The purpose of the study is to assess safety, tolerance, pharmacokinetic, and pharmacodynamics of single doses of ACE-2494 in healthy postmenopausal women.

Subjects will be evaluated for study inclusion/exclusion criteria during the screening period (within 4 weeks prior to Day -1) and eligible subjects who have signed the informed consent form (ICF) will be enrolled and treated with study drug (ACE-2494 or placebo) on Day 1. Subjects will be randomized (3:1, ACE-2494: placebo) to receive one dose of either ACE-2494 or placebo, respectively, on Day 1.

The primary objective of the study is to evaluate the safety and tolerability of single ascending doses of ACE-2494 in healthy postmenopausal women. The secondary objectives are to characterize the pharmacokinetic (PK) profile and pharmacodynamic (PD) effects, including serum biomarkers, fat, lean, and bone mass (DXA), muscle volume and intramuscular fat fraction (MRI).

Inclusion Criteria:

1. Postmenopausal women, with menopause defined by follicle stimulating hormone (FSH) level > 40 IU/L and either 12 months of spontaneous amenorrhea or at least 6 months post-surgical bilateral oophorectomy and/or hysterectomy

2. Age 45-75 years

3. Body mass index (BMI) 18.5-32.0 kg/m2

4. Clinical laboratory values that meet the following criteria prior to dosing on Day 1:

   1. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2 x upper limit of normal (ULN)
   2. Serum creatinine ≤ 1.5 x ULN

5. Ability to adhere to the study visit schedule/procedures, and to understand and comply with protocol requirements

6. Signed written informed consent

Exclusion Criteria:

1. Smokers (use of tobacco products within 3 months prior to screening)
2. History of hepatitis B (HBsAg and HB core Ab), human immunodeficiency virus (HIV) antibody or active hepatitis C
3. Positive drug or alcohol screen test at screening or on Day 1
4. History of drug or alcohol abuse (as defined by the investigator) or required treatment for drug or alcohol use within 2 years of Day 1
5. Donated or lost ≥ 500 mL of whole blood within 2 months prior to Day 1
6. History of opportunistic infection (e.g., invasive candidiasis or pneumocystis pneumonia) within 6 months prior to screening; serious local infection (e.g., cellulitis, abscess) or systemic infection (e.g., septicemia) within 3 months prior to screening
7. History of severe allergic or anaphylactic reaction or hypersensitivity to recombinant proteins or any other drugs
8. Systemic glucocorticoid therapy, statin medication, growth hormone, androgen, insulin, oral hormone replacement therapy or any other therapy (including investigational) with known or intended effects on muscle within 3 months prior to Day 1
9. Anti platelet, anti-coagulant, or any other therapy (including investigational) with known or intended effects on bleeding risk within 1 week prior to Day 1 (Daily low-dose aspirin is allowed)
10. Treatment with another investigational drug, device, or approved therapy for investigational use within 30 days prior to Day 1; administration of a biological product in the context of a clinical research study within 90 days prior to Day 1
11. Participation in another clinical trial involving intervention with or without an investigational drug or device at any time during the study period
12. Unwilling or unable to maintain physical activity at baseline level for the duration of the study
13. For Cohorts 4-6 only, any condition that would prevent MRI scanning or compromise the ability to obtain a clear and interpretable scan of the thigh (e.g., pacemaker, knee/hip replacement, metallic implant, extreme claustrophobia, etc.)