Global landscape for pulmonary fibrosis treatment: a data-driven perspective from clinical trials

Abstract

Objective

To systematically map the global landscape, evolution and key characteristics of interventional clinical trials in pulmonary fibrosis, providing an empirical basis for future trial strategies and resource allocation.

Methods

The INFORMA Pharma Intelligence database was searched to identify 1,203 interventional PF trials. Descriptive statistics were applied to analyse temporal trends, geographic distribution, sponsors, trial phase and status, primary endpoints, drug targets or mechanisms, and the disease spectrum.

Results

Global pulmonary fibrosis trial activity displayed a three-stage growth pattern, with a surge in 2020. Research is highly concentrated geographically: the United States (316 trials) and China (285 trials) dominate, yet only 128 trials are multinational. The pipeline remains centred on nintedanib (94 trials) and pirfenidone (88 trials), while target diversity is expanding, especially toward anti-angiogenic and multi-tyrosine-kinase inhibitors. Primary endpoints focus on safety or tolerability and Forced Vital Capacity change. The disease spectrum has broadened from idiopathic pulmonary fibrosis to include Connective tissue disease-associated fibrosis.

Conclusions

Pulmonary fibrosis clinical research is experiencing unprecedented dynamism and diversification, transitioning from targeted therapy towards precision and multimodal intervention. Enhanced international collaboration, optimized trial design, and deeper precision-based stratification will be critical to advancing the field from slowing disease progression to reversing tissue damage.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s12890-026-04340-w.

Introduction

Pulmonary fibrosis (PF) encompasses a group of chronic, progressive interstitial lung diseases characterized by scarring of the lung parenchyma, impaired gas exchange, dyspnoea, reduced quality of life, and ultimately respiratory failure and death [1].Idiopathic pulmonary fibrosis (IPF), the most emblematic and lethal subtype, typically presents around age 65 and carries a median survival of only 3–5 years, worse than many solid tumours [2]. Pathologically, PF is marked by aberrant activation of fibroblasts and myofibroblasts, excessive extracellular matrix deposition, alveolar destruction, and honeycombing, resulting in irreversible impairment of gas exchange [3, 4]. Beyond IPF, PF includes multiple subtypes such as autoimmune-associated interstitial lung diseases (e.g., systemic sclerosis- and rheumatoid-arthritis-related ILD), environmental exposure-related fibrosis, and more recently, post-COVID-19 fibrosis [5–9].Conventional therapies centred on corticosteroids and immunosuppressants have largely proved ineffective or harmful in large trials, underscoring the urgent need for treatments that target core pathogenic mechanisms [10]. Two landmark phase III trials, ASCEND (pirfenidone) and INPULSIS (nintedanib), demonstrated that these agents significantly slow the annual rate of forced vital capacity (FVC) decline in IPF patients [11, 12]. Pirfenidone is a small-molecule antifibrotic with anti-inflammatory and antioxidant properties, whereas nintedanib is a multi-kinase inhibitor targeting Vascular endothelial growth factor receptor (VEGFR), Fibroblast growth factor receptor (FGFR), and Platelet-derived growth factor receptor (PDGFR). Regulatory approval of these agents marked a milestone, but it also initiated a new phase of clinical development. PF R&D is now experiencing unprecedented dynamism and diversification. Strategies are shifting from broad antifibrotic therapy toward precision interventions targeting specific molecular pathways, while trial designs are evolving to address challenges posed by disease heterogeneity. Conventional endpoints such as all-cause mortality require long durations, high costs, and present ethical challenges. Consequently, the novel surrogate endpoints increasingly explored to detect treatment effects earlier and more sensitively, accelerating drug development.

Given this context, a comprehensive, data-driven appraisal of ongoing PF clinical trials is both timely and essential. Beyond cataloguing individual trial outcomes, this analysis aims to map the overarching Research and development (R&D) architecture, providing clinicians, drug developers, policymakers, and patients with a coherent framework. By doing so, it seeks to inform strategic prioritization, optimize resource allocation, and catalyze the next breakthroughs in the treatment ultimate conquest of this disease.

Materials and methods

Data-screening and extraction workflow

Data were sourced from the INFORMA Pharma Intelligence platform, one of the most authoritative global resources for drug-development analytics. To comprehensively map the worldwide clinical-trial landscape of PF therapeutics, a comprehensive search was conducted on 5 July 2025. The retrieval strategy combined disease-area taxonomy with keyword-based filtering, using the core search string : “(Disease is Autoimmune/Inflammation: PF)”. A hierarchical inclusion and exclusion criteria was applied to delineate the study scope. Inclusion criteria required that each record met al.l of the following: (1) interventional clinical trial (Phases I-IV); (2) explicit diagnosis of PF, encompassing IPF, hypersensitivity pneumonitis, connective-tissue-disease-associated ILD and other fibrotic lung subtypes; (3) therapeutic intervention with a primary aim to treat PF. Exclusion criteria eliminated trials that were: (1) non-therapeutic studies (e.g., diagnostic investigations, epidemiological surveys, or natural-history studies); (2) focused on non-fibrotic lung diseases; (3) evaluating lung transplantation as the sole intervention; (4) Trials that exhibit critical deficiencies in study design, key outcome measures, or the presentation of essential data. During implementation, two reviewers, trained with an identical protocol, independently screened all retrieved records. Discrepancies were reconciled through joint re-examination. When necessary, a third senior investigator adjudicated the final decision to ensure methodological consistency and objectivity. Following this process, 1,203 clinical trials were eligible for final inclusion.

Data extraction followed a standardised, pre-piloted form. Variables collected included: (1) trial identifiers and status, such as registry number, full title, registration date, first-posting date, current status, projected and actual completion dates; (2) design characteristics, such as phase, completion status; (3) intervention details, such as drug or therapy name, mechanism of action, molecular target; (4) population and geography, such as specific PF subtype, key inclusion or exclusion criteria, age range, coordinating centre, countries or regions of participating sites; (5) and sponsor attributes, type of funding organisation.

Statistical analysis

All data cleaning and descriptive analyses were performed using dedicated statistical software. Categorical variables, including trial phase, mechanistic class of intervention, sponsor type, and study status, were summarised as counts (n) and proportions (%), and displayed using frequency tables, stacked bar charts and proportional diagrams. Temporal evolution of global research activity was examined by plotting the annual number of newly registered PF trials. Geographic concentration and cross-border collaboration patterns were analysed by mapping the distribution of participating study sites and quantifying the number of multinational trials.

Results

Global landscape of clinical trials in PF

Viewed chronologically, global PF clinical-research activity has undergone a distinct three-stage escalation since 2000 (Fig. 1A). The period from 2000 to 2006 represents the initial exploration period, during which annual trial numbers remained low and relatively static. Between 2007 and 2019, the field entered a phase of steady expansion, characterised by continuous year- on -year growth. A striking inflection occurred in 2020, when the annual number of registered trials increased by more than 70% compared with the previous year and has remained at this elevated plateau thereafter.

Fig. 1.

Global trends and distribution of clinical trials for PF (A). Distribution of trial time, (B). Distribution of trial status, (C). Distribution of trial stages) *Note: The years of some clinical trials are not shown

Analysis of the trial status shows that completed trials dominate (731 cases). However, 156 terminated studies indicate the high attrition rate typical in fibrotic-disease drug development. The termination of 156 trials in this study reflects the high attrition rate in drug development for pulmonary fibrosis (PF). This phenomenon must be viewed within the broader context of drug development. Reported overall success rates from Phase I to approval are approximately 3–5% in oncology and even lower (around 1–2%) in neurological disorders such as Alzheimer’s disease [13, 14]. Although PF research activity has intensified following the approval of nintedanib and pirfenidone, the overall success rate remains comparatively low, highlighting the unique translational challenges in this field. The slow change and considerable inter‑individual variability of primary clinical endpoints such as FVC, which increase the risk of failure in Phase II trials [2]. Thus, the elevated attrition rate in PF is both a reflection of the generally high failure rate across drug development and a consequence of the distinctive pathophysiological complexity and clinical‑trial hurdles inherent to this disease. Meanwhile, substantial numbers of classified as “planned” and “open” demonstrate sustained future R&D momentum (Fig. 1B). Stage distribution reveals a broad and active pipeline. Phase I (431 trials, accounting for 37%) and Phase II clinical trials together form the main body of current research. At the same time, the presence of Phase III and Phase IV trials—particularly the inclusion of 201 Phase IV trials (representing 17%)—reflects the continuity and comprehensiveness of the research landscape. At the national level, China’s performance is particularly prominent in Phase I clinical trials, whereas the United States demonstrates a more dominant position in Phase II and Phase III trials (Supplementary Fig. 1). Regarding funding sources, “Industry, all other pharma” shows a greater inclination to support early-phase trials, accounting for the highest proportion in Phase I trials. In Phase II, Phase III, and Phase IV trials, Academic institutions emerge as the primary funders (Supplementary Fig. 2). In terms of trial endpoints, Phase I trials primarily focus on Safety and Tolerability and Adverse Events. As trials progress to later phases, FVC becomes the core efficacy endpoint (Supplementary Fig. 3). Furthermore, completed trials constitute a large proportion across all phases (Supplementary Fig. 4).

National distribution of PF clinical trials

Global trials distribution is highly regionally concentrated (Fig. 2A). The United States (316 trials) and China (285 trials) hold a pronounced lead, jointly forming the core hubs of PF clinical research. Although the United Kingdom, Japan, and Germany contribute fewer trials, each plays a significant strategic role, particularly in advanced-phase development and specialised sub-populations.

Fig. 2.

Major participating countries in the clinical trials of PF (A). The top 10 countries with the most trials; (B). The stage distribution of trials in the top 10 countries; (C). Cooperation situation)

Across countries, Phase II trials predominate is a critical bottleneck in PF drug development (Fig. 2B). Phase III studies are fewer in number yet relatively balanced across major countries. Phase IV trials cluster in Japan and Spain. Time-trend analyses indicate that after 2020, both China and the United States experienced a marked acceleration in trial initiation. Regarding research models, single-country trials dominate overwhelmingly (945 trials), whereas multinational collaborative trials only account for 128 trials (Fig. 2C).

Analysis of PF clinical trial funding institutions

Figure 3A shows that academic institutions and pharmaceutical companies constitute the predominant funding bodies. Among industry sponsors, non-Top 20 pharmaceutical companies (457 trials) notably outnumber Top 20 companies (270 trials). Government-funded trials is relatively few (78 trials) but are disproportionately concentrated in early-stage trials. Phase-stratified analysis (Fig. 3B) indicates that Phase IV trials are primarily led by academic institutions (159 trials), followed by Top 20 pharmaceutical companies (34 trials). Temporally, industry activity increased sharply after 2015, with particularly robust growth among non–Top 20 companies between 2020 and 2025.

Fig. 3.

Major funding entities for PF clinical trials (A). Annual distribution of trial funding entities; (B). Distribution of trial funding entities at different trial stages)

Analysis of endpoints in PF clinical trials

Analysis of primary endpoints (Figs. 4A-B) reveals a consistent core evaluation framework dominated by “safety and tolerability” (328 trials), “FVC” (286 trials), and “adverse events” (268 trials) ( “Safety and Tolerability” encompasses comprehensive safety assessments and tolerability metrics; “Adverse Events” refers to specifically reported adverse reactions). In Phase I, endpoints focus on safety and and pharmacokinetic parameters (such as, Cmax and AUC ). As trials progress to Phase II and Phase III, “FVC” emerges as the central surrogate efficacy endpoint,. Time- trend analyses show that since 2020, nendpoints such as patient survival and diffusing capacity of the lung for carbon monoxide (DLCO) have gained traction.

Fig. 4.

Top 10 clinical trial endpoints for PF clinical trials (A). Trial endpoints across different years; (B). Trial endpoints at different stages)

Analysis of drugs, targets, and mechanisms in PF clinical trials

Drug-level analysis indicates that nintedanib (94 trials) and pirfenidone (88 trials) remain the most extensively studied agents. Immunomodulatory agents such as rituximab (40 trials) and natural-product–derived compounds (34 trials) also demonstrate substantial activity (Fig. 5A).

Fig. 5.

Mechanistic analysis of clinical trials for PF clinical trials (A). Distribution of tested drugs; (B). Distribution of targets; (C). Distribution of mechanisms)

Among the investigational agents, emerging therapies such as nerandomilast (28 trials) and admilparant (16 trials) warrant attention, whereas cyclophosphamide (IV) (17 trials), as an established drug, is also being widely reevaluated for new indications; these three represent anti-inflammatory, immunomodulatory, and targeted-intervention therapeutic strategies, respectively (Fig. 5A). Target-level analysis shows that platelet-derived growth factor receptor α (PDGFRα) is the most extensively investigated target (118 clinical trials), followed closely by FMS-like tyrosine kinase 3 (FLT3) and kinase insert domain receptor rank second, each involved in 111 trials (Fig. 5B). Mechanistically, inhibitors of the VEGFR family and related kinases (such as VEGFR tyrosine kinase inhibitors, 134 trials) (Fig. 5C). Additional major mechanistic classes include tumour necrosis factor alpha (TNF-α) antagonist (132 trials), Src inhibitors (128 trials), and FGF receptor tyrosine kinase (FGFR) inhibitor (127 trials).

Major diseases involved in PF clinical trials

Analysis of the comorbidity spectrum in pulmonary fibrosis‑related clinical trials reveals that the scope of research has expanded significantly beyond idiopathic pulmonary fibrosis alone (Table 1). IPF (37.66%) constitutes the largest disease category. Ssc (12.80%) ranks next. Other respiratory comorbidities including COVID-19 (3.99%) and pulmonary hypertension (PH) (3.91%) also contribute meaningfully to the overall distribution. In addition, trials address a wide range of fibrotic and immune-mediated diseases, such as liver fibrosis, dermatomyositis/polymyositis, and rheumatoid arthritis.

Table 1.

Spectrum of Comorbidities in PF Clinical Trials

Disease	Number of trials	rate
IPF [12]	453	37.66% (453/1203)
Ssc [15]	154	12.80% (154/1203)
COVID-19 [16]	48	3.99% (48/1203)
PH [17]	47	3.91% (47/1203)
COPD [18]	38	3.16% (38/1203)
Hepatic Fibrosis [19]	30	2.49% (30/1203)
Dermatomyositis/Polymyositis	27	2.24% (27/1203)
Rheumatoid Arthritis [20]	24	2.00% (24/1203)
Asthma [21]	22	1.83% (22/1203)
Chronic Cough [22]	22	1.83% (22/1203)

Clinical trials of IPF

Based on the tabular data, clinical trials targeting idiopathic pulmonary fibrosis (IPF) overall demonstrate the following characteristics: With regard to trial status distribution, the majority of trials have been completed, followed by a notable proportion of trials that were terminated early, while the numbers of ongoing and planned studies are largely comparable. In terms of trial phases, Phase II trials predominate, followed by Phase I and Phase IV trials. Analysis of gender distribution indicates that a considerable number of trials included both male and female participants, with very few trials focusing exclusively on a single gender. Regarding age distribution, adult participants constitute the largest subgroup, followed by older adults, while pediatric participants represent the smallest proportion (Fig. 6).

Fig. 6.

Comprehensive Analysis of Clinical Trials for IPF (A). Distribution of Study Phases; (B). Distribution of Trial Statuses; (C). Distribution of Participant Gender; (D). Distribution of Participant Age Groups)

Clinical trials of PF associated with systemic sclerosis

Most trials addressing SSc-PF have been completed, followed by studies that are ongoing or planned, whereas terminated trials account for only a small proportion (Fig. 7A). By trial phases, Phase II trials predominante, followed by Phase III and Phase IV trials. In contrast, Phase I and Phase I/II trials are comparatively few (Fig. 7B). Gender analysis shows that male participants outnumber female participants (Fig. 7C). Age distribution shows that adults constitute the largest subgroup, followed by older adults and children (Fig. 7D).

Fig. 7.

Comprehensive analysis of the clinical trials for systemic sclerosis-related PF (A). Distribution of study phases; (B). Distribution of trial statuses; (C). Distribution of participant gender; (D). Distribution of participant age groups)

Clinical trials of PF associated with pulmonary arterial hypertension

Analysis of study completion status shows that trials conducted in several years (e.g., 2004, 2008, and 2017) progressed to successful completion (Fig. 8A). Phase distribution reveals that Phase II studies dominate in many years (e.g., 2004, 2008, and 2016) (Fig. 8B). A subset of trials, such as those initiated in 2007 and 2018, were terminated for unspecified reasons. Similar to other PF subgroups, most designs do not differentiate participants by gender (Fig. 8C). Age distribution shows comparable representation of adults and older-adults populations (Fig. 8D). Overall, PF-PAH trials exhibit clear periodic fluctuations in activity, with consistent dominance of Phase II studies and intermittent increases in early-phase exploration (such as 2015 and 2022).

Fig. 8.

Comprehensive analysis of the clinical trials for pulmonary arterial hypertension-related PF (A). Distribution of study phases; (B). Distribution of trial statuses; (C). Distribution of participant gender; (D). Distribution of participant age groups)

Discussion

PF, a progressive and irreversible interstitial lung disease, has undergone substantial shifts in its clinical-trial landscape over the past two decades. Since the approval of anti-fibrotic drugs, such as pirfenidone and nintedanib, in the early 21st century, the research paradigm has gradually shifted from the initial exploration stage to large-scale efficacy verification stage [23]. Despite these advances, major bottlenecks remain, including pronounced disease heterogeneity, limited availability of validated therapeutic targets, and the inherent complexity of clinical-trial design in PF. Notably, the COVID-19 pandemic triggered a surge of trials on post-infectious PF, temporarily intensifying research activity but potentially diverting attention and resources from other PF subtypes. Against this background, the present study systematically examines the global PF clinical-trial landscape and, for the first time at a macro level, elucidates the characteristics of R&D patterns, the evolution of funding models, endpoint-selection strategies, and subtype-specific research trends, providing valuable guidance for future investigations.

Our analysis reveals that global PF clinical-trial activity exhibits a clear three-stage trajectory: an initial exploration period, a stable growth period, and an explosive expansion period. The stable growth phase from 2007 to 2019 closely related to the R&D breakthroughs of pirfenidone and nintedanib. Two milestone Phase III clinical trials (ASCEND and INPULSIS) during this period provided key evidence for targeted anti-fibrotic therapy. In the pivotal phase III ASCEND trial, treatment with pirfenidone for 52 weeks significantly reduced the risk of the primary endpoint—a decline of ≥ 10% in predicted FVC or death—by 47.9% compared with placebo (16.5% vs. 31.8%, P < 0.001). The mean decline in FVC was also significantly lower in the pirfenidone group than in the placebo group (235 mL vs. 428 mL; difference, 193 mL; P < 0.001). The trial confirmed that pirfenidone significantly slows disease progression in IPF, improves exercise tolerance and progression-free survival, and is characterized by an acceptable safety profile [11]. The INPULSIS study showed that nintedanib attenuated the annual decline in FVC in IPF patients. Nintedanib significantly slowed the annual rate of FVC decline in patients with IPF in two Phase III trials (INPULSIS-1/-2) compared with placebo, with a difference of approximately 94–125 mL/year (P < 0.001); pooled analysis showed a reduction of approximately 110 mL/year in the annual rate of decline, and the efficacy results were robust. Although diarrhea was the most common adverse reaction, treatment discontinuation remained below 5% [12]. These milestone findings not only validated the feasibility of targeted anti-fibrotic intervention but also fundamentally reshaped the R&D framework in the field, establishing both conceptual proof and strategic confidence for the development of next-generation therapies with diverse mechanisms of action.

The dramatic increase in trial numbers observed in 2020 and their subsequent maintenance of the plateau, more than pandemic-driven interest in post-COVID-19 pandemic [24, 25]. Meanwhile, it is also crucial to acknowledge that in 2019, the landmark INBUILD randomized controlled trial provided, for the first time, high-level evidence demonstrating that antifibrotic therapy (nintedanib) is also effective for multiple types of interstitial lung disease exhibiting a progressive fibrosing phenotype, beyond IPF [26]. This study not only established a treatment strategy targeting a “progressive fibrosing phenotype” that transcends specific etiologies but also marked the formal expansion of antifibrotic treatment into a broad spectrum beyond IPF. Consequently, it fundamentally reshaped the clinical management landscape for ILD and propelled new research directions focused on targeting shared pathomechanisms of disease. Taken together, this explosive growth not only reflects the scientific community’s capacity for rapid response mobilization during a global crisis but may also permanently alter operational models for PF clinical research. The long-term implications of these structural shifts, particularly the integration of decentralized methods, evolving regulatory frameworks, and cross-disease mechanistic thinking, warrant continued observation and critical evaluation.

National-level findings indicate that the United States and China together constitute a “dual-core” landscape in global PF clinical trials. This situation profoundly reflects the two countries’ comprehensive advantages in terms of market capacity, capital investment, and policy support. The United States maintains its leadership in foundational innovation through a mature biomedical ecosystem, including the fibrosis research network supported by the National Institutes of Health (NIH) and review system of the Food and Drug Administration (FDA). In contrast, China’s rapid ascent is underpinned by national strategic planning. Guided by the Healthy China 2030 blueprint, reforms in the drug review and approval system have significantly improved the efficiency of clinical research, while China’s accession to the International Council for Harmonisation (ICH) has accelerated its regulatory convergence with global standards. Following the COVID-19 pandemic, intensified national attention to respiratory disease research has further catalyzed China’s breakthroughs and expanded its global influence. This dual-core dynamic reflects the countries’ distinct developmental trajectories and is expected to continue shaping the further direction of global PF R&D. However, the current situation, characterized by a predominance of single-country trials (945 trials) and a relatively small number of multi-country collaborative trials (128 trials), reveals potential efficiency bottlenecks in the current R&D model. The current lack of collaboration is influenced by multiple factors. While challenges in areas such as data sharing and cross‑border ethical oversight may contribute to this, in many cases the primary barriers remain the difficulty in securing sustainable funding and the need to navigate differences among national ethics committees [27]. Addressing challenges related to patient privacy, cross-national data governance, and authorization of future data use will be essential. In the future, promoting international collaboration through unified technical standards, such as unified core data sets and imaging evaluation criteria, and establishing a more efficient international cooperation framework will be the key directions to improve global PF R&D efficiency. Cooperative frameworks established by major regulatory agencies, such as the dialogue mechanisms between the European Medicines Agency and FDA on IPF therapeutics, serve as encouraging precedents.

Analysis of the sex eligibility criteria across the included trials revealed that the majority of trials enrolled both male and female participants (labeled as ‘Both’). However, among the trials that specified a single sex, our dataset showed a higher number of trials labeled for males compared to those labeled for females. This pattern contrasts with the established epidemiology of SSc, which is female-predominant, as well as with the participant composition of key trials (e.g., the SENSCIS trial, in which approximately 75% of participants were female). This discrepancy may reflect specific recruitment strategies or research focuses within a subset of trials in our dataset, such as studies specifically targeting male subgroups with poorer prognosis, or a higher referral rate of male patients to clinical trial centers due to potentially more severe disease. This highlights the importance of carefully distinguishing between the target population defined by trial design and the true epidemiological distribution of the disease when interpreting such aggregated data.

Analysis of trial endpoints reveals the maturation of the PF drug-evaluation system. “Safety and tolerability” and “adverse events” remain central endpoints, reflecting clinical concerns arising from the tolerability profiles of pirfenidone and nintedanib and the need to preserve patients’ quality of life while slowing disease progression. “FVC” continues to serve as the primary endpoint in most randomized controlled trials, and is widely accepted by regulatory agencies. However, its limitations, within-individual variability, modest sensitivity to early or heterogeneous disease, and potential mismatch with patient-reported symptoms, are increasingly recognized [28]. The sustained attention to endpoints such as “patient survival” and “DLCO” underscores efforts to build a more clinically meaningful and mechanistically informative endpoint matrix. DLCO, which reflects impairment in gas exchange, captures physiological defects that may be missed by FVC and is also relevant for PF patients with coexisting pulmonary hypertension [29]. Future evaluation frameworks will likely incorporate composite endpoints integrating radiomic features, circulating biomarkers, functional metrics, and patient-reported outcomes (e.g., cough and dyspnea) [30–33], aiming to more sensitively detect treatment effects and identify subgroups most likely to benefit. For special PF phenotypes, such as SSc- interstitial lung disease, the value of combined endpoints has already been demonstrated. In the SENSCIS trial, combined measures, including decline in FVC, changes in the modified Rodnan skin score from baseline, and changes in the total score of the St. George’s Respiratory Questionnaire at week 52, provided a multidimensional assessment of disease modification and patient well-being [15]. This multi-domain approach holds promise for extension to other PF subtypes, particularly those with systemic manifestations.

In the early stages when effective standard treatments were lacking, placebo-controlled designs served as the cornerstone for validating the efficacy of new drugs (e.g., the ASCEND and INPULSIS trials) [11]. With the successive establishment of nintedanib and pirfenidone as standard therapies for IPF and some forms of progressive fibrosing ILD, the paradigm of trial design underwent a fundamental shift. Data show that after 2015, the “add-on to standard therapy” design has become the mainstream in phase II/III trials, aligning with regulatory requirements and clinical practice [23]. For example, in the field of SSc-ILD, recent trials often compare an add-on drug versus placebo on top of background therapy (with or without mycophenolate mofetil). This evolution better protects patient rights and enhances the clinical relevance of trials, but it also places higher demands on the sensitivity to detect incremental efficacy and on sample size estimation. In the future, for novel mechanism-based drugs, how to flexibly and ethically select control arms (including adaptive designs or external controls) will be a key challenge in improving R&D efficiency.

Analysis of investigational drugs, targets, and mechanisms outlines two parallel paths in current PF drug development. The first is the “optimization and expansion” pathway, which involves in-depth development based on verified biological mechanisms. The continuous high level of R&D activity centered on nintedanib and pirfenidone is not only reflected in their frequent use as positive controls but also in efforts to develop new indications, new formulations, and combination strategies. This “follow-on” approach offers relatively controllable risk and aims to maximize the clinical value of verified targets. The second is the “breakthrough and innovation” pathway, aiming to transcend the existing anti-fibrosis framework. Although the cluster of tyrosine kinase inhibitors centered around PDGFRα, VEGFR, FGFR and related pathways remains dominant, this study also identified a growing number of trials involving targeting emerging targets such as LPA1 and αvβ6 integrin [34–37]. Recently, the two Phase III studies, FIBRONEER-IPF and FIBRONEER-ILD, demonstrated that nerandomilast, a novel oral selective PDE4B inhibitor, significantly slowed the annual rate of decline in lung function (FVC) in patients with IPF or PPF, whether used as monotherapy or in combination with existing antifibrotic agents. The phase III FIBRONEER-IPF trial enrolled 1,177 patients with IPF, of whom 77.7% were receiving background antifibrotic therapy. Results showed that at week 52, the decline in FVC was significantly slowed in the nerandomilast 18 mg group compared with placebo (P < 0.001). A significant treatment effect was also observed in the 9 mg group (P = 0.02). Diarrhea was the most common adverse event (41.3% in the 18 mg group), and the incidence of serious adverse events was balanced across groups[38]. Meanwhile, the broad exploration of therapies for post-COVID-19 PF reflects a pragmatic approach that uses clinical experience to rapidly assess new indications for approved drugs. Such repurposing strategies offer advantages of shorter R&D cycles, lower costs, and better-characterized safety profiles, features particularly suitable for urgent public-health challenges such as post-COVID-19 PF.

The scope of PF clinical trials has significantly expanded, extending far beyond IPF. Among these, SSc, a multisystem autoimmune disease, has become a major focus. SSc is characterized by immune dysregulation, microvascular injury, and progressive fibrosis involving the skin, joints, and internal organs (especially the lungs, esophagus, and kidneys). Excessive collagen deposition and complex interactions among immune, vascular, and fibrotic pathways drive its progression to multi-organ dysfunction [39]. Consistent with this mechanistic clarity, clinical trials for SSc-related PF are predominantly Phase II or later, and termination rates are low, indicating a relatively mature consensus regarding patient selection and endpoint determination. Post-COVID-19 PF, an important long-term sequela of SARS-CoV-2 infection, is characterized by abnormal tissue repair after acute lung injury, resulting in collagen deposition, large-area scarring, and fibrosis in the lungs [40]. Clinically, frequently exhibit persistent dyspnea, cough, chest pain, fatigue, and myalgia after recovery from the acute infection. High-resolution CT commonly demonstrates interstitial thickening, coarse reticulation, bronchiectasis, and parenchymal bands, reflecting fibrotic transformation [41–44]. The dominance of Phase II trials, along with a notably high proportion of Phase IV studies, reflects a dual strategy: rapid exploratory screening of potential treatments (Phase II) and leveraging real-world evidence for repurposed drugs (phase IV). PH is a common and prognostically poor complication of fibrotic lung diseases. Its coexistence with PF PF significantly worsens clinical outcomes, reducing survival and profoundly impairing patients’ quality of life and exercise tolerance [45]. Several established PH therapies, such as prostaglandins, endothelin-1 receptor antagonists, and PDE-5 inhibitors, have significantly improved the quality of life and prognosis of patients [46].Future research will require more refined phenotypic classification of pulmonary vascular lesions and development of integrated treatment strategies capable of simultaneously addressing the fibrotic and vascular components of disease.

In summary, this panoramic analysis of global PF clinical trials reveals a dynamically evolving and multi-dimensional innovative R&D landscape. Following the initial breakthroughs in anti-fibrotic drugs, this field is rapidly developing towards more precise targeting, diversified strategies, and more comprehensive evaluations. The dual-core R&D leadership of China and the United States continues to demonstrate strong innovation vitality, and strengthened international collaboration will be essential to further improve R&D efficiency. The expanding disease spectrum reflects a profound understanding of the systematic and multi-organ nature of fibrosis. In the future, progress will depend on strengthening the translation between basic and clinical research, promoting innovative and adaptive trial designs, developing sensitive and clinically meaningful endpoints, and implementing refined patient stratification strategies. Together, these efforts may enable PF research not only to slow disease progression but ultimately to reverse or prevent fibrosis. However, this study has certain limitations. The dataset is derived from a single commercial platform (INFORMA), which may not fully cover all regional or unregistered trials, particularly early-terminated or non-publicly registered studies. Additionally, some records lack complete information on study timelines or phases, introducing potential bias. Future work should integrate multi-source data from platforms such as ClinicalTrials.gov and the Chinese Clinical Trial Registry to construct a more comprehensive panoramic map. Additionally, incorporating high-quality non-interventional studies and real-world data will further enhance understanding of the natural history of PF and long-term effectiveness of emerging therapies.

Supplementary Information

Supplementary Material 1. ^{(15.7KB, docx)}

Supplementary Material 2. ^{(2.5MB, jpg)}

Supplementary Material 3. ^{(2.5MB, jpg)}

Supplementary Material 4. ^{(2.7MB, jpg)}

Supplementary Material 5. ^{(2.5MB, jpg)}

Authors’ contributions

CZ conceived and designed the work, acquired, analyzed and interpreted the data, and drafted the manuscript. CS interpreted the data and drafted the manuscript. YZ, JL, SZ, XL and YD acquired and analyzed the data. NY and JK substantively revised the manuscript. All authors read and approved the final manuscript.

Funding

Key Research Program of Guangxi Science and Technology Department (AB21196010); Self-funded Scientific Research Project of the Health Commission of Guangxi Zhuang Autonomous Region (No.Z-A20240492, Z-A20240515); National Natural Science Foundation of China (82104499, 82160783); Joint Project on Regional High-Incidence Diseases Research of Guangxi Natural Science Foundation (No.2023GXNSFBA026146); China Postdoctoral Science Foundation (2023MD734158).

Data availability

The dataset supporting the conclusions of this article is are available in the INFORMA repository (https://pharma.id. informa.com/). All individual data collected from this study can be obtained from the corresponding author to anyone who wishes to access the data immediately following publication.

Declarations

Ethics approval and consent to participate

This study was approved by the Medical Ethics Review Committee of the First Affiliated Hospital of Guangxi Medical University (2025-K0216). This study is based on data derived from original clinical trials that have obtained approval from relevant ethics review committees, strictly adhere to the principles of the Declaration of Helsinki and international standards for Good Clinical Practice (GCP), and have completed participant informed consent processes. The INFORMA database solely aggregates and processes anonymized trial project information that has undergone compliant de-identification procedures. It does not involve direct contact with patients or the collection of new personal data. Consequently, this study itself does not involve new human subjects, and its use of data is in compliance with ethical requirements for information obtained from legally and ethically compliant sources.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.