A First-in-Human Study Evaluating AGA2118 in Men and Postmenopausal Women

Study Overview
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Brief Summary
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The primary objectives of the study are to assess the safety and tolerability of AGA2118 after single subcutaneous or intravenous administration in healthy men and postmenopausal women and to assess the safety and tolerability of AGA2118 after multiple subcutaneous administrations in men and postmenopausal women.

Detailed Description
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This is a Phase I, Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Absolute Bioavailability, Pharmacokinetics, and Pharmacodynamics of AGA2118 in Men and Postmenopausal Women. The study consists of the single ascending dose (SAD) part and the multiple ascending dose (MAD) part. In the SAD part, up to 56 healthy men and postmenopausal women will be sequentially enrolled to receive a single subcutaneous (SC) dose of AGA2118 or a single intravenous (IV) dose of AGA2118 or placebo. In the MAD part, up to 32 healthy men and postmenopausal women will be sequentially enrolled in various dose cohorts to receive multiple SC doses every 4 weeks of AGA2118 or placebo.

Official Title
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A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Absolute Bioavailability, Pharmacokinetics, and Pharmacodynamics of AGA2118 in Men and Postmenopausal Women

Conditions
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Osteoporosis

Intervention / Treatment
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* Drug: AGA2118
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy men ≥ 30 and ≤ 65 years of age or postmenopausal women ≥ 45 and ≤ 65 years of age for SAD and MAD; BMI ≥ 18.5 and ≤ 32 kg/m^2 (for SAD and MAD). Generally healthy (as assessed by the investigator). Nonsmokers, or light smokers, defined as ≤ 3 cigarettes/day (or equivalent) (for SAD and MAD). Able and willing to correctly and independently complete all study procedures and able to read, understand, and provide written informed consent after the nature of the study has been fully explained and must be willing to comply with all study requirements and procedures (for SAD and MAD). A male who is sterile or agrees to the following during the Treatment Period and for at least 6 months after the final dose of investigational product Refrain from donating fresh unwashed semen Plus, either Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR Must agree to use contraception as detailed below Agree to use a male condom plus a female partner to use a highly effective method of contraception with a woman of childbearing potential who is not currently pregnant Agree to use a male condom when engaging in any activity that allows for passage of ejaculate to another person Exclusion Criteria: A bone fracture within 6 months (for SAD only). Previous exposure to AGA2118 (for MAD only). Any condition that would affect bone metabolism or has a history of low energy fractures as documented in medical history (for MAD only). Administration of the any medications that known to affect bone metabolism within 6 months of Day 1 unless otherwise specified (for SAD and MAD). Human immunodeficiency virus (HIV) infection (for SAD and MAD). Active chronic hepatitis B (HBV) or hepatitis C (HCV) infection including hepatitis B surface antigen and hepatitis C antigen positive participants with or without abnormal liver enzymes (for SAD and MAD). Evidence of any of the following (for SAD and MAD): creatinine ≥ 1.5 × ULN, or estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m^2 using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula at screening current hyper- or hypocalcemia, defined as albumin-adjusted serum calcium outside the normal range known intolerance to calcium supplements malignancy within the last 5 years, etc.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AGA2118<br>In SAD part, various single doses of AGA2118 will be administered to the participants via either SC injection or IV infusion. The starting dose was 0.3 mg/kg, with sequential escalation up to 15 mg/kg. In MAD part, various multiple doses of AGA2118 will be administered every four weeks (Q4W) to the participants via SC injection for 12 weeks. The starting dose was 1 mg/kg, with sequential escalation up to 12 mg/kg. | Drug: AGA2118<br>* Part 1 - SAD study: SAD participants in various cohorts will receive various single dose of AGA2118 via either SC or IV. Part 2 - MAD study: MAD participants in various cohorts will receive various multiple doses of AGA2118 Q4W via SC.<br>|
| Placebo Comparator: Placebo<br>In SAD part, a single dose of placebo comparator will be used for each cohort of either SC or IV administration. In MAD part, multiple doses of placebo comparator will be used for each cohort of SC administration. | Drug: Placebo<br>* Part 1 - SAD study: SAD participants in various cohorts will receive a single dose of placebo via either SC or IV. Part 2 - MAD study: MAD participants in various cohorts will receive multiple doses of placebo via SC.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-emergent adverse events (TEAE) in Part 1 (SAD). | An adverse event (AE) is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of investigational product (IP), whether or not considered related to the IP. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of IP. | Up to 85 days | 
| Number of participants with clinically significant changes in total calcium (albumin-adjusted) in Part 1 (SAD). | Serum calcium tested at Day 2, 4, 6, 15, 29, 85. | Up to 85 days | 
| Number of participants with clinically significant changes in blood pressure in Part 1 (SAD). | Systolic and diastolic blood pressure measured (mmHg) at all clinic visits (Day 1, 2, 3, 4, 5, 6, 8, 11, 15, 22, 29, 43, 57, 71, 85). | Up to 85 days | 
| Number of participants with clinically significant changes in heart rate in Part 1 (SAD). | Heart rate measured by electrocardiogram (ECG) on Day 1, 2, 4, 6, 15, 29, 85. | Up to 85 days | 
| Number of participants with clinically significant changes in QTcF in Part 1 (SAD). | QTcF (QT interval corrected for heart rate using Fridericia's formula) measured by electrocardiogram (ECG) on Day 1, 2, 4, 6, 15, 29, 43, 57, 71, 85. | Up to 85 days | 
| Number of participants with treatment-emergent adverse events (TEAE) in Part 2 (MAD). | An adverse event (AE) is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of investigational product (IP), whether or not considered related to the IP. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of IP. | Up to 169 days | 
| Number of participants with clinically significant changes in total calcium (albumin-adjusted) in Part 2 (MAD). | Serum calcium tested at Day 2, 8, 15, 29, 36, 57, 64, 85, 169. | Up to 169 days | 
| Number of participants with clinically significant changes in blood pressure in Part 2 (MAD). | Systolic and diastolic blood pressure measured (mmHg) at all clinic visits (Day 1, 2, 4, 6, 8, 15, 22, 29, 36, 43, 57, 58, 60, 62, 64, 71, 78, 85, 99, 113, 127, 141, 155, 169). | Up to 169 days | 
| Number of participants with clinically significant changes in heart rate in Part 2 (MAD). | Heart rate measured by electrocardiogram (ECG) on Day 1, 2, 4, 15, 29, 36, 57, 64, 85, 169. | Up to day 169 | 
| Number of participants with clinically significant changes in QTcF in Part 2 (MAD). | QTcF (QT interval corrected for heart rate using Fridericia's formula) measured by electrocardiogram (ECG) on Day 1, 2, 4, 15, 29, 36, 57, 64, 85, 169. | Up to day 169 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Concentration (Cmax) of AGA2118 | Maximum concentration of AGA2118 after dosing. | Part 1 (SAD): up to day 85; Part 2 (MAD) up to day 169 | 
| Time to maximum concentration (Tmax) of AGA2118 | Time to maximum concentration of AGA2118 after dosing. | Part 1 (SAD): up to day 85; Part 2 (MAD) up to day 169 | 
| Area under the concentration time curve (AUC) | Definite integral of the curve describing the variation of AGA2118 in blood as a function of time. | Part 1 (SAD): up to day 85; Part 2 (MAD) up to day 169 | 
| Terminal elimination half-life (t1/2) | Time it takes for maximum concentration to half of maximum concentration of AGA2118. | Part 1 (SAD): up to day 85; Part 2 (MAD) up to day 169 |