Multiple Ascending Dose Study of AMG 598 in Adults With Obesity

Study Overview
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Brief Summary
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The main objective of this study is to assess the safety and tolerability of multiple doses of AMG 598 administered alone or in combination with liraglutide in adults with obesity.

Official Title
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A Phase 1b, Randomized, Double-blind, Placebo-controlled, Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 598 in Subjects With Obesity

Conditions
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Obesity

Intervention / Treatment
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* Drug: AMG 598
* Drug: Placebo
* Drug: Liraglutide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women with ages between 18 and 65 years old, inclusive, at time of signing consent Body mass index (BMI) between greater than or equal to 30.0 kg/m^2 and less than or equal to 40.0 kg/m^2 at screening Except for obesity, otherwise healthy or medically stable per protocol Have a stable body weight defined as less than 5 kg self-reported change during the previous 8 weeks prior to screening Other Inclusion criteria may apply Stable on liraglutide, depending on cohort Exclusion Criteria: History or clinical evidence of diabetes Inadequate organ function at screening Currently receiving treatment in another investigational device or drug study Women who are pregnant/lactating/breastfeeding or who plan to become pregnant/breastfeed while on study through 5 months after receiving the last dose of investigational product History or evidence of a clinically significant disorder, condition or disease that would pose a risk to subject safety or interfere with the study evaluation, procedures or completion A family or personal history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2; a personal history of non-familial medullary thyroid carcinoma; confirmed chronic pancreatitis or idiopathic acute pancreatitis, or gallbladder disease (ie, cholelithiasis or cholecystitis) not treated with cholecystectomy, for cohorts receiving liraglutide History of major depressive disorder Other Exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants received placebo subcutaneous injection once every 4 weeks (Q4W) for a total of 3 doses. | Drug: Placebo<br>* Placebo matching to AMG 598 administered by subcutaneous injection<br>|
| Active Comparator: Placebo + Liraglutide<br>Participants received placebo subcutaneous injection once every 4 weeks for a total of 3 doses in addition to liraglutide administered by subcutaneous injection once a day for 12 weeks. The starting dose of liraglutide was 0.6 mg/day, increasing in increments of 0.6 mg/day every 7 days to reach the full dosage of 3 mg/day by week 5. | Drug: Placebo<br>* Placebo matching to AMG 598 administered by subcutaneous injection<br>Drug: Liraglutide<br>* Liraglutide administered by subcutaneous injection. The starting dose is 0.6 mg/day, and increased by 0.6 mg/day dose increment every 7 days, up to the full dosage of 3.0 mg/day by week 5.<br>* Other names: Saxenda®;|
| Experimental: AMG 598 70 mg<br>Participants received 70 mg AMG 598 by subcutaneous injection once every 4 weeks (Q4W) for a total of 3 doses. | Drug: AMG 598<br>* AMG 598 administered by subcutaneous injection<br>|
| Experimental: AMG 598 70 mg + Liraglutide<br>Participants received 70 mg AMG 598 by subcutaneous injection once every 4 weeks for a total of 3 doses in addition liraglutide administered by subcutaneous injection once a day for 12 weeks. The starting dose of liraglutide was 0.6 mg/day, increasing in increments of 0.6 mg/day every 7 days to reach the full dosage of 3 mg/day by week 5. | Drug: AMG 598<br>* AMG 598 administered by subcutaneous injection<br>Drug: Liraglutide<br>* Liraglutide administered by subcutaneous injection. The starting dose is 0.6 mg/day, and increased by 0.6 mg/day dose increment every 7 days, up to the full dosage of 3.0 mg/day by week 5.<br>* Other names: Saxenda®;|
| Experimental: AMG 598 210 mg<br>Participants received 210 mg AMG 598 by subcutaneous injection once every 4 weeks for a total of 3 doses. | Drug: AMG 598<br>* AMG 598 administered by subcutaneous injection<br>|
| Experimental: AMG 598 210 mg + Liraglutide<br>Participants received 210 mg AMG 598 by subcutaneous injection once every 4 weeks for a total of 3 doses in addition to liraglutide administered by subcutaneous injection once a day for 12 weeks. The starting dose of liraglutide was 0.6 mg/day, increasing in increments of 0.6 mg/day every 7 days to reach the full dosage of 3 mg/day by week 5. | Drug: AMG 598<br>* AMG 598 administered by subcutaneous injection<br>Drug: Liraglutide<br>* Liraglutide administered by subcutaneous injection. The starting dose is 0.6 mg/day, and increased by 0.6 mg/day dose increment every 7 days, up to the full dosage of 3.0 mg/day by week 5.<br>* Other names: Saxenda®;|
| Experimental: AMG 598 420 mg<br>Participants received 420 mg AMG 598 by subcutaneous injection once every 4 weeks for a total of 3 doses. | Drug: AMG 598<br>* AMG 598 administered by subcutaneous injection<br>|
| Experimental: AMG 598 420 mg + Liraglutide<br>Participants received 420 mg AMG 598 by subcutaneous injection once every 4 weeks for a total of 3 doses in addition to liraglutide administered by subcutaneous injection once a day for 12 weeks. The starting dose of liraglutide was 0.6 mg/day, increasing in increments of 0.6 mg/day every 7 days to reach the full dosage of 3 mg/day by week 5. | Drug: AMG 598<br>* AMG 598 administered by subcutaneous injection<br>Drug: Liraglutide<br>* Liraglutide administered by subcutaneous injection. The starting dose is 0.6 mg/day, and increased by 0.6 mg/day dose increment every 7 days, up to the full dosage of 3.0 mg/day by week 5.<br>* Other names: Saxenda®;|

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 | The investigator assessed the severity of each adverse event reported during the study. The assessment was based on the Amgen Standard Grading Scale: Mild: Aware of sign or symptom, but easily tolerated. Moderate: Discomfort enough to cause interference with usual activity. Severe: Incapacitating with inability to work or do usual activity. A Serious adverse event is defined as any untoward medical occurrence that, met at least 1 of the following serious criteria Death; Was life-threatening; Required in-patient hospitalization or prolongation of existing hospitalization; Resulted in persistent or significant disability/incapacity; Was a congenital anomaly/birth defect; Other medically important serious event. The investigator also assessed whether each adverse event was related to study drug administration based on clinical judgement. | 207 days | 
| Number of Participants With TEAEs Due to Laboratory, Electrocardiogram, and Vital Sign Findings | TEAEs due to laboratory, electrocardiogram (ECG) and vital sign findings include any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or electrocardiogram, or vital signs measurements, including those that worsened from baseline, that were considered clinically significant in the medical and scientific judgment of the investigator (ie, not related to progression of underlying disease). | 207 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Concentration (Cmax) of AMG 598 After Subcutaneous Injection on Day 1 and Day 57 | Serum concentrations of AMG 598 were determined using a validated electrochemiluminescence-based method. The lower limit of quantitation was 50.0 ng/mL. | Day 1, predose, and days 6, 8, 15, 22, and 29; Day 57 predose and days 62, 64, 71, 85, 99, 113, 127, 169, and 207 | 
| Time to Maximum Observed Concentration (Tmax) of AMG 598 After Subcutaneous Injection on Day 1 and Day 57 | Serum concentrations of AMG 598 were determined using a validated electrochemiluminescence-based method. The lower limit of quantitation was 50.0 ng/mL. | Day 1, predose, and days 6, 8, 15, 22, and 29; Day 57 predose and days 62, 64, 71, 85, 99, 113, 127, 169, and 207 | 
| Dose-normalized Cmax of AMG 598 After Subcutaneous Injection on Day 1 and Day 57 | Serum concentrations of AMG 598 were determined using a validated electrochemiluminescence-based method. The lower limit of quantitation was 50.0 ng/mL. | Day 1, predose, and days 6, 8, 15, 22, and 29; Day 57 predose and days 62, 64, 71, 85, 99, 113, 127, 169, and 207 | 
| Area Under the Concentration-time Curve From Time 0 to 28 Days (AUC0-28) for AMG 598 After Subcutaneous Injection on Day 1 and Day 57 | Serum concentrations of AMG 598 were determined using a validated electrochemiluminescence-based method. The lower limit of quantitation was 50.0 ng/mL. | Day 1, predose, and days 6, 8, 15, 22, and 29; Day 57 predose and days 62, 64, 71, and 85 | 
| Dose-normalized AUC0-28 for AMG 598 After Subcutaneous Injection on Day 1 and Day 57 | Serum concentrations of AMG 598 were determined using a validated electrochemiluminescence-based method. The lower limit of quantitation was 50.0 ng/mL. | Day 1, predose, and days 6, 8, 15, 22, and 29; Day 57 predose and days 62, 64, 71, and 85 | 
| Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUClast) of AMG 598 After Subcutaneous Injection on Day 57 | Serum concentrations of AMG 598 were determined using a validated electrochemiluminescence-based method. The lower limit of quantitation was 50.0 ng/mL. | Day 57 predose and days 62, 64, 71, 85, 99, 113, 127, 169, and 207 | 
| Accumulation Ratio (AR) for Cmax of AMG 598 After Subcutaneous Injection on Day 1 and Day 57 | Serum concentrations of AMG 598 were determined using a validated electrochemiluminescence-based method. The lower limit of quantitation was 50.0 ng/mL. Accumulation ratio for Cmax = Day 57 Cmax / Day 1 Cmax. | Day 1, predose, and days 6, 8, 15, 22, and 29; Day 57 predose and days 62, 64, 71, 85, 99, 113, 127, 169, and 207 | 
| Accumulation Ratio of AUC0-28 for AMG 598 After Subcutaneous Injection on Day 1 and Day 57 | Serum concentrations of AMG 598 were determined using a validated electrochemiluminescence-based method. The lower limit of quantitation was 50.0 ng/mL. The accumulation ratio for AUC0-28 = Day 57 AUC0-28 / Day 1 AUC0-28. | Day 1, predose, and days 6, 8, 15, 22, and 29; Day 57 predose and days 62, 64, 71, and 85 | 
| Terminal Half-life (T1/2,z) of AMG 598 After Subcutaneous Injection on Day 57 | Serum concentrations of AMG 598 were determined using a validated electrochemiluminescence-based method. The lower limit of quantitation was 50.0 ng/mL. | Day 57 predose and days 62, 64, 71, 85, 99, 113, 127, 169, and 207 |