The Last 5 Years: Lessons in Progressive Pulmonary Fibrosis Treatment

As researchers look to the future of progressive pulmonary fibrosis (PPF), one key message has emerged: the field is moving beyond rigid consensus-based criteria toward a more personalized, data-driven approach to early diagnosis and treatment.

During a session at the American Thoracic Society (ATS) 2025 International Conference, experts reflected on the evolution of PPF over the past 5 years and presented a future vision rooted in biomarker integration, risk stratification, and improved clinical trial design.

Revisiting the Past 5 Years in PPF

Researchers discussed advancements in diagnosing and treating progressive pulmonary fibrosis at the ATS 2025 International Conference. | Image credit: Nadzeya – stock.adobe.com

Although the concept of progression in interstitial lung disease (ILD) has existed for over 70 years, it remained largely overlooked until recently, noted Yet Hong Khor, PhD, MBBS, associate professor at Monash University and respiratory and sleep physician at Austin Health.

Idiopathic pulmonary fibrosis (IPF) long served as the prototypical progressive phenotype, with most patients’ function deteriorating at varying rates. The 2019 INBUILD trial helped formalize the broader concept of progressive fibrosing ILD, using criteria based on lung function decline, worsening symptoms, or radiologic changes.

This laid the groundwork for the 2022 international guidelines that introduced the term PPF, standardizing diagnosis across three domains: respiratory symptoms, lung function decline—most notably ≥10% decline in forced vital capacity (FVC)—and imaging progression. These guidelines were designed for clinical practicality but were also influenced by the structure and needs of drug trials.

“We are where we are because of the clinical trials,” said Philip Molyneaux, MD, PhD, professor of interstitial lung disease, Imperial College London. “It brought people together. It wasn't perfect, but it unified everything, and it acts as a starting point. I think as long as we are, as a community, willing to embrace some change and refinement, we've got a good starting point, but it's not perfect.”

Molyneaux presented data showing that a ≥ 10% FVC decline remains the most consistently predictive marker of poor outcomes, whereas symptom worsening or imaging progression are less reliable as standalone indicators. He stressed that not all criteria perform equally and that a more nuanced approach is needed.

Joyce Lee, MD, professor of pulmonary sciences and critical care at the University of Colorado Anschutz Medical Campus, emphasized that etiology still matters. While PPF is described as a progressive phenotype of fibrosing ILDs, it is not a diagnosis itself, and the underlying ILD diagnosis still impacts prognosis, diagnostic evaluation, and treatment. Up to a third of patients with fibrotic ILD may go on to develop a progressive phenotype, but that likelihood varies based on disease subtype, comorbidities, and exposures. In fibrotic hypersensitivity pneumonitis, for example, Lee shared data showing that clinicians were able to identify the antigen in 96% of cases, achieve avoidance in 54%, and observe sustained clinical improvement in 42% of patients.

The ATS session also focused on the need for greater diagnostic precision using multidisciplinary teams and tools beyond spirometry. Manoj Maddali, MD, clinical scholar of pulmonary, allergy, and critical care medicine at Stanford University, discussed how blood-based proteomics and radiographic metrics are emerging as potential tools to identify high-risk patients earlier in the disease course. However, implementation remains limited due to gaps in validation, regulatory approval, and integration into clinical workflows.

Looking Ahead at the Next 5 Years

Pivoting the conversation towards the future, Fernando J. Martinez, MD, MS, vice chair for clinical and translational research at UMass Chan Medical School, outlined a vision for how PPF management could evolve over the next 5 years, with an emphasis on early, individualized intervention.

Martinez described current diagnostic tools as insufficiently sensitive, saying the sensitivity of 0.5 that is seen in some tests is a “coin flip” and calling for better tools to identify high-risk patients at the time of diagnosis, not just after they’ve already progressed. This leaves room for a better predictive approach that can help providers make decisions in a clinic setting.

To that end, the global PRIME-PPF cohort study is underway to refine how PPF is defined and predicted. Conducted across 40 sites worldwide—though Martinez noted the need for more representation from Asia and South America—the study is supported by multiple industry partners in a pre-competitive collaboration and will incorporate circulating biomarkers, imaging data, clinical characteristics, and physiologic measurements to build a more comprehensive model for risk stratification. The first patient was enrolled in April.

The goal, Martinez said, is to establish a model where patients can be assessed and treated based on their individualized risk of progression before they meet traditional PPF criteria. This would mark a significant shift from the current approach, which often delays therapy until lung function has already deteriorated. The focus is on a narrow 1- to 2-year window to facilitate timely interventions and inform trial design. Ultimately, PRIME-PPF seeks to support early, personalized treatment decisions by identifying the optimal combination of biomarkers to guide care.

“This is trying to identify, when you first see that patient with fibrotic lung disease, how are we going to define progression in a practical manner that you and your office can use when that is linked to a clinical outcome,” Martinez explained.

He pointed to the MAVRICK-IPF trial as a prototype for this kind of personalized strategy. Funded by the US Department of Defense, the trial uses a validated biomarker risk score to identify patients with IPF who are at high risk of progression and randomizes them to receive either metformin or placebo. While metformin is not a traditional antifibrotic, it was chosen for its safety, affordability, and ease of access, allowing researchers to test the trial design itself.

“That is the future, guys, and it ain't that hard,” Martinez said.

Martinez also acknowledged the need for greater diversity in trial populations and improved integration of real-world data to ensure findings are generalizable across care settings, saying registry-based studies give broad snapshots, but lack granularity.

Reference

Wijsenbeek MS, Oldham J, Cottin V, et al. Progressive pulmonary fibrosis: five years later. Presented at: ATS 2025 International Conference; May 19, 2025; San Francisco, CA.