopause

About Menopause

Menopause is marked by the end of monthly menstruation and is typically confirmed after a woman has missed her period for 12 consecutive months. An estimated 45 million women in the U.S. are approaching or in menopause, which results in a decrease in estrogen and other hormones.1  Hot flashes, vaginal dryness and loss of bone density are frequently associated with menopause. An estimated 75% of menopausal women experience hot flashes.2  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 Menopause Society 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.4

Our Investigational Candidate, DARE-HRT1

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.

Daré intends to seek FDA approval of DARE-HRT1 for the treatment of moderate to severe VMS due to menopause in women with intact uteri.

2022 Hormone Therapy Position Statement of The Menopause Society3

  • Hormone therapy remains the most effective treatment for vasomotor symptoms (VMS) and the genitourinary syndrome of menopause and has been shown to prevent bone loss and fracture.
  • The risks of hormone therapy differ depending on type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is used. Treatment should be individualized using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation of the benefits and risks of continuing therapy.
  • Non-oral routes of administration (eg, transdermal, vaginal) may offer potential advantages because non-oral routes bypass the first-pass hepatic effect.

The non-oral delivery of hormone therapy over 28 consecutive days with no daily intervention 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.

Phase 1 Clinical Study, Completed

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.

Topline Phase 1 Study Results

  1. 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
  1. 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.
  2. 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.
  3. 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.

The study was conducted by the company’s wholly owned subsidiary in Australia.

Read more about the results of the DARE-HRT1 Phase 1 clinical study here.

Phase 1/2 Clinical Study, Completed

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.

Topline Results of Phase 1/2  Study

  • 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.

PK data from Phase 1/2 Study

  1. Topline data from the study demonstrate that DARE-HRT1 successfully delivered estradiol and progesterone over the 12-week evaluation period.
  2. 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 in month 3 of the 12-week study as shown in the table below:
 Steady State Cavg
(standard deviation)
DARE-HRT1 IVR1 (n=11)
Estradiol  22.17 (4.47) pg/mL
Progesterone  1.25 (0.34) ng/mL
DARE-HRT1 IVR2 (n=10)
Estradiol  38.97 (10.79) pg/mL
Progesterone 1.80 0.28) ng/mL
  1. 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 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.
  2. Based on the estradiol PK data in the DARE-HRT1 Phase 1 / 2 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.
  3. 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.
  4. Menopausal symptoms, including hot flashes and night sweats, were reduced compared with baseline in both DARE-HRT1 dose groups (p<0.01).
  5. 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.
  6. Finally, 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 company submitted data from the study for publication in a peer-reviewed publication, Menopause. [add link]

The study was conducted by the company’s wholly owned subsidiary in Australia.

Read more about the DARE-HRT1 Phase 1/2 clinical study here.

Regulatory Strategy for DARE-HRT1: Next Steps

Based on pre-IND communications with the FDA and the topline PK data from the DARE-HRT1 Phase 1 / 2 study, Daré believes FDA approval of DARE-HRT1 for that indication is achievable via the 505(b)(2) pathway supported by a single, placebo-controlled, Phase 3 clinical trial of DARE-HRT1 and a scientifically justified PK “bridge” (via a relative bioavailability trial) between DARE-HRT1 and the selected listed estradiol and progesterone drugs.

Ongoing activities to support progressing directly into a single Phase 3 study to support registration include manufacturing and non-clinical studies to support the IND submission and the planned IND-opening Phase 3 study.

At the conclusion of the development program, if successful, Daré 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.

*This page includes forward-looking statements subject to qualifications described in the Terms of Service, including Section 13.4, Forward-Looking Statements; Disclaimer.

DARE-HRT1 Footnotes:

1  https://my.clevelandclinic.org/health/diseases/21841-menopause Kuhl, H. (2005) Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric, 8:sup1, 3–63. DOI: 10.1080/13697130500148875

2  https://www.hopkinsmedicine.org/health/conditions-and-diseases/introduction-to-menopause
3 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.
4 THE Menopause Society (formerly NAMS) Position Statement.  https://www.menopause.org/docs/default-source/professional/nams-2022-hormone-therapy-position-statement.pdf

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