Key Clinical Summary: Optimizing Therapy and Supporting Persistence

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

The landscape of pulmonary fibrosis research is expanding rapidly. Our improved understanding of the cellular and molecular pathways that drive fibrosis has opened the door to a rich pipeline of immunomodulatory and fibromodulatory therapies. In 2025, clinicians can not only offer approved treatments to slow disease progression but also discuss a robust portfolio of investigational therapies designed to target distinct mechanisms throughout the fibrotic cascade.

Brief Patient Recap

Mr. Rice, a 70-year-old man diagnosed with idiopathic pulmonary fibrosis (IPF) based on a definite UIP pattern and progressive respiratory symptoms, is now processing the complexity of treatment options. After hearing about FDA-approved antifibrotic therapies, expected benefits, and potential side effects, he expresses feeling overwhelmed and asks whether anything more can be done, specifically, whether research trials or emerging therapies may offer additional hope.

Understanding Emerging Mechanistic Targets

Fibrosis develops through a multi-step process involving epithelial injury, macrophage activation, lymphocyte signalling, fibroblast recruitment, and myofibroblast transformation. Each step presents a potential therapeutic target.

Emerging therapies fall into two broad categories:

1. Immunomodulatory Targets

Focused on upstream drivers of inflammation and immune dysregulation, including:

• Pathological macrophage signals (e.g., tocilizumab)
• Pathological lymphocyte signals (e.g., cyclophosphamide, mycophenolate, abatacept)
• Pathological B-cell signals (e.g., rituximab)

These aim to modulate the immune responses that initiate or perpetuate fibrotic injury.

2. Fibromodulatory Targets

Focused on downstream profibrotic pathways, including:

• Epithelial cell dysfunction
• Pro-fibrotic cytokines (e.g., TGF-β)
• Fibroblast-to-myofibroblast differentiation
• Extracellular matrix deposition

Agents in this category aim to slow or halt the structural progression of fibrosis.

Key Emerging Therapies Under Investigation

1. LPA₁ Receptor Antagonism (Admilparant)

Lysophosphatidic acid (LPA) promotes fibroblast migration into the alveolar space, a key driver of IPF and PPF progression. Mouse models lacking the LPA₁ receptor demonstrate protection against lung injury.

Admilparant, an LPA₁ receptor antagonist, showed slowed FVC decline in both IPF and progressive pulmonary fibrosis (PPF) cohorts in a phase 2 trial. A phase 3 study for both IPF and PPF is now nearing completion, with results expected within the next year.

2. Inhaled Prostacyclin Analogue (Treprostinil)

Already used in pulmonary hypertension (PAH), inhaled treprostinil exhibits distinct antifibrotic properties, including:

• Inhibition of TGF-β–driven stimulated collagen production in fibroblasts
• Reduction of fibrocyte recruitment to areas of vascular remodelling

Most of the medications used to treat PAH exclude patients with lung disease due to contraindications of vasodilation that can result in paradoxical worsening of hypoxemia, especially in the case of systemic therapies. Inhaled therapies, in contrast could be an avenue to explore. In the INCREASE trial for ILD associated with PAH, patients not only improved their six-minute walk distance but also demonstrated unexpected gains in FVC. These results indicate that there is now one therapy available for patients with PAH and lung disease.

As a next step, the TETON trials started focusing on patients with FVC ≥45% predicted, if on background pirfenidone or nintedanib for IPF, stable dose for at least 30 days prior to baseline and HRCT done within the last 12 months. In this cohort, two trials are ongoing: TETON-1 (patients from the US and Canada and TETON-2 (outside the US/Canada). Data from TETON-2 presented at ERS 2025 showed a statistically significant slowing of FVC decline over 52 weeks in IPF patients treated with inhaled treprostinil. TETON-1 study is also close to being finished.

Additionally, there is another trial, TETON-PPF, that is focusing on progressive pulmonary fibrosis.

These studies may position inhaled treprostinil as an additional antifibrotic therapy pending final results.

3. Additional Phase 2 Agents in Development

Multiple phase 2 studies have completed or are ongoing, with several demonstrating positive early results. Examples include:

• CAL101: anti–S100A4 monoclonal antibody targeting the DAMP protein.
• MTX-463: anti-WISP1 antibody designed to neutralize WISP1-mediated fibrotic signaling.
• Ifetroban: oral thromboxane-prostanoid receptor (TPr) antagonist
• Bersiporocin: oral Prolyl-tRNA Synthetase (PRS) inhibitor
• Deupirfenidone: enhanced pirfenidone analogue (deuterated pirfenidone) for higher plasma exposure
• CC-90001: oral c-Jun N-terminal kinase 1 (JNK) inhibitor.
• Buloxibutid: angiotensin II receptor agonist, promoting tissue repair.
• Vixarelimab: monoclonal antibody targeting oncostatin M receptor-beta (OSMRβ)

These investigational agents target diverse pathways, offering hope for more personalised and mechanistically precise treatments in the future.

Conclusion

The therapeutic landscape for pulmonary fibrosis is evolving at unprecedented speed. Alongside FDA-approved antifibrotics, numerous agents are advancing through clinical development, targeting multiple mechanistic checkpoints in the fibrotic cascade. For patients like Mr. Rice, this means deeper hope, more options, and a future in which personalised antifibrotic therapy may yield even better outcomes.

Clinicians should be ready to guide patients through available treatments, emerging opportunities, and the importance of persistence in therapy as the field continues to expand.

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