Key Clinical Summary: Decoding Molecular Pathways Driving Pulmonary Fibrosis

This is a micro-learning module summary of Prof. Corey Kershaw’s session which you can find here. Before participating, please read our CME and disclosure information which can be found here.

Acknowledgment: This activity is supported by an educational grant from This program is supported by an independent educational grant from Bristol Myers Squibb (BMS). This online education program has been designed solely for healthcare professionals in the USA. The content is not available for healthcare professionals in any other country.

Introduction

Understanding the molecular drivers of pulmonary fibrosis is essential for explaining to patients why antifibrotic therapies work, how they differ, and what emerging options may add. IPF results from dysregulated wound-repair signalling, ongoing myofibroblast activation, and unchecked extracellular matrix deposition. Modern therapies target key pathways within this cascade to slow, but not reverse, disease progression.

Patient Case

Mr. Rice is a 70-year-old man with a chronic dry cough, progressive exertional dyspnoea, restrictive PFTs, and a definite UIP pattern on HRCT. After exclusion of secondary causes, he was diagnosed with idiopathic pulmonary fibrosis (IPF). Upon hearing the diagnosis, he asks the common question: “There’s no treatment for this, right?” Currently, there are 3 options available that can slow the progression of IPF.

Understanding the Molecular Targets in Pulmonary Fibrosis

Pulmonary fibrosis develops through a cascade of dysregulated wound-repair mechanisms. Central to this process are:

• Myofibroblast differentiation, leading to excessive collagen deposition
• Profibrotic signaling pathways, including TGF-β, PDGF, and downstream cytokines
• Extracellular matrix accumulation, which progressively restricts lung function

Modern antifibrotic therapies aim to interrupt these pathways at key molecular checkpoints.

1. Nerandomilast: A Novel PDE4B Inhibitor

Nerandomilast represents the newest therapeutic avenue.

Mechanism of action:

• Inhibits phosphodiesterase 4B (PDE4B)
• May dedifferentiate myofibroblasts in the lung, preventing further fibrosis
• Interferes with multiple profibrotic pathways, including TGF-β, a central driver of fibroblast activation

Clinical data:

• In a 12-week phase 2 trial, nerandomilast stabilised lung function with a favourable safety profile
• Advanced into a large phase 3 study:
• 18 mg vs 9 mg twice daily vs placebo
• Enrolled 1,177 patients with IPF
• Background antifibrotics allowed (77% on nintedanib or pirfenidone)
• Required mild to moderate disease: FVC ≥45% and DLCO ≥25% predicted
• Results: Both 18 mg and 9 mg doses slowed FVC decline at 52 weeks relative to placebo

Subgroup findings (exploratory):

• In patients not taking background antifibrotics, nerandomilast markedly slowed disease progression (~70 mL decline vs ~150 mL on placebo)
• When combined with pirfenidone, the 9 mg dose showed no benefit, likely due to a drug-drug interaction reducing pirfenidone exposure
• The trial was not powered to formally assess combination therapy

2. Pirfenidone: Targeting Profibrotic Cytokine Signaling

Pirfenidone modulates multiple fibrotic pathways, including TGF-β–driven collagen synthesis.

Key evidence:

• Evaluated in 555 patients with IPF
• Dose: 801 mg three times daily
• Primary endpoint: change in FVC or death at 52 weeks
• Demonstrated consistent benefit at weeks 13, 26, 39, and 52
• Produced a ~48% relative reduction in the proportion of patients with significant FVC decline or death

3. Nintedanib: Blocking Multiple Tyrosine Kinase Pathways

Nintedanib inhibits VEGF, FGF, and PDGF receptors, central mediators of fibroblast proliferation and migration.

Key evidence:

• Studied in two parallel phase 3 trials (INPULSIS-1 and INPULSIS-2) involving >1,000 patients
• Dose: 150 mg twice daily
• Primary endpoint: annual rate of FVC decline
• Across both trials, nintedanib reduced the rate of decline by ~50% compared with placebo
• Approved for IPF in 2014

Therapy Beyond IPF: Nintedanib for Progressive Pulmonary Fibrosis (PPF)

PPF behaves biologically like untreated IPF, with comparable rates of lung function loss. As of today, nintedanib is the only approved therapy for PPF.

INBUILD trial:

• 663 patients with non-IPF ILD showing progression
• Excluded IPF and excluded most background treatments
• ~50% had chronic hypersensitivity pneumonitis or CTD-ILD
• 62% had a UIP-like pattern
• Nintedanib reduced the annual rate of FVC decline (–80.8 mL/yr vs –187.8 mL/yr) across both UIP and non-UIP phenotypes

Final Message to Patients like Mr. Rice

While fibrosis cannot be reversed, three approved therapies, pirfenidone, nintedanib, and nerandomilast, can meaningfully slow disease progression. Understanding the molecular pathways behind fibrosis helps clinicians tailor therapy and reassures patients that effective options exist.

Content is accurate as of the date of release on 6 January 2026.