Proof of Concept Study of Vaginal AZU-101 in Vulvovaginal Atrophy in Postmenopausal Women

A Double-blind, Randomized, Placebo-controlled Proof oF Concept Clinical Study to Evaluate the Safety, Pharmacokinetics, AND Pharmacodynamics of Vaginal AZU-101 (Lasofoxifene Tartrate) in Postmenopausal Women

This is a randomized, double-blind, placebo-controlled Phase 2A study of vaginal AZU-101 in healthy postmenopausal female participants with moderate to severe vulvovaginal atrophy (VVA) with no contraindications to selective estrogen receptor modulators (SERMs). AZU-101 is a vaginal formulation of lasofoxifene tartrate, a SERM that has high affinity to both estrogen receptor (ER) alpha (ERα) and ER beta (ERβ). This study plans to evaluate 3 doses of AZU-101 (1, 0.5, and 0.1μg) and placebo. Results of the first cohort (1μg AZU-101) will direct additional dosing cohorts (0.5 and 0.1μg AZU-101).

Safety and tolerability will be measured by vital signs, electrocardiogram (ECG) parameters, and the incidence of Treatment-Emergent Adverse Events (TEAEs) and concomitant treatments. The PK profile will be assessed using peak plasma concentration (Cmax), time to peak plasma concentration (tmax), and area-under-the-concentration-time-curve from time zero to infinity (AUC0-∞). Efficacy will be evaluated using vaginal pH, the vaginal Maturation Index (percentage of vaginal parabasal cells and superficial cells), and identification of the most bothersome symptom to the subject (dyspareunia, vaginal dryness, or vaginal irritation/itching).

Number of participants (planned): Up to approximately 90 healthy postmenopausal females, 45 to 60 years of age.

Inclusion Criteria:

1. 1\. Postmenopausal female participants between 45 and 60 years old, inclusive (at the time of signing informed consent) with at least:

1. 3 years of spontaneous amenorrhea; or
2. At least 6 months postsurgical bilateral oophorectomy.
2. Pain associated with sexual activity (dyspareunia)
3. Vaginal pH ≥5.0
4. Vaginal smear with the percentage of superficial cells less than 5%
5. In the opinion of the Investigator, the participant will comply with the protocol and has a high probability of completing the study.
6. Normal gynecological examination including Papanicolaou (Pap) smear (required for all participants, including those with prior hysterectomy)
7. Good general health as evaluated by physical exam and lab assessments
8. Agrees to not take any OTC medication, herbal product or nutritional supplement containing soy or plant extracts during the study conduct until final visit
9. Agrees to not use any vaginal lubricants.
10. If taking statin as a concomitant medication, must be on a stable dose for 3 months without plan to change during the course of the study and through study completion
11. Agree to use a condom during sexual intercourse with a male partner during the study and for 1 month after the last dose.

Exclusion Criteria:

1. 1\. Any contraindication to SERMs
2. High risk for breast cancer and women with ductal carcinoma in situ (DCIS)
3. A history of liver cancer
4. A history of lung cancer
5. Conditions resulting in an increased risk of hypercoagulability, including immobility and strong family history of hypercoagulability
6. Documented coronary artery disease or at increased risk for major coronary events
7. History of developing hypertriglyceridemia resulting from previous estrogen product treatment
8. History of symptomatic cataracts
9. History of endometrial polyps or abnormal endometrial findings on transvaginal ultrasound evaluation
10. Use of any of the following:

1. Oral estrogen-, progestin-, androgen-, or SERM-containing drug products within 3 months before Screening Visit
2. Transdermal hormone products within 3 months before Screening Visit
3. Vaginal hormone products (rings, creams, gels) within 3 months before Screening Visit
4. Intrauterine progestins within 8 weeks before Screening Visit
5. Progestin implants/injectables or estrogen pellets/injectables within 6 months before Screening Visit
6. Any OTC medication, herbal product or nutritional supplement containing soy or plant extracts within 2 weeks prior to Screening Visit
11. A history or active presence of clinically important medical disease that might confound the study or be detrimental to the participant, including but not limited to:

1. Endometrial hyperplasia
2. Undiagnosed vaginal bleeding
3. History of a chronic liver or kidney dysfunction/disorder (e.g., hepatitis C or chronic renal failure)
4. Thrombophlebitis, thrombosis, or thromboembolic disorders
5. Cerebrovascular accident, stroke, or transient ischemic attack
6. Myocardial infarction or ischemic heart disease
7. Malignancy or treatment for malignancy, within the previous 5 years, with the exception of basal cell carcinoma of the skin or squamous cell carcinoma of the skin
8. History of estrogen dependent neoplasia, breast cancer, melanoma, or any gynecologic cancer, at any time
9. Endocrine disease (except for controlled hypothyroidism or controlled non-insulin dependent diabetes mellitus)
10. Known breast cancer gene (BRCA) mutation associated with increased risk of neoplasia
12. TVUS of the endometrium at Screening with a double-wall thickness measurement greater than 5 mm
13. A body mass index (BMI) \<18 and \>34 kg/m2
14. History of known alcohol or drug abuse within 1 year of the Screening Visit
15. Positive urine drug or alcohol screen at Screening Visit
16. Daily use of cigarettes or use of any electronic cigarettes
17. Use of an investigational drug or biologic within 60 days before administration of the first dose of study drug. Participants must agree not to participate in another research study of an investigational drug or device while enrolled in this study and for at least 30 days after completion of it.
18. Any clinically important abnormalities on Screening physical examination, assessments, ECG, or laboratory tests, including but not limited to:

1. Unresolved cervical cytologic smear report of atypical glandular cells of undetermined significance (AGUS) or atypical squamous cells of undetermined significance (ASCUS). Cervical cytologic smear report of low-grade squamous intraepithelial lesion (SIL) or greater, cervical intraepithelial neoplasia (CIN) grade 1 or greater, or any reported dysplasia; Participants with ASCUS are eligible only if high risk human papilloma virus (HPV) result is negative.
2. Unresolved findings suspicious for malignancy on the breast exam; incomplete mammogram result (Breast Imaging Reporting and Data System \[BI-RADS\] category 0) or unresolved findings suggestive of malignant changes or findings requiring short interval follow-up on the pre-study mammogram (participants must have mammography result of BI-RADS category 1 or 2 to enroll). Mammogram performed within 9 months prior to Screening Visit with documentation available may be used to evaluate study eligibility. The site must obtain a copy of the official report for the participant's study file, and it must be verified that the mammogram itself is available if needed for additional assessment.
3. Hematocrit \<35% or \>45%
4. Serum creatinine \>1.5 mg/dL.
5. Serum alanine aminotransferase (ALT) or serum aspartate aminotransferase (AST) \>1.5 times the ULN for the laboratory used
6. Fasting total cholesterol \>300 mg/dL (7.77 mmol/L) or triglycerides \>300 mg/dL (3.39 mmol/L)
7. Positive laboratory finding for Factor V Leiden mutation
8. Fasting glucose \>125 mg/dL
9. Uncontrolled hypertension (participants with sitting BP \>139 mmHg systolic or \>89 mmHg diastolic) and may not be using more than 2 antihypertensive medications for the treatment of hypertension
10. Hypotension; participants with sitting BP \<95 mmHg systolic or \<65 mmHg diastolic
11. A clinically significant abnormal 12-lead ECG (e.g., showing previous myocardial infarction or other findings suggestive of ischemia)
12. Positive human immunodeficiency virus (HIV), hepatitis B, hepatitis C, or active STD
13. Untreated vaginal or urinary tract infection, or chronic urinary tract infections requiring repeated antibiotic treatment.
14. Serum estradiol ≥20 pg/mL (≥73 pmol/L) at screening
15. Thyroid-stimulating hormone (TSH) \<0.4 or \>8.0 mIU/L
16. History of lichen sclerosis vulvae
17. Serum follicle-stimulating hormone (FSH) ≤30 IU/L
19. Poor venous access

1.0 ug for 14 daily doses

Vaginal administration 14 days

Placebo administered 14 days