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

NCT04370873 | Completed Phase 1 Results FDA Drug

• 3 other identifiers: 5475-006MK-5475-0062020-000488-22
• Study Type: interventional
• Target: 22
• Locations: 3 countries
• Sites: 9

Brief Summary

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.

Conditions

Pulmonary Hypertension

Outcome Measures

Primary Outcomes (3)

• Percentage of Participants Who Experienced at Least 1 Adverse Event (AE)

  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.

  Up to approximately 139 days

• Percentage of Participants Who Discontinued Study Drug Due to an AE

  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.

  Up to approximately 32 days

• Percentage Change From Baseline to Day 28 in Pulmonary Vascular Resistance (PVR): Part 2

  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.

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

Secondary Outcomes (18)

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

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

  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

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

  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 24 Hours Postdose (C24) of MK-5475: Part 1

  24 hours postdose on Day 7

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

  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

Study Arms (4)

Part 1: Frespaciguat

EXPERIMENTAL

Participants receive frespaciguat 360 μg once daily (QD) via inhalation from Days 1-7. Following review of pharmacokinetic (PK) and safety data, a second 7 days of dosing may be initiated. A dose of up to 360 μg up to twice a day may be administered based on PK data in these participants.

Drug: Frespaciguat

Part 1: Placebo

PLACEBO COMPARATOR

Participants receive placebo QD via inhalation from Days 1-7.

Drug: Placebo

Part 2: Frespaciguat

EXPERIMENTAL

Participants receive frespaciguat 32 µg, 100 µg, 195 µg or 380 μg QD via inhalation from Days 1-28.

Drug: Frespaciguat

Part 2: Placebo

PLACEBO COMPARATOR

Participants receive placebo QD via inhalation from Days 1-28.

Drug: Placebo

Interventions

Frespaciguat DRUG

Frespaciguat 32 µg, 100 µg, 195 µg, 360 µg or 380 µg administered as dry powder inhalation according to randomization. Following review of pharmacokinetic (PK) and safety data, a second 7 days of dosing may be initiated. A dose of up to 360 μg up to twice a day may be administered based on PK data. Dosage may be adjusted downwards in Part 2, if indicated by PK results in Part 1.

Also known as: MK-5475

Part 1: Frespaciguat; Part 2: Frespaciguat

Placebo DRUG

Placebo administered as dry powder inhalation according to randomization

Part 1: Placebo; Part 2: Placebo

Eligibility Criteria

• Age: 40 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Is male or female, from 40 to 80 years of age inclusive at the time of signing informed consent.
• Be judged to have no untreated, clinically significant health issue from other comorbidities based on medical history, physical examination, vital signs and electrocardiograms performed at the screening visit(s)
• Be judged to have no untreated, clinically significant health issue from other comorbidities based on laboratory safety tests performed at the screening visit(s)
• Male participants are eligible to participate if they agree to the following during the intervention period and for at least 14 days, corresponding to time needed to eliminate study intervention(s) (eg, 5 terminal half-lives) plus an additional 90 days (a spermatogenesis cycle) after the last dose of study intervention. Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent or agrees to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause
• A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: She is a woman of nonchildbearing potential (WONCBP) or is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of \<1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis)
• Have been diagnosed with mild to severe Chronic Obstructive Pulmonary Disease (COPD) according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) diagnostic criteria (postbronchodilator forced expiratory volume in 1 second (FEV1)/ forced vital capacity (FVC) ratio \< 0.7)
• Has Modified Medical Research Council (MMRC) Dyspnea Score in the range of 1 through 3 at screening
• Be deemed clinically stable by the investigator
• Be or have suspected Pulmonary Hypertension Group 3 in particular: COPD
• Have a history of right heart catheterization (RHC) within 3 years of starting study medication demonstrating mean pulmonary artery pressure (mPAP) ≥ 25mmHg and pulmonary vascular resistance (PVR) ≥ 3.75 Woods units or 300 dynes/sec/cm or have an echocardiogram performed by the investigator (or appropriate designee) at screening or within 1 year of screening demonstrating pulmonary artery systolic pressure ≥ 38 mmHg (Part 1 only) or ≥ 50 mmHg (Part 2 only) in conjunction with one or more of the following: tricuspid regurgitation velocity \>3 m/s or significant right heart enlargement and or reduced right heart function

You may not qualify if:

• Has pulmonary hypertension subtypes including the following according to Nice 2013 Clinical classification. This includes Group 1 Pulmonary arterial hypertension (PAH): Idiopathic PAH, Heritable PAH including Bone morphogenetic protein receptor type II (BMPR2), Activin A receptor type II-like kinase-1 (ALK1), endoglin, Sterile alpha motif domain-containing protein 9 (SMAD9), caveolin 1 (CAV1), potassium two-pore-domain channel subfamily K member 3 (KCNK3) and unknown, Drug and toxin-induced PAH, PAH associated with Connective tissue disease, HIV infection, Portal hypertension, Congenital heart disease (unrepaired and not requiring repair or repaired simple cardiac defects at least 1year status post corrective surgery, with no clinically significant residual shunt), Schistosomiasis, Chronic hemolytic anemia, Persistent pulmonary hypertension of the newborn (PPHN), and Pulmonary veno-occlusive disease (PVOD) and or pulmonary capillary hemangiomatosis (PCH); Group 2 Pulmonary hypertension owing to left heart diseases including Left ventricular Systolic dysfunction, Left ventricular Diastolic dysfunction, Valvular disease, Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies; Group 3 Pulmonary hypertension owing to lung diseases or hypoxia not associated with COPD including Interstitial lung disease, Other pulmonary diseases with mixed restrictive and obstructive pattern, Sleep-disordered breathing (mild obstructive sleep apnea (OSA) may be permitted with sponsor consultation), Alveolar hypoventilation disorders. Chronic exposure to high altitude, Developmental abnormalities; Group 4 Pulmonary hypertension defined as Chronic thromboembolic pulmonary hypertension \[CTEPH\]); and Group 5 Pulmonary Hypertension with unclear multifactorial mechanisms including Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders, Splenectomy, Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleimyomatosis, neurofibromatosis, vasculitis, Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders, and Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental pulmonary hypertension.
• Has a history of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic (not including chronic stable Hep B and C), immunological, renal, respiratory (not including PH-COPD), genitourinary, or major neurological (including stroke and chronic seizures) abnormalities or diseases
• Is mentally or legally incapacitated, has significant emotional problems at the time of pre-study (screening) visit or expected during the conduct of the study or has a history of clinically significant psychiatric disorder of the last 5 years. Participants who have had situational depression may be enrolled in the study at the discretion of the investigator
• Has a history of cancer (malignancy) except adequately treated nonmelanomatous skin carcinoma or carcinoma in situ of the cervix or other malignancies which have been successfully treated with appropriate follow up and therefore unlikely to recur for the duration of the study, in the opinion of the investigator and with agreement of the Sponsor
• Has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy), or has had an anaphylactic reaction or significant intolerability (ie, systemic allergic reaction) to prescription or non-prescription drugs or food
• Is positive for hepatitis B surface antigen (HBsAg) \[acute infection\] or HIV (participants with positive HBsAG that demonstrate low viral load (chronic stable infection) are permitted.
• Part 2 only: Has known sensitivity to iodine or iodine containing products
• Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to the prestudy (screening) visit.
• Has persistent or permanent atrial fibrillation with uncontrolled ventricular rate (participants with paroxysmal atrial fibrillation or controlled atrial fibrillation with no clinically significant arrhythmia may be allowed per the judgement of the investigator)
• Has history of combined pulmonary fibrosis and emphysema (CPFE) or severe bullous emphysema. If no history, a confirmed negative high-resolution computerized tomography scan (HRCT) for these conditions needs to have been performed within last 2 ears.
• Has an active respiratory infection (common cold, influenza, pneumonia, acute bronchitis) with lung function values (FEV1 and/or FEV1/FVC ratio) that do not meet eligibility range
• Has a physical limitation that will inhibit the participant to effectively perform low intensity exercise testing (e.g. severe arthritis of the hip or knee)
• Is unable to refrain from or anticipates the use of any medication, including prescription and nonprescription drugs or herbal remedies beginning approximately 2 weeks (or 5 half-lives) prior to administration of the initial dose of study drug, throughout the study (including washout intervals between treatment periods), until the poststudy visit. There may be certain medications that are permitted
• Is currently on monotherapy calcium channel blockers as a specific treatment for pulmonary hypertension
• Is currently taking nitrates, inhaled prostacyclin, immediate or extended release diltiazem, phosphodiesterase 5 (PDE5) inhibitors or soluble guanylate cyclase (sGC) or activators for the treatment of pulmonary hypertension. Participants previously using medications to treat pulmonary arterial hypertension may be enrolled provided they have been off therapy for at least 2 weeks prior to the start of the screening period

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Study Sites (9)

Lexington VA- Health Care System ( Site 0034)

Lexington, Kentucky, 40502, United States

Location

Johns Hopkins - University ( Site 0003)

Baltimore, Maryland, 21205, United States

Location

Massachusetts General Hospital ( Site 0005)

Boston, Massachusetts, 02114, United States

Location

Brigham & Women's Hospital ( Site 0001)

Boston, Massachusetts, 02115, United States

Location

University of Rochester Medical Center ( Site 0012)

Rochester, New York, 14642, United States

Location

Medical Universtiy of South Carolina ( Site 0011)

Charleston, South Carolina, 29425, United States

Location

Rambam Medical Center ( Site 0037)

Haifa, 3109601, Israel

Location

Rabin Medical Center ( Site 0035)

Petah Tikva, 4941492, Israel

Location

Republican Clinical Hospital of Moldova ( Site 0013)

Chisinau, 2025, Moldova

Location

Related Publications (1)

• Bajwa EK, Cislak D, Kumar A, Li D, Messina EJ, Reynders T, Denef JF, Corcea V, Buch KP, Lai E, Stoch SA. Phase 1 Study of MK-5475, an Inhaled Soluble Guanylate Cyclase Stimulator, in Participants with Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Disease. Int J Chron Obstruct Pulmon Dis. 2024 May 23;19:1105-1121. doi: 10.2147/COPD.S454905. eCollection 2024.

  PMID: 38803412 RESULT

MeSH Terms

Conditions

Hypertension, Pulmonary

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Hypertension; Vascular Diseases; Cardiovascular Diseases

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme LLC

ClinicalTrialsDisclosure@msd.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Part 1 enrolled immediately. Part 2 enrolled following review of Part 1 pharmacokinetic data. A third part was planned but did not enroll because Part 2 yielded sufficient data and Part 3 was optional per protocol.

Study Record Dates

• First Submitted: April 29, 2020
• First Posted: May 1, 2020
• Study Start: June 5, 2020
• Primary Completion: January 12, 2022
• Study Completion: January 12, 2022
• Last Updated: May 28, 2025
• Results First Posted: April 26, 2024

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will share

Locations

MO (1); US (6); IL (2)