A Dose-ranging Study of the Efficacy of ESN364 in Postmenopausal Women Suffering Vasomotor Symptoms (Hot Flashes)

This is a 12-week randomized, double-blind, placebo-controlled, dose-ranging, parallel-group,
multicenter study to assess the efficacy of ESN364 in postmenopausal women suffering from
vasomotor symptoms (hot flashes).

This study will consist of a screening period (Days -35 to -1, including the screening visit
[Visit 1] and a minimum 7-day collection of baseline vasomotor symptom frequency and severity
assessments), a 12 week treatment period (Day 1 [Visit 2] to Week 12 [Visit 5]), and a follow
up visit (Week 15 [Visit 6]) 3 weeks after the last dose of study drug.

The study will be performed on an ambulatory basis. The screening visit (Visit 1) will occur
up to 35 days prior to randomization. Eligibility will be assessed via physical examination,
clinical laboratory testing, vital signs, ECG, Pap smear, mammography, and endometrial
biopsy. Subjects will receive an electronic diary in which to record daily vasomotor symptoms
during the duration of the screening period. Subjects must have ≥7 consecutive days of
vasomotor symptom recordings to participate in the study. Subjects are encouraged to continue
recording for the duration of the whole screening period. The electronic diary will be
reviewed by study site staff on Day 1 (Visit 2) to confirm study eligibility. Subjects may be
rescreened 1 time upon approval of the medical monitor.

During the treatment period, subjects will return to the study site every 4 weeks for
assessments.

The follow-up visit will occur approximately 3 weeks following the last dose of study drug.

Inclusion Criteria:

- Women >40 years and ≤65 years of age at the screening visit;

- A body mass index between 18 kg/sqm to 38 kg/sqm (extremes included);

- Spontaneous amenorrhea for ≥12 consecutive months; or spontaneous amenorrhea for ≥6
months with biochemical criteria of menopause (follicle-stimulating hormone [FSH] >40
IU/L); or having had bilateral oophorectomy ≥6 weeks prior to the screening visit
(with or without hysterectomy);

- At least 50 moderate to severe vasomotor symptoms per week (ie, 7 consecutive days),
as recorded in the daily diary during the screening period;

- In good general health as determined on the basis of medical history and general
physical examination, including a bimanual clinical pelvic examination and clinical
breast examination devoid of relevant clinical findings, performed at the screening
visit; hematology and biochemistry parameters, pulse rate and/or blood pressure, and
ECG within the reference range for the population studied, or showing no clinically
relevant deviations, as judged by the Investigator;

- Women >40 years of age who have documentation of a normal/negative or no clinically
significant findings mammogram (obtained at Screening or within the prior 9 months of
trial enrollment.) Appropriate documentation includes a written report or an
electronic report indicating normal/negative or no clinically significant mammographic
findings;

- Willing to undergo a transvaginal ultrasound to assess endometrial thickness at
Screening and at Week 12 (end-of-treatment, - and subjects) who are withdrawn from the
study prior to completion, at the Early Termination (ET) Visit. This is not required
for subjects who have had a partial (supracervical) or full hysterectomy;

- Willing to undergo an endometrial biopsy at Screening (in the event that the subject's
transvaginal ultrasound shows endometrial thickness ≥4 mm) and at Week 12
(end--of--treatment) - all subjects), for subjects with uterine bleeding, and for
subjects who are withdrawn from the study prior to completion, at the ET Visit if
study drug exposure is ≥10 weeks. This is not required for subjects who have had a
partial (supracervical) or full hysterectomy;

- Negative alcohol breath test and negative urine test for selected drugs of abuse
(amphetamines, tricyclic antidepressants, cocaine, or opiates) at the screening visit;

- Negative urine pregnancy test;

- Negative serology panel (including hepatitis B surface antigen, hepatitis C virus
antibody, and human immunodeficiency virus antibody screens);

- Informed Consent Form signed voluntarily before any study-related procedure is
performed, indicating that the subject understands the purpose of and procedures
required for the study and is willing to participate in the study; and

- Documentation of a normal Pap smear (or equivalent cervical cytology) or of no
clinical significance in the opinion of the Investigator within the previous 9 months
or at Screening.

Exclusion Criteria:

- Use of a prohibited therapy (hormone therapy, hormonal contraceptive, or vasomotor
symptom medication [prescription, over the counter, or herbal]) or not willing to wash
out drugs

- History (in the past year) or presence of drug or alcohol abuse;

- Previous or current history of a malignant tumor, except for basal cell carcinoma;

- Uncontrolled hypertension and a systolic blood pressure ≥140 mmHg and/or a diastolic
blood pressure ≥90 mmHg;

- Judged by the Investigator to be unsuited to participate in the study based on
findings observed during physical examination, vital sign assessment, or 12-lead
electrocardiogram (ECG);

- History of severe allergy, hypersensitivity, or intolerance to drugs in general,
including the study drug and any of its excipients;

- Exclusion criterion 7 has been removed in Amendment 1;

- An unacceptable result from endometrial biopsy (performed when endometrial thickness
is ≥ 4mm measured by transvaginal ultrasound) of endometrial hyperplasia, endometrial
cancer, or inadequate specimen at Screening (1 repeat biopsy permitted if technically
possible);

- History of endometrial hyperplasia or uterine/endometrial cancer;

- History of unexplained uterine bleeding;

- History of seizures or other convulsive disorders;

- Medical condition or chronic disease (including history of neurological [including
cognitive], hepatic, renal, cardiovascular, gastrointestinal, pulmonary [eg, moderate
asthma], endocrine, or gynecological disease) or malignancy that could confound
interpretation of the study outcome;

- Presence or sequelae of gastrointestinal, liver, kidney, or other conditions known to
interfere with the absorption, distribution, metabolism, or excretion (ADME)
mechanisms of drugs as judged by the Investigator;

- Active liver disease or jaundice, or values of alanine aminotransferase (ALT) and
aspartate aminotransferase (AST) >1.5 x the upper limit of normal (ULN); or total
bilirubin >1.5 x ULN; or creatinine >1.5 x ULN; or estimated glomerular filtration
rate (eGFR) using the Modification of Diet in Renal Disease formula ≤59 mL/min/1.73
sqm at the screening visit;

- Concurrent participation in another interventional study (or participation within 3
months prior to screening in this study);

- Suicide attempt in the past 3 years;

- Unable or unwilling to complete the study procedures; or

- Subject is the Investigator or any sub-Investigator, research assistant, pharmacist,
study coordinator, or other staff or relative thereof, who is directly involved in the
conduct of the study.