Inhaled sGC Stimulator for Pulmonary Hypertension and COPD

Not currently recruiting at 113 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Merck Sharp & Dohme LLC

Must be taking: PDE5 inhibitors

Must not be taking: PAH-specific therapies

Disqualifiers: Group 1 PAH, Sleep apnea, Heart disease, Renal insufficiency, Cancer, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 24 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a new inhaled medication, frespaciguat (also known as MK-5475), can help people with pulmonary hypertension caused by chronic obstructive pulmonary disease (PH-COPD) walk farther in six minutes after 24 weeks. The study compares frespaciguat to a placebo (a pill without active medicine) to determine which works better. Suitable candidates include those with PH-COPD who are stable on current medication and not expecting major changes to their treatment plan. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop your current medications. However, if you are on a PDE5 inhibitor, antihypertensives, diuretics, or anticoagulants, you must have stable use of these medications. Changes to PDE5 inhibitor dosing are not allowed during the trial.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that frespaciguat, also known as MK-5475, is safe for people with pulmonary hypertension (PH). Previous studies found that patients tolerated this treatment well, with no major side effects. One study indicated that it didn't cause any systemic side effects. Instead, it specifically helped reduce pressure in the lung blood vessels.

The treatment is now in Phase 2 trials, indicating that earlier tests have already demonstrated its safety. This phase is crucial for confirming safety in larger groups. While more research continues, initial results are promising for those considering joining a trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for pulmonary hypertension?

Unlike the standard treatments for pulmonary hypertension and COPD, which often include oral medications and inhalers targeting symptoms, frespaciguat offers a unique approach. This treatment is an inhaled sGC stimulator, which directly targets the underlying vascular issues by enhancing nitric oxide signaling in the lungs. This mechanism can potentially improve blood flow and reduce pulmonary artery pressure more effectively. Researchers are excited about frespaciguat because its inhalation method delivers the medication directly to the lungs, which could lead to faster and more targeted effects compared to systemic treatments.

What evidence suggests that frespaciguat might be an effective treatment for pulmonary hypertension caused by COPD?

Research has shown that frespaciguat, a treatment under study in this trial, may help treat pulmonary hypertension, which is high blood pressure in the lungs. In earlier studies, frespaciguat lowered resistance to blood flow in the lungs by stimulating an enzyme called soluble guanylate cyclase. This could improve blood flow and reduce heart strain. Participants in this trial may receive frespaciguat, and early results suggest it might help those with pulmonary hypertension due to COPD walk longer distances, potentially enhancing their quality of life. ^{1 3 4 5 6}

Who Is on the Research Team?

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Are You a Good Fit for This Trial?

Adults aged 40-85 with Pulmonary Hypertension associated with Chronic Obstructive Pulmonary Disease (PH-COPD) can join this trial. They must have stable oxygen, anticoagulant, and COPD therapy regimens, and not be pregnant or planning a transplant. Exclusions include significant heart disease, recent severe COPD exacerbations, certain past medical conditions like cancer or drug abuse.

Inclusion Criteria

My oxygen use is consistent and hasn't changed recently.

My COPD treatment is stable and optimized.

I am between 40 and 85 years old.

Exclusion Criteria

I had a serious COPD flare-up in the last 2 months.

I started a lung rehab program within the last 2 months.

I have had right heart failure in the last 2 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 380 µg of MK-5475 or placebo as an oral inhalation once daily for 24 weeks

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension (optional)

Participants may opt into continuation of treatment with MK-5475 for up to 42 months

Up to 42 months

What Are the Treatments Tested in This Trial?

Interventions

• MK-5475

Trial Overview The study tests the effectiveness of MK-5475 (an inhaled sGC stimulator) against a placebo in improving walking distance over six minutes after 24 weeks. Participants will use MK-5475 daily through inhalation to see if it helps better than a non-active treatment.

How Is the Trial Designed?

Group I: Frespaciguat Experimental Treatment 1 Intervention

Participants with PH-COPD will receive 380 µg of frespaciguat as an oral inhalation once daily for 24 weeks (base period) and thereafter for up to 42 months (optional extension period).

Group II: Placebo Placebo Group 2 Interventions

Participants with PH-COPD will receive matching placebo as an oral inhalation once daily for 24 weeks (base period) and then 380 µg of frespaciguat as an oral inhalation once daily for up to 42 months (optional extension period).

Who Is Running the Clinical Trial?

Merck Sharp & Dohme LLC

Lead Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Published Research Related to This Trial

The self-carried nanodrug SCND-SIS3, developed from the Smad3 inhibitor SIS3, significantly improves solubility and bioavailability while reducing nephrotoxicity, making it a safer option for lung cancer treatment.

In a mouse model of lung cancer, SCND-SIS3 demonstrated superior anti-cancer effects, inducing tumor cell death and enhancing immune responses, achieving comparable efficacy to unmodified SIS3 at only one-fifth the dose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Self-carried nanodrug (SCND-SIS3): A targeted therapy for lung cancer with superior biocompatibility and immune boosting effects. Lian, GY., Wan, Y., Mak, TS., et al.[2022]

Recent research has made significant strides in understanding squamous cell lung cancer (SCC), identifying new genomic and signaling pathways that could lead to targeted therapies.

Emerging prognostic gene signatures and predictive biomarkers are paving the way for innovative clinical trials, such as the Lung-MAP master protocol, aimed at improving treatment options for patients with advanced SCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Squamous cell lung cancer: from tumor genomics to cancer therapeutics. Gandara, DR., Hammerman, PS., Sos, ML., et al.[2023]

Using a computational simulator, the study found that a soluble guanylate cyclase (sGC) modulator can worsen oxygen levels (PaO2) and increase carbon dioxide levels (PaCO2) when administered systemically in patients with COPD and pulmonary hypertension, consistent with previous clinical findings.

However, when the sGC modulator is delivered via dry powder inhalation (DPI), it does not negatively affect oxygenation and actually improves oxygen levels during exercise, suggesting a more effective delivery method for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhaled sGC Modulator Can Lower PH in Patients With COPD Without Deteriorating Oxygenation. Saffaran, S., Wang, W., Das, A., et al.[2019]

In the 12-week PATENT-1 study, riociguat significantly improved the 6-minute walking distance and WHO functional class in patients with pulmonary arterial hypertension associated with connective tissue disease (PAH-CTD), with these benefits lasting for up to 2 years.

The safety profile of riociguat in PAH-CTD patients was comparable to that of the overall study population, and the 2-year survival rate for these patients was 93%, similar to those with idiopathic PAH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Riociguat for the treatment of pulmonary arterial hypertension associated with connective tissue disease: results from PATENT-1 and PATENT-2. Humbert, M., Coghlan, JG., Ghofrani, HA., et al.[2022]

The METxMET-M114 antibody-drug conjugate (ADC) shows significant and lasting tumor regression in models of lung cancer with high MET expression, including those resistant to existing MET-targeted therapies.

In a toxicology study on cynomolgus monkeys, METxMET-M114 was well tolerated at effective doses, indicating its potential safety and efficacy for treating MET-overexpressing tumors in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Biparatopic Antibody-Drug Conjugate to Treat MET-Expressing Cancers, Including Those that Are Unresponsive to MET Pathway Blockade. DaSilva, JO., Yang, K., Surriga, O., et al.[2023]

Bevacizumab, an angiogenesis inhibitor, has been shown to significantly prolong overall survival and progression-free survival in patients with inoperable, advanced non-small-cell lung cancer when used with chemotherapy, based on two recent phase-III studies.

While bevacizumab can cause manageable side effects like hypertension and proteinuria, careful patient selection can minimize the risk of serious complications such as pulmonary bleeding.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Bevacizumab in the first-line therapy of advanced NSCLC]. Hasenöhrl, N.[2018]

Combining bevacizumab with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) significantly prolongs progression-free survival (PFS) and increases the objective response rate (ORR) in patients with advanced non-small cell lung cancer (NSCLC), based on a meta-analysis of five randomized controlled trials involving 1301 articles.

However, this combination treatment does not significantly improve overall survival (OS) and is associated with an increased risk of serious adverse events, indicating a need for careful consideration of safety when using this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of bevacizumab combined with EGFR-TKIs in advanced non-small cell lung cancer: A meta-analysis. Yang, Y., Wang, L., Li, X., et al.[2022]

In the PATENT-1 trial, riociguat significantly improved the 6-minute walking distance (6MWD) by an average of 39 meters in patients with pulmonary arterial hypertension after congenital heart disease correction, compared to no improvement in the placebo group.

Riociguat was well tolerated over the long term in the PATENT-2 extension study, showing sustained efficacy in improving clinical outcomes such as pulmonary vascular resistance (PVR) and WHO functional class over a 2-year period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Riociguat for pulmonary arterial hypertension associated with congenital heart disease. Rosenkranz, S., Ghofrani, HA., Beghetti, M., et al.[2020]

BAY-1165747 (BAY-747) is a highly potent second-generation soluble guanylate cyclase (sGC) stimulator that demonstrated a long-lasting decrease in mean arterial blood pressure in hypertensive models, indicating its potential effectiveness in treating hypertension.

With an excellent pharmacokinetic profile, including a long half-life and low peak-to-trough ratio, BAY-747 could serve as a valuable treatment option for patients with resistant hypertension, especially those who do not respond to standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification and characterization of the new generation soluble guanylate cyclase stimulator BAY-747 designed for the treatment of resistant hypertension. Wunder, F., Stasch, JP., Knorr, A., et al.[2023]

Soluble guanylate cyclase (sGC) stimulators, particularly riociguat, have shown significant efficacy in improving pulmonary vascular function and exercise capacity in patients with pulmonary hypertension (PH), as demonstrated in clinical trials.

Riociguat not only reduces mean pulmonary arterial pressure but also improves cardiac output and vascular resistance in various forms of PH, indicating its potential as a valuable new therapy for this condition and possibly other diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Soluble guanylate cyclase stimulators in pulmonary hypertension. Stasch, JP., Evgenov, OV.[2022]

Riociguat is a newly approved medication by the FDA specifically designed to treat pulmonary arterial hypertension in adults, representing a significant advancement in treatment options.

The approval of riociguat is supported by the results of the PATENT-1 study, which demonstrated its efficacy as a potent and specific stimulator of soluble guanylate cyclase.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Riociguat: PATENT-1 Study. Said, K.[2020]

Riociguat is a newly identified potent stimulator of soluble guanylate cyclase (sGC) that shows promise for treating pulmonary hypertension (PH) due to its improved drug metabolism and pharmacokinetic properties compared to previous sGC stimulators.

In clinical trials, riociguat has demonstrated strong effects on pulmonary blood flow and exercise capacity in patients with PH, indicating its potential as an effective oral treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discovery of riociguat (BAY 63-2521): a potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension. Mittendorf, J., Weigand, S., Alonso-Alija, C., et al.[2016]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05612035

Study Details | NCT05612035 | Frespaciguat (MK-5475) ... Researchers are looking for ways to treat pulmonary hypertension (PH) caused by chronic obstructive pulmonary disease (COPD). The goal of the study is to ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11129706/

Phase 1 Study of MK-5475, an Inhaled Soluble Guanylate ... This phase 1 study (NCT04370873) evaluated safety and pharmacokinetics/pharmacodynamics (PK/PD) of MK-5475 in participants with pulmonary hypertension ...

3. merckclinicaltrials.com merckclinicaltrials.com/trial/nct05612035/

MK-5475-013 INSIGNIA-PH-COPD: A Study of the Efficacy ... The purpose of this study is to evaluate the safety and efficacy of once daily oral inhalation dose of MK-5475 380 μg in participants 40 to 85 years (inclusive)

4. publications.ersnet.org publications.ersnet.org/content/erj/64/5/2401110

MK-5475, an inhaled soluble guanylate cyclase stimulator, for ... The inhaled soluble guanylate cyclase stimulator MK-5475 reduced PVR and was well tolerated in patients with PAH, without evidence of systemic side-effects ...

5. clinicaltrial.be clinicaltrial.be/en/details/188163?per_page=20&only_recruiting=0&only_eligible=0&only_active=0

Frespaciguat (MK-5475) INSIGNIA-PH-COPD: A Study of ... The goal of the study is to learn if people who take frespaciguat can walk farther in 6 minutes at Week 24 compared to people who take placebo.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38803412/

Phase 1 Study of MK-5475, an Inhaled Soluble Guanylate ... Conclusion: The favorable safety profile and numerical reductions in PVR observed support further clinical development of inhaled MK-5475 for PH ...