NCT04370873

Frespaciguat (MK-5475) in Participants With Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease (PH-COPD) (MK-5475-006)

Completed Phase 1 Results posted Last updated 28 May 2025

What this trial tests

Phase 1 trial testing Frespaciguat in Pulmonary Hypertension in 22 participants. Completed in 12 January 2022.

Timeline

5 June 2020

Primary endpoint
12 January 2022

12 January 2022

Quick facts

Lead sponsor	Merck Sharp & Dohme LLC
Phase	Phase 1
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	sequential
Masking	double
Primary purpose	treatment
Enrollment	22
Start date	5 June 2020
Primary completion	12 January 2022
Estimated completion	12 January 2022
Sites	9 locations across United States, Israel, Moldova

Drugs / interventions tested

• Frespaciguat — full drug profile →
• Placebo

Conditions studied

• Pulmonary Hypertension — all drugs for Pulmonary Hypertension →

Sponsor

Merck Sharp & Dohme LLC — full company profile →

Who can join

Adults 40 to 80, any sex, with Pulmonary Hypertension. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Participants Who Experienced at Least 1 Adverse Event (AE) Primary · Up to approximately 139 days

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.

Group	Value	95% CI
Part 1: MK-5475 360 μg	33.3
Part 1: Placebo	33.3
Part 2: MK-5475 380 μg	33.3
Part 2: Placebo	80.0

Percentage of Participants Who Discontinued Study Drug Due to an AE Primary · Up to approximately 32 days

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.

Group	Value	95% CI
Part 1: MK-5475 360 μg	0.0
Part 1: Placebo	0.0
Part 2: MK-5475 380 μg	0.0
Part 2: Placebo	0.0

Percentage Change From Baseline to Day 28 in Pulmonary Vascular Resistance (PVR): Part 2 Primary · Baseline (between Day -5 and Day -1) 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.

Group	Value	95% CI
Part 2: MK-5475 380 μg	-21.23	± 16.98
Part 2: Placebo	-5.39	± 49.21

Plasma Area Under the Concentration Time-Curve From 0 to Infinity (AUC0-inf) of MK-5475: Part 1 Secondary · 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

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.

Day 1

Group	Value	95% CI
Part 1: MK-5475 360 μg	3.32	± 68.9

Day 7

Group	Value	95% CI
Part 1: MK-5475 360 μg	4.03	± 90.2

Plasma Area Under the Concentration Time-Curve From 0 to 24 Hours (AUC0-24) of MK-5475: Part 1 Secondary · 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

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.

Day 1

Group	Value	95% CI
Part 1: MK-5475 360 μg	3.31	± 68.7

Day 7

Group	Value	95% CI
Part 1: MK-5475 360 μg	4.22	± 83.5

Maximum Observed Plasma Concentration (Cmax) of MK-5475: Part 1 Secondary · 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

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

Day 1

Group	Value	95% CI
Part 1: MK-5475 360 μg	0.830	± 50.8

Day 7

Group	Value	95% CI
Part 1: MK-5475 360 μg	0.970	± 59.1

Plasma Concentration 24 Hours Postdose (C24) of MK-5475: Part 1 Secondary · 24 hours postdose on Day 7

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.

Group	Value	95% CI
Part 1: MK-5475 360 μg	0.02	± 0.3

Time to Maximum Concentration (Tmax) of MK-5475: Part 1 Secondary · 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

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.

Day 1

Group	Value	95% CI
Part 1: MK-5475 360 μg	1.00	1.00 – 2.00

Day 7

Group	Value	95% CI
Part 1: MK-5475 360 μg	1.00	1.00 – 2.00

Plasma Apparent Terminal Half-Life (t½) of MK-5475: Part 1 Secondary · 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

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

Day 1

Group	Value	95% CI
Part 1: MK-5475 360 μg	2.13	± 18.5

Day 7

Group	Value	95% CI
Part 1: MK-5475 360 μg	2.81	± 48.4

Cmax Accumulation Ratio of MK-5475: Part 1 Secondary · 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

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.

Group	Value	95% CI
Part 1: MK-5475 360 μg	1.17	± 28.8

AUC0-24 Accumulation Ratio of MK-5475: Part 1 Secondary · 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

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.

Group	Value	95% CI
Part 1: MK-5475 360 μg	1.27	± 30.1

AUC0-inf Accumulation Ratio of MK-5475: Part 1 Secondary · 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

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.

Group	Value	95% CI
Part 1: MK-5475 360 μg	1.21	± 31.1

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to approximately 139 days. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

MK-5475 360 µg (Part 1)

Serious: 0/6 (0%)

Deaths: 0/6

Placebo (Part 1)

Serious: 0/3 (0%)

Deaths: 0/3

MK-5475 380 µg (Part 2)

Serious: 1/9 (11%)

Deaths: 0/9

Placebo (Part 2)

Serious: 1/5 (20%)

Deaths: 0/5

Serious adverse events (5 terms)

Reaction	System	MK-5475 360 µg (Part 1)	Placebo (Part 1)	MK-5475 380 µg (Part 2)	Placebo (Part 2)
Cardiac failure	Cardiac disorders	—	—	—	—
COVID-19	Infections and infestations	—	—	—	—
COVID-19 pneumonia	Infections and infestations	—	—	—	—
Encephalopathy	Nervous system disorders	—	—	—	—
Acute respiratory distress syndrome	Respiratory, thoracic and mediastinal disorders	—	—	—	—

Other adverse events (8 terms — click to expand)

Reaction	System	MK-5475 360 µg (Part 1)	Placebo (Part 1)	MK-5475 380 µg (Part 2)	Placebo (Part 2)
Headache	Nervous system disorders	—	—	—	—
Lacrimation increased	Eye disorders	—	—	—	—
Infusion site extravasation	General disorders	—	—	—	—
Urinary tract infection	Infections and infestations	—	—	—	—
Accidental overdose	Injury, poisoning and procedural complications	—	—	—	—
Blood creatinine increased	Investigations	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—
Agitation	Psychiatric disorders	—	—	—	—

Most-reported serious reactions: Cardiac failure, COVID-19, COVID-19 pneumonia, Encephalopathy, Acute respiratory distress syndrome.

Data from ClinicalTrials.gov NCT04370873 adverse events section.

Sponsor's own description

The primary objectives of this study are to assess the safety/tolerability and efficacy (by evaluating changes in pulmonary vascular resistance \[PVR\] and pulmonary blood volume \[PBV\]) of frespaciguat in participants with pulmonary hypertension associated with chronic obstructive pulmonary disease (PH-COPD). The primary hypothesis is that 28 days of frespaciguat treatment is superior to placebo treatment in reduction of PVR.

Publications & conference data

2 peer-reviewed publications reference this trial (live from Europe PMC):

1. Phase 1 Study of MK-5475, an Inhaled Soluble Guanylate Cyclase Stimulator, in Participants with Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Disease.
   Bajwa EK, Cislak D, Kumar A, Li D, et al · · 2024 · cited 7× · PMID 38803412 · DOI 10.2147/copd.s454905
2. Management of Pulmonary Hypertension Due to Chronic Lung Disease.
   Sugarman J, Weatherald J. · · 2021 · cited 6× · PMID 34326932 · DOI 10.14797/zkut3813