Trial Outcomes & Findings for Frespaciguat (MK-5475) in Participants With Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease (PH-COPD) (MK-5475-006) (NCT NCT04370873)

Results Overview

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The percentage of participants who experienced an AE was assessed.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

22 participants

Primary outcome timeframe

Up to approximately 139 days

Results posted on

2025-05-28

Participant Flow

Adult participants with pulmonary hypertension (PH) associated with chronic obstructive pulmonary disease (COPD) were recruited to evaluate safety, pharmacokinetics (PK) and pharmacodynamics (PD) of multiple doses of MK-5475.

There were three planned parts in the study. Participants in part 1 received MK-5475 360 μg. Participants in part 2 received MK-5475 380 μg. Part 3 was not performed because, as allowed by the protocol, it was decided that sufficient data had already been obtained. One participant in Part 1 also participated in Part 2. That participant is counted only in Part 1 for the participant flow.

Participant milestones

Participant milestones
Measure	Part 1: MK-5475 360 μg Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.	Part 1: Placebo Participants received placebo QD via inhalation from Days 1-7.	Part 2: MK-5475 380 μg Participants received MK-5475 380 μg QD via inhalation from Days 1-28.	Part 2: Placebo Participants received placebo QD via inhalation from Days 1-28.
Part 1: 7-day Dosing STARTED	6	3	0	0
Part 1: 7-day Dosing COMPLETED	6	3	0	0
Part 1: 7-day Dosing NOT COMPLETED	0	0	0	0
Part 2: 28-day Dosing STARTED	0	0	8	5
Part 2: 28-day Dosing COMPLETED	0	0	8	5
Part 2: 28-day Dosing NOT COMPLETED	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

The analysis population consisted of all participants in part 2 who received at least one dose of MK-5475 380 μg and complied with the protocol without major protocol deviations.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part 1: MK-5475 360 μg n=6 Participants Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.	Part 1: Placebo n=3 Participants Participants received placebo QD via inhalation from Days 1-7.	Part 2: MK-5475 380 μg n=8 Participants Participants received MK-5475 380 μg QD via inhalation from Days 1-28.	Part 2: Placebo n=5 Participants Participants received placebo QD via inhalation from Days 1-28.	Total n=22 Participants Total of all reporting groups
Age, Continuous	62.2 Years STANDARD_DEVIATION 12.7 • n=6 Participants	62.3 Years STANDARD_DEVIATION 8.7 • n=3 Participants	69.4 Years STANDARD_DEVIATION 4.8 • n=8 Participants	66.6 Years STANDARD_DEVIATION 5.6 • n=5 Participants	65.8 Years STANDARD_DEVIATION 8.4 • n=22 Participants
Sex: Female, Male Female	1 Participants n=6 Participants	2 Participants n=3 Participants	0 Participants n=8 Participants	0 Participants n=5 Participants	3 Participants n=22 Participants
Sex: Female, Male Male	5 Participants n=6 Participants	1 Participants n=3 Participants	8 Participants n=8 Participants	5 Participants n=5 Participants	19 Participants n=22 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=6 Participants	0 Participants n=3 Participants	0 Participants n=8 Participants	0 Participants n=5 Participants	0 Participants n=22 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	6 Participants n=6 Participants	3 Participants n=3 Participants	8 Participants n=8 Participants	5 Participants n=5 Participants	22 Participants n=22 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=6 Participants	0 Participants n=3 Participants	0 Participants n=8 Participants	0 Participants n=5 Participants	0 Participants n=22 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=6 Participants	0 Participants n=3 Participants	0 Participants n=8 Participants	0 Participants n=5 Participants	0 Participants n=22 Participants
Race (NIH/OMB) Asian	0 Participants n=6 Participants	0 Participants n=3 Participants	0 Participants n=8 Participants	0 Participants n=5 Participants	0 Participants n=22 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=6 Participants	0 Participants n=3 Participants	0 Participants n=8 Participants	0 Participants n=5 Participants	0 Participants n=22 Participants
Race (NIH/OMB) Black or African American	0 Participants n=6 Participants	0 Participants n=3 Participants	0 Participants n=8 Participants	0 Participants n=5 Participants	0 Participants n=22 Participants
Race (NIH/OMB) White	6 Participants n=6 Participants	3 Participants n=3 Participants	8 Participants n=8 Participants	5 Participants n=5 Participants	22 Participants n=22 Participants
Race (NIH/OMB) More than one race	0 Participants n=6 Participants	0 Participants n=3 Participants	0 Participants n=8 Participants	0 Participants n=5 Participants	0 Participants n=22 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=6 Participants	0 Participants n=3 Participants	0 Participants n=8 Participants	0 Participants n=5 Participants	0 Participants n=22 Participants
Pulmonary Vascular Resistance (PVR): Part 2	—	—	409.52 dynesscm^-5 STANDARD_DEVIATION 166.47 • n=8 Participants • The analysis population consisted of all participants in part 2 who received at least one dose of MK-5475 380 μg and complied with the protocol without major protocol deviations.	394.32 dynesscm^-5 STANDARD_DEVIATION 141.18 • n=4 Participants • The analysis population consisted of all participants in part 2 who received at least one dose of MK-5475 380 μg and complied with the protocol without major protocol deviations.	404.46 dynesscm^-5 STANDARD_DEVIATION 152.08 • n=12 Participants • The analysis population consisted of all participants in part 2 who received at least one dose of MK-5475 380 μg and complied with the protocol without major protocol deviations.

PRIMARY outcome

Timeframe: Up to approximately 139 days

Population: All participants who received ≥1 dose of investigational treatment were analyzed according to treatment received.

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The percentage of participants who experienced an AE was assessed.

Outcome measures

Outcome measures
Measure	Part 1: MK-5475 360 μg n=6 Participants Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.	Part 1: Placebo n=3 Participants Participants received placebo QD via inhalation from Days 1-7.	Part 2: MK-5475 380 μg n=9 Participants Participants received MK-5475 380 μg QD via inhalation from Days 1-28.	Part 2: Placebo n=5 Participants Participants received placebo QD via inhalation from Days 1-28.
Percentage of Participants Who Experienced at Least 1 Adverse Event (AE)	33.3 Percentage of Participants	33.3 Percentage of Participants	33.3 Percentage of Participants	80.0 Percentage of Participants

PRIMARY outcome

Timeframe: Up to approximately 32 days

Population: All participants who received ≥1 dose of investigational treatment were analyzed according to treatment received.

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who discontinued treatment due to an AE was assessed.

Outcome measures

Outcome measures
Measure	Part 1: MK-5475 360 μg n=6 Participants Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.	Part 1: Placebo n=3 Participants Participants received placebo QD via inhalation from Days 1-7.	Part 2: MK-5475 380 μg n=9 Participants Participants received MK-5475 380 μg QD via inhalation from Days 1-28.	Part 2: Placebo n=5 Participants Participants received placebo QD via inhalation from Days 1-28.
Percentage of Participants Who Discontinued Study Drug Due to an AE	0.0 Percentage of Participants	0.0 Percentage of Participants	0.0 Percentage of Participants	0.0 Percentage of Participants

PRIMARY outcome

Timeframe: Baseline (between Day -5 and Day -1) and Day 28

Population: All Part 2 participants who complied with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model, and who had available data at baseline and Day 28.

PVR was calculated in participants after MK-5475 dosing at baseline and Day 28. Based on the variables obtained by right heart catheterization (RHC), the fold change from baseline individual PVR was calculated. The difference from baseline was assessed on the log scale and then back-transformed for reporting (percent change from baseline). Per protocol, this outcome measure was only assessed during the Part 2 and was not assessed during part 1.

Outcome measures

Outcome measures
Measure	Part 1: MK-5475 360 μg n=8 Participants Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.	Part 1: Placebo n=4 Participants Participants received placebo QD via inhalation from Days 1-7.	Part 2: MK-5475 380 μg Participants received MK-5475 380 μg QD via inhalation from Days 1-28.	Part 2: Placebo Participants received placebo QD via inhalation from Days 1-28.
Percentage Change From Baseline to Day 28 in Pulmonary Vascular Resistance (PVR): Part 2	-21.23 Percentage change Standard Deviation 16.98	-5.39 Percentage change Standard Deviation 49.21	—	—

SECONDARY outcome

Timeframe: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose

Population: The analysis population consisted of all participants in part 1 who received at least one dose of MK-5475 360 μg and who contributed blood samples for analysis of AUC0-inf. Per protocol, AUC0-inf was calculated for the participants who had concentration values.

Blood samples were taken predose and at specified times postdose to determine the AUC0-inf of MK-5475. Plasma AUC0-inf was defined as the area under the concentration vs. time curve for MK-5475 from 0 to infinite hours.

Outcome measures

Outcome measures
Measure	Part 1: MK-5475 360 μg n=6 Participants Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.	Part 1: Placebo Participants received placebo QD via inhalation from Days 1-7.	Part 2: MK-5475 380 μg Participants received MK-5475 380 μg QD via inhalation from Days 1-28.	Part 2: Placebo Participants received placebo QD via inhalation from Days 1-28.
Plasma Area Under the Concentration Time-Curve From 0 to Infinity (AUC0-inf) of MK-5475: Part 1 Day 1	3.32 hr*nM Geometric Coefficient of Variation 68.9	—	—	—
Plasma Area Under the Concentration Time-Curve From 0 to Infinity (AUC0-inf) of MK-5475: Part 1 Day 7	4.03 hr*nM Geometric Coefficient of Variation 90.2	—	—	—

SECONDARY outcome

Timeframe: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose

Population: The analysis population consisted of all participants in part 1 who received at least one dose of MK-5475 360 μg and who contributed blood samples for analysis of AUC0-24. Per protocol, AUC0-24 was calculated for the participants who had concentration values.

Blood samples were taken predose and at specified times postdose on Day 7 to determine the AUC0-24 of MK-5475. AUC0-24 values for Day 1 correspond to extrapolated values since collection on Day 1 stopped at 8 hours.

Outcome measures

Outcome measures
Measure	Part 1: MK-5475 360 μg n=6 Participants Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.	Part 1: Placebo Participants received placebo QD via inhalation from Days 1-7.	Part 2: MK-5475 380 μg Participants received MK-5475 380 μg QD via inhalation from Days 1-28.	Part 2: Placebo Participants received placebo QD via inhalation from Days 1-28.
Plasma Area Under the Concentration Time-Curve From 0 to 24 Hours (AUC0-24) of MK-5475: Part 1 Day 1	3.31 hr*nM Geometric Coefficient of Variation 68.7	—	—	—
Plasma Area Under the Concentration Time-Curve From 0 to 24 Hours (AUC0-24) of MK-5475: Part 1 Day 7	4.22 hr*nM Geometric Coefficient of Variation 83.5	—	—	—

SECONDARY outcome

Timeframe: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose

Population: The analysis population consisted of all participants in part 1 who received at least one dose of MK-5475 360 μg and who contributed blood samples for analysis of Cmax. Per protocol, Cmax was calculated for the participants who had concentration values.

Plasma concentration of MK-5475 was quantified for each arm to determine Cmax.

Outcome measures

Outcome measures
Measure	Part 1: MK-5475 360 μg n=6 Participants Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.	Part 1: Placebo Participants received placebo QD via inhalation from Days 1-7.	Part 2: MK-5475 380 μg Participants received MK-5475 380 μg QD via inhalation from Days 1-28.	Part 2: Placebo Participants received placebo QD via inhalation from Days 1-28.
Maximum Observed Plasma Concentration (Cmax) of MK-5475: Part 1 Day 1	0.830 nM Geometric Coefficient of Variation 50.8	—	—	—
Maximum Observed Plasma Concentration (Cmax) of MK-5475: Part 1 Day 7	0.970 nM Geometric Coefficient of Variation 59.1	—	—	—

SECONDARY outcome

Timeframe: 24 hours postdose on Day 7

Population: The analysis population consisted of all participants in part 1 who received at least one dose of MK-5475 360 μg and who contributed blood samples for analysis of C24. Per protocol, C24 was calculated for the participants who had concentration.

Blood samples were taken to determine the C24 of MK-5475. Data are reported as Mean with Standard Deviation. Concentration values below the lower limit of quantification were treated as having a value of 0.

Outcome measures

Outcome measures
Measure	Part 1: MK-5475 360 μg n=6 Participants Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.	Part 1: Placebo Participants received placebo QD via inhalation from Days 1-7.	Part 2: MK-5475 380 μg Participants received MK-5475 380 μg QD via inhalation from Days 1-28.	Part 2: Placebo Participants received placebo QD via inhalation from Days 1-28.
Plasma Concentration 24 Hours Postdose (C24) of MK-5475: Part 1	0.02 nM Standard Deviation 0.3	—	—	—

SECONDARY outcome

Timeframe: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose

Population: The analysis population consisted of all participants in part 1 who received at least one dose of MK-5475 360 μg and who contributed blood samples for analysis of Tmax. Per protocol, Tmax was calculated for the participants who had concentration values.

Blood samples were taken at predose and at specified time points postdose to determine the Tmax of MK-5475. Tmax was defined as the time to maximum concentration of MK-5475.

Outcome measures

Outcome measures
Measure	Part 1: MK-5475 360 μg n=6 Participants Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.	Part 1: Placebo Participants received placebo QD via inhalation from Days 1-7.	Part 2: MK-5475 380 μg Participants received MK-5475 380 μg QD via inhalation from Days 1-28.	Part 2: Placebo Participants received placebo QD via inhalation from Days 1-28.
Time to Maximum Concentration (Tmax) of MK-5475: Part 1 Day 1	1.00 Hours Interval 1.0 to 2.0	—	—	—
Time to Maximum Concentration (Tmax) of MK-5475: Part 1 Day 7	1.00 Hours Interval 1.0 to 2.0	—	—	—

SECONDARY outcome

Timeframe: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose

Population: The analysis population consisted of all participants in part 1 who received at least one dose of MK-5475 360 μg and who contributed blood samples for analysis of t½. Per protocol, t½ was calculated for the participants who had concentration values.

Blood samples were taken at predose and at specified time points postdose to determine the t½ of MK-5475.

Outcome measures

Outcome measures
Measure	Part 1: MK-5475 360 μg n=6 Participants Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.	Part 1: Placebo Participants received placebo QD via inhalation from Days 1-7.	Part 2: MK-5475 380 μg Participants received MK-5475 380 μg QD via inhalation from Days 1-28.	Part 2: Placebo Participants received placebo QD via inhalation from Days 1-28.
Plasma Apparent Terminal Half-Life (t½) of MK-5475: Part 1 Day 1	2.13 Hours Geometric Coefficient of Variation 18.5	—	—	—
Plasma Apparent Terminal Half-Life (t½) of MK-5475: Part 1 Day 7	2.81 Hours Geometric Coefficient of Variation 48.4	—	—	—

SECONDARY outcome

Timeframe: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose

Population: The analysis population consisted of all participants in part 1 who received at least one dose of MK-5475 360 μg and who contributed blood samples for analysis of Cmax accumulation ratio. Per protocol, Cmax accumulation ratio was calculated for the participants who had concentration values.

Blood samples were taken predose and at specified times postdose to determine the Cmax accumulation ratio of MK-5475. Accumulation ratio is the ratio of the Day 7 Cmax to the Day 1 Cmax.

Outcome measures

Outcome measures
Measure	Part 1: MK-5475 360 μg n=6 Participants Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.	Part 1: Placebo Participants received placebo QD via inhalation from Days 1-7.	Part 2: MK-5475 380 μg Participants received MK-5475 380 μg QD via inhalation from Days 1-28.	Part 2: Placebo Participants received placebo QD via inhalation from Days 1-28.
Cmax Accumulation Ratio of MK-5475: Part 1	1.17 Ratio Geometric Coefficient of Variation 28.8	—	—	—

SECONDARY outcome

Timeframe: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose

Population: The analysis population consisted of all participants in part 1 who received at least one dose of MK-5475 360 μg and who contributed blood samples for analysis of AUC0-24 accumulation ratio. Per protocol, AUC0-24 accumulation ratio was calculated for the participants who had concentration values.

Blood samples were taken predose and at specified times postdose to determine the AUC0-24 accumulation ratio of MK-5475. Accumulation ratio is the ratio of the Day 7 AUC0-24 to the Day 1 AUC0-24.

Outcome measures

Outcome measures
Measure	Part 1: MK-5475 360 μg n=6 Participants Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.	Part 1: Placebo Participants received placebo QD via inhalation from Days 1-7.	Part 2: MK-5475 380 μg Participants received MK-5475 380 μg QD via inhalation from Days 1-28.	Part 2: Placebo Participants received placebo QD via inhalation from Days 1-28.
AUC0-24 Accumulation Ratio of MK-5475: Part 1	1.27 Ratio Geometric Coefficient of Variation 30.1	—	—	—

SECONDARY outcome

Timeframe: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose

Population: The analysis population consisted of all participants in part 1 who received at least one dose of MK-5475 360 μg and who contributed blood samples for analysis of AUC0-inf accumulation ratio. Per protocol, AUC0-inf accumulation ratio was calculated for the participants who had concentration values.

Blood samples were taken predose and at specified times postdose on Days 1-7 to determine the AUC0-inf accumulation ratio of MK-5475. Accumulation ratio is the ratio of the Day 7 AUC0-inf to the Day 1 AUC0-inf.

Outcome measures

Outcome measures
Measure	Part 1: MK-5475 360 μg n=6 Participants Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.	Part 1: Placebo Participants received placebo QD via inhalation from Days 1-7.	Part 2: MK-5475 380 μg Participants received MK-5475 380 μg QD via inhalation from Days 1-28.	Part 2: Placebo Participants received placebo QD via inhalation from Days 1-28.
AUC0-inf Accumulation Ratio of MK-5475: Part 1	1.21 Ratio Geometric Coefficient of Variation 31.1	—	—	—

SECONDARY outcome

Timeframe: Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose

Population: The analysis population consisted of all participants in part 2 who received at least one dose of MK-5475 380 μg and who contributed blood samples for analysis of AUC0-inf. Per protocol, AUC0-inf was calculated for the participants who had concentration values.

Blood samples were taken pre-dose and at specified times post-dose to determine the AUC0-inf of MK-5475. Concentrations for samples collected pre-RHC in a time window of 6-8 hours postdose on Day 28 were used to derive PK parameter values on Day 28. A nominal elapsed time of 6.01 hours postdose was used in the calculation.

Outcome measures

Outcome measures
Measure	Part 1: MK-5475 360 μg n=8 Participants Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.	Part 1: Placebo Participants received placebo QD via inhalation from Days 1-7.	Part 2: MK-5475 380 μg Participants received MK-5475 380 μg QD via inhalation from Days 1-28.	Part 2: Placebo Participants received placebo QD via inhalation from Days 1-28.
AUC0-inf of MK-5475: Part 2 Day 28	1.98 hr*nM Geometric Coefficient of Variation 105.9	—	—	—
AUC0-inf of MK-5475: Part 2 Day 1	NA hr*nM Geometric Coefficient of Variation NA NA= AUC0-inf could not be calculated due to insufficient data.	—	—	—

SECONDARY outcome

Timeframe: Day 28: Predose, 0.5, 1, 2 and 3 hours postdose

Population: The analysis population consisted of all participants in part 2 who received at least one dose of MK-5475 380 μg and who contributed blood samples for analysis of AUC0-24. Per protocol, AUC0-24 was calculated for the participants who had concentration values.

Blood samples were taken predose and at specified times postdose on Day 28 to determine the AUC0-24 of MK-5475. Concentrations for samples collected pre-RHC in a time window of 6-8 hours postdose on Day 28 were used to derive PK parameter values on Day 28. A nominal elapsed time of 6.01 hours postdose was used in the calculation. AUC0-24 was calculated using extrapolated concentration at 24 hours postdose.

Outcome measures

Outcome measures
Measure	Part 1: MK-5475 360 μg n=8 Participants Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.	Part 1: Placebo Participants received placebo QD via inhalation from Days 1-7.	Part 2: MK-5475 380 μg Participants received MK-5475 380 μg QD via inhalation from Days 1-28.	Part 2: Placebo Participants received placebo QD via inhalation from Days 1-28.
AUC0-24 of MK-5475: Part 2 Day 1	NA hr*nM Geometric Coefficient of Variation NA NA= AUC0-24 could not be calculated due to insufficient data.	—	—	—
AUC0-24 of MK-5475: Part 2 Day 28	1.97 hr*nM Geometric Coefficient of Variation 105.7	—	—	—

SECONDARY outcome

Timeframe: Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose

Population: The analysis population consisted of all participants in part 2 who received at least one dose of MK-5475 380 μg and who contributed blood samples for analysis of Cmax. Per protocol, Cmax was calculated for the participants who had concentration values.

Blood samples were taken predose and at specified times postdose to determine the Cmax of MK-5475.

Outcome measures

Outcome measures
Measure	Part 1: MK-5475 360 μg n=8 Participants Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.	Part 1: Placebo Participants received placebo QD via inhalation from Days 1-7.	Part 2: MK-5475 380 μg Participants received MK-5475 380 μg QD via inhalation from Days 1-28.	Part 2: Placebo Participants received placebo QD via inhalation from Days 1-28.
Cmax of MK-5475: Part 2 Day 1	0.348 nM Geometric Coefficient of Variation 48.4	—	—	—
Cmax of MK-5475: Part 2 Day 28	0.397 nM Geometric Coefficient of Variation 71.4	—	—	—

SECONDARY outcome

Timeframe: 24 hours postdose on Day 7

Population: The analysis population consisted of all participants in part 2 who received at least one dose of MK-5475 380 μg and who contributed blood samples for analysis of C24. Per protocol, 24 hours samples were not collected. Therefore, no participants were analyzed.

Blood samples were taken to determine the C24 of MK-5475. Data are reported as Mean with Coefficient of Variation, but due to data entry limitations the table below labels them as Geometric Mean and Geometric Coefficient of Variation. Concentration values below the lower limit of quantification were treated as having a value of 0.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose

Population: The analysis population consisted of all participants in part 2 who received at least one dose of MK-5475 380 μg and who contributed blood samples for analysis of Tmax. Per protocol, Tmax was calculated for the participants who had concentration values.

Blood samples were taken predose and at specified times postdose to determine the Tmax of MK-5475.

Outcome measures

Outcome measures
Measure	Part 1: MK-5475 360 μg n=8 Participants Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.	Part 1: Placebo Participants received placebo QD via inhalation from Days 1-7.	Part 2: MK-5475 380 μg Participants received MK-5475 380 μg QD via inhalation from Days 1-28.	Part 2: Placebo Participants received placebo QD via inhalation from Days 1-28.
Tmax of MK-5475: Part 2 Day 1	1.50 Hours Interval 1.0 to 2.0	—	—	—
Tmax of MK-5475: Part 2 Day 28	1.50 Hours Interval 1.0 to 2.0	—	—	—

SECONDARY outcome

Timeframe: Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose

Population: The analysis population consisted of all participants in part 2 who received at least one dose of MK-5475 380 μg and who contributed blood samples for analysis of t½. Per protocol, t½ was calculated for the participants who had concentration values.

Blood samples were taken predose and at specified times postdose to determine the t½ of MK-5475.

Outcome measures

Outcome measures
Measure	Part 1: MK-5475 360 μg n=8 Participants Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.	Part 1: Placebo Participants received placebo QD via inhalation from Days 1-7.	Part 2: MK-5475 380 μg Participants received MK-5475 380 μg QD via inhalation from Days 1-28.	Part 2: Placebo Participants received placebo QD via inhalation from Days 1-28.
t½ of MK-5475: Part 2 Day 1	NA Hours Geometric Coefficient of Variation NA NA= t½ could not be calculated due to insufficient data.	—	—	—
t½ of MK-5475: Part 2 Day 28	2.06 Hours Geometric Coefficient of Variation 62.4	—	—	—

SECONDARY outcome

Timeframe: Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose

Population: The analysis population consisted of all participants who received at least 1 treatment and who contributed blood samples for analysis of accumulation. Per protocol, accumulation was calculated for the participants who had concentration values.

Blood samples were taken predose and at specified times postdose on to determine the AUC0-3 accumulation ratio of MK-5475. Accumulation ratio is the ratio of the Day 7 AUC0-3 to the Day 1 AUC0-3.

Outcome measures

Outcome measures
Measure	Part 1: MK-5475 360 μg n=8 Participants Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.	Part 1: Placebo Participants received placebo QD via inhalation from Days 1-7.	Part 2: MK-5475 380 μg Participants received MK-5475 380 μg QD via inhalation from Days 1-28.	Part 2: Placebo Participants received placebo QD via inhalation from Days 1-28.
AUC0-3 Accumulation Ratio of MK-5475: Part 2	1.11 Ratio Geometric Coefficient of Variation 53.8	—	—	—

SECONDARY outcome

Timeframe: Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 15: 1 hour postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose

Population: The analysis population consisted of all participants in part 2 who received at least one dose of MK-5475 380 μg and who contributed blood samples for analysis of Cmax accumulation ratio. Per protocol, Cmax accumulation ratio was calculated for the participants who had concentration values.

Blood samples were taken predose and at specified times postdose to determine the Cmax accumulation ratio of MK-5475. Cmax accumulation ratio is the ratio of the Day 7 Cmax to the Day 1 Cmax.

Outcome measures

Outcome measures
Measure	Part 1: MK-5475 360 μg n=8 Participants Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.	Part 1: Placebo Participants received placebo QD via inhalation from Days 1-7.	Part 2: MK-5475 380 μg Participants received MK-5475 380 μg QD via inhalation from Days 1-28.	Part 2: Placebo Participants received placebo QD via inhalation from Days 1-28.
Cmax Accumulation Ratio of MK-5475: Part 2	1.14 Ratio Geometric Coefficient of Variation 51.6	—	—	—

SECONDARY outcome

Timeframe: Baseline (between Day -5 and Day -1) and Day 28

Population: All Part 2 participants who complied with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model, and who had available data at baseline and Day 28.

Participants underwent a series of computed tomography (CT) scans with an intravenous (IV) iodinated contrast agent to facilitate assessment of PBV at baseline and at several times points after MK-5475 dosing. Percentage change from baseline (CFB) in PBV was calculated and reported for each dose group that underwent FRI in Part 2. As pre-specified, central tendency for PBV percentage CFB was provided as numerical values rounded to whole numbers. Per protocol, this outcome measure was only assessed during the Part 2 FRI Period for each panel and was not assessed during part 1 and part 3.

Outcome measures

Outcome measures
Measure	Part 1: MK-5475 360 μg n=9 Participants Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.	Part 1: Placebo n=5 Participants Participants received placebo QD via inhalation from Days 1-7.	Part 2: MK-5475 380 μg Participants received MK-5475 380 μg QD via inhalation from Days 1-28.	Part 2: Placebo Participants received placebo QD via inhalation from Days 1-28.
Percent Change From Baseline in Pulmonary Blood Volume (PBV) at Day 28: Part 2	-0.3 Percentage Change Standard Deviation 4.7	-2.8 Percentage Change Standard Deviation 10.6	—	—

Adverse Events

MK-5475 360 µg (Part 1)

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Placebo (Part 1)

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

MK-5475 380 µg (Part 2)

Serious events: 1 serious events

Other events: 2 other events

Deaths: 0 deaths

Placebo (Part 2)

Serious events: 1 serious events

Other events: 4 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	MK-5475 360 µg (Part 1) n=6 participants at risk Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.	Placebo (Part 1) n=3 participants at risk Participants received placebo QD via inhalation from Days 1-7.	MK-5475 380 µg (Part 2) n=9 participants at risk Participants received MK-5475 380 μg QD via inhalation from Days 1-28.	Placebo (Part 2) n=5 participants at risk Participants received placebo QD via inhalation from Days 1-28.
Cardiac disorders Cardiac failure	0.00% 0/6 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	0.00% 0/3 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	0.00% 0/9 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	20.0% 1/5 • Number of events 1 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.
Infections and infestations COVID-19	0.00% 0/6 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	0.00% 0/3 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	11.1% 1/9 • Number of events 1 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	0.00% 0/5 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.
Infections and infestations COVID-19 pneumonia	0.00% 0/6 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	0.00% 0/3 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	11.1% 1/9 • Number of events 1 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	0.00% 0/5 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.
Nervous system disorders Encephalopathy	0.00% 0/6 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	0.00% 0/3 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	11.1% 1/9 • Number of events 1 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	0.00% 0/5 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.
Respiratory, thoracic and mediastinal disorders Acute respiratory distress syndrome	0.00% 0/6 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	0.00% 0/3 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	11.1% 1/9 • Number of events 1 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	0.00% 0/5 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.

Other adverse events

Other adverse events
Measure	MK-5475 360 µg (Part 1) n=6 participants at risk Participants received MK-5475 360 μg once daily (QD) via inhalation from Days 1-7.	Placebo (Part 1) n=3 participants at risk Participants received placebo QD via inhalation from Days 1-7.	MK-5475 380 µg (Part 2) n=9 participants at risk Participants received MK-5475 380 μg QD via inhalation from Days 1-28.	Placebo (Part 2) n=5 participants at risk Participants received placebo QD via inhalation from Days 1-28.
Eye disorders Lacrimation increased	0.00% 0/6 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	0.00% 0/3 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	0.00% 0/9 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	20.0% 1/5 • Number of events 1 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.
General disorders Infusion site extravasation	0.00% 0/6 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	0.00% 0/3 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	11.1% 1/9 • Number of events 1 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	0.00% 0/5 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.
Infections and infestations Urinary tract infection	0.00% 0/6 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	0.00% 0/3 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	0.00% 0/9 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	20.0% 1/5 • Number of events 1 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.
Injury, poisoning and procedural complications Accidental overdose	0.00% 0/6 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	0.00% 0/3 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	0.00% 0/9 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	20.0% 1/5 • Number of events 2 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.
Investigations Blood creatinine increased	0.00% 0/6 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	0.00% 0/3 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	0.00% 0/9 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	20.0% 1/5 • Number of events 1 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.
Nervous system disorders Dizziness	0.00% 0/6 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	0.00% 0/3 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	0.00% 0/9 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	20.0% 1/5 • Number of events 1 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.
Nervous system disorders Headache	33.3% 2/6 • Number of events 2 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	33.3% 1/3 • Number of events 1 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	0.00% 0/9 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	0.00% 0/5 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.
Psychiatric disorders Agitation	0.00% 0/6 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	0.00% 0/3 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	11.1% 1/9 • Number of events 1 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.	20.0% 1/5 • Number of events 1 • Up to approximately 139 days All-cause mortality includes all randomized participants and adverse events include all participants who received at least one dose of study treatment.

Additional Information

Senior Vice President, Global Clinical Development

Merck Sharp & Dohme LLC

Phone: 1-800-672-6372

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee If publication activity is not directed by the Sponsor, the investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect proprietary information and to provide comments.
Publication restrictions are in place

Restriction type: OTHER