Clinical trials in pulmonary fibrosis have accelerated sharply in the past decade, moving well beyond the two approved antifibrotic drugs and into a landscape of new molecular targets, smarter trial designs, and growing pressure to include patients historically shut out of research. Most trials still measure how quickly lung function declines rather than how long patients survive, and that measurement choice shapes nearly everything about how new therapies are tested and evaluated. For anyone living with the disease, considering enrollment, or simply trying to understand where treatment is headed, the trial landscape in 2024 and 2025 looks markedly different from even five years ago.
Why Trials Measure Lung Function Instead of Survival
Pulmonary fibrosis is fatal, so you might expect survival to be the obvious yardstick for a clinical trial. In practice, it is not. People with mild-to-moderate disease, the population most commonly enrolled in trials, progress slowly enough that death rates during a typical study period are too low to produce statistically meaningful comparisons between a drug and a placebo. That is why change in forced vital capacity, or FVC (the total amount of air you can forcefully exhale), has become the standard primary endpoint.
1PubMed Central. Association of hospital admission and forced vital capacity endpoints with survival in patients with idiopathic pulmonary fibrosis: analysis of a pooled cohort from three clinical trialsFVC is not a perfect stand-in for how a patient actually feels or how long they will live, but pooled analyses from large trials have shown that FVC decline correlates with both hospital admissions and mortality. A drug that slows FVC loss by a meaningful margin is assumed to be slowing disease progression overall. That assumption underpins nearly every major trial discussed below, so understanding it matters: when you see a trial reporting a difference of, say, 70 milliliters in FVC decline over a year, that number reflects a slowed rate of scarring, not a cure.
Nerandomilast and the New Wave of Antifibrotics
The most prominent new compound to emerge from recent trials is nerandomilast, an oral drug that preferentially blocks an enzyme called phosphodiesterase 4B. Early-phase results were striking: in a phase 2 trial, patients not already on existing antifibrotics who took nerandomilast saw their lung function essentially hold steady over 12 weeks, while the placebo group lost a median of about 82 milliliters of FVC.
2PubMed. Trial of a Preferential Phosphodiesterase 4B Inhibitor for Idiopathic Pulmonary FibrosisThose results were encouraging enough to launch two large phase 3 trials. In patients with idiopathic pulmonary fibrosis (IPF), the most common and aggressive form of the disease, the higher dose of nerandomilast reduced FVC decline by about 69 milliliters compared with placebo over 52 weeks. The lower dose showed a smaller but still statistically significant benefit.
3PubMed. Nerandomilast in Patients with Idiopathic Pulmonary FibrosisA parallel phase 3 trial tested nerandomilast in progressive pulmonary fibrosis (PPF), a broader category that includes forms of lung scarring caused by autoimmune disease, chronic hypersensitivity, and other conditions. Here, both the 9-mg and 18-mg doses outperformed placebo, with the 9-mg group actually showing a slightly larger numerical advantage of about 81 milliliters in preserved FVC.
4PubMed. Nerandomilast in Patients with Progressive Pulmonary FibrosisWhy does this matter beyond numbers on a chart? Right now, only two antifibrotic drugs, pirfenidone and nintedanib, are approved, and both slow decline without stopping it. A third effective agent, especially one that works through a different biological pathway, opens the door to combination strategies and gives options to patients who cannot tolerate the existing drugs. Diarrhea was the most common side effect of nerandomilast in these trials, which is also the main complaint with nintedanib, so tolerability will be an important factor as the drug moves toward regulatory review.
Autotaxin Inhibitors and a Cautionary Tale
Not every promising target pans out. The autotaxin-lysophosphatidic acid pathway drew attention because patients with IPF have elevated levels of these signaling molecules in their lungs, and blocking them reduced fibrosis in animal models.
5PubMed Central. Inhibitors of the Autotaxin-Lysophosphatidic Acid Axis and Their Potential in the Treatment of Interstitial Lung Disease: Current PerspectivesAn early phase 2a trial of one autotaxin inhibitor, GLPG1690, showed a modest FVC gain of about 25 milliliters over 12 weeks compared with a 70-milliliter loss in the placebo group.
6The Lancet Respiratory Medicine. Efficacy and safety of the autotaxin inhibitor GLPG1690 in patients with idiopathic pulmonary fibrosis: a randomised, double-blind, placebo-controlled phase 2a trialBut the larger phase 3 program, called ISABELA, failed. The drug was renamed ziritaxestat and tested in two large randomized trials, neither of which showed a significant benefit on FVC. The reasons are still being investigated, and researchers have pointed out that other autotaxin inhibitors with different chemical properties and LPA receptor blockers remain in development.
7JAMA. Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis: The ISABELA 1 and 2 Randomized Clinical TrialsA separate high-profile failure involved pamrevlumab, an antibody targeting connective tissue growth factor. In the ZEPHYRUS-1 trial, the drug did not significantly reduce FVC decline compared with placebo over 48 weeks, and none of the secondary or patient-reported outcomes showed a meaningful difference either.
8PubMed Central. Pamrevlumab for Idiopathic Pulmonary Fibrosis: The ZEPHYRUS-1 Randomized Clinical TrialThese failures are not just setbacks. They highlight how difficult it is to translate laboratory biology into real clinical benefit in a disease as complex as pulmonary fibrosis. Every failed trial also feeds back into the design of the next one, refining which patients are enrolled, how outcomes are measured, and which targets are worth pursuing.
Integrins and Other Emerging Targets
One newer class of drug targets integrins, the cell-surface proteins that help activate a growth factor called TGF-beta, widely considered a master driver of fibrosis. Bexotegrast, which blocks two specific integrins involved in lung scarring, has completed a phase 2 open-label study showing that it can reach its target in the lungs in a dose-dependent way. At higher doses, the drug occupied roughly 90 percent or more of its target receptor in lung tissue.
9Annals of the American Thoracic Society. Bexotegrast Shows Dose-Dependent Integrin αvβ6 Receptor Occupancy in Lungs of Participants with Idiopathic Pulmonary Fibrosis: A Phase 2, Open-Label Clinical TrialProving that a drug reaches its target is an early step. What matters next is whether that engagement translates into slower disease progression and fewer symptoms. Larger efficacy trials are underway. The integrin approach is conceptually appealing because it intervenes upstream in the fibrotic process, potentially complementing drugs like nintedanib and pirfenidone that work through different mechanisms.
Combining Existing Drugs
Since both approved antifibrotics work through different pathways, clinicians have naturally asked whether using them together might produce a larger benefit. A long-term retrospective study of patients who received both nintedanib and pirfenidone together found that while the combination was tolerable for many, side effects were common. About 84 percent of patients experienced at least one adverse reaction, with weight loss being the most frequent: more than half lost at least five percent of their body weight. Diarrhea, abdominal pain, loss of appetite, and fatigue were also common.
10Archivos de BronconeumologÃa. Nintedanib Combined With Pirfenidone in Patients With Idiopathic Pulmonary Fibrosis or Progressive Pulmonary Fibrosis: A Long-Term Retrospective Multicentre Study (Combi-PF)These findings explain why interest is growing in inhaled formulations. Because oral pirfenidone causes significant gastrointestinal issues, an inhaled version has been developed and showed a more favorable safety profile in early testing. A randomized placebo-controlled trial is now assessing whether inhaled pirfenidone, added on top of standard care, can preserve lung function in patients with progressive pulmonary fibrosis over 52 weeks.
11European Respiratory Society (ERS) / Breathe. A new era in the treatment of progressive fibrosing interstitial lung diseasesIf inhaled delivery proves effective, it could change how combination therapy is approached. The main barrier to stacking antifibrotics has been tolerability, and delivering one drug directly to the lungs while taking the other orally could sidestep the worst gastrointestinal side effects.
Biomarkers for Sorting Out Who Benefits
One of the central frustrations in pulmonary fibrosis trials is that patients with the same diagnosis can progress at wildly different rates. A drug that looks modestly effective across a whole trial population might actually work very well in a subgroup of rapid progressors and barely at all in others, but those differences get averaged away in the overall results. Blood-based biomarkers are increasingly seen as a way to stratify patients before and during trials.
Analyses from the pirfenidone pivotal trials found that among a panel of blood proteins, CCL18 was the most consistent predictor of disease progression across different study cohorts. Patients with high CCL18 at baseline tended to decline faster.
12The Lancet Respiratory Medicine. Assessment of prognostic and predictive properties of blood biomarkers in pivotal clinical studies of pirfenidone in idiopathic pulmonary fibrosisMore recent work from the failed ISABELA trials identified a combination of high baseline MMP-7 and CCL18, along with changes in CCL18 over time, as particularly useful for stratifying risk and potentially monitoring treatment response.
13ERJ Open Research. Prognostic biomarkers for idiopathic pulmonary fibrosis: findings from ISABELA clinical trialsNone of these biomarkers are ready for routine clinical use yet, but they are shaping how future trials are designed. Instead of enrolling a broad population and hoping the drug signal is strong enough to show through the noise, researchers can enrich trials with patients who are more likely to progress, making smaller and shorter studies more informative.
Imaging as a Trial Tool
CT scans have always been central to diagnosing pulmonary fibrosis, but quantitative analysis of those scans is now being used as a trial endpoint. Automated software can measure the extent of fibrosis and vascular changes in lung tissue and track them over time. One such tool, CALIPER, has shown that its measurements of fibrosis progression correlate with FVC changes and can distinguish between treated and untreated patients.
14PubMed. Automated Computed Tomography analysis in the assessment of Idiopathic Pulmonary Fibrosis severity and progressionQuantitative CT is starting to be used as a surrogate biomarker in trials for both pulmonary fibrosis and chronic obstructive pulmonary disease, offering a way to detect disease burden that a simple breathing test might miss, particularly in early-stage disease where FVC can still appear relatively preserved.
15Journal of Thoracic Imaging. Using Quantitative Computed Tomographic Imaging to Understand Chronic Obstructive Pulmonary Disease and Fibrotic Interstitial Lung DiseaseWhat Patients Actually Care About
FVC decline is a useful number for researchers, but patients living with pulmonary fibrosis tend to care most about breathlessness, cough, fatigue, and how the disease affects their daily life. Patient-reported outcome measures have become a growing focus in trial design, and disease-specific questionnaires have been developed and validated for interstitial lung disease.
16European Respiratory Review. Patient-reported outcomes and patient-reported outcome measures in interstitial lung disease: where to go from here?Data from the INPULSIS trials of nintedanib showed that the link between FVC decline and quality of life is real but not always straightforward. Patients with more advanced disease at baseline experienced greater worsening in quality-of-life scores, and acute flare-ups of the disease led to clear deteriorations in both symptoms and daily functioning. Among those with advanced disease, nintedanib slowed the worsening of several patient-reported measures, particularly on activity-related quality-of-life scores.
17PubMed Central. Health-related quality of life and symptoms in patients with IPF treated with nintedanib: analyses of patient-reported outcomes from the INPULSIS trialsRegulatory agencies are increasingly interested in these outcomes. A drug that slows FVC decline but does nothing for breathlessness or cough will face harder questions at the approval stage than it once would have. Patients and advocacy groups have also pushed for trials to capture not just symptoms but the overall experience of participating in a study, including treatment burden and communication with the clinical team.
18PubMed. What Patients With Idiopathic Pulmonary Fibrosis and Caregivers Want: Filling the Gaps With Patient Reported Outcomes and Experience MeasuresRethinking Who Gets Into Trials
A systematic review of antifibrotic trials for pulmonary fibrosis found significant gaps in who participates. Across 43 trials that reported results, about three-quarters of participants were male, 77 percent were White, 16 percent were Asian, and fewer than one percent were Black. Five trials included only White participants and three included only Asian participants. No trials reported on broader social factors that could affect access or outcomes.
19PubMed Central. Lack of diversity in antifibrotic trials for pulmonary fibrosis: a systematic reviewBeyond demographics, the eligibility criteria themselves exclude a large segment of real-world patients. Trials typically require a certain minimum level of lung function, which means people with the most advanced disease, those who arguably have the most to gain from a new therapy, are systematically left out. Researchers have argued that expanding inclusion criteria would both address an ethical concern and generate data on how treatments perform in the sicker patients who will ultimately use them.
20European Respiratory Journal. The moving target of progressive pulmonary fibrosis: insights for future clinical trialsNew Trial Architectures
Traditional pulmonary fibrosis trials test one drug against placebo over 12 to 18 months, recruit hundreds of patients, and cost tens of millions of dollars. Adaptive platform trials aim to change that equation. A concept called REMAP-ILD has been proposed: a single ongoing trial infrastructure in which multiple drugs can be tested simultaneously, with patients randomized to different treatment arms that can be added or dropped as evidence accumulates.
21Thorax. Adaptive multi-interventional trial platform to improve patient care for fibrotic interstitial lung diseasesThe appeal of this approach goes beyond efficiency. Biomarker-based enrichment, alternative endpoints, and decentralized study components, where patients do some monitoring from home rather than traveling to a study center, can all be embedded in such platforms.
22Thorax. Challenging the status quo for therapeutic clinical trials in fibrotic interstitial lung diseasesHome spirometry is one practical example already showing results. A randomized controlled trial of a home monitoring program for IPF patients found that daily spirometry at home produced reliable measurements comparable to hospital-based testing. The program did not improve overall health-related quality of life, but patients appreciated it, it allowed doctors to adjust treatment individually, and it did not increase anxiety about the disease.
23American Journal of Respiratory and Critical Care Medicine. Home Monitoring in Patients with Idiopathic Pulmonary Fibrosis. A Randomized Controlled TrialDaily home measurements also provide a far more granular picture of FVC changes than the quarterly hospital visits typical of current trials, which could make smaller studies more sensitive to drug effects.
24American Journal of Respiratory and Critical Care Medicine. Daily Home Spirometry: An Effective Tool for Detecting Progression in Idiopathic Pulmonary FibrosisStem Cell Therapies
Cell-based treatments occupy a speculative but active corner of the trial landscape. The idea is that mesenchymal stem cells, which can be harvested from bone marrow or fat tissue, might dampen the overactive immune and scarring responses that drive fibrosis. Several early-phase trials have established that infusing these cells appears safe.
A phase 1 trial infusing bone-marrow-derived stem cells into nine IPF patients found no treatment-related serious adverse events over 60 weeks. Lung function still declined, with FVC dropping about 3 percent and gas-exchange capacity falling about 5 percent, which is roughly in line with the natural progression of untreated disease.
25PubMed Central. Allogeneic Human Mesenchymal Stem Cells in Patients With Idiopathic Pulmonary Fibrosis via Intravenous Delivery (AETHER): A Phase I Safety Clinical TrialA separate small trial using adipose-derived stromal cells also reported no serious adverse events and no deterioration in lung function or quality-of-life measures among treated patients.
26PubMed Central. A prospective, non-randomized, no placebo-controlled, phase Ib clinical trial to study the safety of the adipose derived stromal cells-stromal vascular fraction in idiopathic pulmonary fibrosisA more ambitious trial used high cumulative doses of stem cells in patients with rapidly declining lung function. Over 12 months, the treated group’s FVC increased by about 8 percent from baseline, while the placebo group lost about 6 percent. Walking distance and gas exchange also improved in the treatment group. However, mortality was the same in both groups, with two deaths on each side, and CT scans showed no change in the amount of visible fibrosis.
27PubMed Central. First-in-human high-cumulative-dose stem cell therapy in idiopathic pulmonary fibrosis with rapid lung function declineThese are very small studies, and the fact that imaging showed no structural improvement even when breathing tests got better raises real questions about what the cells are actually doing. It is too early to consider stem cells a treatment option, but the safety data justify larger and longer trials.
Trials in Children and Familial Disease
Pulmonary fibrosis in children is rare but can be devastating, and until recently no antifibrotic drugs had been tested in pediatric patients at all. The first international placebo-controlled study in childhood interstitial lung disease enrolled 29 children aged 6 to 17 and tested weight-based doses of nintedanib over 24 weeks. The drug achieved blood levels comparable to adult dosing and had an acceptable safety profile, though diarrhea was a significant side effect, mirroring the adult experience.
28eBioMedicine. Precision treatments for familial pulmonary fibrosis: a position paperRunning trials in pediatric lung fibrosis faces unique hurdles. The disease is rare enough that multi-center international collaboration is essential just to recruit enough participants. Children also lack validated outcome measures for fibrosis progression, making it hard to define what “better” looks like in a trial setting. Researchers have called the development of meaningful, child-specific endpoints an urgent priority.
29American Journal of Respiratory and Critical Care Medicine. Approaching Clinical Trials in Childhood Interstitial Lung Disease and Pediatric Pulmonary FibrosisFamilial pulmonary fibrosis, where the disease runs in families due to inherited mutations, represents another underserved population. These patients often develop fibrosis at younger ages and may respond differently to standard antifibrotics. Position papers from European research groups have advocated for precision-medicine approaches in familial cases, potentially matching specific therapies to the underlying genetic defect rather than treating all fibrosis patients identically.
Compassionate Use and Early Access
Between a drug’s successful trial results and its formal regulatory approval, there can be a gap of months or years during which patients with progressive disease have no access to a therapy that has already been shown to work. Compassionate-use programs attempt to bridge that gap. A well-documented example is the German compassionate-use program for nintedanib, which opened in 2014 after the pivotal trial results were published but before formal approval. Among the patients treated, about 63 percent had stable disease at six months, defined as losing less than five percent of their FVC. About a third required a dose reduction because of side effects.
30Karger. Insights from the German Compassionate Use Program of Nintedanib for the Treatment of Idiopathic Pulmonary FibrosisCompassionate-use data also serve a research purpose. Because these programs include patients who would not have qualified for the pivotal trials, often people with more advanced disease or more comorbidities, they provide a real-world check on whether trial results hold up outside the controlled setting. As more drugs approach approval, the design and availability of early-access programs will remain a practical concern for patients and their physicians.