Pathogenesis of pulmonary hypertension caused by left heart disease

Nerandomilast Improves Lung Function In Progressive Pulmonary Fibrosis: FIBRONEER-ILD

Patients with progressive pulmonary fibrosis who received nerandomilast showed improved forced vital capacity from baseline at 52 weeks in the phase 3 FIBRONEER-ILD trial.

Nerandomilast met its primary end point of absolute change from baseline in forced vital capacity (FVC) vs placebo in the FIBRONEER-ILD trial (NCT05321082), which assessed the agent in patients with progressive pulmonary fibrosis (PPF).1 Boehringer Ingelheim will submit a new drug application for the investigational agent to the FDA and other health authorities based on the findings, according to a press release.

The FIBRONEER-ILD trial was a double-blind, randomized trial that included 1178 patients in more than 40 countries, and the primary end point was absolute change from baseline in FVC (mL) at week 52 vs placebo. Topline data showed that the trial met its primary end point, with full efficacy and safety data to be shared in the second quarter of 2025.

Nerandomilast is an investigational oral, preferential inhibitor of phosphodiesterase 4B that has shown promise in IPF and PPF.Image credit: Елена Бутусова - stock.Adobe.Com

FIBRONEER-ILD is the second phase 3 trial of nerandomilast that met its primary end point. The first was the FIBRONEER-IPF study (NCT05321069), which showed an increase in FVC from baseline at week 52 in patients with idiopathic pulmonary fibrosis (IPF).2 In both the FIBRONEER-ILD and FIBRONEER-IPF trials, initial safety and tolerability results are consistent with those seen in phase 2 trials conducted in patients with IPF, with overall adverse events comparable in the treatment and placebo cohorts.1

A key secondary end point in FIBRONEER-ILD is a composite measure including time to first acute interstitial lung disease (ILD) exacerbation, first hospitalization for respiratory cause, or death—whichever occurs first—during the trial. This is also the key secondary end point in the FIBRONEER-IPF trial.

Nerandomilast is an investigational oral, preferential inhibitor of phosphodiesterase 4B, and patients treated in the FIBRONEER-ILD trial received either 9 mg of nerandomilast, 18 mg of nerandomilast, or a placebo twice per day for at least 52 weeks. Phase 2 results support the twice-daily dose of 18 mg, and the twice-daily 9 mg dose was added to provide additional dose-response and exposure-response data and assess the benefit-risk profile at a reduced dose.

In February 2022, nerandomilast was granted FDA breakthrough therapy designation for IPF, which is a type of progressive fibrosing ILD that causes symptoms including activity-induced breathlessness, a persistent dry cough, fatigue, and weakness. PPF is phenotype of non-IPF fibrosing ILD that is characterized by worsened respiratory symptoms and disease progression based on physiological and radiological evidence.

"The positive FIBRONEER-ILD topline result shows the potential of nerandomilast in progressive pulmonary fibrosis. The hope is that the safety and tolerability profile we are initially seeing could potentially help to reduce treatment challenges," Shashank Deshpande, head of Human Pharma and member of the board of managing directors at Boehringer Ingelheim, said in a statement. "The recent milestones of the FIBRONEER trial program underscore our commitment to transforming the lives of patients with this debilitating disease, and are a testament to Boehringer Ingelheim's position at the forefront of pulmonary fibrosis research."

References

1. Boehringer's nerandomilast meets primary endpoint in phase III study FIBRONEER-ILD, in progressive pulmonary fibrosis. News release. Boehringer Ingelheim. February 10, 2025. Accessed February 13, 2025. Https://www.Boehringer-ingelheim.Com/human-health/lung-diseases/pulmonary-fibrosis/nerandomilast-primary-endpoint-phase-3-fibroneer-ild-pulmonary-fibrosis

2. Boehringer's nerandomilast meets primary endpoint in pivotal phase-III FIBRONEER-IPF study. News release. Boehringer Ingelheim. September 16, 2024. Accessed February 13, 2025. Https://www.Boehringer-ingelheim.Com/us/topline-results-boehringers-phase-iii-ipf-study

Pulmonary Fibrosis: Study Targets Proteins To Reverse Lung Scarring

A discovery at Duke-NUS Medical School offers new hope in the battle against pulmonary fibrosis, a debilitating lung condition that progressively makes it harder for patients to breathe. Scientists have pinpointed proteins in immune cells that, when blocked, could significantly reduce lung tissue scarring.

Current treatments primarily manage symptoms and improving quality of life, without addressing the underlying cause of pulmonary fibrosis.

Although macrophages, a type of immune cell, had previously been known to contribute to inflammation and scarring in pulmonary fibrosis, the underlying mechanisms remained unclear. After discovering that two proteins in macrophages -- YAP and TAZ -- are involved in heart scarring, researchers from the School sought to determine whether these proteins play a similar role in the lungs and to better understand how their activity influences disease progression.

YAP and TAZ are part of a critical molecular pathway that usually helps cells grow and repair. However, in a preclinical model of pulmonary fibrosis, the researchers discovered that these proteins can also contribute to harmful scarring.

In their study, published in the European Respiratory Journal, the researchers found that blocking YAP and TAZ can curb scar formation and restore the immediate environment to one that encourages regeneration in three ways:

Dampening a loud call to arms: YAP and TAZ drive inflammation by amplifying the effect of a molecule called CCL2. Like a homing beacon, this signalling molecule attracts various immune cells to the affected areas of the lungs during injuries. However, when recruited to the lungs in excess, these immune cells can harm the organs by causing uncontrolled inflammation, leading to tissue scarring. Disrupting the connection between the two proteins and CCL2 reduces the number of immune cells recruited, impeding tissue scarring.

Maintaining a healthy immune cell ratio: YAP and TAZ can harm the lungs by increasing inflammatory immune cell levels, amplifying tissue inflammation. When these proteins are removed, immune cells that help to repair and regenerate damaged tissue outnumber their inflammatory counterparts, reducing lung inflammation and allowing the organ to heal more effectively.

Disrupting the proteins' communication with a nearby pathway: These proteins can also exacerbate pulmonary fibrosis by influencing macrophages' interaction with fibroblasts, which are nearby cells that are key to repairing damaged tissue and maintaining organ structure. Unregulated macrophage activity excessively signals fibroblasts to respond to an injury in the lungs, leading to tissue scarring. Inhibiting YAP and TAZ interrupts the communication between macrophages and fibroblasts, reducing damage to the lungs.

Principal Research Scientist Dr Md Masum Mia from Duke-NUS' Cardiovascular and Metabolic Disorders Programme, the study's first author, said of the findings:

"This breakthrough not only deepens our understanding of the specific molecular mechanisms responsible for pulmonary fibrosis, but could also lead to treatments that halt or even reverse lung scarring in the disease."

Paving the way for new treatment options for pulmonary fibrosis

Global early-phase clinical trials for novel therapies that target YAP and TAZ in cancers, which are characterised by immune-driven inflammation and scarring, are underway, and the research team is exploring if such therapies are viable for treating patients with pulmonary fibrosis.

Associate Professor Manvendra Kumar Singh from Duke-NUS' Cardiovascular and Metabolic Disorders Programme, the study's senior author, said of the next steps for the project:

"Pulmonary fibrosis is strongly linked to the unregulated activity of immune and connective tissue cells as well as the loss of epithelial cells. By delving into these interactions that drive tissue scarring, we can gain deeper insights and uncover potential therapeutic targets for treatment. Next, we will further validate the roles of YAP and TAZ in the disease and confirm the effectiveness of therapies that inhibit these proteins, offering patients better outcomes."

In addition to pulmonary fibrosis, YAP and TAZ are also implicated in heart, liver and kidney fibrosis, suggesting that therapies targeting these proteins could offer broader therapeutic potential for a range of fibrotic diseases.

Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, commented:

"By focusing on the root causes of fibrosis, our novel therapeutic approach offers the potential not just to manage but to significantly halt or reverse the progression of pulmonary fibrosis. This breakthrough could dramatically improve patient outcomes, reduce long-term healthcare costs, and ultimately enhance life expectancy and quality for sufferers globally."

This new research, part of Duke-NUS' efforts to develop biomedical solutions that improve the lives of patients, is supported by the National Research Foundation, Singapore under the National Medical Research Council (NMRC) Open Fund-Individual Research Grant (MOH-001625) and the Open Fund-Young Individual Research Grant (MOH-001130) and administered by the Singapore Ministry of Health through the NMRC Office, MOH Holdings Pte Ltd.

Researchers Uncover The Source Of Cells That Contribute To Pulmonary Fibrosis

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