A Study to Examine the Safety, Tolerability and Biological Effects of REGN4461 in Healthy Volunteers

Study Overview
=================
Brief Summary
-----------------
The primary objective of the study is to evaluate the safety and tolerability of REGN4461 in healthy participants. The secondary objectives of the study are to: Characterize the Pharmacokinetic (PK) profile of single and repeated doses of REGN4461 and evaluate the effects of baseline covariates on PK profile Estimate the effects of repeated doses of REGN4461 on body weight over 12 weeks in overweight and obese participants Assess the effects of repeated doses of REGN4461 on ad lib energy intake in overweight and obese participants Evaluate the effects of single and repeated doses of REGN4461 on soluble forms of lipid-regulating proteins levels over time Assess the immunogenicity of single and repeated doses of REGN4461

Detailed Description
-----------------
This is a 2-part study of the safety, tolerability, PK and pharmacodynamic (PD) of single and repeated doses of REGN4461 in healthy participants. In Part A, healthy lean or overweight participants will be enrolled to evaluate the safety, tolerability, PK, and PD of single ascending intravenous (IV) and subcutaneous (SC) doses. Interim PK and safety information from Part A will be used to select the dose level, frequency, and mode of administration (IV or SC) for repeat dosing in Part B. In Part B, overweight/obese participants with body mass index (BMI) 25-40 kg/m2 will be enrolled to evaluate the safety, tolerability, PK, and PD of repeated doses of REGN4461 in 4 distinct cohorts defined by baseline leptin levels.

Official Title
-----------------
A Phase 1 Randomized, Double-Blind, Placebo-Controlled, 2-Part Study to Assess the Safety and Tolerability, Pharmacokinetics, And Pharmacodynamics of Single and Multiple Doses of REGN4461 in Healthy Subjects

Conditions
-----------------
Healthy Volunteers

Intervention / Treatment
-----------------
* Drug: REGN4461
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria Part A: Males and females 18 to 50 years of age, inclusive Body mass index (BMI) from 18.5 to <30.0 kg/m^2 Participant is judged by the investigator to be in good health and free from major comorbidities based on medical history, physical examination, laboratory safety tests performed at screening and/or prior to administration of initial dose of study drug Part B: Males and females 18 to 65 years of age, inclusive Have a body mass index (BMI) from 25.0 to 40.0 kg/m^2 Participant is judged by the investigator to be free from major comorbidities based upon medical history, physical examination, laboratory safety tests performed at screening and/or prior to administration of initial dose of study drug. Participants can have a history of mild hyperlipidemia and/or mild hypertension but should be on stable doses of lipid lowering or blood pressure lowering medicines for at least 2 months prior to screening Key Exclusion Criteria Part A: History of type 1 or 2 diabetes or prediabetes or with fasting blood glucose (FBG) at screening ≥ 100mg/dL or with HbA1c at screening of ≥ 5.7%. Fasting LDL-C ≥ 130mg/dL, TG ≥ 250 mg/dL Part B: History of type 1 or 2 diabetes or with FBG at screening ≥ 126 mg/dL or with HbA1c at screening of ≥ 6.5%. A diagnosis of pre-diabetes is allowed. Fasting LDL-C ≥ 160 or TG ≥ 500 mg/dL Key Exclusion Criteria (Parts A and B): Hospitalization (ie, >24 hours) for any reason within 60 days of the screening visit History of hypothalamic amenorrhea or lipodystrophy. Change in body weight of more than 5% over the past 3 months prior to screening. Previous history of bariatric procedures for obesity (eg, sleeve gastrectomy, gastric bypass, banding, etc). Procedures for weight reduction (eg, liposuction) or body contouring in the past 6 months. Treatment with medications for (over-the-counter [OTC] or prescribed) weight loss (eg, lorcaserin, phentermine/topiramate, naltrexone HCl/bupropion HCl, liraglutide) in the past 3 months. History of major psychiatric disorders, eating disorders (eg, bulimia, anorexia). Current cigarette smoker or former smoker (cigarettes or e-cigarettes) who stopped smoking within 3 months prior to screening. History of recreational drug (including marijuana) or alcohol abuse (>2 drinks per day) within a year prior to the screening visit. History of hepatitis B infection or a positive hepatitis B surface antigen (HbsAg+) at screening History of HIV infection or HIV seropositive at the screening visit. History of hepatitis C infection or positive hepatitis C antibody test result at screening. Pregnant or breastfeeding women. Note: Other inclusion/ exclusion criteria apply

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Single dose cohort 1<br>Cohort 1 will receive a single IV dose of REGN4461 or matching placebo | Drug: REGN4461<br>* REGN4461<br>Drug: Placebo<br>* Placebo-matching REGN4461<br>|
| Experimental: Part A: Single dose cohort 2<br>Cohort 2 will receive a sequential ascending single IV dose of REGN4461 or matching placebo | Drug: REGN4461<br>* REGN4461<br>Drug: Placebo<br>* Placebo-matching REGN4461<br>|
| Experimental: Part A: Single dose cohort 3<br>Cohort 3 will receive a sequential ascending single IV dose of REGN4461 or matching placebo | Drug: REGN4461<br>* REGN4461<br>Drug: Placebo<br>* Placebo-matching REGN4461<br>|
| Experimental: Part A: Single dose cohort 4<br>Cohort 4 will receive a sequential ascending single SC dose of REGN4461 or matching placebo | Drug: REGN4461<br>* REGN4461<br>Drug: Placebo<br>* Placebo-matching REGN4461<br>|
| Experimental: Part A: Single dose cohort 5<br>Cohort 5 will receive a sequential ascending single IV dose of REGN4461 or matching placebo | Drug: REGN4461<br>* REGN4461<br>Drug: Placebo<br>* Placebo-matching REGN4461<br>|
| Experimental: Part A: Single dose cohort 6<br>Cohort 6 will receive a sequential ascending single SC dose of REGN4461 or matching placebo | Drug: REGN4461<br>* REGN4461<br>Drug: Placebo<br>* Placebo-matching REGN4461<br>|
| Experimental: Part A: Single dose cohort 7<br>Cohort 7 will receive a sequential ascending single IV dose of REGN4461 or matching placebo | Drug: REGN4461<br>* REGN4461<br>Drug: Placebo<br>* Placebo-matching REGN4461<br>|
| Experimental: Part A: Single dose cohort 8<br>Cohort 8 will receive a single IV dose of REGN4461 or matching placebo | Drug: REGN4461<br>* REGN4461<br>Drug: Placebo<br>* Placebo-matching REGN4461<br>|
| Experimental: Part A: Single dose cohort 9<br>Cohort 9 will receive a single IV dose of REGN4461 or matching placebo | Drug: REGN4461<br>* REGN4461<br>Drug: Placebo<br>* Placebo-matching REGN4461<br>|
| Experimental: Part B: Repeated dose cohort 10<br>Cohort 10 will receive repeated IV or SC doses of REGN4461 or matching placebo | Drug: REGN4461<br>* REGN4461<br>Drug: Placebo<br>* Placebo-matching REGN4461<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of treatment-emergent adverse events (TEAEs) |  | Up to week 27 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentrations of REGN4461 in serum over time |  | Up to week 27 | 
| Percent change from baseline to week 12 in body weight in overweight or obese participants |  | Baseline to week 12 | 
| Absolute change from baseline to week 12 in body weight in overweight or obese participants |  | Baseline to week 12 | 
| Change from baseline in caloric intake in response to standardized meals in overweight or obese participants |  | Baseline to week 12 | 
| Change in lipid-regulating protein levels over time after single doses of REGN4461 |  | Up to week 16 | 
| Change in lipid-regulating protein levels over time after repeated doses of REGN4461 |  | Up to week 27 | 
| Incidence of anti-drug antibodies to REGN4461 over time after single doses of REGN4461 |  | Up to week 16 | 
| Incidence of anti-drug antibodies to REGN4461 over time after repeated doses of REGN4461 |  | Up to week 27 | 
| Pharmacokinetic (PK) parameter: Area under curve (AUC) computed from time zero to the time of the last positive concentration (AUClast) |  | Up to week 27 | 
| PK parameter: AUC computed across a dosing interval with length τ (AUCo-τ) |  | Upt to week 27 | 
| PK parameter: peak concentration (Cmax) |  | Up to week 27 | 
| PK parameter: time to Cmax (tmax) |  | Up to week 27 | 
| PK parameter: clearance (CL) |  | Up to week 27 | 
| PK parameter: trough concentration (Ctrough) |  | Up to week 27 |