Edema formation in congestive heart failure and the underlying mechanisms
Pulmovant Receives Orphan Drug Designation In Japan For Mosliciguat For The Treatment Of Pulmonary Hypertension Associated With Interstitial Lung Disease (PH-ILD)
WALTHAM, Mass., Sept. 04, 2025 (GLOBE NEWSWIRE) -- Pulmovant, a clinical-stage biotechnology company committed to transforming the lives of patients with pulmonary diseases, and a Roivant (Nasdaq: ROIV) company, today announced that Japan's Ministry of Health, Labour and Welfare (MHLW) has granted orphan drug designation (ODD) to mosliciguat, a novel, once-daily, inhaled soluble guanylate cyclase (sGC) activator, currently being studied for the treatment of Pulmonary Hypertension associated with Interstitial Lung Disease (PH-ILD), which is a progressive and life-threatening condition with significant unmet medical need.
"Obtaining orphan drug designation for mosliciguat in Japan validates the significant unmet need that exists for people living with PH-ILD, a progressive and life-threatening cardiopulmonary condition with poor prognosis and limited or no treatment options," said Drew Fromkin, Chief Executive Officer of Pulmovant. "We appreciate the MHLW's recognition of this challenge for PH-ILD patients and look forward to continued collaboration with Japanese regulators as we advance mosliciguat through the next stages of clinical development."
ODD designation is based on the recommendation of Japan's Pharmaceuticals and Medical Devices Agency (PMDA) and provides key regulatory and development incentives, including priority consultation, reduced regulatory fees, and up to 10 years of market exclusivity following potential approval. For more information about Japan's ODD, please visit the MHLW website.
Mosliciguat is a potential first-in-class, once-daily, inhaled sGC activator with a differentiated mechanism of action designed to deliver targeted pulmonary vasodilation with limited systemic side effects for the treatment of PH-ILD. Mosliciguat is currently being evaluated in the Phase 2 PHocus clinical study (NCT06635850), a randomized, double-blind, placebo-controlled, global trial assessing its safety and efficacy in approximately 120 adult patients with PH-ILD. A study-in-progress poster outlining the design of PHocus will be presented at the European Respiratory Society (ERS) International Congress 2025 on September 28th.
About Pulmonary Hypertension and Interstitial Lung DiseasePulmonary hypertension (PH) is a progressive and debilitating condition characterized by high blood pressure in the blood vessels of the lungs. This elevated pressure forces the heart to work harder to pump blood through the lungs, leading to symptoms such as shortness of breath, fatigue, chest pain, and dizziness. The WHO has classified PH into five groups based on their underlying causes, symptoms, and treatment approaches. Group 3 PH is a subtype of PH that arises from lung diseases, such as interstitial lung disease (ILD). ILD describes a large group of diseases that cause progressive damage to the lungs, making it difficult for patients to breathe. Up to 200,000 patients across the U.S. And Europe are living with PH-ILD, a subset of Group 3 PH, and have limited or no approved treatment options. For more information, please visit https://www.Pulmovant.Com/our-science.
About MosliciguatMosliciguat is a potential first-in-class, once-daily, inhaled sGC activator with a differentiated mechanism of action, which may have broad application across the spectrum of pulmonary hypertension (PH). Mosliciguat targets sGC, a key enzyme in the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling pathway that catalyzes cGMP production. Elevated cGMP levels are known to promote vasodilation, reduce inflammation and apoptosis, reverse vascular remodeling, and contribute to anti-fibrotic effects. Unlike sGC stimulators, which require reduced heme and NO to exert their effect, mosliciguat is an sGC activator that is thought to work independently of heme and NO. In the Phase 1b ATMOS study of mosliciguat, a single dose of inhaled mosliciguat in PH patients was well tolerated and led to clinically meaningful, mean peak reduction in pulmonary vascular resistance (PVR) of up to 38%, one of the highest reductions seen in pulmonary hypertension trials to date. For information on the Phase 2 PHocus study of mosliciguat, please visit https://phocusstudy.Com.
About PulmovantPulmovant is a clinical-stage biotechnology company committed to transforming the lives of patients with pulmonary diseases and is a Roivant (Nasdaq: ROIV) company. Pulmovant's first investigational candidate, mosliciguat, is designed to provide a novel, once-daily, inhaled treatment option for patients with pulmonary hypertension associated with Interstitial Lung Disease (PH-ILD). Mosliciguat is a potential first-in-class soluble guanylate cyclase activator with a differentiated mechanism of action currently being evaluated in the Phase 2 PHocus global clinical trial in PH-ILD. For more information, please visit https://www.Pulmovant.Com.
About Roivant
Roivant (Nasdaq: ROIV) is a biopharmaceutical company that aims to improve the lives of patients by accelerating the development and commercialization of medicines that matter. Roivant's pipeline includes brepocitinib, a potent small molecule inhibitor of TYK2 and JAK1 in development for the treatment of dermatomyositis, non-infectious uveitis and cutaneous sarcoidosis; IMVT-1402 and batoclimab, fully human monoclonal antibodies targeting FcRn in development across several IgG-mediated autoimmune indications; and mosliciguat, an inhaled sGC activator in development for pulmonary hypertension associated with interstitial lung disease. We advance our pipeline by creating nimble subsidiaries or "Vants" to develop and commercialize our medicines and technologies. Beyond therapeutics, Roivant also incubates discovery-stage companies and health technology startups complementary to its biopharmaceutical business. For more information, visit www.Roivant.Com.
Forward-Looking Statements
This press release contains forward-looking statements. Statements in this press release may include statements that are not historical facts and are considered forward-looking, which are usually identified by the use of words such as "anticipate," "believe," "continue," "could," "estimate," "expect," "intends," "may," "might," "plan," "possible," "potential," "predict," "project," "should," "would" and variations of such words or similar expressions. The words may identify forward-looking statements, but the absence of these words does not mean that a statement is not forward-looking.
Our forward-looking statements include, but are not limited to, statements regarding our or our management team's expectations, hopes, beliefs, intentions or strategies regarding the future, and statements that are not historical facts, including statements about the clinical and therapeutic potential of our product candidate. In addition, any statements that refer to projections, forecasts or other characterizations of future events or circumstances, including any underlying assumptions, are forward-looking statements.
Although we believe that our plans, intentions, expectations and strategies as reflected in or suggested by those forward-looking statements are reasonable, we can give no assurance that the plans, intentions, expectations or strategies will be attained or achieved. Furthermore, actual results may differ materially from those described in the forward-looking statements and will be affected by a number of risks, uncertainties and assumptions. Moreover, we operate in a very competitive and rapidly changing environment in which new risks emerge from time to time. These forward-looking statements are based upon the current expectations and beliefs of our management as of the date of this press release and are subject to certain risks and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. Except as required by applicable law, we assume no obligation to update publicly any forward-looking statements, whether as a result of new information, future events or otherwise.
© 2025 Pulmovant, Inc. All Rights Reserved. All trademarks are the property of their respective owners.
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Pulmonary Hypertension Requires Multidisciplinary Approach For ... - Healio
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Hospitalizations for pulmonary hypertension have increased from 1980 to 2002, resulting in 200,000 hospitalizations for the condition as a primary or secondary diagnosis during that time. Accurate diagnosis and optimal treatment for pulmonary hypertension is paramount for all health care professionals involved in the management of these patients. Patients with pulmonary hypertension are often treated by cardiologists, pulmonologists or a combination of both. At some centers, fellows may train an extra year in pulmonary hypertension, but formal fellowship training does not currently exist.
"Pulmonary hypertension is a condition that physicians learn about to varying degrees during internal medicine training as well as general pulmonary or cardiology fellowship," Paul Forfia, MD, director of the Pulmonary Hypertension/Right Heart Failure and Pulmonary Thromboendarterectomy Program at the Lewis Katz School of Medicine at Temple University, told Cardiology Today. "There are virtually no dedicated fellowships specific to pulmonary hypertension, and no board certification in pulmonary hypertension."
Over time, awareness and knowledge of pulmonary hypertension and how it affects the heart has grown in the cardiology community.
Over the yearstime, awareness and knowledge of cardiologists have been learning more about pulmonary hypertension and how it affects the heart has grown in the cardiology community.
"There's a lot of excitement in the field because, although we've helped these patients enormously and improved their outcomes and made it more of a chronic disease, we're now looking toward pathways that are not vasodilatory pathways," Mardi I. Gomberg-Maitland, MD, MSc, FACEE, professor of medicine at Virginia Commonwealth University in Maryland and director of the Right Ventricular Failure and HF with Preserved Ejection Fraction unit at Inova Fairfax Heart and Vascular Institute in Virginia, said in an interview.
Robert P. Frantz, MD, FACC, from Mayo Clinic, said cardiologists and pulmonologists are working together closely to optimize diagnosis and treatment of pulmonary hypertension.Source: Ben Hanson/Mayo Clinic. Printed with permission.Despite a wealth of current research and a number of new drugs approved in recent years, patients and cardiologists still face obstacles regarding the diagnosis and treatment of pulmonary hypertension.
"The patients who suffer with this condition, in my mind, are heroes," Robert P. Frantz, MD, FACC, director of the pulmonary hypertension clinic and professor of medicine at Mayo Clinic, told Cardiology Today. "They're remarkable people ... Who need to have attention to their disease that can get overlooked when we're so focused on other, more common problems."
Challenges of pulmonary hypertensionPulmonary hypertension is classified by WHO into five groups: pulmonary artery hypertension, left-heart related, lung/hypoxia related, chronic thromboembolic pulmonary hypertension (CTEPH) and other pulmonary arterial/multifactorial disease. There are multiple pathological drivers of PAH, including abnormal proliferation, inflammation, metabolism, neurohumoral, oxidative stress and dysregulation of vascular tone.
Raymond L. BenzaAlthough the groups appear to be distinct, one of the major issues that heath care providers face is distinguishing between types of pulmonary hypertension.
"The reason why that's so critical is that some of the therapeutics that we use to treat one form of pulmonary hypertension could be deleterious in other forms," Raymond L. Benza, MD, FACC, professor of medicine and program director of advanced HF, transplant, mechanical circulatory system and pulmonary hypertension at Allegheny Health Network in Pittsburgh, told Cardiology Today.
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Guideline-based algorithms are recommended to accurately identify in which group a patient belongs, and that information can help distinguish what type of therapy a patient needs. Without proper tools and knowledge, it commonly takes more than a year to diagnose a patient with pulmonary hypertension, Victor F. Tapson, MD, FCCP, FRCP, professor of medicine, director of clinical research for the Women's Guild Lung Institute, director of the venous thromboembolism and pulmonary vascular disease research program, and associate director of the pulmonary and critical care division at Cedars-Sinai, said in an interview.
A high level of expertise in pulmonary hypertension is not particularly common, including among well-trained cardiologists and well-trained pulmonologists," Forfia said. "You could imagine how difficult it could be for patients when they're short of breath and it ultimately turns out to be related to pulmonary hypertension, and the health care providers that they're seeing are not knowledgeable about the condition itself."
Proper evaluation of pulmonary hypertension requires achieving the best possible understanding of both the context in which it is occurring and its severity. This includes carefully seeking out any associated heart or lung diseases and systemic disorders that may help to explain the pulmonary hypertension.
Incorrect identification or classification of pulmonary hypertension can have devastating consequences. For example, patients with PAH or CTEPH who are not treated may develop right HF that can lead to death. These patients also have increased risk for hospitalizations for right ventricular failure, which can increase the risk for mortality up to 50%.
Nonspecific symptoms of pulmonary hypertension can severely affect a person's life, and some of these include shortness of breath, exercise intolerance, fainting, palpitations, feeling lightheaded and chest discomfort.
Victor F. TapsonAnother challenge is access to medication. Although many medications to treat PAH have been shown to be effective, they are also expensive, even with programs available to partially reduce the cost.
"It can be a difficult disease, causing severe symptoms," Tapson said. "Until a patient is on an appropriate treatment regimen, they can be symptomatic, which is a huge challenge."
Available treatment optionsOnce a patient is diagnosed with pulmonary hypertension, there are many treatment options available based on the type of condition and the underlying disease (see Table below for selected medical therapies).
PAH is treated with medications belonging to one of three classes: endothelin receptor antagonists, nitric oxide pathway drugs and prostanoid therapies.
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"Generally, everyone agrees that therapy should be managed on a risk-associated basis, meaning that higher-risk patients get the higher combinations of drugs and the more invasive medications, the intravenous prostacyclins," Benza said. "The less ill patients possibly can get away with double oral concentrations and maybe in some cases monotherapy."
When operable, patients with WHO group 4 pulmonary hypertension, which is related to CTEPH, should be treated with pulmonary endarterectomy, which involves the removal of chronic thromboembolic material from the pulmonary arteries. Balloon pulmonary angioplasty is another promising treatment option, particularly for patients who are not candidates for open thromboendarterectomy or have residual disease and symptoms despite prior endarterectomy.
When surgical and interventional options are not available or not sufficient, patients with WHO group 4 pulmonary hypertension are treated with medical therapies including riociguat (Adempas, Bayer Healthcare), which is the only FDA-approved treatment for CTEPH. Macitentan (Opsumit, Actelion) may be approved for this indication in the future, Benza said. In the MERIT-1 study published in The Lancet in October, macitentan was well-tolerated in patients with CTEPH. Although riociguat has been shown to be effective for treatment of WHO group 4 pulmonary hypertension, it is expensive, so careful patient selection is important, experts said.
Selexipag (Uptravi, Actelion) is a prostacyclin receptor agonist approved in 2015 that was shown to effectively treat patients with PAH, including many patients already receiving a phosphodiesterase type 5 inhibitor and an endothelin receptor antagonist, in the GRIPHON trial published in The New England Journal of Medicine in 2015.
Treating patients with group 3 or 4 pulmonary hypertension requires multiple approaches.
"The sickest people with PAH need to be started on parenteral prostanoid therapy," Tapson said. "Sometimes we use substantaneous prostanoid therapy, and then we strongly consider adding a second drug subsequently."
In the AMBITION trial, which was published in NEJM in 2015, patients with PAH who were treated with an upfront combination of ambrisentan (Letairis, Gilead) and tadalafil (Adcirca, United Therapeutics) had a decreased risk for clinical-failure events compared with those who were treated with monotherapy.
The role of cardiologists
Paul ForfiaWhether a pulmonologist or a cardiologist cares for a patient with pulmonary hypertension varies from center to center, although cardiologists have assumed a much larger role in care over the past 10 years. At least half of the major pulmonary hypertension programs in the U.S. Listed by the Pulmonary Hypertension Association are either cardiology or combined cardiology/pulmonary centers, Forfia said.
"We should not think of pulmonary hypertension as a condition that belongs to a particular specialty," Forfia said.
According to Benza, the cardiologists' experience in managing right HF lends credence to the greater role with pulmonary hypertension.
However, there are instances where a pulmonologist may be better suited to primarily care for a patient with pulmonary hypertension, such as those with group 3 pulmonary hypertension, as it is related to respiratory diseases.
Regardless of the type of pulmonary hypertension, cardiologists and pulmonologists can work together to care for these patients, and there are centers across the country that utilize health care providers from both areas. One example is Frantz's pulmonary hypertension clinic.
"In our pulmonary hypertension clinic, we deliberately over time have both pulmonologists and cardiologists staffing the clinics so that patients got the best of both worlds," Frantz said.
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Further researchResearch continues into the diagnosis and treatment of pulmonary hypertension.
Ralinepag (Arena) is an oral, next-generation, selective IP receptor agonist that has shown promising results in a phase 2 study, and a phase 3 study is under development.
Pyruvate dehydrogenase kinase inhibitors, used in treating cancer and other diseases, are also being considered as a pulmonary hypertension treatment, Tapson said, noting that similar potential could be seen with certain tyrosine kinase inhibitors.
In addition, he said, tocilizumab (Actemra, Genentech), a monoclonal antibody against the interleukin-6 receptor currently approved for treating rheumatoid arthritis, is being tested as a treatment for PAH, as is rituximab, a generic chimeric monoclonal antibody against the protein CD20 currently used to treat certain cancers and autoimmune diseases.
A potentially simpler way to deliver inhaled treprostinil with a dry powder inhaler is also entering phase 3 clinical trials.
Implantable hemodynamic monitors have been shown benefit in congestive HF and could also be applied to patients with pulmonary arterial hypertension. This allows health care providers to have daily touch points with their patients' hemodynamics.
The pathways involved in pulmonary vascular disease are also not well-understood. Frantz and colleagues at multiple centers across the United States are currently looking at various forms of pulmonary hypertension and performing genomic, proteomic and metabolomic analyses to learn more about the pathways, as part of the NIH-funded Pulmonary Vascular Disease OMICs consortium.
Monitoring the right ventricle when following patients can be a critical tool, but figuring out how to do so is necessary. Experts told Cardiology Today there is a need for proper risk stratification with tools such as algorithms to help identify the presence and type of pulmonary hypertension; this can potentially be done through echocardiography, right heart catheterizations or another technique, and a major focus on echocardiography can help prevent patients from having to undergo right heart catheterizations as frequently.
Another focus area moving forward is expanding the medication landscape for pulmonary hypertension. Although there are currently three classes of drugs, it would be beneficial to find other novel pathways that impact the disease, elicit remodeling of the pulmonary arteries and right ventricle and reverse the proliferative process, Frantz and others said.
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"The holy grail in pulmonary hypertension is trying to identify drugs that will prevent scarring and proliferation of the lung vessels so that they stop thickening and obstructing or even reverse that by favoring what we call apoptosis or programmed cell death so that the cells would actually regress instead of staying in the way. That has been slow-going," Frantz said.
Experts said research is needed on treatment of patients with WHO group 2 and group 3 pulmonary hypertension, especially since most patients present with these kinds of conditions at clinics. The medications available to treat WHO group 1 pulmonary hypertension have generally not been effective or have even been harmful in patients with group 2 and 3 pulmonary hypertension.
Tapson and colleagues at Cedars-Sinai including Eduardo Marban, MD, PhD, and Michael I. Lewis, MD, are currently working on new research on therapies, including bardoxolone, an anti-inflammatory medication, as well as stem cell-type therapy with cardiosphere-derived cell therapy.
"We'd love to see new therapies get us to the point where we don't need parenteral therapies, and maybe not even inhaled therapy," Tapson said. "Perhaps diagnostic testing will be advanced to the point that we no longer need right heart catherization. And we'd like to avoid lung transplantation, which can be necessary occasionally in patients with severe pulmonary hypertension."
Mardi I. Gomberg-MaitlandThe area of pulmonary hypertension is currently evolving, and research in progress could one day lead to vast improvements in treatment.
"In pulmonary vascular disease, there are current and emerging genetic data that should enable us to prioritize better targets and drug development," Gomberg-Maitland said. "The field is moving very quickly." – by Darlene Dobkowski
Disclosures: Benza reports he received research grants from Actelion, Belleraphone, Liquidia and United Therapeutics. Frantz reports he consults for Arena Pharmaceuticals and St. Jude Medical; serves on the steering committee, data and safety monitoring board and adjudication committee for United Therapeutics and is on the steering committee for Actelion Pharmaceuticals. Forfia reports he consulted for Bayer and United Therapeutics. Gomberg-Maitland reports she received Inova Health System from Actelion, AADi and United Therapeutics and consults for Actelion, Acceleron, Bayer, Complexa, Janssen, St. Jude/Abbott, Merck and United Therapeutics. Tapson reports he received research support from Actelion, Arena, Riata and United Therapeutics and consults for Actelion, Riata and United Therapeutics.
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Targeting Molecular Pathway That Causes Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH) is a type of high blood pressure in the lungs, in which blood vessels are narrowed, blocked or destroyed, causing the heart to work harder and, in time, result in cardiac weakness and failure.
The disease is relatively rare, but affects an estimated 100,000 persons in the United States, and results in 20,000 deaths annually. There is no cure.
In a study published May 4, 2022 in Science Translational Medicine, researchers at the University of California San Diego School of Medicine describe the underlying signaling pathway that results in PAH -- and a novel monoclonal antibody therapy that blocks the abnormal blood vessel formation characterizing the disease.
At the cellular level, PAH progresses with proliferation of vascular smooth muscle cells (vSMC) that cause small arteries in the lungs to become narrowed, leading to progressively less oxygen in the blood. A research team, led by senior author Patricia A. Thistlethwaite, MD, PhD, professor of surgery in at UC San Diego School of Medicine and a cardiothoracic surgeon at UC San Diego Health, focused on overexpression of the NOTCH ligand JAGGED-1, a binding protein involved in cell signaling and, in this case, the development of small pulmonary vSMCs.
They found that overexpression of the NOTCH3 ligand, JAGGED-1, spurs vSMC proliferation, but the NOTCH3 ligand DELTA-LIKE 4 inhibits it. The researchers then developed a therapeutic monoclonal antibody that selectively blocks JAGGED-1-induced NOTCH3 signaling, effectively reversing pulmonary hypertension in two rodent models of the disease, without toxic side effects.
"These findings reveal two opposing roles of NOTCH ligands," said Thistlethwaite. "Importantly, it opens the door to a potentially new, safe treatment for PAH, using a monoclonal antibody that selectively inhibits NOTCH3 activation in the lung vasculature."
Co-authors include: Yu Zhang, Moises Hernandez, Jonathan Gower, Nolan Winicki, Xena Morataya, Sebastian Alvarez, Jason X.-J. Yuan and John Shyy, all at UC San Diego.
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