A Single and Multiple-Dose Study of MK-8521 in Healthy and Obese Males (MK-8521-002)

A Single and Multiple-Dose Clinical Trial to Study the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MK-8521 in Subjects

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02055547

Enrollment

Registered

2014-02-05

Start date

2013-05-10

Completion date

2013-09-17

Last updated

2020-07-02

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Type 2 Diabetes Mellitus

Brief summary

This study will evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of MK-8521. Part 1 primary hypothesis: Administration of single subcutaneous (SC) doses of MK-8521 is sufficiently safe and well- tolerated in healthy participants, based on assessment of clinical and laboratory adverse experiences, to permit continued clinical investigation. Part 2: Administration of multiple once daily SC doses of MK-8521 is sufficiently safe and well-tolerated in healthy lean and obese participants, based on assessment of clinical and laboratory adverse experiences, to permit continued clinical investigation.

Detailed description

This was a 3 part, randomized, single and multiple ascending-dose trial that evaluated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of MK-8521 in healthy non-obese male (Part 1-Panels A and B, Panels C, D, and E of Part 2, and Part 3 Panel H) participants between the ages of 18 and 45 years and obese male participants (Part 2, Panel F) 45 to 65 years of age. An optional Panel G in Part 2 per protocol did not occur. Part 1 was a single rising dose study to assess the safety and pharmacokinetics of single subcutaneous (SC) doses of MK-8521. Two panels of 8 healthy young non-obese male participants were dosed in up to 3 alternating dosing periods of MK-8521 or placebo (in a 6:2 ratio). Participants had a minimum 7 day washout between dosing periods. Part 2 was a multiple-rising dose study to assess the safety and pharmacokinetics of multiple SC doses of MK-8521. Three panels (C-E) of 8 healthy young non-obese male participants received daily SC doses of MK-8521 or placebo (in a 6:2 ratio) as a titration regimen for 10 consecutive days. One panel (Panel F) of 8 older obese male participants received daily SC doses of MK-8521 or placebo (in a 6:2 ratio) as a titration regimen for 14 consecutive days. Part 3 was a single dose, 3-period crossover study in 12 healthy lean male participants. Participants were randomized into 6 treatment groups and received a sequence of 3 treatments (MK-8521 at 35μg, 125μg and placebo). All participants in Part 3 received MK-8521 (high dose of 125μg and low dose of 35 μg) and placebo. There was a minimum 7 day washout between each dosing period for each individual participant.

Interventions

DRUGMK-8521 35μg

Single dose 35μg subcutaneous (SC) injection in a treatment period (Part 3, Panel H)

DRUGMK-8521 100μg

Single dose 100μg SC injection in a treatment period (Part 1, Panel A) and (Part 2, Panel D)

DRUGMK-8521 125μg

Single dose 125μg SC injection in a treatment period (Part 2, Panel E) and (Part 3, Panel H)

DRUGMK-8521 150μg

Single dose 150μg SC injection in a treatment period (Part 1, Panel B)

DRUGMK-8521 175μg

Single dose 175μg SC injection in a treatment period (Part 1, Panel B)

DRUGMK-8521 200μg

Single dose MK-8521 200μg SC injection in a treatment period (Part 1, Panel B)

DRUGMK-8521 300μg

Single dose 300μg SC injection in a treatment period (Part 1, Panel A)

DRUGMK-8521 50/72μg

MK-8521 50μg SC injection Days 1-5 and 72μg Days 6-10 (Part 2, Panel C)

DRUGMK-8521 72/125μg

MK-8521 72μg SC injection Days 1-7 and 125μg Days 8-14 (Part 2, Panel F)

DRUGMK-8521 100/150μg

MK-8521 100μg SC injection Days 1-5 and 150μg Days 6-10 SC in a treatment period (Part 2, Panel D)

DRUGMK-8521 125/150μg

MK-8521 SC 125μg SC injection Days 1-5 and 150μg Days 6-10 (Part 2, Panel E)

DRUGPlacebo

Placebo to MK-8521 SC injection in a treatment period (Parts 1, 2, and 3)

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Intervention model description

Parts 1 and 2 were parallel in design and Part 3 was crossover in design.

Eligibility

Sex/Gender

MALE

Age

18 Years to 70 Years

Healthy volunteers

Yes

Inclusion criteria

* Males of either 18 to 45 or 45 to 70 years of age depending on the component of the study * Body Mass Index between either 18-25 or 30-40 kg/m\^2 depending on the component of the study * Is in good health * Is a non-smoker and/or has not used nicotine for at least 3 months

Exclusion criteria

* Is mentally or legally incapacitated, has significant emotional problems or has a history of psychiatric disorders in the past 5 years * Has a history of the following abnormalities or diseases: endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary, or major neurological. * History of cancer * History of significant multiple or severe allergies or has had an anaphylactic reaction or significant intolerability to drugs or food * Positive for hepatitis B surface antigen, hepatitis C antibodies or human immunodeficiency virus (HIV) * Had major surgery, donated or lost 1 unit (500 mL) of blood or participated in another study within prior 4 weeks * Has irritable bowel disease or recurrent nausea, vomiting, diarrhea or abdominal pain * History of acute or chronic pancreatitis * Uses 2 weeks prior to trial, or anticipates using during trial, medications, drugs or herbal remedies such as St. John's Wort * Consumes greater than 3 glasses of alcohol per day * Consumes greater than 6 servings of caffeinated beverages per day * Regularly uses illicit drugs or has a history of drug (including alcohol) abuse within prior 3 months * Has known hypersensitivity to glucagon or any glucagon like peptide 1 (GLP-1) receptor agonist * Is unwilling/unable to consume standardized meals and/or is on a carbohydrate restricted diet * Has history of hypersensitivity to pharmacologic insulins

Design outcomes

Primary

Measure	Time frame	Description
Average Concentration (Cave) of MK-8521 Corresponding to Slope of Insulin Secretion Rate/Glucose (ISR/G) During Graded Glucose Infusion (GGI) at Tmax After a Single Dose of MK-8521 (Part 3)	From -10 to 160 minutes after GGI on Day 1 (Part 3)	Pancreatic beta cell sensitivity to ambient glucose concentration after a single dose of MK-8521 125μg/35μg or placebo at Tmax was quantified as the slope of insulin secretion rate relative to glucose concentration (ISR/G) during GGI (160 minutes duration) and assessed against MK-8521 average plasma concentration (Cave) during the GGI to preliminarily characterize the PK/ pharmacodynamic (PD) relationship. Study drug was administered on Day -1. Plasma concentrations of MK-8521 were determined at -10 min pre-GGI and 40, 80, 120 & 160 min and blood concentrations of glucose, insulin & C-peptide were determined at -10, -5 (pre-GGI), 20, 40, 60, 80, 100, 120, 140 & 160 minutes after start of GGI on Day 1 of each period. ISR calculated by deconvolution of C-peptide concentrations using a two-compartmental model was regressed on glucose concentration via simple linear regression; beta cell glucose sensitivity was defined as slope from the regression line.
Area Under the Concentration Time Curve of MK-8521 From 0 to Infinity (AUC0-∞) After a Single Dose (Part 1)	Pre-dose, 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24, 30, 34, 48, 72, 96, 120 hrs. post-dose (Part 1)	AUC0-∞ is a measure of the mean concentration levels of drug in the plasma after the dose. A summary of pharmacokinetic parameters following administration of single SC (subcutaneous) injection of MK-8521 in healthy non-obese male participants (Part I, Panels A-B, Period 1-3 \[100-300μg\]) is presented. Method of dispersion is coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo.
Peak Plasma Concentration (Cmax) of Participants Treated With a Single Dose of MK-8521 (Part 1)	Pre-dose, 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24, 30, 34, 48, 72, 96, 120 hrs. post-dose (Part 1)	Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. A summary of pharmacokinetic parameters following administration of single SC (subcutaneous) injection of MK-8521 in healthy non-obese male participants (Part I, Panels A-B, Period 1-3 \[100-300μg\]) is presented. Method of dispersion is coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo.
Time Taken to Reach Cmax (Tmax) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 1)	Pre-dose, 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24, 30, 34, 48, 72, 96, 120 hrs. post-dose (Part 1)	Tmax is a measure of the time to reach the maximum concentration in the plasma after the drug dose. A summary of pharmacokinetic parameters following administration of single SC (subcutaneous) injection of MK-8521 in healthy non-obese male participants (Part I, Panels A-B, Period 1-3 \[100-300μg\]) is presented. No pharmacokinetic analysis was performed on participants receiving Placebo.
Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 1)	Pre-dose, 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24, 30, 34, 48, 72, 96, 120 hrs. post-dose (Part 1)	Apparent Terminal Half-life (t1/2) is the time required for a given drug concentration in the plasma to decrease by 50%. A summary of pharmacokinetic parameters following administration of single SC (subcutaneous) injection of MK-8521 in healthy non-obese male participants (Part I, Panels A-B, Period 1-3 \[100-300μg\]) is presented. Method of dispersion is coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo.
Number of Participants With an Adverse Event (AE) (Part 2)	From Day 1 through post-trial visit (Up to 7 weeks)	An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.
Number of Participants Who Discontinued Treatment Due to an AE (Part 2)	Up to 7 weeks (Part 2)	An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.
AUC 0-24hr for Plasma Concentration of Participants Treated After Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Days 1, 5 and 10 (Part 2) (Panels C, D, E)	AUC0-24hr is a measure of the mean concentration levels of drug in the plasma 0 to 24 hrs. after the dose. Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 10 Days (with dose escalation on Day 5) to healthy non-obese male participants (Part II, Panel C, D, and E) are presented. Method of dispersion coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo. Blood collections for the determination of plasma MK-8521 concentrations were collected at the following time points for Part 2, Panel C, D, and E: Days 1, 4, 5, 9, 10 pre-dose; Days 1, 5, 10: 2, 4, 8, 10, 12, 16, 24 hrs. post dose; Day 10: 72, 96, 120 hrs. post-dose.
AUC 0-24hr for Plasma Concentration of Participants Treated After Multiple Doses of MK-8521 (Part 2, Panel F)	Days 1, 7 and 14 (Part 2) (Panel F)	AUC0-24hr is a measure of the mean concentration levels of drug in the plasma 0 to 24 hrs. after the dose. Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 14 Days (with dose escalation on Day 7) to obese male participants (Part 2, Panel F) are presented. Method of dispersion coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo. Blood collections for the determination of plasma MK-8521 concentrations were collected at the following time points for Part 2, Panel F: Days 1, 3, 4, 5, 7, 9, 11, 13, 14 pre-dose; Days 1, 7, 14: 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24 hrs. post-dose; Day 14: 72, 96, 120 hrs. post-dose.
Cmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Days 1, 5 and 10 (Part 2) (Panels C, D, E)	Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 10 Days (with dose escalation on Day 5) to healthy non-obese male participants (Part 2, Panel C, D, E and F) are presented. Method of dispersion is coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo. Blood collections for the determination of plasma MK-8521 concentrations were collected at the following time points for Part 2, Panel C-E: Days 1, 4, 5, 9, 10 pre-dose; Days 1, 5, 10: 2, 4, 8, 10, 12, 16, 24 hrs. post dose; Day 10: 72, 96, 120 hrs. post-dose.
Cmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Days 1, 7 and 14 (Part 2) (Panel F)	AUC0-24hr is a measure of the mean concentration levels of drug in the plasma 0 to 24 hrs. after the dose. Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 14 Days (with dose escalation on Day 7) to obese male participants (Part 2, Panel F) are presented. Method of dispersion coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo. Blood collections for the determination of plasma MK-8521 concentrations were collected at the following time points for Part 2, Panel F: Days 1, 3, 4, 5, 7, 9, 11, 13, 14 pre-dose; Days 1, 7, 14: 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24 hrs. post-dose; Day 14: 72, 96, 120 hrs. post-dose.
Trough Plasma Concentration (Ctrough) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Days 1, 5 and 10 (Part 2) (Panels C, D, E)	Trough plasma concentration (measured concentration at the end of a dosing interval at steady state \[taken directly before next administration\]). Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 10 Days (with dose escalation on Day 5) to healthy non-obese male participants (Part 2, Panel C, D, and E) are presented. Method of dispersion is coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo. Blood collections for the determination of plasma MK-8521 concentrations were collected for Part 2, Panel C, D, and E: Days 1, 4, 5, 9, 10 pre-dose; Days 1, 5, 10: 2, 4, 8, 10, 12, 16, 24 hrs. post dose; Day 10: 72, 96, 120 hrs. post-dose.
Trough Plasma Concentration (Ctrough) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Days 1, 7 and 14 (Part 2) (Panel F)	Trough plasma concentration (measured concentration at the end of a dosing interval at steady state \[taken directly before next administration\]). Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 14 Days (with dose escalation on Day 7) to obese male participants (Part 2, Panel F) are presented. Method of dispersion is coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo. Blood collections for the determination of plasma MK-8521 concentrations were collected at the following time points for Part 2, Panel F: Days 1, 3, 4, 5, 7, 9, 11, 13, 14 pre-dose; Days 1, 7, 14: 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24 hrs. post-dose; Day 14: 72, 96, 120 hrs. post-dose.
Tmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Days 1, 5 and 10 (Part 2) (Panels C, D, E)	Tmax is a measure of the time to reach the maximum concentration in the plasma after the drug dose. Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 10 Days (with dose escalation on Day 5) to healthy non-obese male participants (Part 2, Panel C, D, and E) are presented. Method of dispersion is coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo. Blood collections for the determination of plasma MK-8521 concentrations were collected at the following time points for Part 2, Panel C, D, and E: Days 1, 4, 5, 9, 10 pre-dose; Days 1, 5, 10: 2, 4, 8, 10, 12, 16, 24 hrs. post dose; Day 10: 72, 96, 120 hrs. post-dose.
Tmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Days 1, 7 and 14 (Part 2) (Panel F)	Tmax is a measure of the time to reach the maximum concentration in the plasma after the drug dose. Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 14 Days (with dose escalation on Day 7) to obese male participants (Part 2, Panel F) are presented. Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 14 Days (with dose escalation on Day 7) to obese male participants (Part 2, Panel F) are presented. Method of dispersion is coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo. Blood collections occurred at the following time points for Part 2, Panel F: Days 1, 3, 4, 5, 7, 9, 11, 13, 14 pre-dose; Days 1, 7, 14: 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24 hrs. post-dose; Day 14: 72, 96, 120 hrs. post-dose.
Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part C, D, and E)	Days 1, 5 and 10 (Part 2) (Panels C, D, E)	Apparent Terminal Half-life (t1/2) is the time required for a given drug concentration in the plasma to decrease by 50%. Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 10 Days (with dose escalation on Day 5) to healthy non-obese male participants (Part 2, Panel C, D, and E) are presented. Method of dispersion is coefficient of variation (%CV). Apparent terminal t1/2 was not reported for certain days since the terminal phase was not adequately captured with sampling up to 24hr post dose. No pharmacokinetic analysis was performed on participants receiving Placebo. Blood was collected for Part 2, Panel C, D, and E: Days 1, 4, 5, 9, 10 pre-dose; Days 1, 5, 10: 2, 4, 8, 10, 12, 16, 24 hrs. post dose; Day 10: 72, 96, 120 hrs. post-dose.
Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part F)	Days 1, 7 and 14 (Part 2) (Panel F)	Apparent Terminal Half-life (t1/2) is the time required for a given drug concentration in the plasma to decrease by 50%. Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 14 Days (with dose escalation on Day 7) to obese male participants (Part 2, Panel F) are presented. Method of dispersion is coefficient of variation (%CV). Apparent terminal t1/2 was not reported for certain days since the terminal phase was not adequately captured with sampling up to 24hr post dose. No pharmacokinetic analysis was performed on participants receiving Placebo. Blood collections occurred at the following time points for Part 2, Panel F: Days 1, 3, 4, 5, 7, 9, 11, 13, 14 pre-dose; Days 1, 7, 14: 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24 hrs. post-dose; Day 14: 72, 96, 120 hrs. post-dose.
Number of Participants With an Adverse Event (AE) (Part 3)	Up to 6 weeks (Part 3)	An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.
Number of Participants Who Discontinued Treatment Due to an AE (Part 3)	Up to 6 weeks (Part 3)	An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.
Number of Participants Who Experienced at Least One Adverse Event (AE) (Part 1)	From Day 1 through post-trial visit (Up to 8 weeks)	An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.
Number of Participants Who Discontinued Treatment Due to an AE (Part 1)	Up to 8 weeks (Part 1)	An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.

Secondary

Measure	Time frame	Description
Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)	Baseline (predose), up to 24 hours post-dose on Day 1, up to 24 hours post-dose on Day 2 (Part 1)	Systolic blood pressure was assessed on Day 1 (predose and 1, 4, 8, 12, 16 and 24 hrs. postdose) and Day 2 (36 and 48 hrs. postdose). Predose and postdose SBP were assessed using triplicate and duplicate measurements, respectively. The repeated measurements were averaged before conducting the statistical analysis. TWA0-24hr. of SBP on Day 1 and Day 2 of MK-8521 single dosing was calculated as the area under the measurement-time curve divided by the time period of over which the measurements were made (i.e., 24 hrs.). The change from baseline TWA0-24hr SBP was calculated for each participant where baseline was defined as predose baseline on Day 1.
Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)	Baseline (predose), up to 24 hours post-dose on Day 1, up to 24 hours post-dose on Day 2 (Part 1)	Diastolic blood pressure was assessed on Day 1 (predose and 1, 4, 8, 12, 16 & 24 hrs postdose) and Day 2 (36 and 48 hrs postdose). Predose and postdose DBP were assessed using triplicate and duplicate measurements, respectively. The repeated measurements were averaged before conducting the statistical analysis. TWA0-24hr of DBP on Day 1 and Day 2 of MK-8521 single dosing was calculated as the area under the measurement-time curve divided by the time period of over which the measurements were made (i.e., 24 hrs.). The change from baseline TWA0-24hr DBP was calculated for each participant where baseline was defined as predose baseline on Day 1.
Change From Baseline in TWA 0-24 Hrs. Heart Rate (HR) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel C, D, and E)	Baseline (predose; up to 16 hrs on Day -1), predose & up to 24 hours postdose on Days 1, 6, and 10	Heart rate was assessed on Day -1 (at 2, 4, 6, 8, 12, and 16 hrs post admission), Day 1 and Day 6 (predose and 2, 4, 6, 8, 12, 16, 24, 36 and 48 hrs postdose) and Day 10 (predose & 2, 4, 6, 8, 12, 16, and 24 hrs. postdose). Predose HR on Day 1 was assessed using triplicate measurements while Day -1, Day 1 (postdose), Day 6, and Day 10 HR were assessed using duplicate measurements. The repeated measurements were averaged before conducting the statistical analysis. TWA0-24hr of HR on Day 1, Day 6, and Day 10 of MK-8521 multiple dose treatment was calculated as the area under the measurement-time curve divided by the time period of over which the measurements were made (i.e., 24 hrs). The change from baseline TWA0-24hr HR was calculated for each participant using TWA0-24hr on Day -1 as the baseline.
Change From Baseline in TWA 0-24 Hrs. Heart Rate (HR) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Baseline (predose; up to 16 hrs on Day -1), predose & up to 24 hours postdose on Days 1, 8, and 14	Heart rate was assessed on Day -1 (at 2, 4, 6, 8, 12, and 16 hrs post admission), Day 1 & Day 8 (predose and 2, 4, 6, 8, 12, 16, 24, 36, and 48 hrs. post dose) & Day 14 (predose and 2, 4, 6, 8, 12, 16, and 24 hrs. postdose). Predose HR on Day 1 was assessed using triplicate measurements while Day -1, Day 1 (postdose), Day 8, and Day 14 HR were assessed as duplicate measurements. The repeated measurements were averaged before conducting the statistical analysis. TWA0-24hr of HR on Day 1, Day 8, and Day 14 of MK-8521 multiple dose treatment was calculated as the area under the measurement-time curve divided by the time period of over which the measurements were made (i.e., 24 hrs.). The change from baseline TWA0-24hr. HR was calculated for each participant using TWA0-24hr. on Day -1 as the baseline.
Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Baseline (predose; up to 16 hrs on Day -1), predose & up to 24 hours postdose on Days 1, 6, and 10	Systolic blood pressure was assessed on Day -1 (at 2, 4, 6, 8, 12, and 16 hrs. post admission), Day 1 and Day 6 (predose & 2, 4, 6, 8, 12, 16, 24, 36, and 48 hrs. postdose) and Day 10 (predose & 2, 4, 6, 8, 12, 16, and 24 hrs. postdose). Predose SBP on Day 1 was assessed using triplicate measurements while Day -1, Day 1 (postdose), Day 6, and Day 10 SBP were assessed using duplicate measurements. The repeated measurements were averaged before conducting the statistical analysis. TWA0-24hr SBP on Day 1, Day 6 and Day 10 of MK-8521 multiple dose treatment was calculated as the area under the measurement-time curve divided by the time period of over which the measurements were made (i.e., 24 hrs). The change from baseline TWA0-24hr SBP was calculated for each participant using TWA0-24hr on Day -1 as the baseline.
Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Baseline (predose; up to 16 hrs on Day -1), up to 16 hrs on Day -1, predose & up to 24 hours postdose on Days 1, 8, and 14	Systolic blood pressure was assessed on Day -1 (at 2, 4, 6, 8, 12, and 16 hrs. post admission), Day 1 and Day 8 (predose and 2, 4, 6, 8, 12, 16, 24, 36, and 48 hrs. post dose) and Day 14 (predose and 2, 4, 6, 8, 12, 16, and 24 hrs. postdose). Predose SBP on Day 1 was assessed using triplicate measurements while Day -1, Day 1 (postdose), Day 8, and Day 14 SBP were assessed as duplicate measurements. The repeated measurements were averaged before conducting the statistical analysis. TWA0-24hr of SBP on Day 1, Day 8, and Day 14 of MK-8521 multiple dose treatment was calculated as the area under the measurement-time curve divided by the time period of over which the measurements were made (i.e., 24 hrs.). The change from baseline TWA0-24hr SBP was calculated for each participant using TWA0-24hr on Day -1 as the baseline.
Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part C, D, and E)	Baseline (predose; up to 16 hrs on Day -1), predose & up to 24 hours postdose on Days 1, 6, and 10	Diastolic blood pressure was assessed on Day -1 (at 2, 4, 6, 8, 12, and 16 hrs. post admission), Day 1 and Day 6 (predose and 2, 4, 6, 8, 12, 16, 24, 36 and 48 hrs. postdose) and Day 10 (predose and 2, 4, 6, 8, 12, 16, and 24 hrs. postdose). Predose DBP on Day 1 was assessed using triplicate measurements while Day -1, Day 1 (postdose), Day 6, and Day 10 DBP were assessed using duplicate measurements. The repeated measurements were averaged before conducting the statistical analysis. TWA0-24hr. DBP on Day 1, Day 6, and Day 10 of MK-8521 multiple dose treatment was calculated as the area under the measurement-time curve divided by the time period of over which the measurements were made (i.e., 24 hrs.). The change from baseline TWA0-24hr DBP was calculated for each participant using TWA0-24hr. on Day -1 as the baseline.
Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Baseline (predose; up to 16 hrs on Day -1), predose & up to 24 hours postdose on Days 1, 8, and 14	Diastolic blood pressure was assessed on Day -1 (at 2, 4, 6, 8, 12, and 16 hrs. post admission), Day 1 and Day 8 (predose and 2, 4, 6, 8, 12, 16, 24, 36, and 48 hrs. post dose) and Day 14 (predose and 2, 4, 6, 8, 12, 16, and 24 hrs. postdose). Predose DBP on Day 1 was assessed using triplicate measurements while Day -1, Day 1 (postdose), Day 8, and Day 14 DBP were assessed as duplicate measurements. The repeated measurements were averaged before conducting the statistical analysis. TWA0-24hr of DBP on Day 1, Day 8, Day 14 of MK-8521 multiple dose treatment was calculated as the area under the measurement-time curve divided by the time period of over which the measurements were made (i.e., 24 hrs). The change from baseline TWA0-24hr. DBP was calculated for each participant using TWA0-24hr. on Day -1 as the baseline.
Slope of Insulin Secretion Rate/Glucose (ISR/G) During Graded Glucose Infusion (GGI) at Tmax After a Single Dose of MK-8521 (Part 3)	From -10 to 160 minutes after GGI on Day 1	Pancreatic beta cell sensitivity to ambient glucose concentration after a single dose of MK-8521 125μg/35μg or placebo at Tmax was quantified as the slope of insulin secretion rate relative to glucose concentration (ISR/G) during GGI (160 minutes duration). Study drug was administered on Day -1 and blood concentrations of glucose, insulin & C-peptide were determined at -10, -5 (pre-GGI), 20, 40, 60, 80, 100, 120, 140, and 160 minutes after start of GGI on Day 1 of each period. ISR calculated by deconvolution of C-peptide concentrations using a two compartmental model was regressed on glucose concentration via simple linear regression; beta cell glucose sensitivity was defined as slope from the regression line.
Ratio of ISR/G at the Highest Glucose Infusion Rate During GGI Due to Treatment With A Single Dose of MK-8521 (Part 3)	From -10 to 160 minutes after GGI on Day 1	Pancreatic beta cell sensitivity to ambient glucose concentration after a single dose of MK-8521 125μg/35μg or placebo at Tmax was quantified as the ratio of the insulin secretion rate to glucose (ISR/G) at the highest glucose infusion rate during GGI (i.e., time weighted average between 120 to 160 minutes \[TWA120-160min\] of ratio \[ISR/G\]). Study drug was administered on Day -1 and blood concentrations of glucose, insulin, and C-peptide were determined at -10, -5 (pre-GGI), 20, 40, 60, 80, 100, 120, 140, and 160 minutes after start of GGI on Day 1 of each period.
Glucose (TWA0-160min) During GGI at Tmax After a Single Dose of MK-8521 (Part 3)	From -10 to 160 minutes after GGI on Day 1	Glycemic effect during GGI after administration of a single dose of MK 8521 125mcg/35mcg or placebo at Tmax was evaluated as the time-weighted average of glucose concentration throughout the 160 minutes (TWA0-160min) of the GGI. Study drug was administered on Day -1 and blood glucose concentrations were determined at -10, -5 (pre GGI), 20, 40, 60, 80, 100, 120, 140, 160 minutes after start of GGI on Day 1 of each period. The parameter glucose (TWA0-160min) reflects ambient glucose concentration during the GGI.
Maximum Glycemic Excursion (Gmax) During GGI and Tmax After a Single Dose of MK-8521 (Part 3)	From -10 to 160 minutes after GGI on Day 1	Glycemic effect during GGI after administration of a single dose of MK-8521 125μg/35μg or placebo at Tmax was evaluated as the Gmax during the GGI. Study drug was administered on Day -1 and blood glucose concentrations were determined at -10, -5 (pre-GGI), 20, 40, 60, 80, 100, 120, 140, and 160 minutes after start of GGI on Day 1 of each period. The parameter Gmax reflects ambient glucose concentration during the GGI.
Area Under the Curve (AUC) 0-∞ for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 3)	Day 1: predose, -60, -10 min pre-GGI, 40 min, 80 min, 120 min, 160 min, 360 min, and 600 min after start of GGI (Part 3)	AUC0-∞ is a measure of the mean concentration levels of drug in the plasma after the dose. A summary of pharmacokinetic parameters following administration of single SC (subcutaneous) injection of MK-8521 in healthy non-obese male participants (Part III \[35 and 125 μg\]) is presented. Method of dispersion is actually Coefficient of Variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo. No pharmacokinetic data was available for AUC0-∞ for Part 3 due to sparse issues during the treatment period.
Area Under the Curve (AUC) 0-24hr. for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 3)	Day 1: predose, -60, -10 min pre-GGI, 40 min, 80 min, 120 min, 160 min, 360 min, and 600 min after start of GGI (Part 3)	AUC0-24hr is a measure of the mean concentration levels of drug in the plasma 0 to 24 hrs. after the dose. Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 10 Days (with dose escalation on Day 5) to healthy non-obese male participants (Part II, Panel C, D, and E) are presented. Method of dispersion coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo. No pharmacokinetic data was available for AUC0-24hr. for Part 3 due to sampling issues during the treatment period.
Peak Plasma Concentration (Cmax) of Participants Treated With a Single Dose of MK-8521 (Part 3)	Day 1: predose, -60, -10 min pre-GGI, 40 min, 80 min, 120 min, 160 min, 360 min, and 600 min after start of GGI (Part 3)	Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. A summary of pharmacokinetic parameters following administration of single SC (subcutaneous) injection of MK-8521 in healthy non-obese male participants (Part III \[35 and 125 μg\]) is presented. Method of dispersion is actually Coefficient of Variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo.
Time Taken to Reach Cmax (Tmax) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 3)	Day 1: predose, -60, -10 min pre-GGI, 40 min, 80 min, 120 min, 160 min, 360 min, and 600 min after start of GGI (Part 3)	Tmax is a measure of the time to reach the maximum concentration in the plasma after the drug dose. A summary of pharmacokinetic parameters following administration of single SC (subcutaneous) injection of MK-8521 in healthy non-obese male participants (Part III \[35 and 125 μg\]) is presented. No pharmacokinetic analysis was performed on participants receiving Placebo.
Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 3)	Day 1: predose, -60, -10 min pre-GGI, 40 min, 80 min, 120 min, 160 min, 360 min, and 600 min after start of GGI(Part 3)	Apparent Terminal Half-life (t1/2) is the time required for a given drug concentration in the plasma to decrease by 50%. A summary of pharmacokinetic parameters following administration of single SC (subcutaneous) injection of MK-8521 in healthy non-obese male participants (Part III \[35 and 125 μg\]) is presented. Method of dispersion is actually Coefficient of Variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo. No pharmacokinetic data was available for t1/2 for Part 3 due to sampling issues during the treatment period.
Change From Baseline in Time-weighted Average From 0 to 24 Hrs (TWA0-24hr) of Heart Rate (HR) After a Single Dose of MK-8521 (Part 1)	Baseline (predose), up to 24 hours post-dose on Day 1, up to 24 hours post-dose on Day 2 (Part 1)	Heart rate was assessed on Day 1 (predose & 1, 4, 8, 12, 16 & 24 hrs. postdose) & Day 2 (36 & 48 hrs. postdose). Predose and postdose HR were assessed using triplicate and duplicate measurements, respectively. The repeated measurements were averaged before conducting the statistical analysis. TWA0-24hr of HR on Day 1 & Day 2 of MK-8521 single dosing was calculated as the area under the measurement-time curve divided by the time period of over which the measurements were made (i.e., 24 hrs.). The change from baseline TWA0-24hr HR was calculated for each participant where baseline was defined as predose baseline on Day 1.

Participant flow

Recruitment details

Participants were recruited at one clinical site in Belgium.

Pre-assignment details

An optional Panel G in Part 2 per protocol did not occur. Period-level data were not collected for each treatment sequence.

Participants by arm

Arm	Count
Part 1 - 3, Panel A, B, C, D, E, F, and H All participants who received a dose of MK-8521 or placebo in any study period.	61
Total	61

Withdrawals & dropouts

Period	Reason	FG001	FG002	FG004	FG005	FG006	FG008	FG009	FG010	FG013	FG015
Overall Study	Adverse Event	0	0	0	0	1	1	0	0	0	0
Overall Study	Lost to Follow-up	0	1	0	0	0	0	0	0	0	0
Overall Study	Physician Decision	1	1	1	0	0	0	1	1	0	0
Overall Study	Protocol Violation	0	1	0	0	1	0	0	0	0	0
Overall Study	Withdrawal by Subject	0	0	0	1	0	1	0	0	1	1

Baseline characteristics

Characteristic	Part 1 - 3, Panel A, B, C, D, E, F, and H
Age, Continuous	33.5 Years STANDARD_DEVIATION 11.6
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	61 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	0 Participants
Race (NIH/OMB) Black or African American	1 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	60 Participants
Sex: Female, Male Female	0 Participants
Sex: Female, Male Male	61 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk	EG006 affected / at risk	EG007 affected / at risk	EG008 affected / at risk	EG009 affected / at risk	EG010 affected / at risk	EG011 affected / at risk
deaths Total, all-cause mortality	0 / 7	0 / 5	0 / 6	0 / 3	0 / 5	0 / 6	0 / 6	0 / 6	0 / 6	0 / 11	0 / 12	0 / 29
other Total, other adverse events	3 / 7	4 / 5	2 / 6	0 / 3	5 / 5	5 / 6	5 / 6	5 / 6	4 / 6	5 / 11	8 / 12	16 / 29
serious Total, serious adverse events	0 / 7	0 / 5	0 / 6	0 / 3	0 / 5	0 / 6	0 / 6	0 / 6	0 / 6	0 / 11	0 / 12	0 / 29

Outcome results

Primary

Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 1)

Apparent Terminal Half-life (t1/2) is the time required for a given drug concentration in the plasma to decrease by 50%. A summary of pharmacokinetic parameters following administration of single SC (subcutaneous) injection of MK-8521 in healthy non-obese male participants (Part I, Panels A-B, Period 1-3 \[100-300μg\]) is presented. Method of dispersion is coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo.

Time frame: Pre-dose, 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24, 30, 34, 48, 72, 96, 120 hrs. post-dose (Part 1)

Population: The analysis population included a subset of participants in Part 1 who complied with the protocol sufficiently to ensure that their data exhibited the effects of treatment, according to the underlying scientific model. Compliance included exposure to treatment, availability of measurements, and absence of major protocol violations.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Part 1 Panel A MK-8521 100μg	Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 1)	13.8 Hours	Geometric Coefficient of Variation 15.5
Part 1 Panel A MK-8521 300μg	Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 1)	13.7 Hours	Geometric Coefficient of Variation 8.93
Part 1 Panel B MK-8521 150μg	Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 1)	14.8 Hours	Geometric Coefficient of Variation 6.45
Part 1 Panel B MK-8521 175μg	Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 1)	14.1 Hours	Geometric Coefficient of Variation 2.64
Part 1 Panel B MK-8521 200μg	Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 1)	13.8 Hours	Geometric Coefficient of Variation 12.9

Primary

Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part C, D, and E)

Apparent Terminal Half-life (t1/2) is the time required for a given drug concentration in the plasma to decrease by 50%. Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 10 Days (with dose escalation on Day 5) to healthy non-obese male participants (Part 2, Panel C, D, and E) are presented. Method of dispersion is coefficient of variation (%CV). Apparent terminal t1/2 was not reported for certain days since the terminal phase was not adequately captured with sampling up to 24hr post dose. No pharmacokinetic analysis was performed on participants receiving Placebo. Blood was collected for Part 2, Panel C, D, and E: Days 1, 4, 5, 9, 10 pre-dose; Days 1, 5, 10: 2, 4, 8, 10, 12, 16, 24 hrs. post dose; Day 10: 72, 96, 120 hrs. post-dose.

Time frame: Days 1, 5 and 10 (Part 2) (Panels C, D, E)

Population: The analysis population included a subset of participants in Part 2 (Panels C, D, and E) who complied with the protocol sufficiently to ensure that their data exhibited the effects of treatment. Compliance included exposure to treatment, availability of measurements, and absence of major protocol violations.

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
Part 1 Panel A MK-8521 100μg	Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part C, D, and E)	Day 10	14.7 Hours	Geometric Coefficient of Variation 17.7
Part 1 Panel A MK-8521 300μg	Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part C, D, and E)	Day 10	15.9 Hours	Geometric Coefficient of Variation 10.9
Part 1 Panel B MK-8521 150μg	Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part C, D, and E)	Day 10	15.5 Hours	Geometric Coefficient of Variation 12.5
Unknown	Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part C, D, and E)	Day 1	— Hours	—
Unknown	Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part C, D, and E)	Day 5	— Hours	—

Primary

Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part F)

Apparent Terminal Half-life (t1/2) is the time required for a given drug concentration in the plasma to decrease by 50%. Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 14 Days (with dose escalation on Day 7) to obese male participants (Part 2, Panel F) are presented. Method of dispersion is coefficient of variation (%CV). Apparent terminal t1/2 was not reported for certain days since the terminal phase was not adequately captured with sampling up to 24hr post dose. No pharmacokinetic analysis was performed on participants receiving Placebo. Blood collections occurred at the following time points for Part 2, Panel F: Days 1, 3, 4, 5, 7, 9, 11, 13, 14 pre-dose; Days 1, 7, 14: 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24 hrs. post-dose; Day 14: 72, 96, 120 hrs. post-dose.

Time frame: Days 1, 7 and 14 (Part 2) (Panel F)

Population: The analysis population included a subset of participants in Part 2 (Panels F) who complied with the protocol sufficiently to ensure that their data exhibited the effects of treatment. Compliance included exposure to treatment, availability of measurements, and absence of major protocol violations.

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
Part 1 Panel A MK-8521 100μg	Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part F)	Day 14	16.2 Hours	Geometric Coefficient of Variation 8.4
Unknown	Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part F)	Day 1	— Hours	—
Unknown	Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part F)	Day 7	— Hours	—

Primary

Area Under the Concentration Time Curve of MK-8521 From 0 to Infinity (AUC0-∞) After a Single Dose (Part 1)

AUC0-∞ is a measure of the mean concentration levels of drug in the plasma after the dose. A summary of pharmacokinetic parameters following administration of single SC (subcutaneous) injection of MK-8521 in healthy non-obese male participants (Part I, Panels A-B, Period 1-3 \[100-300μg\]) is presented. Method of dispersion is coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo.

Time frame: Pre-dose, 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24, 30, 34, 48, 72, 96, 120 hrs. post-dose (Part 1)

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Part 1 Panel A MK-8521 100μg	Area Under the Concentration Time Curve of MK-8521 From 0 to Infinity (AUC0-∞) After a Single Dose (Part 1)	48.7 nM•hr	Geometric Coefficient of Variation 16.4
Part 1 Panel A MK-8521 300μg	Area Under the Concentration Time Curve of MK-8521 From 0 to Infinity (AUC0-∞) After a Single Dose (Part 1)	163 nM•hr	Geometric Coefficient of Variation 6.37
Part 1 Panel B MK-8521 150μg	Area Under the Concentration Time Curve of MK-8521 From 0 to Infinity (AUC0-∞) After a Single Dose (Part 1)	84.4 nM•hr	Geometric Coefficient of Variation 20.3
Part 1 Panel B MK-8521 175μg	Area Under the Concentration Time Curve of MK-8521 From 0 to Infinity (AUC0-∞) After a Single Dose (Part 1)	101 nM•hr	Geometric Coefficient of Variation 6.07
Part 1 Panel B MK-8521 200μg	Area Under the Concentration Time Curve of MK-8521 From 0 to Infinity (AUC0-∞) After a Single Dose (Part 1)	109 nM•hr	Geometric Coefficient of Variation 25.7

Primary

AUC 0-24hr for Plasma Concentration of Participants Treated After Multiple Doses of MK-8521 (Part 2, Panel F)

AUC0-24hr is a measure of the mean concentration levels of drug in the plasma 0 to 24 hrs. after the dose. Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 14 Days (with dose escalation on Day 7) to obese male participants (Part 2, Panel F) are presented. Method of dispersion coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo. Blood collections for the determination of plasma MK-8521 concentrations were collected at the following time points for Part 2, Panel F: Days 1, 3, 4, 5, 7, 9, 11, 13, 14 pre-dose; Days 1, 7, 14: 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24 hrs. post-dose; Day 14: 72, 96, 120 hrs. post-dose.

Time frame: Days 1, 7 and 14 (Part 2) (Panel F)

Population: The analysis population included a subset of participants in Part 2 (Panel F) who complied with the protocol sufficiently to ensure that their data exhibited the effects of treatment. Compliance included exposure to treatment, availability of measurements, and absence of major protocol violations.

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
Part 1 Panel A MK-8521 100μg	AUC 0-24hr for Plasma Concentration of Participants Treated After Multiple Doses of MK-8521 (Part 2, Panel F)	Day 1	8.85 nM•hr	Geometric Coefficient of Variation 22.1
Part 1 Panel A MK-8521 100μg	AUC 0-24hr for Plasma Concentration of Participants Treated After Multiple Doses of MK-8521 (Part 2, Panel F)	Day 7	24.8 nM•hr	Geometric Coefficient of Variation 21.6
Part 1 Panel A MK-8521 100μg	AUC 0-24hr for Plasma Concentration of Participants Treated After Multiple Doses of MK-8521 (Part 2, Panel F)	Day 14	54.6 nM•hr	Geometric Coefficient of Variation 17.9

Primary

AUC 0-24hr for Plasma Concentration of Participants Treated After Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)

AUC0-24hr is a measure of the mean concentration levels of drug in the plasma 0 to 24 hrs. after the dose. Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 10 Days (with dose escalation on Day 5) to healthy non-obese male participants (Part II, Panel C, D, and E) are presented. Method of dispersion coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo. Blood collections for the determination of plasma MK-8521 concentrations were collected at the following time points for Part 2, Panel C, D, and E: Days 1, 4, 5, 9, 10 pre-dose; Days 1, 5, 10: 2, 4, 8, 10, 12, 16, 24 hrs. post dose; Day 10: 72, 96, 120 hrs. post-dose.

Time frame: Days 1, 5 and 10 (Part 2) (Panels C, D, E)

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
Part 1 Panel A MK-8521 100μg	AUC 0-24hr for Plasma Concentration of Participants Treated After Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 5	22.8 nM•hr	Geometric Coefficient of Variation 20.7
Part 1 Panel A MK-8521 100μg	AUC 0-24hr for Plasma Concentration of Participants Treated After Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 1	12.0 nM•hr	Geometric Coefficient of Variation 21.3
Part 1 Panel A MK-8521 100μg	AUC 0-24hr for Plasma Concentration of Participants Treated After Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 10	35.1 nM•hr	Geometric Coefficient of Variation 19
Part 1 Panel A MK-8521 300μg	AUC 0-24hr for Plasma Concentration of Participants Treated After Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 5	43.3 nM•hr	Geometric Coefficient of Variation 23.6
Part 1 Panel A MK-8521 300μg	AUC 0-24hr for Plasma Concentration of Participants Treated After Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 1	23.1 nM•hr	Geometric Coefficient of Variation 18.9
Part 1 Panel A MK-8521 300μg	AUC 0-24hr for Plasma Concentration of Participants Treated After Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 10	86.8 nM•hr	Geometric Coefficient of Variation 34.4
Part 1 Panel B MK-8521 150μg	AUC 0-24hr for Plasma Concentration of Participants Treated After Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 1	33.5 nM•hr	Geometric Coefficient of Variation 16.4
Part 1 Panel B MK-8521 150μg	AUC 0-24hr for Plasma Concentration of Participants Treated After Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 10	77.8 nM•hr	Geometric Coefficient of Variation 15
Part 1 Panel B MK-8521 150μg	AUC 0-24hr for Plasma Concentration of Participants Treated After Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 5	60.7 nM•hr	Geometric Coefficient of Variation 19.8

Primary

Average Concentration (Cave) of MK-8521 Corresponding to Slope of Insulin Secretion Rate/Glucose (ISR/G) During Graded Glucose Infusion (GGI) at Tmax After a Single Dose of MK-8521 (Part 3)

Pancreatic beta cell sensitivity to ambient glucose concentration after a single dose of MK-8521 125μg/35μg or placebo at Tmax was quantified as the slope of insulin secretion rate relative to glucose concentration (ISR/G) during GGI (160 minutes duration) and assessed against MK-8521 average plasma concentration (Cave) during the GGI to preliminarily characterize the PK/ pharmacodynamic (PD) relationship. Study drug was administered on Day -1. Plasma concentrations of MK-8521 were determined at -10 min pre-GGI and 40, 80, 120 & 160 min and blood concentrations of glucose, insulin & C-peptide were determined at -10, -5 (pre-GGI), 20, 40, 60, 80, 100, 120, 140 & 160 minutes after start of GGI on Day 1 of each period. ISR calculated by deconvolution of C-peptide concentrations using a two-compartmental model was regressed on glucose concentration via simple linear regression; beta cell glucose sensitivity was defined as slope from the regression line.

Time frame: From -10 to 160 minutes after GGI on Day 1 (Part 3)

Population: The analysis population included a subset of participants in Part 3 who complied with the protocol sufficiently to ensure that their data exhibited the effects of treatment, according to the underlying scientific model. Compliance included exposure to treatment, availability of measurements, and absence of major protocol violations.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Part 1 Panel A MK-8521 100μg	Average Concentration (Cave) of MK-8521 Corresponding to Slope of Insulin Secretion Rate/Glucose (ISR/G) During Graded Glucose Infusion (GGI) at Tmax After a Single Dose of MK-8521 (Part 3)	0.376 nM	Geometric Coefficient of Variation 37.8
Part 1 Panel A MK-8521 300μg	Average Concentration (Cave) of MK-8521 Corresponding to Slope of Insulin Secretion Rate/Glucose (ISR/G) During Graded Glucose Infusion (GGI) at Tmax After a Single Dose of MK-8521 (Part 3)	1.64 nM	Geometric Coefficient of Variation 24.4

Primary

Cmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)

Time frame: Days 1, 7 and 14 (Part 2) (Panel F)

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
Part 1 Panel A MK-8521 100μg	Cmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Day 1	0.511 nM	Geometric Coefficient of Variation 22.7
Part 1 Panel A MK-8521 100μg	Cmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Day 7	1.15 nM	Geometric Coefficient of Variation 22.8
Part 1 Panel A MK-8521 100μg	Cmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Day 14	2.56 nM	Geometric Coefficient of Variation 19.6

Primary

Cmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)

Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 10 Days (with dose escalation on Day 5) to healthy non-obese male participants (Part 2, Panel C, D, E and F) are presented. Method of dispersion is coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo. Blood collections for the determination of plasma MK-8521 concentrations were collected at the following time points for Part 2, Panel C-E: Days 1, 4, 5, 9, 10 pre-dose; Days 1, 5, 10: 2, 4, 8, 10, 12, 16, 24 hrs. post dose; Day 10: 72, 96, 120 hrs. post-dose.

Time frame: Days 1, 5 and 10 (Part 2) (Panels C, D, E)

Population: The analysis population included participants in Part 2 (Panels C, D, and E) who complied with the protocol sufficiently to ensure that their data exhibited the effects of treatment. Compliance included exposure to treatment, availability of measurements, and absence of major protocol violations.

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
Part 1 Panel A MK-8521 100μg	Cmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 5	1.11 nM	Geometric Coefficient of Variation 22.6
Part 1 Panel A MK-8521 100μg	Cmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 1	0.642 nM	Geometric Coefficient of Variation 21.8
Part 1 Panel A MK-8521 100μg	Cmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 10	1.73 nM	Geometric Coefficient of Variation 20.4
Part 1 Panel A MK-8521 300μg	Cmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 5	2.21 nM	Geometric Coefficient of Variation 23.1
Part 1 Panel A MK-8521 300μg	Cmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 1	1.25 nM	Geometric Coefficient of Variation 20
Part 1 Panel A MK-8521 300μg	Cmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 10	4.31 nM	Geometric Coefficient of Variation 35.9
Part 1 Panel B MK-8521 150μg	Cmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 1	1.85 nM	Geometric Coefficient of Variation 23.1
Part 1 Panel B MK-8521 150μg	Cmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 10	3.73 nM	Geometric Coefficient of Variation 13
Part 1 Panel B MK-8521 150μg	Cmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 5	3.12 nM	Geometric Coefficient of Variation 16

Primary

Number of Participants Who Discontinued Treatment Due to an AE (Part 1)

An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.

Time frame: Up to 8 weeks (Part 1)

Population: The analysis population included all participants in Part 1 who received at least one dose of the investigational drug.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Part 1 Panel A MK-8521 100μg	Number of Participants Who Discontinued Treatment Due to an AE (Part 1)	0 Participants
Part 1 Panel A MK-8521 300μg	Number of Participants Who Discontinued Treatment Due to an AE (Part 1)	0 Participants
Part 1 Panel B MK-8521 150μg	Number of Participants Who Discontinued Treatment Due to an AE (Part 1)	0 Participants
Part 1 Panel B MK-8521 175μg	Number of Participants Who Discontinued Treatment Due to an AE (Part 1)	0 Participants
Part 1 Panel B MK-8521 200μg	Number of Participants Who Discontinued Treatment Due to an AE (Part 1)	0 Participants
Part 1, Pooled Placebo	Number of Participants Who Discontinued Treatment Due to an AE (Part 1)	1 Participants

Primary

Number of Participants Who Discontinued Treatment Due to an AE (Part 2)

Time frame: Up to 7 weeks (Part 2)

Population: The analysis population included all participants in Part 2 who received at least one dose of the investigational drug.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Part 1 Panel A MK-8521 100μg	Number of Participants Who Discontinued Treatment Due to an AE (Part 2)	0 Participants
Part 1 Panel A MK-8521 300μg	Number of Participants Who Discontinued Treatment Due to an AE (Part 2)	1 Participants
Part 1 Panel B MK-8521 150μg	Number of Participants Who Discontinued Treatment Due to an AE (Part 2)	0 Participants
Part 1 Panel B MK-8521 175μg	Number of Participants Who Discontinued Treatment Due to an AE (Part 2)	0 Participants
Part 1 Panel B MK-8521 200μg	Number of Participants Who Discontinued Treatment Due to an AE (Part 2)	0 Participants

Primary

Number of Participants Who Discontinued Treatment Due to an AE (Part 3)

Time frame: Up to 6 weeks (Part 3)

Population: The analysis population included all participants in Part 3 who received at least one dose of the investigational drug.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Part 1 Panel A MK-8521 100μg	Number of Participants Who Discontinued Treatment Due to an AE (Part 3)	0 Participants
Part 1 Panel A MK-8521 300μg	Number of Participants Who Discontinued Treatment Due to an AE (Part 3)	0 Participants
Part 1 Panel B MK-8521 150μg	Number of Participants Who Discontinued Treatment Due to an AE (Part 3)	0 Participants

Primary

Number of Participants Who Experienced at Least One Adverse Event (AE) (Part 1)

Time frame: From Day 1 through post-trial visit (Up to 8 weeks)

Population: The analysis population included all participants in Part 1 who received at least one dose of the investigational drug.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Part 1 Panel A MK-8521 100μg	Number of Participants Who Experienced at Least One Adverse Event (AE) (Part 1)	3 Participants
Part 1 Panel A MK-8521 300μg	Number of Participants Who Experienced at Least One Adverse Event (AE) (Part 1)	4 Participants
Part 1 Panel B MK-8521 150μg	Number of Participants Who Experienced at Least One Adverse Event (AE) (Part 1)	2 Participants
Part 1 Panel B MK-8521 175μg	Number of Participants Who Experienced at Least One Adverse Event (AE) (Part 1)	0 Participants
Part 1 Panel B MK-8521 200μg	Number of Participants Who Experienced at Least One Adverse Event (AE) (Part 1)	5 Participants
Part 1, Pooled Placebo	Number of Participants Who Experienced at Least One Adverse Event (AE) (Part 1)	10 Participants

Primary

Number of Participants With an Adverse Event (AE) (Part 2)

Time frame: From Day 1 through post-trial visit (Up to 7 weeks)

Population: The analysis population included all participants in Part 2 who received at least one dose of the investigational drug.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Part 1 Panel A MK-8521 100μg	Number of Participants With an Adverse Event (AE) (Part 2)	5 Participants
Part 1 Panel A MK-8521 300μg	Number of Participants With an Adverse Event (AE) (Part 2)	5 Participants
Part 1 Panel B MK-8521 150μg	Number of Participants With an Adverse Event (AE) (Part 2)	5 Participants
Part 1 Panel B MK-8521 175μg	Number of Participants With an Adverse Event (AE) (Part 2)	4 Participants
Part 1 Panel B MK-8521 200μg	Number of Participants With an Adverse Event (AE) (Part 2)	3 Participants

Primary

Number of Participants With an Adverse Event (AE) (Part 3)

Time frame: Up to 6 weeks (Part 3)

Population: The analysis population included all participants in Part 3 who received at least one dose of the investigational drug.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Part 1 Panel A MK-8521 100μg	Number of Participants With an Adverse Event (AE) (Part 3)	5 Participants
Part 1 Panel A MK-8521 300μg	Number of Participants With an Adverse Event (AE) (Part 3)	8 Participants
Part 1 Panel B MK-8521 150μg	Number of Participants With an Adverse Event (AE) (Part 3)	3 Participants

Primary

Peak Plasma Concentration (Cmax) of Participants Treated With a Single Dose of MK-8521 (Part 1)

Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. A summary of pharmacokinetic parameters following administration of single SC (subcutaneous) injection of MK-8521 in healthy non-obese male participants (Part I, Panels A-B, Period 1-3 \[100-300μg\]) is presented. Method of dispersion is coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo.

Time frame: Pre-dose, 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24, 30, 34, 48, 72, 96, 120 hrs. post-dose (Part 1)

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Part 1 Panel A MK-8521 100μg	Peak Plasma Concentration (Cmax) of Participants Treated With a Single Dose of MK-8521 (Part 1)	1.24 nM	Geometric Coefficient of Variation 30.2
Part 1 Panel A MK-8521 300μg	Peak Plasma Concentration (Cmax) of Participants Treated With a Single Dose of MK-8521 (Part 1)	4.29 nM	Geometric Coefficient of Variation 23.5
Part 1 Panel B MK-8521 150μg	Peak Plasma Concentration (Cmax) of Participants Treated With a Single Dose of MK-8521 (Part 1)	2.63 nM	Geometric Coefficient of Variation 20
Part 1 Panel B MK-8521 175μg	Peak Plasma Concentration (Cmax) of Participants Treated With a Single Dose of MK-8521 (Part 1)	3.10 nM	Geometric Coefficient of Variation 20.8
Part 1 Panel B MK-8521 200μg	Peak Plasma Concentration (Cmax) of Participants Treated With a Single Dose of MK-8521 (Part 1)	3.54 nM	Geometric Coefficient of Variation 18.4

Primary

Time Taken to Reach Cmax (Tmax) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 1)

Tmax is a measure of the time to reach the maximum concentration in the plasma after the drug dose. A summary of pharmacokinetic parameters following administration of single SC (subcutaneous) injection of MK-8521 in healthy non-obese male participants (Part I, Panels A-B, Period 1-3 \[100-300μg\]) is presented. No pharmacokinetic analysis was performed on participants receiving Placebo.

Time frame: Pre-dose, 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24, 30, 34, 48, 72, 96, 120 hrs. post-dose (Part 1)

Arm	Measure	Value (MEDIAN)
Part 1 Panel A MK-8521 100μg	Time Taken to Reach Cmax (Tmax) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 1)	14 Hours
Part 1 Panel A MK-8521 300μg	Time Taken to Reach Cmax (Tmax) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 1)	10 Hours
Part 1 Panel B MK-8521 150μg	Time Taken to Reach Cmax (Tmax) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 1)	11 Hours
Part 1 Panel B MK-8521 175μg	Time Taken to Reach Cmax (Tmax) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 1)	12 Hours
Part 1 Panel B MK-8521 200μg	Time Taken to Reach Cmax (Tmax) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 1)	14 Hours

Primary

Tmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)

Tmax is a measure of the time to reach the maximum concentration in the plasma after the drug dose. Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 14 Days (with dose escalation on Day 7) to obese male participants (Part 2, Panel F) are presented. Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 14 Days (with dose escalation on Day 7) to obese male participants (Part 2, Panel F) are presented. Method of dispersion is coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo. Blood collections occurred at the following time points for Part 2, Panel F: Days 1, 3, 4, 5, 7, 9, 11, 13, 14 pre-dose; Days 1, 7, 14: 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24 hrs. post-dose; Day 14: 72, 96, 120 hrs. post-dose.

Time frame: Days 1, 7 and 14 (Part 2) (Panel F)

Arm	Measure	Group	Value (MEDIAN)
Part 1 Panel A MK-8521 100μg	Tmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Day 1	24 Hours
Part 1 Panel A MK-8521 100μg	Tmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Day 7	9 Hours
Part 1 Panel A MK-8521 100μg	Tmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Day 14	10 Hours

Primary

Tmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)

Tmax is a measure of the time to reach the maximum concentration in the plasma after the drug dose. Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 10 Days (with dose escalation on Day 5) to healthy non-obese male participants (Part 2, Panel C, D, and E) are presented. Method of dispersion is coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo. Blood collections for the determination of plasma MK-8521 concentrations were collected at the following time points for Part 2, Panel C, D, and E: Days 1, 4, 5, 9, 10 pre-dose; Days 1, 5, 10: 2, 4, 8, 10, 12, 16, 24 hrs. post dose; Day 10: 72, 96, 120 hrs. post-dose.

Time frame: Days 1, 5 and 10 (Part 2) (Panels C, D, E)

Population: The analysis population included participants in Part 2 (Panels C, D, and E) who complied with the protocol sufficiently to ensure that their data exhibited the effects of treatment, according to the underlying scientific model. Compliance included exposure to treatment, availability of measurements, and absence of major protocol violations.

Arm	Measure	Group	Value (MEDIAN)
Part 1 Panel A MK-8521 100μg	Tmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 5	9 Hours
Part 1 Panel A MK-8521 100μg	Tmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 1	12 Hours
Part 1 Panel A MK-8521 100μg	Tmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 10	8 Hours
Part 1 Panel A MK-8521 300μg	Tmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 5	8 Hours
Part 1 Panel A MK-8521 300μg	Tmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 1	10 Hours
Part 1 Panel A MK-8521 300μg	Tmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 10	10 Hours
Part 1 Panel B MK-8521 150μg	Tmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 1	10 Hours
Part 1 Panel B MK-8521 150μg	Tmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 10	10 Hours
Part 1 Panel B MK-8521 150μg	Tmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 5	9 Hours

Primary

Trough Plasma Concentration (Ctrough) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)

Trough plasma concentration (measured concentration at the end of a dosing interval at steady state \[taken directly before next administration\]). Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 14 Days (with dose escalation on Day 7) to obese male participants (Part 2, Panel F) are presented. Method of dispersion is coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo. Blood collections for the determination of plasma MK-8521 concentrations were collected at the following time points for Part 2, Panel F: Days 1, 3, 4, 5, 7, 9, 11, 13, 14 pre-dose; Days 1, 7, 14: 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24 hrs. post-dose; Day 14: 72, 96, 120 hrs. post-dose.

Time frame: Days 1, 7 and 14 (Part 2) (Panel F)

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
Part 1 Panel A MK-8521 100μg	Trough Plasma Concentration (Ctrough) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Day 1	0.498 nM	Geometric Coefficient of Variation 22.8
Part 1 Panel A MK-8521 100μg	Trough Plasma Concentration (Ctrough) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Day 7	0.935 nM	Geometric Coefficient of Variation 18.6
Part 1 Panel A MK-8521 100μg	Trough Plasma Concentration (Ctrough) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Day 14	2.09 nM	Geometric Coefficient of Variation 15.3

Primary

Trough Plasma Concentration (Ctrough) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)

Trough plasma concentration (measured concentration at the end of a dosing interval at steady state \[taken directly before next administration\]). Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 10 Days (with dose escalation on Day 5) to healthy non-obese male participants (Part 2, Panel C, D, and E) are presented. Method of dispersion is coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo. Blood collections for the determination of plasma MK-8521 concentrations were collected for Part 2, Panel C, D, and E: Days 1, 4, 5, 9, 10 pre-dose; Days 1, 5, 10: 2, 4, 8, 10, 12, 16, 24 hrs. post dose; Day 10: 72, 96, 120 hrs. post-dose.

Time frame: Days 1, 5 and 10 (Part 2) (Panels C, D, E)

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
Part 1 Panel A MK-8521 100μg	Trough Plasma Concentration (Ctrough) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 10	1.20 nM	Geometric Coefficient of Variation 14.4
Part 1 Panel A MK-8521 100μg	Trough Plasma Concentration (Ctrough) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 5	0.721 nM	Geometric Coefficient of Variation 18.8
Part 1 Panel A MK-8521 100μg	Trough Plasma Concentration (Ctrough) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 1	0.493 nM	Geometric Coefficient of Variation 17.6
Part 1 Panel A MK-8521 300μg	Trough Plasma Concentration (Ctrough) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 10	2.92 nM	Geometric Coefficient of Variation 40.5
Part 1 Panel A MK-8521 300μg	Trough Plasma Concentration (Ctrough) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 1	1.00 nM	Geometric Coefficient of Variation 25
Part 1 Panel A MK-8521 300μg	Trough Plasma Concentration (Ctrough) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 5	1.33 nM	Geometric Coefficient of Variation 30
Part 1 Panel B MK-8521 150μg	Trough Plasma Concentration (Ctrough) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 5	2.01 nM	Geometric Coefficient of Variation 15.7
Part 1 Panel B MK-8521 150μg	Trough Plasma Concentration (Ctrough) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 1	1.33 nM	Geometric Coefficient of Variation 19.6
Part 1 Panel B MK-8521 150μg	Trough Plasma Concentration (Ctrough) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 10	2.82 nM	Geometric Coefficient of Variation 17.7

Secondary

Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 3)

Apparent Terminal Half-life (t1/2) is the time required for a given drug concentration in the plasma to decrease by 50%. A summary of pharmacokinetic parameters following administration of single SC (subcutaneous) injection of MK-8521 in healthy non-obese male participants (Part III \[35 and 125 μg\]) is presented. Method of dispersion is actually Coefficient of Variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo. No pharmacokinetic data was available for t1/2 for Part 3 due to sampling issues during the treatment period.

Time frame: Day 1: predose, -60, -10 min pre-GGI, 40 min, 80 min, 120 min, 160 min, 360 min, and 600 min after start of GGI(Part 3)

Secondary

Area Under the Curve (AUC) 0-24hr. for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 3)

AUC0-24hr is a measure of the mean concentration levels of drug in the plasma 0 to 24 hrs. after the dose. Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 10 Days (with dose escalation on Day 5) to healthy non-obese male participants (Part II, Panel C, D, and E) are presented. Method of dispersion coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo. No pharmacokinetic data was available for AUC0-24hr. for Part 3 due to sampling issues during the treatment period.

Time frame: Day 1: predose, -60, -10 min pre-GGI, 40 min, 80 min, 120 min, 160 min, 360 min, and 600 min after start of GGI (Part 3)

Secondary

Area Under the Curve (AUC) 0-∞ for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 3)

AUC0-∞ is a measure of the mean concentration levels of drug in the plasma after the dose. A summary of pharmacokinetic parameters following administration of single SC (subcutaneous) injection of MK-8521 in healthy non-obese male participants (Part III \[35 and 125 μg\]) is presented. Method of dispersion is actually Coefficient of Variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo. No pharmacokinetic data was available for AUC0-∞ for Part 3 due to sparse issues during the treatment period.

Time frame: Day 1: predose, -60, -10 min pre-GGI, 40 min, 80 min, 120 min, 160 min, 360 min, and 600 min after start of GGI (Part 3)

Secondary

Change From Baseline in Time-weighted Average From 0 to 24 Hrs (TWA0-24hr) of Heart Rate (HR) After a Single Dose of MK-8521 (Part 1)

Heart rate was assessed on Day 1 (predose & 1, 4, 8, 12, 16 & 24 hrs. postdose) & Day 2 (36 & 48 hrs. postdose). Predose and postdose HR were assessed using triplicate and duplicate measurements, respectively. The repeated measurements were averaged before conducting the statistical analysis. TWA0-24hr of HR on Day 1 & Day 2 of MK-8521 single dosing was calculated as the area under the measurement-time curve divided by the time period of over which the measurements were made (i.e., 24 hrs.). The change from baseline TWA0-24hr HR was calculated for each participant where baseline was defined as predose baseline on Day 1.

Time frame: Baseline (predose), up to 24 hours post-dose on Day 1, up to 24 hours post-dose on Day 2 (Part 1)

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)
Part 1 Panel A MK-8521 100μg	Change From Baseline in Time-weighted Average From 0 to 24 Hrs (TWA0-24hr) of Heart Rate (HR) After a Single Dose of MK-8521 (Part 1)	Day 1	6.67 Beats per minute
Part 1 Panel A MK-8521 100μg	Change From Baseline in Time-weighted Average From 0 to 24 Hrs (TWA0-24hr) of Heart Rate (HR) After a Single Dose of MK-8521 (Part 1)	Day 2	11.77 Beats per minute
Part 1 Panel A MK-8521 300μg	Change From Baseline in Time-weighted Average From 0 to 24 Hrs (TWA0-24hr) of Heart Rate (HR) After a Single Dose of MK-8521 (Part 1)	Day 1	19.03 Beats per minute
Part 1 Panel A MK-8521 300μg	Change From Baseline in Time-weighted Average From 0 to 24 Hrs (TWA0-24hr) of Heart Rate (HR) After a Single Dose of MK-8521 (Part 1)	Day 2	20.91 Beats per minute
Part 1 Panel B MK-8521 150μg	Change From Baseline in Time-weighted Average From 0 to 24 Hrs (TWA0-24hr) of Heart Rate (HR) After a Single Dose of MK-8521 (Part 1)	Day 1	0.06 Beats per minute
Part 1 Panel B MK-8521 150μg	Change From Baseline in Time-weighted Average From 0 to 24 Hrs (TWA0-24hr) of Heart Rate (HR) After a Single Dose of MK-8521 (Part 1)	Day 2	1.69 Beats per minute
Part 1 Panel B MK-8521 175μg	Change From Baseline in Time-weighted Average From 0 to 24 Hrs (TWA0-24hr) of Heart Rate (HR) After a Single Dose of MK-8521 (Part 1)	Day 1	9.28 Beats per minute
Part 1 Panel B MK-8521 175μg	Change From Baseline in Time-weighted Average From 0 to 24 Hrs (TWA0-24hr) of Heart Rate (HR) After a Single Dose of MK-8521 (Part 1)	Day 2	15.43 Beats per minute
Part 1 Panel B MK-8521 200μg	Change From Baseline in Time-weighted Average From 0 to 24 Hrs (TWA0-24hr) of Heart Rate (HR) After a Single Dose of MK-8521 (Part 1)	Day 1	7.99 Beats per minute
Part 1 Panel B MK-8521 200μg	Change From Baseline in Time-weighted Average From 0 to 24 Hrs (TWA0-24hr) of Heart Rate (HR) After a Single Dose of MK-8521 (Part 1)	Day 2	13.73 Beats per minute
Part 1, Pooled Placebo	Change From Baseline in Time-weighted Average From 0 to 24 Hrs (TWA0-24hr) of Heart Rate (HR) After a Single Dose of MK-8521 (Part 1)	Day 1	2.76 Beats per minute
Part 1, Pooled Placebo	Change From Baseline in Time-weighted Average From 0 to 24 Hrs (TWA0-24hr) of Heart Rate (HR) After a Single Dose of MK-8521 (Part 1)	Day 2	7.76 Beats per minute

Secondary

Change From Baseline in TWA 0-24 Hrs. Heart Rate (HR) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel C, D, and E)

Heart rate was assessed on Day -1 (at 2, 4, 6, 8, 12, and 16 hrs post admission), Day 1 and Day 6 (predose and 2, 4, 6, 8, 12, 16, 24, 36 and 48 hrs postdose) and Day 10 (predose & 2, 4, 6, 8, 12, 16, and 24 hrs. postdose). Predose HR on Day 1 was assessed using triplicate measurements while Day -1, Day 1 (postdose), Day 6, and Day 10 HR were assessed using duplicate measurements. The repeated measurements were averaged before conducting the statistical analysis. TWA0-24hr of HR on Day 1, Day 6, and Day 10 of MK-8521 multiple dose treatment was calculated as the area under the measurement-time curve divided by the time period of over which the measurements were made (i.e., 24 hrs). The change from baseline TWA0-24hr HR was calculated for each participant using TWA0-24hr on Day -1 as the baseline.

Time frame: Baseline (predose; up to 16 hrs on Day -1), predose & up to 24 hours postdose on Days 1, 6, and 10

Population: The analysis population included a subset of participants in Part 2, Panels C, D, and E who complied with the protocol sufficiently to ensure that their data exhibited the effects of treatment. Compliance included exposure to treatment, availability of measurements, and absence of major protocol violations.

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)
Part 1 Panel A MK-8521 100μg	Change From Baseline in TWA 0-24 Hrs. Heart Rate (HR) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel C, D, and E)	Day 1	1.18 Beats per minute
Part 1 Panel A MK-8521 100μg	Change From Baseline in TWA 0-24 Hrs. Heart Rate (HR) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel C, D, and E)	Day 10	9.30 Beats per minute
Part 1 Panel A MK-8521 100μg	Change From Baseline in TWA 0-24 Hrs. Heart Rate (HR) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel C, D, and E)	Day 6	4.24 Beats per minute
Part 1 Panel A MK-8521 300μg	Change From Baseline in TWA 0-24 Hrs. Heart Rate (HR) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel C, D, and E)	Day 1	0.30 Beats per minute
Part 1 Panel A MK-8521 300μg	Change From Baseline in TWA 0-24 Hrs. Heart Rate (HR) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel C, D, and E)	Day 10	12.42 Beats per minute
Part 1 Panel A MK-8521 300μg	Change From Baseline in TWA 0-24 Hrs. Heart Rate (HR) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel C, D, and E)	Day 6	7.96 Beats per minute
Part 1 Panel B MK-8521 150μg	Change From Baseline in TWA 0-24 Hrs. Heart Rate (HR) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel C, D, and E)	Day 6	8.52 Beats per minute
Part 1 Panel B MK-8521 150μg	Change From Baseline in TWA 0-24 Hrs. Heart Rate (HR) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel C, D, and E)	Day 1	4.15 Beats per minute
Part 1 Panel B MK-8521 150μg	Change From Baseline in TWA 0-24 Hrs. Heart Rate (HR) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel C, D, and E)	Day 10	9.88 Beats per minute
Part 1 Panel B MK-8521 175μg	Change From Baseline in TWA 0-24 Hrs. Heart Rate (HR) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel C, D, and E)	Day 1	-1.91 Beats per minute
Part 1 Panel B MK-8521 175μg	Change From Baseline in TWA 0-24 Hrs. Heart Rate (HR) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel C, D, and E)	Day 10	0.81 Beats per minute
Part 1 Panel B MK-8521 175μg	Change From Baseline in TWA 0-24 Hrs. Heart Rate (HR) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel C, D, and E)	Day 6	-0.74 Beats per minute

Secondary

Change From Baseline in TWA 0-24 Hrs. Heart Rate (HR) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)

Heart rate was assessed on Day -1 (at 2, 4, 6, 8, 12, and 16 hrs post admission), Day 1 & Day 8 (predose and 2, 4, 6, 8, 12, 16, 24, 36, and 48 hrs. post dose) & Day 14 (predose and 2, 4, 6, 8, 12, 16, and 24 hrs. postdose). Predose HR on Day 1 was assessed using triplicate measurements while Day -1, Day 1 (postdose), Day 8, and Day 14 HR were assessed as duplicate measurements. The repeated measurements were averaged before conducting the statistical analysis. TWA0-24hr of HR on Day 1, Day 8, and Day 14 of MK-8521 multiple dose treatment was calculated as the area under the measurement-time curve divided by the time period of over which the measurements were made (i.e., 24 hrs.). The change from baseline TWA0-24hr. HR was calculated for each participant using TWA0-24hr. on Day -1 as the baseline.

Time frame: Baseline (predose; up to 16 hrs on Day -1), predose & up to 24 hours postdose on Days 1, 8, and 14

Population: The analysis population included a subset of participants in Part 2, Panel F who complied with the protocol sufficiently to ensure that their data exhibited the effects of treatment, according to the underlying scientific model. Compliance included exposure to treatment, availability of measurements, and absence of major protocol violations.

Arm	Measure	Group	Value (MEAN)	Dispersion
Part 1 Panel A MK-8521 100μg	Change From Baseline in TWA 0-24 Hrs. Heart Rate (HR) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Day 8	5.22 Beats per minute	Standard Error 1.43
Part 1 Panel A MK-8521 100μg	Change From Baseline in TWA 0-24 Hrs. Heart Rate (HR) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Day 1	0.14 Beats per minute	Standard Error 1.33
Part 1 Panel A MK-8521 100μg	Change From Baseline in TWA 0-24 Hrs. Heart Rate (HR) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Day 14	9.25 Beats per minute	Standard Error 2.14
Part 1 Panel A MK-8521 300μg	Change From Baseline in TWA 0-24 Hrs. Heart Rate (HR) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Day 1	0.52 Beats per minute	Standard Error 1.42
Part 1 Panel A MK-8521 300μg	Change From Baseline in TWA 0-24 Hrs. Heart Rate (HR) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Day 8	0.29 Beats per minute	Standard Error 0.66
Part 1 Panel A MK-8521 300μg	Change From Baseline in TWA 0-24 Hrs. Heart Rate (HR) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Day 14	-1.11 Beats per minute	Standard Error 1.04

Secondary

Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)

Diastolic blood pressure was assessed on Day 1 (predose and 1, 4, 8, 12, 16 & 24 hrs postdose) and Day 2 (36 and 48 hrs postdose). Predose and postdose DBP were assessed using triplicate and duplicate measurements, respectively. The repeated measurements were averaged before conducting the statistical analysis. TWA0-24hr of DBP on Day 1 and Day 2 of MK-8521 single dosing was calculated as the area under the measurement-time curve divided by the time period of over which the measurements were made (i.e., 24 hrs.). The change from baseline TWA0-24hr DBP was calculated for each participant where baseline was defined as predose baseline on Day 1.

Time frame: Baseline (predose), up to 24 hours post-dose on Day 1, up to 24 hours post-dose on Day 2 (Part 1)

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)
Part 1 Panel A MK-8521 100μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)	Day 1	0.30 mmHg
Part 1 Panel A MK-8521 100μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)	Day 2	-1.41 mmHg
Part 1 Panel A MK-8521 300μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)	Day 1	5.60 mmHg
Part 1 Panel A MK-8521 300μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)	Day 2	5.55 mmHg
Part 1 Panel B MK-8521 150μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)	Day 1	-3.73 mmHg
Part 1 Panel B MK-8521 150μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)	Day 2	-2.56 mmHg
Part 1 Panel B MK-8521 175μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)	Day 1	-0.80 mmHg
Part 1 Panel B MK-8521 175μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)	Day 2	0.90 mmHg
Part 1 Panel B MK-8521 200μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)	Day 1	2.54 mmHg
Part 1 Panel B MK-8521 200μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)	Day 2	2.14 mmHg
Part 1, Pooled Placebo	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)	Day 1	-0.07 mmHg
Part 1, Pooled Placebo	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)	Day 2	0.57 mmHg

Secondary

Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)

Diastolic blood pressure was assessed on Day -1 (at 2, 4, 6, 8, 12, and 16 hrs. post admission), Day 1 and Day 8 (predose and 2, 4, 6, 8, 12, 16, 24, 36, and 48 hrs. post dose) and Day 14 (predose and 2, 4, 6, 8, 12, 16, and 24 hrs. postdose). Predose DBP on Day 1 was assessed using triplicate measurements while Day -1, Day 1 (postdose), Day 8, and Day 14 DBP were assessed as duplicate measurements. The repeated measurements were averaged before conducting the statistical analysis. TWA0-24hr of DBP on Day 1, Day 8, Day 14 of MK-8521 multiple dose treatment was calculated as the area under the measurement-time curve divided by the time period of over which the measurements were made (i.e., 24 hrs). The change from baseline TWA0-24hr. DBP was calculated for each participant using TWA0-24hr. on Day -1 as the baseline.

Time frame: Baseline (predose; up to 16 hrs on Day -1), predose & up to 24 hours postdose on Days 1, 8, and 14

Arm	Measure	Group	Value (MEAN)	Dispersion
Part 1 Panel A MK-8521 100μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Day 1	-0.15 mmHg	Standard Error 1.3
Part 1 Panel A MK-8521 100μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Day 8	0.41 mmHg	Standard Error 1.54
Part 1 Panel A MK-8521 100μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Day 14	0.78 mmHg	Standard Error 2.32
Part 1 Panel A MK-8521 300μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Day 1	1.45 mmHg	Standard Error 1.43
Part 1 Panel A MK-8521 300μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Day 8	-2.63 mmHg	Standard Error 1.11
Part 1 Panel A MK-8521 300μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Day 14	-3.19 mmHg	Standard Error 0.3

Secondary

Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part C, D, and E)

Diastolic blood pressure was assessed on Day -1 (at 2, 4, 6, 8, 12, and 16 hrs. post admission), Day 1 and Day 6 (predose and 2, 4, 6, 8, 12, 16, 24, 36 and 48 hrs. postdose) and Day 10 (predose and 2, 4, 6, 8, 12, 16, and 24 hrs. postdose). Predose DBP on Day 1 was assessed using triplicate measurements while Day -1, Day 1 (postdose), Day 6, and Day 10 DBP were assessed using duplicate measurements. The repeated measurements were averaged before conducting the statistical analysis. TWA0-24hr. DBP on Day 1, Day 6, and Day 10 of MK-8521 multiple dose treatment was calculated as the area under the measurement-time curve divided by the time period of over which the measurements were made (i.e., 24 hrs.). The change from baseline TWA0-24hr DBP was calculated for each participant using TWA0-24hr. on Day -1 as the baseline.

Time frame: Baseline (predose; up to 16 hrs on Day -1), predose & up to 24 hours postdose on Days 1, 6, and 10

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)
Part 1 Panel A MK-8521 100μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part C, D, and E)	Day 1	1.22 mmHg
Part 1 Panel A MK-8521 100μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part C, D, and E)	Day 10	1.58 mmHg
Part 1 Panel A MK-8521 100μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part C, D, and E)	Day 6	0.37 mmHg
Part 1 Panel A MK-8521 300μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part C, D, and E)	Day 1	2.38 mmHg
Part 1 Panel A MK-8521 300μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part C, D, and E)	Day 10	0.56 mmHg
Part 1 Panel A MK-8521 300μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part C, D, and E)	Day 6	2.63 mmHg
Part 1 Panel B MK-8521 150μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part C, D, and E)	Day 6	-1.22 mmHg
Part 1 Panel B MK-8521 150μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part C, D, and E)	Day 1	0.06 mmHg
Part 1 Panel B MK-8521 150μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part C, D, and E)	Day 10	3.29 mmHg
Part 1 Panel B MK-8521 175μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part C, D, and E)	Day 1	0.25 mmHg
Part 1 Panel B MK-8521 175μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part C, D, and E)	Day 10	0.53 mmHg
Part 1 Panel B MK-8521 175μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part C, D, and E)	Day 6	0.68 mmHg

Secondary

Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)

Systolic blood pressure was assessed on Day 1 (predose and 1, 4, 8, 12, 16 and 24 hrs. postdose) and Day 2 (36 and 48 hrs. postdose). Predose and postdose SBP were assessed using triplicate and duplicate measurements, respectively. The repeated measurements were averaged before conducting the statistical analysis. TWA0-24hr. of SBP on Day 1 and Day 2 of MK-8521 single dosing was calculated as the area under the measurement-time curve divided by the time period of over which the measurements were made (i.e., 24 hrs.). The change from baseline TWA0-24hr SBP was calculated for each participant where baseline was defined as predose baseline on Day 1.

Time frame: Baseline (predose), up to 24 hours post-dose on Day 1, up to 24 hours post-dose on Day 2 (Part 1)

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)
Part 1 Panel A MK-8521 100μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)	Day 1	-1.09 mmHg
Part 1 Panel A MK-8521 100μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)	Day 2	-2.55 mmHg
Part 1 Panel A MK-8521 300μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)	Day 1	8.43 mmHg
Part 1 Panel A MK-8521 300μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)	Day 2	7.81 mmHg
Part 1 Panel B MK-8521 150μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)	Day 1	-2.24 mmHg
Part 1 Panel B MK-8521 150μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)	Day 2	-0.73 mmHg
Part 1 Panel B MK-8521 175μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)	Day 1	3.18 mmHg
Part 1 Panel B MK-8521 175μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)	Day 2	2.03 mmHg
Part 1 Panel B MK-8521 200μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)	Day 1	0.10 mmHg
Part 1 Panel B MK-8521 200μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)	Day 2	1.71 mmHg
Part 1, Pooled Placebo	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)	Day 1	0.78 mmHg
Part 1, Pooled Placebo	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)	Day 2	1.9 mmHg

Secondary

Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)

Systolic blood pressure was assessed on Day -1 (at 2, 4, 6, 8, 12, and 16 hrs. post admission), Day 1 and Day 8 (predose and 2, 4, 6, 8, 12, 16, 24, 36, and 48 hrs. post dose) and Day 14 (predose and 2, 4, 6, 8, 12, 16, and 24 hrs. postdose). Predose SBP on Day 1 was assessed using triplicate measurements while Day -1, Day 1 (postdose), Day 8, and Day 14 SBP were assessed as duplicate measurements. The repeated measurements were averaged before conducting the statistical analysis. TWA0-24hr of SBP on Day 1, Day 8, and Day 14 of MK-8521 multiple dose treatment was calculated as the area under the measurement-time curve divided by the time period of over which the measurements were made (i.e., 24 hrs.). The change from baseline TWA0-24hr SBP was calculated for each participant using TWA0-24hr on Day -1 as the baseline.

Time frame: Baseline (predose; up to 16 hrs on Day -1), up to 16 hrs on Day -1, predose & up to 24 hours postdose on Days 1, 8, and 14

Arm	Measure	Group	Value (MEAN)	Dispersion
Part 1 Panel A MK-8521 100μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Day 1	-2.19 mmHg	Standard Error 2.33
Part 1 Panel A MK-8521 100μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Day 8	-3.99 mmHg	Standard Error 2.86
Part 1 Panel A MK-8521 100μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Day 14	-2.25 mmHg	Standard Error 4.15
Part 1 Panel A MK-8521 300μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Day 1	1.82 mmHg	Standard Error 1
Part 1 Panel A MK-8521 300μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Day 8	-6.55 mmHg	Standard Error 0.24
Part 1 Panel A MK-8521 300μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)	Day 14	-9.43 mmHg	Standard Error 0.39

Secondary

Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)

Systolic blood pressure was assessed on Day -1 (at 2, 4, 6, 8, 12, and 16 hrs. post admission), Day 1 and Day 6 (predose & 2, 4, 6, 8, 12, 16, 24, 36, and 48 hrs. postdose) and Day 10 (predose & 2, 4, 6, 8, 12, 16, and 24 hrs. postdose). Predose SBP on Day 1 was assessed using triplicate measurements while Day -1, Day 1 (postdose), Day 6, and Day 10 SBP were assessed using duplicate measurements. The repeated measurements were averaged before conducting the statistical analysis. TWA0-24hr SBP on Day 1, Day 6 and Day 10 of MK-8521 multiple dose treatment was calculated as the area under the measurement-time curve divided by the time period of over which the measurements were made (i.e., 24 hrs). The change from baseline TWA0-24hr SBP was calculated for each participant using TWA0-24hr on Day -1 as the baseline.

Time frame: Baseline (predose; up to 16 hrs on Day -1), predose & up to 24 hours postdose on Days 1, 6, and 10

Arm	Measure	Group	Value (GEOMETRIC_LEAST_SQUARES_MEAN)
Part 1 Panel A MK-8521 100μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 1	-0.12 mmHg
Part 1 Panel A MK-8521 100μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 10	-0.01 mmHg
Part 1 Panel A MK-8521 100μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 6	-2.08 mmHg
Part 1 Panel A MK-8521 300μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 1	1.57 mmHg
Part 1 Panel A MK-8521 300μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 10	-5.78 mmHg
Part 1 Panel A MK-8521 300μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 6	-2.26 mmHg
Part 1 Panel B MK-8521 150μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 6	-6.73 mmHg
Part 1 Panel B MK-8521 150μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 1	-2.65 mmHg
Part 1 Panel B MK-8521 150μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 10	-2.35 mmHg
Part 1 Panel B MK-8521 175μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 1	1.19 mmHg
Part 1 Panel B MK-8521 175μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 10	-3.25 mmHg
Part 1 Panel B MK-8521 175μg	Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)	Day 6	-1.18 mmHg

Secondary

Glucose (TWA0-160min) During GGI at Tmax After a Single Dose of MK-8521 (Part 3)

Glycemic effect during GGI after administration of a single dose of MK 8521 125mcg/35mcg or placebo at Tmax was evaluated as the time-weighted average of glucose concentration throughout the 160 minutes (TWA0-160min) of the GGI. Study drug was administered on Day -1 and blood glucose concentrations were determined at -10, -5 (pre GGI), 20, 40, 60, 80, 100, 120, 140, 160 minutes after start of GGI on Day 1 of each period. The parameter glucose (TWA0-160min) reflects ambient glucose concentration during the GGI.

Time frame: From -10 to 160 minutes after GGI on Day 1

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Part 1 Panel A MK-8521 100μg	Glucose (TWA0-160min) During GGI at Tmax After a Single Dose of MK-8521 (Part 3)	118.38 mg/dL
Part 1 Panel A MK-8521 300μg	Glucose (TWA0-160min) During GGI at Tmax After a Single Dose of MK-8521 (Part 3)	95.73 mg/dL
Part 1 Panel B MK-8521 150μg	Glucose (TWA0-160min) During GGI at Tmax After a Single Dose of MK-8521 (Part 3)	147.94 mg/dL

p-value: <0.00190% CI: [0.6, 0.7]Linear mixed effect model

p-value: <0.00190% CI: [0.74, 0.87]Linear mixed effect model

p-value: <0.00190% CI: [0.75, 0.87]Linear mixed effect model

Secondary

Maximum Glycemic Excursion (Gmax) During GGI and Tmax After a Single Dose of MK-8521 (Part 3)

Glycemic effect during GGI after administration of a single dose of MK-8521 125μg/35μg or placebo at Tmax was evaluated as the Gmax during the GGI. Study drug was administered on Day -1 and blood glucose concentrations were determined at -10, -5 (pre-GGI), 20, 40, 60, 80, 100, 120, 140, and 160 minutes after start of GGI on Day 1 of each period. The parameter Gmax reflects ambient glucose concentration during the GGI.

Time frame: From -10 to 160 minutes after GGI on Day 1

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Part 1 Panel A MK-8521 100μg	Maximum Glycemic Excursion (Gmax) During GGI and Tmax After a Single Dose of MK-8521 (Part 3)	154.37 mg/dL
Part 1 Panel A MK-8521 300μg	Maximum Glycemic Excursion (Gmax) During GGI and Tmax After a Single Dose of MK-8521 (Part 3)	120.43 mg/dL
Part 1 Panel B MK-8521 150μg	Maximum Glycemic Excursion (Gmax) During GGI and Tmax After a Single Dose of MK-8521 (Part 3)	217.53 mg/dL

p-value: <0.00190% CI: [0.49, 0.63]Linear mixed effect model

p-value: <0.00190% CI: [0.62, 0.81]Linear mixed effect model

p-value: 0.00490% CI: [0.69, 0.89]Linear mixed effect model

Secondary

Peak Plasma Concentration (Cmax) of Participants Treated With a Single Dose of MK-8521 (Part 3)

Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. A summary of pharmacokinetic parameters following administration of single SC (subcutaneous) injection of MK-8521 in healthy non-obese male participants (Part III \[35 and 125 μg\]) is presented. Method of dispersion is actually Coefficient of Variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo.

Time frame: Day 1: predose, -60, -10 min pre-GGI, 40 min, 80 min, 120 min, 160 min, 360 min, and 600 min after start of GGI (Part 3)

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Part 1 Panel A MK-8521 100μg	Peak Plasma Concentration (Cmax) of Participants Treated With a Single Dose of MK-8521 (Part 3)	0.418 nM	Geometric Coefficient of Variation 26.8
Part 1 Panel A MK-8521 300μg	Peak Plasma Concentration (Cmax) of Participants Treated With a Single Dose of MK-8521 (Part 3)	1.80 nM	Geometric Coefficient of Variation 21.7

Secondary

Ratio of ISR/G at the Highest Glucose Infusion Rate During GGI Due to Treatment With A Single Dose of MK-8521 (Part 3)

Pancreatic beta cell sensitivity to ambient glucose concentration after a single dose of MK-8521 125μg/35μg or placebo at Tmax was quantified as the ratio of the insulin secretion rate to glucose (ISR/G) at the highest glucose infusion rate during GGI (i.e., time weighted average between 120 to 160 minutes \[TWA120-160min\] of ratio \[ISR/G\]). Study drug was administered on Day -1 and blood concentrations of glucose, insulin, and C-peptide were determined at -10, -5 (pre-GGI), 20, 40, 60, 80, 100, 120, 140, and 160 minutes after start of GGI on Day 1 of each period.

Time frame: From -10 to 160 minutes after GGI on Day 1

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Part 1 Panel A MK-8521 100μg	Ratio of ISR/G at the Highest Glucose Infusion Rate During GGI Due to Treatment With A Single Dose of MK-8521 (Part 3)	0.0164 (ng/min)/(mg/dL)
Part 1 Panel A MK-8521 300μg	Ratio of ISR/G at the Highest Glucose Infusion Rate During GGI Due to Treatment With A Single Dose of MK-8521 (Part 3)	0.0256 (ng/min)/(mg/dL)
Part 1 Panel B MK-8521 150μg	Ratio of ISR/G at the Highest Glucose Infusion Rate During GGI Due to Treatment With A Single Dose of MK-8521 (Part 3)	0.0084 (ng/min)/(mg/dL)

p-value: <0.00190% CI: [2.62, 3.53]Linear mixed effect model

p-value: <0.00190% CI: [1.67, 2.26]Linear mixed effect model

p-value: <0.00190% CI: [1.35, 1.82]Linear mixed effect model

Secondary

Slope of Insulin Secretion Rate/Glucose (ISR/G) During Graded Glucose Infusion (GGI) at Tmax After a Single Dose of MK-8521 (Part 3)

Pancreatic beta cell sensitivity to ambient glucose concentration after a single dose of MK-8521 125μg/35μg or placebo at Tmax was quantified as the slope of insulin secretion rate relative to glucose concentration (ISR/G) during GGI (160 minutes duration). Study drug was administered on Day -1 and blood concentrations of glucose, insulin & C-peptide were determined at -10, -5 (pre-GGI), 20, 40, 60, 80, 100, 120, 140, and 160 minutes after start of GGI on Day 1 of each period. ISR calculated by deconvolution of C-peptide concentrations using a two compartmental model was regressed on glucose concentration via simple linear regression; beta cell glucose sensitivity was defined as slope from the regression line.

Time frame: From -10 to 160 minutes after GGI on Day 1

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Part 1 Panel A MK-8521 100μg	Slope of Insulin Secretion Rate/Glucose (ISR/G) During Graded Glucose Infusion (GGI) at Tmax After a Single Dose of MK-8521 (Part 3)	0.0314 (ng/min.)/(mg/dL)
Part 1 Panel A MK-8521 300μg	Slope of Insulin Secretion Rate/Glucose (ISR/G) During Graded Glucose Infusion (GGI) at Tmax After a Single Dose of MK-8521 (Part 3)	0.0543 (ng/min.)/(mg/dL)
Part 1 Panel B MK-8521 150μg	Slope of Insulin Secretion Rate/Glucose (ISR/G) During Graded Glucose Infusion (GGI) at Tmax After a Single Dose of MK-8521 (Part 3)	0.0118 (ng/min.)/(mg/dL)

p-value: <0.00190% CI: [3.69, 5.76]Linear mixed effect model

p-value: <0.00190% CI: [2.12, 3.36]Linear mixed effect model

p-value: <0.00190% CI: [1.38, 2.16]Linear mixed effect model

Secondary

Time Taken to Reach Cmax (Tmax) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 3)

Tmax is a measure of the time to reach the maximum concentration in the plasma after the drug dose. A summary of pharmacokinetic parameters following administration of single SC (subcutaneous) injection of MK-8521 in healthy non-obese male participants (Part III \[35 and 125 μg\]) is presented. No pharmacokinetic analysis was performed on participants receiving Placebo.

Time frame: Day 1: predose, -60, -10 min pre-GGI, 40 min, 80 min, 120 min, 160 min, 360 min, and 600 min after start of GGI (Part 3)

Arm	Measure	Value (MEDIAN)
Part 1 Panel A MK-8521 100μg	Time Taken to Reach Cmax (Tmax) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 3)	11.8 Hours
Part 1 Panel A MK-8521 300μg	Time Taken to Reach Cmax (Tmax) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 3)	12.7 Hours

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026

A Single and Multiple-Dose Study of MK-8521 in Healthy and Obese Males (MK-8521-002)

Conditions

Brief summary

Detailed description

Related papers

Interventions

Sponsors

Study design

Intervention model description

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Participant flow

Recruitment details

Pre-assignment details

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 1)

Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part C, D, and E)

Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part F)

Area Under the Concentration Time Curve of MK-8521 From 0 to Infinity (AUC0-∞) After a Single Dose (Part 1)

AUC 0-24hr for Plasma Concentration of Participants Treated After Multiple Doses of MK-8521 (Part 2, Panel F)

AUC 0-24hr for Plasma Concentration of Participants Treated After Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)

Average Concentration (Cave) of MK-8521 Corresponding to Slope of Insulin Secretion Rate/Glucose (ISR/G) During Graded Glucose Infusion (GGI) at Tmax After a Single Dose of MK-8521 (Part 3)

Cmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)

Cmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)

Number of Participants Who Discontinued Treatment Due to an AE (Part 1)

Number of Participants Who Discontinued Treatment Due to an AE (Part 2)

Number of Participants Who Discontinued Treatment Due to an AE (Part 3)

Number of Participants Who Experienced at Least One Adverse Event (AE) (Part 1)

Number of Participants With an Adverse Event (AE) (Part 2)

Number of Participants With an Adverse Event (AE) (Part 3)

Peak Plasma Concentration (Cmax) of Participants Treated With a Single Dose of MK-8521 (Part 1)

Time Taken to Reach Cmax (Tmax) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 1)

Tmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)

Tmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)

Trough Plasma Concentration (Ctrough) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)

Trough Plasma Concentration (Ctrough) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)

Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 3)

Area Under the Curve (AUC) 0-24hr. for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 3)

Area Under the Curve (AUC) 0-∞ for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 3)

Change From Baseline in Time-weighted Average From 0 to 24 Hrs (TWA0-24hr) of Heart Rate (HR) After a Single Dose of MK-8521 (Part 1)

Change From Baseline in TWA 0-24 Hrs. Heart Rate (HR) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel C, D, and E)

Change From Baseline in TWA 0-24 Hrs. Heart Rate (HR) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)

Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)

Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)

Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part C, D, and E)

Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)

Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)

Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)

Glucose (TWA0-160min) During GGI at Tmax After a Single Dose of MK-8521 (Part 3)

Maximum Glycemic Excursion (Gmax) During GGI and Tmax After a Single Dose of MK-8521 (Part 3)

Peak Plasma Concentration (Cmax) of Participants Treated With a Single Dose of MK-8521 (Part 3)

Ratio of ISR/G at the Highest Glucose Infusion Rate During GGI Due to Treatment With A Single Dose of MK-8521 (Part 3)

Slope of Insulin Secretion Rate/Glucose (ISR/G) During Graded Glucose Infusion (GGI) at Tmax After a Single Dose of MK-8521 (Part 3)

Time Taken to Reach Cmax (Tmax) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 3)