Phase 1 Study of ACE-083 in Healthy Subjects

Study Overview
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Brief Summary
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This study will evaluate the safety and tolerability of single and multiple doses of ACE-083 as a local injection into selected skeletal muscles of healthy subjects. The study will also determine the amount of ACE-083 that reaches the systemic circulation following local administration. Additionally, the study will assess whether local administration into skeletal muscle results in an increase in the size and/or strength of the injected muscle.

Detailed Description
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ACE-083 is a molecule that has been shown to increase skeletal muscle mass in animals and, therefore, has potential utility in certain diseases that affect skeletal muscle. This initial study in healthy human subjects will help determine the properties of ACE-083 (safety, tolerability, drug absorption and biologic activity), following local administration into skeletal muscle, in advance of clinical trials in patients. The study will consist of up to 7 planned groups of 8 or 9 subjects each. Subjects in each cohort will be randomized to receive either ACE-083 or placebo. ACE-083 (or placebo) will be administered locally into the right quadriceps (thigh) muscle or right tibialis anterior (lower leg) muscle. Subjects will receive a total of either one dose (on Day 1) or two doses (on Day 1 and Day 22). Each dose administered could include up to 4 injections of study drug into pre-defined locations in the muscle. A Safety Review Team (SRT) will review blinded, preliminary data from each treatment group to make recommendations regarding escalation to the next treatment group. Subjects will be assessed for safety throughout the treatment and follow-up periods. Follow-up visits will occur over 12 weeks following the last dose of study drug.

Official Title
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A Phase 1, Double-Blind, Placebo-Controlled, Dose-Ranging Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Effects of Local Muscle Injections of ACE-083 in Healthy Postmenopausal Women

Conditions
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Musculoskeletal Diseases

Intervention / Treatment
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* Drug: ACE-083


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Postmenopausal women, 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 BMI 18.5-32 kg/m2 Clinical laboratory values that meet the following criteria prior to dosing on Study Day 1: (i) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2 x upper limit of normal (ULN), (ii) Calculated creatinine clearance ≥ 60 mL/min, (iii) Platelet count ≥ 100 x109/L Able to adhere to the study visit schedule, understand and comply with protocol requirements Understand and sign written informed consent Exclusion Criteria: History of hepatitis B (HBsAg and HB core Ab), human immunodeficiency virus (HIV) antibody or active hepatitis C Positive drug or alcohol screen test at screening or on Day 1 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 Donation or loss ≥ 500 mL of whole blood within 2 months prior to Day 1 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 History of severe allergic or anaphylactic reaction or hypersensitivity to recombinant proteins History of active malignancy, with the exception of fully excised or treated basal cell carcinoma, cervical carcinoma in-situ, or ≤ 2 squamous cell carcinomas of the skin History of clinically significant (as determined by the Investigator) cardiac, endocrine, hematologic, hepatic, immune, metabolic, urologic, pulmonary, neurologic, neuromuscular, dermatologic, psychiatric, renal, and/or other disease Treatment with systemic glucocorticoid therapy, statin medication, 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 Treatment with 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 Treatment with another investigational drug, or approved therapy for investigational use within 4 weeks prior to Day 1, or if the half-life of the previous product is known, within 5 times the half-life prior to Day 1, whichever is longer Treatment within 3 months prior to Day 1 with any potent cytochrome P450 (CYP) 3A4/5 inhibitors (e.g., verapamil, ketoconazole, micronazole, itraconazole, erythromycin, telithromycin, clarithromycin, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir, delavirdine) or CYP3A4/5 inducers (carbamazepine, dexamethasone, felbamate, omeprazole, phenobarbital, phenytoin, amobarbital, nevirapine, primidone, rifabutin, rifampin, St. John's wort) Subject is unwilling or unable to maintain physical activity at baseline level for the duration of the study Subject has any condition that would prevent MRI scanning (e.g., pacemaker, knee/hip replacement, metallic implant, or extreme claustrophobia) Subject is unsuitable for enrollment in the opinion of the Investigator or Sponsor for other unspecified reasons

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 50 mg single dose<br>8 subjects in total; 6 subjects to received ACE-083 (50 mg) and 2 subjects to receive placebo, single injection, intramuscularly | Drug: ACE-083<br>* recombinant fusion protein<br>|
| Experimental: 100 mg single dose<br>8 subjects in total; 6 subjects to received ACE-083 (100 mg) and 2 subjects to receive placebo, single injection, intramuscularly | Drug: ACE-083<br>* recombinant fusion protein<br>|
| Experimental: 200 mg single dose<br>8 subjects in total; 6 subjects to received ACE-083 (200 mg) and 2 subjects to receive placebo, single injection, intramuscularly | Drug: ACE-083<br>* recombinant fusion protein<br>|
| Experimental: 100 mg multiple dose<br>8 subjects in total; 6 subjects to received ACE-083 (100 mg) and 2 subjects to receive placebo, two injections 3 weeks apart, intramuscularly | Drug: ACE-083<br>* recombinant fusion protein<br>|
| Experimental: 200 mg multiple dose<br>8 subjects in total; 6 subjects to received ACE-083 (200 mg) and 2 subjects to receive placebo, two injections 3 weeks apart, intramuscularly | Drug: ACE-083<br>* recombinant fusion protein<br>|
| Experimental: 100 mg (multiple dose)<br>9 subjects in total; 6 subjects to received ACE-083 (100 mg) and 3 subjects to receive placebo, two injections 3 weeks apart, intramuscularly | Drug: ACE-083<br>* recombinant fusion protein<br>|
| Experimental: 150 mg multiple dose<br>9 subjects in total; 6 subjects to received ACE-083 (150 mg) and 3 subjects to receive placebo, two injections 3 weeks apart, intramuscularly | Drug: ACE-083<br>* recombinant fusion protein<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ACE-083 Safety and Tolerability: Number of Subjects With Adverse Events | Safety/tolerability assessment, following intramuscular administration, includes adverse events, injection site reactions, laboratory measurements, vital signs, etc. | From initiation of treatment (Study Day 1) to end of follow up period (up to Study Day 106) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ACE-083 Pharmacokinetics: Maximum Measured Plasma Concentrations | Assessment of systemic absorption and exposure following local injection of ACE-083 into the thigh or lower leg muscle | PK samples were collected predose, and at 3 hours and 6 hours postdose. | 
| ACE-083 Pharmacodynamics | Pharmacodynamic assessments include measurements of thigh or lower leg volume and composition (by MRI) and muscle strength testing (by hand-held dynamometer and fixed system) | From initiation of treatment (Study Day 1) to end of follow up period (up to Study Day 106) | 
| ACE-083 Pharmacokinetics: Time of the Maximum Measured Plasma Concentration | Assessment of systemic absorption and exposure following local injection of ACE-083 into the thigh or lower leg muscle | PK samples were collected predose, and at 3 hours and 6 hours postdose. |