Pulmonary fibrosis: evolving therapeutic pipeline

Introduction Pulmonary fibrosis describes a heterogeneous group of diseases encompassing interstitial lung diseases characterised by varied inflammation and fibrosis of the lung parenchyma. Progressive interstitial scarring results in impaired gas exchange, with exertional breathlessness and cough as the most common presenting symptoms. Interstitial lung diseases typically present in later adulthood, with the incidence increasing with age, and are more frequently seen in men and in smokers, particularly for the most common interstitial lung disease type, idiopathic pulmonary fibrosis. Idiopathic pulmonary fibrosis is an archetypal progressive pulmonary fibrosis with an unknown cause. Interstitial lung diseases of known cause include systemic autoimmune rheumatic diseases or connective tissue disease related interstitial lung diseases (eg, rheumatoid arthritis and systemic sclerosis; drug induced interstitial lung diseases; and environmental and occupational exposures, such as mould and asbestos, termed hypersensitivity pneumonitis). Development of pulmonary fibrosis in interstitial lung diseases varies in onset, severity, and extent, but inherently has a poor prognosis with an associated increased mortality. 1 The overall incidence of interstitial lung disease is up to 31.5 per 100 000 people/year, with prevalence ranging from 6.3 to 71 per 100 000 people.2 The complex pathogenesis of interstitial lung disease involves an interplay between genetic susceptibility and environmental exposures, with loss of epithelial integrity, resulting in fibroblast proliferation and extracellular matrix deposition, rather than inflammation alone.3 Although management strategies differ between idiopathic and secondary interstitial lung diseases, particularly in relation to immunosuppression, recognition of a shared progressive fibrotic phenotype has driven the development of antifibrotic treatments applicable across a range of interstitial lung diseases. In this review, we focus on the pathogenesis of pulmonary fibrosis and link the evolving mechanistic insights to current and emerging therapeutic strategies.Sources and selection criteria Embase and Medline databases were searched for studies between 1 January 1974 and 9 February 2025. Based on Ovid search criteria and a combination of terms including “pulmonary fibrosis,” “drug,” and “randomised controlled trial,” we identified 3452 studies. We excluded studies that focused on possible pulmonary fibrosis treatments that were not directly related to the fibrotic process, such as randomised controlled trials targeting oxygen treatment or pulmonary hypertension. Studies on herbal and traditional medicine with no mention of a specific therapeutic agent were also excluded. After exclusion of these studies, 136 randomised controlled trials and meta-analyses were identified and analysed.Clinical course and disease monitoring Pulmonary fibrosis typically presents with progressive exertional breathlessness, often accompanied by dry cough, without an immediately identifiable cause. Examination may show fine inspiratory crackles and digital clubbing. Given the non-specific nature of early symptoms, diagnosis can be delayed. The disease course varies based on the subtype of interstitial lung disease and underlying cause, with individual variation related to genetics, environmental exposures, and the effect of disease modifying treatments currently in use. A subset of patients develop a progressive pulmonary fibrosis phenotype, defined by worsening symptoms, decline in lung function (forced vital capacity and transfer factor), and radiological progression.In clinical practice, monitoring is both multimodal and longitudinal, with an emphasis on trends rather than single measurements. Patients are typically reviewed every three to six months, with assessment comprising symptom progression, serial pulmonary function testing, exercise capacity (six minute walk test), oxygenation (at rest and on exertion), and interval imaging, where indicated. The reduction in forced vital capacity is the main marker of disease progression and is closely associated with prognosis. Clinical decision making is guided by the rate of change over time, however, rather than absolute values only.Prognosis varies widely across subtypes of interstitial lung disease. Idiopathic pulmonary fibrosis has a poorer prognosis, with a median survival of about three to five years, whereas outcomes in other interstitial lung diseases depend on disease behaviour and response to treatment. Recognition of progressive pulmonary fibrosis allows earlier identification of patients with a progressive phenotype and enables more targeted treatment in those whose trajectory may mirror idiopathic pulmonary fibrosis.Current management aims to slow disease progression, alleviate symptoms, and maintain quality of life, and is discussed in more detail below (see section on Current treatments). The antifibrotic drugs, pirfenidone and nintedanib, are established treatments for idiopathic pulmonary fibrosis globally, with nintedanib increasingly used in non-idiopathic progressive pulmonary fibrosis. Adjunctive management includes pulmonary rehabilitation, oxygen treatment, optimisation of comorbidities, and early integration of palliative care.Pathophysiology Pulmonary fibrosis involves a complex interplay between host and environment, reflecting a failure of normal tissue repair and homeostasis. External triggers include a diverse range of factors, such as environmental pollutants, infectious agents, autoantibodies, drugs, or allergens, resulting in repetitive alveolar epithelial injury. Impaired epithelial repair is influenced by genetic susceptibility, such as mutations in the genes TERT, TERC, and MUC5B that promote fibrotic remodelling. 3 Repetitive epithelial damage leads to inflammatory cell activation with the release of cytokines and chemokines, activation of transforming growth factor beta (TGF-β) signalling pathways, and fibroblast proliferation. These processes are mediated through complex interactions between epithelial, endothelial, immune, and mesenchymal cells that perpetuate fibrotic signalling. Repetitive epithelial injury and protein release activate the coagulation cascade, which propagates fibroblast migration, proliferation, and differentiation, ultimately leading to extracellular matrix deposition. Rather than passive accumulation, the extracellular matrix undergoes dynamic remodelling, with changes in composition and stiffness that further amplify profibrotic signalling. Cellular senescence of alveolar epithelial cells and fibroblasts further contributes to persistent fibrosis by impairing resolution and promoting a profibrotic phenotype. Dysregulated repair mechanisms, including activation of the coagulation cascade and epithelial-mesenchymal transition, further promote myofibroblast differentiation and reinforce maladaptive tissue remodelling.3–8 Ultimately, these pathways result in excessive and disordered deposition of extracellular matrix, particularly collagen, causing progressive distortion of the architecture of the lung tissue. In this review, we provide further details on the pathogenesis of pulmonary fibrosis and explore emerging treatments targeting these pathophysiological mechanisms (figure 1).3–8 Figure 1Targets for drug treatments in pulmonary fibrosis. Summary of currently approved treatments and investigational treatments evaluated in phase 2 and phase 3 clinical trials across key cellular pathways implicated in pulmonary fibrosis. Treatments are colour coded according to clinical outcomes: green indicates treatments that showed clinical efficacy; orange indicates treatments that are under review; and red indicates treatments that have not shown clinical benefit. ECM=extracellular matrix; EMT=epithelial-mesenchymal transition; PDE 4=phosphodiesterase 4; TGF-β=transforming growth factor beta; BAFF=B cell activating factor; GPR=G protein coupled receptor; CCL2=CC-chemokine ligand 2; CTGF=connective tissue growth factor; LOXL2=lysyl oxidase-like 2; LPA1=lysophosphatidic acid receptor 1; IL=interleukin; TNF-α=tumour necrosis factor alphaCurrent treatments Current treatments for idiopathic and progressive pulmonary fibrosis reduce the rate of lung function decline and may modestly affect survival, but these treatments do not reverse established fibrosis and have limited effects on symptom burden or quality of life. In the past two decades, most randomised controlled trials have focused on idiopathic pulmonary fibrosis, the most common and progressive interstitial lung disease. Pirfenidone and nintedanib are established treatments for idiopathic pulmonary fibrosis and are widely used in clinical practice. More recently, nerandomilast has shown positive results in phase 3 trials and was approved in the US for both idiopathic and progressive pulmonary fibrosis in 2025. In progressive pulmonary fibrosis, nintedanib is licensed for use globally.Pirfenidone Pirfenidone is an anti-inflammatory, antifibrotic agent with pleiotropic effects. Three phase 3 multicentre randomised controlled trials of pirfenidone in idiopathic pulmonary fibrosis have been performed:CAPACITY 004 (a three arm study of the safety and efficacy of pirfenidone in patients with idiopathic pulmonary fibrosis), CAPACITY 006 (looking at the safety and efficacy of pirfenidone in patients with idiopathic pulmonary fibrosis), and ASCEND (looking at the efficacy and safety of pirfenidone in patients with idiopathic pulmonary fibrosis). The CAPACITY 004 and 006 studies had conflicting results for the primary end point. CAPACITY 004 showed a significant reduction in forced vital capacity decline with pirfenidone (–8.0%, standard deviation 16.5 v –12.4%, 18.5; difference 4.4%, 95% confidence interval (CI) 0.7% to 9.1%; P=0.001), whereas CAPACITY 006 showed no significant difference (0.6%, –3.5% to 4.7%; P=0.50).9 This discrepancy led to the ASCEND study, which showed a 45.1% relative reduction in forced vital capacity decline over 52 weeks (–235 mL v –428 mL; difference 193 mL; P<0.001). Furthermore, fewer patients had a reduction in forced vital capacity ≥10% or death (16.5% v 31.8%).10 Common side effects included nausea (36% v 13% for placebo), fatigue (21% v 17% for placebo), skin rash (28% v 9% for placebo), dyspepsia (18% v 6% for placebo), anorexia (16% v 7% for placebo), and weight loss (13% v 8% for placebo).9 10 Nintedanib Nintedanib, a tyrosine kinase inhibitor, targets fibroblast growth factor, platelet derived growth factor, and vascular endothelial growth factor receptors. Two parallel phase 3 randomised controlled trials explored the role of nintedanib in idiopathic pulmonary fibrosis, enrolling 1066 patients for 52 weeks. 11 Both reduced the decline in forced vital capacity; INPULSIS 1 (looking at the safety and efficacy of BIBF 1120 at high dose in patients with idiopathic pulmonary fibrosis) showed a difference of 125.3 mL/year (95% CI 77.7 to 172.8; P<0.001) and INPULSIS-2 showed a difference of 93.7 mL (44.8 to 142.7; P<0.001).11 Common side effects were diarrhoea (61-63% v 18% for placebo) and nausea (22-26% v 5.9-7.3% for placebo) with 6-8% of patients discontinuing treatment because of gastrointestinal side effects.11 Nerandomilast More recently, a third disease modifying treatment has emerged, BI 1015550, now known as nerandomilast. Nerandomilast is an oral selective phosphodiesterase 4B inhibitor that increases intracellular cyclic AMP. 12 In a phase 2 trial in 147 patients with idiopathic pulmonary fibrosis, nerandomilast considerably reduced the rate of forced vital capacity decline over 12 weeks.12 These encouraging findings led to the phase 3, 52 week FIBRONEER-IPF trial (a study to find out whether BI 1015550 improves lung function in 1177 people with idiopathic pulmonary fibrosis). At 52 weeks, the adjusted mean reduction in forced vital capacity was −114.7 mL (95% CI −141.8 to −87.5) in the nerandomilast 18 mg group and −138.6 mL (−165.6 to −111.6) in the nerandomilast 9 mg group compared with −183.5 mL (−210.9 to −156.1) in the placebo group.13 This finding corresponded to adjusted treatment differences of 68.8 mL (30.3 to 107.4; P<0.001) for the 18 mg dose and 44.9 mL (6.4 to 83.3; P=0.02) for the 9 mg dose.13 A pharmacokinetic interaction with concomitant pirfenidone was seen mostly with the lower 9 mg dose of nerandomilast, whereas effects at the 18 mg dose seemed consistent, irrespective of background use of pirfenidone.13 Similarly, in the FIBRONEER-ILD trial (a study to determine whether BI 1015550 improves lung function in 1176 participants with progressive fibrosing interstitial lung diseases), nerandomilast significantly reduced the 52 week forced vital capacity decline in patients with progressive pulmonary fibrosis.14 The adjusted mean forced vital capacity decline was −98.6 mL (95% CI −123.7 to −73.4) with the 18 mg dose and −84.6 mL (−109.6 to −59.7) with the 9 mg dose compared with −165.8 mL (−190.5 to −141.0) in the placebo group.14 The corresponding adjusted differences were 67.2 mL (31.9 to 102.5; P<0.001) and 81.1 mL (46.0 to 116.3; P<0.001) respectively, showing consistent treatment benefit.14 Across both trials, diarrhoea was the most common adverse effect, particularly when combined with nintedanib. Other reported adverse events included cough, worsening of pulmonary fibrosis, depression, anxiety, nausea, weight loss, and nasopharyngitis.13 14 Although treatments have focused on idiopathic pulmonary fibrosis as the archetypal progressive pulmonary fibrosis, other non-idiopathic pulmonary fibrosis interstitial lung diseases also pose a risk of developing progressive pulmonary fibrosis despite maximal treatments. Progressive pulmonary fibrosis is a recognised phenotype that can occur in non-idiopathic pulmonary fibrosis interstitial lung diseases, such as fibrotic hypersensitivity pneumonitis and systemic autoimmune rheumatic diseases-interstitial lung diseases. Guidelines define progressive pulmonary fibrosis as having at least two of these features within 12 months: worsening respiratory symptoms (without alternative cause), radiological progression of fibrosis, or decline in lung function (absolute decline in forced vital capacity >5% or carbon monoxide transfer factor (TLCO) >10%).15 The prevalence of progressive pulmonary fibrosis varies, reaching up to 45% in systemic autoimmune rheumatic diseases-interstitial lung disease, 51% in unclassifiable interstitial lung diseases, and 58% in fibrotic hypersensitivity pneumonitis, shown in a large Canadian registry study of 2746 patients.16 Survival for progressive pulmonary fibrosis was similar to idiopathic pulmonary fibrosis (hazard ratio 1.06, 95% CI 0.84 to 1.35; P=0.6) and significantly worse than for non-progressive pulmonary fibrosis (hazard ratio 3.32, 2.53 to 4.37; P<0.001).17 Recognising the effect of nintedanib in the INBUILD trial (efficacy and safety of nintedanib in patients with progressive fibrosing interstitial lung disease), nintedanib has now been licensed for use globally in progressive pulmonary fibrosis.18 This double blind, phase 3 study enrolled 663 patients with non-idiopathic progressive pulmonary fibrosis over 52 weeks. Progression was defined over 24 months by a decline in forced vital capacity >10% or decline in forced vital capacity of 5-10% with symptoms or radiological progression, or both. INBUILD included patients with hypersensitivity pneumonitis (26.1%), idiopathic non-specific interstitial pneumonia (18.9%), unclassifiable interstitial lung disease (17.2%), and systemic autoimmune rheumatic diseases-interstitial lung diseases (25.6%). Nintedanib reduced the annual forced vital capacity decline to –80.8 mL/year versus –187.8 mL/year with placebo (difference 107 mL/year; 95% CI 65.4 to 148.5; P<0.001), with a similar adverse event profile to previous randomised controlled trials of idiopathic pulmonary fibrosis.18 Two further studies have evaluated pirfenidone in progressive pulmonary fibrosis, with mixed results. The RELIEF trial (looking at pirfenidone in patients with progressive fibrotic interstitial lung diseases other than idiopathic pulmonary fibrosis) was a multicentre, double blind, phase 2b randomised controlled trial in 127 patients with progressive pulmonary fibrosis (including collagen or vascular disease, fibrotic non-specific interstitial pneumonia, chronic hypersensitivity pneumonitis, and asbestos related fibrosis).19 Progression criteria varied from INBUILD, with absolute decline in forced vital capacity of ≥5%/year. Pirfenidone reduced the decline in forced vital capacity (–17.8 mL v –113.0 mL; difference 95.3 mL; P=0.04), but the trial was underpowered and ended early because of poor recruitment.19 Another multicentre, double blind, phase 2 randomised controlled trial of 253 patients with progressive pulmonary fibrosis failed to meet its primary endpoint (home spirometry) because of technical problems.20 Clinic based spirometry, however, reduced the decline in forced vital capacity with pirfenidone (–87.7 mL v –157.1 mL), and fewer patients had a decline in forced vital capacity of >5% (odds ratio 0.42; 95% CI 0.25 to 0.69; P=0.001).20 Although both studies suggested benefit with pirfenidone, early termination limits interpretation and hence further trials are needed.Despite approved treatments, these interstitial lung diseases are relentlessly progressive with high morbidity and mortality. Antifibrotic drugs neither stabilise nor reverse fibrosis, with side effects causing 20-25% of patients to discontinue treatment.21 Drug development is a complex and costly process. Of 176 studies reviewed, 65 showed no benefit or had to be stopped prematurely because of adverse events. Ongoing efforts are focusing on new treatments targeting the pathogenesis of pulmonary fibrosis. Online supplemental table S1 provides details of emerging treatments and their underlying mechanisms, which are discussed below.SP110.1136/bmjmed-2025-001886.supp1Supplementary data Emerging therapeutic pipeline Therapeutic development in pulmonary fibrosis has increasingly focused on targeting specific pathogenic pathways rather than broad antifibrotic effects. These pathways include epithelial injury, fibroblast activation, extracellular matrix remodelling, immune dysregulation, and cellular senescence. Although many trials have reported promising early phase results, few have shown consistent benefit in phase 3 trials.Targeting epithelial cells Pulmonary fibrosis begins with repetitive alveolar epithelial injury in response to both endogenous (eg, genetic predisposition or cellular senescence) and exogenous (eg, smoking or pollutants) stimuli. These insults trigger the release of cytokines, chemokines, growth factors, and enzymes that dysregulate healing, contributing to fibrosis. Epithelial-mesenchymal transition enables epithelial cells to acquire mesenchymal traits, such as motility and apoptosis resistance, producing activated fibroblasts and myofibroblasts that deposit extracellular matrix, driven by multiple signalling pathways, leading to fibrosis. 3–8 Within these pathways, type II alveolar epithelial cells contribute to fibrotic signalling through expression of components of the renin-angiotensin system, including angiotensin converting enzyme, and increased local angiotensin II generation after epithelial injury. Angiotensin II promotes epithelial dysfunction and fibroblast activation, including myofibroblast differentiation, alongside upregulation and activation of TGF-β1, thereby linking epithelial injury to profibrotic remodelling. TGF-β1, mainly derived from macrophages, has a key role in fibroblast activation and extracellular matrix production through multiple pathways. TGF-β1 is challenging to target therapeutically, however, likely because of the difficulty of balancing its physiological and pathological effects.22 Phase 2 trials Angiotensin-converting-enzyme related signalling was assessed with buloxibutid, a selective angiotensin type 2 receptor agonist. In a 36 week, phase 2a, open label trial (looking at the safety, efficacy, and pharmacokinetics of C21 in people with idiopathic pulmonary fibrosis, NCT04533022), preliminary data showed a change in forced vital capacity of 47 mL at 24 weeks (90% CI −108 to 203; n=27), an increase in forced vital capacity by 235 mL at 36 weeks (8 to 389; n=19), and a reduction in TGF-β1 of 57%, whereas matrix metallopeptidase 13 (MMP-13) increased by 67%.23 A phase 2b randomised controlled trial (to evaluate efficacy and safety of buloxibutid in people with idiopathic pulmonary fibrosis (ASPIRE), NCT06588686) is currently underway to evaluate the efficacy of buloxibutid in a larger cohort.24 Buloxibutid has the potential to improve forced vital capacity and possibly reverse progression, which would surpass the effectiveness of current antifibrotic treatments that only slow the decline in disease.BG00011, a monoclonal antibody targeting and deactivating TGF-β, was reviewed in two randomised controlled trials. A phase 2b trial (an efficacy and safety study of BG00011 in participants with idiopathic pulmonary fibrosis, NCT03573505) of 106 patients with idiopathic pulmonary fibrosis was ended early because of serious adverse events (including four deaths and increased exacerbations) with no significant benefit.25 26 Phase 1 trial TRK-250, a nucleic acid that suppresses expression of TGF-β1, was safe and well tolerated in a phase 1 randomised controlled trial (a safety, tolerability, and pharmacokinetic study of TRK-250 for patients with idiopathic pulmonary fibrosis, NCT03727802) of 34 patients with idiopathic pulmonary fibrosis.27 No serious adverse events were reported, but TRK-250 has not proceeded to a phase 2 trial.27 Targeting fibroblasts Fibroblasts, derived from bone marrow progenitor cells, are activated into myofibroblasts by profibrogenic and proinflammatory factors released in response to epithelial injury. TGF-β induces epithelial-mesenchymal transition in alveolar epithelial cells, leading to further myofibroblast generation and excessive extracellular matrix deposition, resulting in fibrosis. Several antifibrotic drugs targeting fibroblasts have been investigated. 3–8 Phase 3 trials Autotaxin catalyses the conversion of lysophosphatidylcholine into lysophosphatidic acid. Ziritaxestat, an autotaxin inhibitor, showed modest benefits in slowing the decline in forced vital capacity in a phase 2 randomised controlled trial. 28 The phase 3 ISABELA trials (a clinical study to test how effective and safe GLPG1690 is for people with idiopathic pulmonary fibrosis when used together with standard of care (ISABELA1), NCT03711162 and its second trial (ISABELA2), NCT03733444) of 1306 patients with idiopathic pulmonary fibrosis, however, ended early because of a lack of significant improvement in forced vital capacity or secondary outcomes.28 29 As well as targeting lysophosphatidic acid, drugs like PBI-4050 act on G protein coupled receptors GPR40 and GPR84 to regulate inflammation and fibrosis by modulating fibroblast activity.30 Preclinical models showed that PBI-4050, especially with nintedanib or pirfenidone, modestly improved forced vital capacity and reduced fibrosis with minimal side effects. In a 12 week, phase 2, open label study (to evaluate the safety and tolerability of PBI-4050 in 41 patients with idiopathic pulmonary fibrosis, NCT02538536), only the PBI-4050-pirfenidone group significantly reduced forced vital capacity (−2.69%, P=0.024; −102 mL, P=0.01). One patient with serious pneumonia was reported. Phase 3 development was stopped after the sponsor, Liminal BioSciences, shifted focus to sodium phenylbutyrate, which was also discontinued after poor results.30 Phase 2 trials An early drug trial in 2018 (looking at the safety and efficacy of a lysophosphatidic acid receptor antagonist in idiopathic pulmonary fibrosis, NCT01766817) targeted lysophosphatidic acid receptor 1 (LPA1).31 Lysophosphatidic acid binding to G protein coupled lysophosphatidic acid receptors drives fibroblast activation, myofibroblast differentiation, and collagen deposition. Lysophosphatidic acid has multiple other roles, including immune cell recruitment, vascular permeability, and epithelial injury, which collectively exacerbate and sustain the fibrotic process. Furthermore, the association of lysophosphatidic acid with fibroblast recruitment, activation, and proliferation makes LPA1 antagonists potential drug targets for pulmonary fibrosis.31 32 The LPA1 antagonist, BMS-986020, significantly slowed the decline in forced vital capacity and improved quantitative lung fibrosis scores in a 26 week phase 2, parallel arm, multicentre, double blind, placebo controlled randomised controlled trial of 144 patients with idiopathic pulmonary fibrosis.31 The decline in forced vital capacity for BMS-986020 was −0.042 L (95% CI −0.106 to −0.022) versus −0.134 L (−0.201 to −0.068; P=0.05) for placebo. Four patients developed serious adverse events related to raised liver function tests and gallstones, resulting in the study being terminated.31 Post hoc analysis of the early drug trial in 2018 (NCT01766817) showed that BMS-986020 significantly reduced extracellular matrix-neoepitope serum biomarkers, including C1M, C3A, C3M, C4M2, C6M, PRO-C4, and VICM compared with placebo (P<0.05).31 32 Baseline quantitative lung fibrosis scores inversely correlated with forced vital capacity (linear regression −0.254±0.058, P<0.001), and the decline in forced vital capacity correlated with increased whole lung quantitative lung fibrosis scores over time (linear regression−0.249±0.084, P<0.01). Baseline whole lung quantitative lung fibrosis scores were significantly correlated with PRO-C4 (r=0.311, P<0.001) and C6M (r=0.397, P<0.001). Not all biomarker correlations were significant, although an overall positive trend was observed.32 The hepatotoxicity seen with BMS-986020 was considered drug specific, prompting development of a second generation LPA1 antagonist, admilparant (BMS-986278).33 34 A 26 week, phase 2, double blind, placebo controlled randomised controlled trial (measuring the effectiveness, safety, and tolerability of BMS-986278 in lung fibrosis, NCT04308681) was conducted in patients with idiopathic pulmonary fibrosis (n=278 randomised, n=276 treated) and progressive pulmonary fibrosis (n=125 randomised, n=123 treated). Both cohorts were receiving concomitant antifibrotic drugs and immunosuppressants, respectively. Admilparant reduced the decline in forced vital capacity compared with placebo by 1.4% in idiopathic pulmonary fibrosis (95% CI –0.1 to 3.0) and by 3.2% in progressive pulmonary fibrosis (0.7 to 5.7), with benefits seen irrespective of concomitant treatment. Acute exacerbations occurred in six (2%) patients with idiopathic pulmonary fibrosis and in four (3%) patients with progressive pulmonary fibrosis; 30 serious events and seven treatment emergent deaths were reported but no concerns for hepatotoxicity. Consequently, phase 3 trials are currently recruiting.33 34 Integrins are transmembrane glycoprotein receptors that regulate the interactions between the extracellular matrix, fibroblasts, and inflammatory cells, enabling cell adhesion, motility, and invasion.35 Specifically, αV integrins activate latent TGF-β, an important step that regulates TGF-β activity through the activation of fibroblasts and promotes extracellular matrix deposition, making integrins attractive therapeutic targets for pulmonary fibrosis.35 Abituzumab, a monoclonal antibody against αV integrins, was evaluated in the STRATUS trial (a phase 2, randomised, double blind, placebo controlled, parallel group, multicentre trial to evaluate the efficacy and safety of abituzumab in people with systemic sclerosis associated interstitial lung disease, NCT02745145), but was ended early because of slow recruitment with only 24 participants.36 Although the placebo group showed a greater decline in forced vital capacity, no significant differences were observed. Four serious adverse events occurred, including one death from sepsis, but none was considered to be related to the study.36 Bexotegrast, a selective integrin inhibitor, was well tolerated in INTEGRIS-IPF—a 12 week, randomised, double blind, dose ranging, placebo controlled phase 2a trial to evaluate the safety, tolerability, and pharmacokinetics of PLN-74809 in 119 patients with idiopathic pulmonary fibrosis (NCT04396756).35 Bexotegrast showed an adjusted mean forced vital capacity decline of −25 to −30 mL compared with −70 to −90 mL in the placebo group, corresponding to a treatment difference of 40-60 mL, including in those receiving concomitant antifibrotic drugs.35 Despite these encouraging results from a phase 2a trial, the subsequent BEACON-IPF (bexotegrast for treatment of idiopathic pulmonary fibrosis) phase 2b-3 trial ended early after an independent data monitoring committee review.35 The hedgehog pathway represents another pathway for fibroblast activation. ENV-101, a hedgehog pathway inhibitor, blocks protein activation involved in fibroblast activation and the differentiation of myofibroblasts which reduces extracellular matrix production, thereby reducing fibrosis.37 A 12 week, phase 2, double blind placebo controlled randomised controlled trial (n=41) showed safety and efficacy for the outcomes mean delta per cent predicted forced vital capacity 1.9 versus −1.3 (P=0.04), absolute forced vital capacity 60 mL versus −46.8 mL (P=0.07), mean delta total lung capacity 200 mL versus –56 mL (P=0.005), percentage of quantitative interstitial lung disease (mean change –9.4% v 1.1%; P<0.05), lung fibrosis (mean change –2% v 0.87%), and ground glass (mean change –4.6% v 0.29%).37 By significantly improving forced vital capacity in treated patients but not in patients who received placebo, these results suggest potential, but the full results have not been published. The WHISTLE-PF trial (a phase 2, multicentre, randomised, double blind, controlled trial evaluating the safety and efficacy of ENV-101 in patients with lung fibrosis, NCT06422884) is actively recruiting.37 Phase 1 trials Inhaled GSK3008348 is a selective αVβ6 integrin inhibitor that triggers receptor internalisation and limits subsequent activation of TGF-β pathways. This inhibitor was assessed in a phase 1b, double blind, placebo controlled randomised controlled trial (single doses of GSK3008348 in idiopathic pulmonary fibrosis participants using positron emission tomography imaging, NCT03069989) of eight patients with suspected or confirmed idiopathic pulmonary fibrosis.38 The primary outcome, lung volume distribution, showed a 20% change (95% CI −9% to 42%) 30 minutes after inhalation.38 Effective targeted lung engagement was achieved without adverse events.38 39 Targeting extracellular matrix Endoplasmic reticulum stress results from the accumulation of misfolded or mutated proteins, activating the unfolded protein response pathway, which influences apoptosis, epithelial-mesenchymal transition, and myofibroblast activation, all of which contribute to excessive extracellular matrix and a profibrotic environment. 3–8 The extracellular matrix provides structural support while also regulating cellular behaviour. Matrix metalloproteinases (MMPs) are zinc dependent enzymes that catalyse extracellular matrix and basement membrane breakdown, facilitating inflammatory cell migration. The absence of MMP-2 and MMP-9 impairs clearance of alveolar inflammatory debris, leading to asphyxia, highlighting their role in inflammation regulation. MMP-3 and MMP-7 are potential fibrosis biomarkers.3–8 Galectin 3, a β galactoside binding lectin, further contributes to extracellular matrix remodelling by promoting fibroblast activation, myofibroblast differentiation, and collagen deposition, reinforcing fibrotic progression.40 Phase 3 trials The role of connective tissue growth factor was explored, a profibrotic protein that contributes to pulmonary fibrosis by promoting extracellular matrix remodelling and excessive collagen deposition. A connective tissue growth factor targeting agent, pamrevlumab, showed encouraging results in the PRAISE study (a phase 2, randomised, double blind, placebo controlled study to evaluate the safety and efficacy of FG-3019 in 103 patients with idiopathic pulmonary fibrosis). 41 The phase 3 version of the trial (NCT03955146) failed to replicate these findings, however, showing no significant change in forced vital capacity (70 mL; P=0.29) or secondary outcome benefit.41 Phase 2 trials Lysyl oxidase-like 2 (LOXL2) catalyses collagen and elastin crosslinking, stabilising the extracellular matrix and contributing to tissue stiffening. Increased levels of LOXL2 are linked to progression of idiopathic pulmonary fibrosis. 42 Simtuzumab, a monoclonal antibody targeting LOXL2, was evaluated in a phase 2 randomised controlled trial (to assess the efficacy and safety of simtuzumab (GS-6624) in adults with idiopathic pulmonary fibrosis, NCT01769196) of 544 patients with idiopathic pulmonary fibrosis but concluded with no significant effect on disease progression.42 Another target for extracellular matrix remodelling is TD139, an inhaled selective galectin 3 inhibitor that reduces fibroblast activation and collagen deposition, with potential to slow the progression of pulmonary fibrosis.43 44 In a phase 1-2a trial of 60 participants (randomised control trial of TD139 v placebo in human volunteers and in patients with idiopathic pulmonary fibrosis, NCT02257177), TD139 significantly reduced galectin 3 expression on bronchoalveolar lavage macrophages in a dose dependent manner.44 In the subsequent GALACTIC-1 (NCT03832946) phase 2b, double blind, placebo controlled randomised controlled trial, inhaled TD139 (GB0139) was evaluated in idiopathic pulmonary fibrosis. TD139 did not significantly reduce the rate of decline in forced vital capacity compared with placebo.45 Phase 1 trials SHR-1906, a fully humanised monoclonal antibody against connective tissue growth factor, was well tolerated in a phase 1, placebo controlled dose escalation study ( NCT04986540) in 72 healthy participants.46 A phase 2 multicentre randomised controlled trial (looking at the intravenous injection of SHR-1906 in the treatment of idiopathic pulmonary fibrosis, NCT05722964) has been registered, with recruitment yet to begin.47 MMPs represent another promising target for extracellular matrix regulation. Aderamastat (FP-025), a selective MMP-12 inhibitor, was evaluated in two phase 1 single and multiple ascending dose, double blind, placebo controlled randomised controlled trials (a phase 1, safety, tolerability, and pharmacokinetics study of FP-025 in 74 healthy volunteers, NCT02238834; and a study of FP-025 in 32 healthy volunteers (Multiple Ascending Dose Study), NCT03304964).48 FP-025 was well tolerated (only eight mild, self-limiting adverse events) with favourable pharmacokinetics, supporting further investigation of its role in pulmonary fibrosis.48 As well as MMP inhibition, collagen biosynthesis is a potential therapeutic target, particularly through prolyl-tRNA synthetase. Dysregulation of collagen biosynthesis instigates excessive extracellular matrix deposition. Bersiporocin, a first-in-class prolyl-tRNA synthetase inhibitor, reduces collagen synthesis, fibroblast activation, and fibrotic progression.49 In a phase 1, double blind, placebo controlled randomised controlled trial (ACTRN12619001239156), bersiporocin was safe and well tolerated in 72 participants, with linear pharmacokinetics up to 600 mg (single dose) and 200 mg (twice daily) over 14 days.49 Treatment also reduced levels of Pro-C3, a potential biomarker of idiopathic pulmonary fibrosis (P<0.001).49 Further studies targeting MMPs are eagerly awaited.Targeting monocytes and macrophages, and related pathways Inflammation in pulmonary fibrosis is triggered by the coagulation cascade and alveolar epithelial and endothelial injuries, which result in monocyte infiltration and macrophage formation, which in turn polarise into M1 (proinflammatory) or M2 (anti-inflammatory) subtypes. M2 polarisation is induced by interleukin (IL) 4, IL-10, IL-13, IL-33, TGF-β, and a CC-chemokine ligand 2 dependent pathway, which are also involved in fibroblast recruitment, making them attractive antifibrotic targets. 8 Activated monocytes and macrophages secrete growth factors, such as platelet derived growth factor and proangiogenic vascular endothelial growth factor, particularly vascular endothelial growth factor-A165b, which is targeted by nintedanib. M2 activation is also promoted by hypoxia induced oxidative stress and mitochondrial calcium influx. Although the mechanisms are unclear, macrophages contribute substantially to fibroblast recruitment and activation, epithelial-mesenchymal transition, and extracellular matrix remodelling.8 Phase 2 trials Outcomes for several drugs targeting monocytes and macrophages have shown disappointing outcomes. GLPG1205, a G protein coupled receptor 84 modulator involved in macrophage activation was investigated in 68 patients with idiopathic pulmonary fibrosis patients over 26 weeks (in a phase 2 randomised, double blind, placebo controlled, 26 week study to evaluate the efficacy, safety, and tolerability of GLPG1205 in participants with idiopathic pulmonary fibrosis, NCT03725852). Carlumab, which targets CC-chemokine ligand 2 and blocks monocyte recruitment, was examined in a randomised controlled trial of 126 patients with idiopathic pulmonary fibrosis (to evaluate the safety and effectiveness of intravenous CNTO 888 in participants with idiopathic pulmonary fibrosis, NCT00786201). The studies had no positive impact, with serious adverse effects, resulting in early termination of both trials.50 51 Pentraxin 2 (serum amyloid P) is a potent inhibitor of monocyte differentiation into profibrotic fibrocytes and is reduced in patients with idiopathic pulmonary fibrosis, supporting its role in modulating fibrosis.52 PRM-151, a recombinant form of pentraxin 2, binds to monocytes, promotes differentiation into antifibrotic macrophages, suppresses myofibroblast activation, and hence reduces inflammation and fibrosis.53 The role of PRM-151 in idiopathic pulmonary fibrosis was evaluated in a double blind, placebo controlled, phase 2, randomised controlled trial (NCT02550873) of 117 patients with idiopathic pulmonary fibrosis over 28 weeks, followed by a 72 week open label extension; 84 patients had previously been treated with nintedanib or pirfenidone. At 28 weeks, patients treated with PRM-151 had a reduced forced vital capacity decline of −2.5% versus −4.8% for placebo (P=0.001), and patients receiving placebo were switched to PRM-151. In the open label extension study, patients who continued PRM-151 had a forced vital capacity decline of −3.6% (95% CI −4.3 to −2.9) from baseline to week 52, whereas those who switched from placebo at week 28 had a change of −5.1% (−6.1 to −4.2). In crossover patients, the annual decline in forced vital capacity improved from −8.7% (weeks 0-28) to −0.9% (weeks 28-52; P<0.001). Similarly, the decline in the six minute walk test improved from −54.9 m/year to −3.5 m/year (P=0.02). Serious adverse events occurred in 31 patients, including two life threatening events, but these were known fibrosis related complications, such as pneumonia, disease progression or exacerbation, and lung cancer. PRM-151 was generally well tolerated, supporting progression to a phase 3 trial.54 Phase 3 trials The phase 3 STARSCAPE trial (a randomised, double blind, placebo controlled trial to evaluate the efficacy and safety of PRM-151 in 664 patients with idiopathic pulmonary fibrosis, NCT04552899) was ended early after a prespecified futility analysis showed no benefit of PRM-151.45 The discrepancy between phase 2 and phase 3 results was attributed to limited sample size, high variability in the six minute walk test, confounding bias from acute exacerbations or hospital admissions, and a higher use of concurrent antifibrotic drugs in phase 2 compared with phase 3 (21.6% v 17.0%). Also, two extreme outliers may have skewed the results of the phase 2 trial. A major limitation of the phase 3 trial was premature termination, with only 16% completing the study and most providing <6 months of data.53 54 Targeting B and T cells Although the monocyte-macrophage pathway of innate immunity is vital in pulmonary fibrosis, the acquired immune system also has an important role. Dysregulated B and T lymphocyte activity contributes to chronic inflammation and fibrotic remodelling. CD4 T cells exert profibrotic effects through the release of TGF-β and platelet derived growth factor, while CD20+ B cell aggregates are found in areas of fibrosis. B cells from patients with idiopathic pulmonary fibrosis produce increased levels of IL-6, IL-8, and MMP-7 in response to microbial antigens, partly mediated by vascular endothelial growth factor A, a pathway inhibited by nintedanib. B cell effects are also driven by mTOR activation, making it another therapeutic target. Thus immunomodulatory strategies targeting B and T cell pathways have been explored extensively. 55 Immune mediated mechanisms have a more prominent role in immune predominant fibrotic interstitial lung diseases, such as connective tissue disease-interstitial lung disease, compared with idiopathic pulmonary fibrosis, where epithelial injury and aberrant repair predominate.Phase 2 trials Building on the role of lymphocyte mediated pathways, pomalidomide targets the cereblon pathway, modifying transcription factors leading to modulation of myeloid and lymphocyte responses. Pomalidomide had antifibrotic effects in preclinical dermal fibrosis models. 56 A phase 2, proof-of-concept, randomised, double blind, placebo controlled trial (to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of pomalidomide (CC-4047) in participants with systemic sclerosis with interstitial lung disease, NCT01559129) in 23 patients with systemic sclerosis-interstitial lung disease assessed its impact on forced vital capacity, modified Rodnan Skin Score, and gastrointestial symptoms over 52 weeks. Mean forced vital capacity declined by −5.2% with pomalidomide compared with −2.8% with placebo. Because of recruitment challenges, however, the study was ended early with no significant differences in primary endpoints.57 In contrast, more favourable results were seen with rituximab, a monoclonal antibody targeting CD20 on B cells. A meta-analysis reported that rituximab was well tolerated and may stabilise or improve pulmonary function in connective tissue disease-interstitial lung disease.58 In a meta-analysis of 10 trials (three randomised and seven non-randomised controlled trials), forced vital capacity was significantly improved over 6-12 months (standarised mean difference 0.66, 95% CI 0.23 to 1.09; P=0.003), although the analysis was limited by small sample sizes.59 In another meta-analysis of 20 studies (two randomised controlled trials, six prospective studies, five retrospective studies, and seven conference abstracts, n=575) in systemic sclerosis-interstitial lung disease, forced vital capacity was improved by 4.49% at six months (95% CI 0.25% to 8.73%) and by 7.03% at 12 months (4.37% to 9.7%).60 Building on these findings, in a multicentre, double blind placebo controlled trial (to evaluate the efficacy and safety of rituximab with mycophenolate mofetil in patients with interstitial lung diseases, NCT02990286), mycophenolate mofetil with rituximab was compared with mycophenolate mofetil alone in interstitial lung disease (n=122). At six months, the mycophenolate mofetil-rituximab group significantly improved forced vital capacity by 1.60% compared with −2.01% in the mycophenolate mofetil only group (difference 3.60%, 95% CI 0.41% to 6.80%; P=0.03). When combined, however, severe adverse events occurred in 26 (41%) patients versus 23 (39%) patients in the mycophenolate mofetil only group.61 Other B cell targeting treatments are also being investigated for their therapeutic benefit. Belimumab, a B cell activating factor inhibitor that suppresses B cell activation and differentiation, is currently being assessed in an ongoing 52 week phase 2-3 randomised controlled trial in patients with systemic sclerosis-interstitial lung disease (target n=300), although the results have not yet been published.62 Early clinical trial In terms of T cells, abatacept (CTLA-4-Ig), which inhibits T cell activation, has shown potential in autoimmune related interstitial lung disease. In a multicentre observational study in 263 patients with rheumatoid arthritis-interstitial lung disease, forced vital capacity was stable or improved (≥10%) in 87.7% of patients and TLCO in 90.6%. 63 Furthermore, a small 48 week randomised controlled trial (n=20) reported a median forced vital capacity change of +140 mL with abatacept in contrast with −40 mL for placebo (P=0.15), although a larger randomised controlled trial would be needed given the acknowledged study limitations (the former being an observational study and the latter study having a small study size).64 Targeting cytokines (tocilizumab, lebrikizumab, and tralokumab) Cytokines such as IL-6, IL-13, and tumour necrosis factor alpha (TNF-α) mediate the interplay between immune cells, epithelial cells, and fibroblasts, promoting inflammation and augmenting extracellular matrix and collagen deposition that leads to fibrosis. Because of their role, these cytokines are potential therapeutic targets for pulmonary fibrosis. 3–7 Phase 3 trials Tocilizumab, a monoclonal antibody that inhibits IL-6, reduces inflammation and hence is a potential treatment for inflammatory interstitial lung diseases, such as systemic autoimmune rheumatic diseases-interstitial lung diseases. The phase 2 faSScinate trial (a phase 2/3, multicentre, randomised, double blind, placebo controlled study to assess the efficacy and safety of tocilizumab versus placebo in 87 patients with systemic sclerosis, NCT01532869) in early diffuse cutaneous systemic sclerosis (65% had confirmed interstitial lung disease on high resolution computed tomography) did not achieve its primary endpoint of skin score improvement but forced vital capacity was preserved, leading to a phase 3 trial.65 The phase 3 FocuSSced randomised controlled trial (a study of the efficacy and safety of tocilizumab in participants with systemic sclerosis, NCT02453256) enrolled 210 participants with early systemic sclerosis-interstitial lung disease with no change in skin score, its primary endpoint, but forced vital capacity was preserved over 48 weeks compared with placebo (−20 mL v −190 mL; P=0.001).66 The subgroup of patients with preserved forced vital capacity had early interstitial lung disease (excluding patients with forced vital capacity ≤55% or TLCO ≤45%) and an inflammatory phenotype (indicated by increased levels of acute phase blood markers).66 Results were also sustained in an open label phase of the trial. Based on these findings, tocilizumab has been approved for systemic sclerosis-interstitial lung disease in the US only.65 66 Phase 2 trials The role of IL-13 in idiopathic pulmonary fibrosis was explored in two randomised controlled trials (a phase 2, randomised, double blind, placebo controlled study to assess the efficacy and safety of lebrikizumab in patients with idiopathic pulmonary fibrosis, NCT01872689, n=154; and a phase 2, randomised dose ranging study to evaluate the efficacy of tralokinumab in adults with idiopathic pulmonary fibrosis, NCT01629667, n=173), both of which failed to show significant differences in forced vital capacity over 52 weeks.67 68 TNF-α inhibition with etanercept was evaluated in a phase 2 trial (a randomized, double-blind, placebo-controlled trial of etanercept in patients with idiopathic pulmonary fibrosis, NCT00063869) in 88 patients with progressive idiopathic pulmonary fibrosis (≥10% forced vital capacity decline) over 48 weeks. No significant difference in forced vital capacity or TLCO compared with placebo was found.69 Early clinical trials Other inflammatory mediators, such as leucotrienes, have been implicated in pulmonary fibrosis, with increased levels suggesting a role in disease progression. Leucotriene receptor antagonists reduce inflammation and fibrosis in pulmonary fibrosis by blocking leucotrienes, which promote tissue scarring and inflammation, thereby slowing progression of the disease. 6 7 Tipelukast (MN-001), which blocks leucotriene receptors and inhibits phosphodiesterase 5 and 5-lipoxygenase, was studied in a phase 2, single centre trial (a randomised, placebo controlled, double blind, six month study followed by an open label extension phase to evaluate the efficacy, safety, and tolerability of MN-001 in participants with idiopathic pulmonary fibrosis, NCT02503657) of 15 patients with idiopathic pulmonary fibrosis over six months, followed by an open label phase.70 Although tipelukast showed no significant difference in forced vital capacity at 26 weeks, secondary outcomes were favourable, including the absence of acute exacerbations or hospital admissions and reduced levels of lysyl oxidase-like 2 (a fibrosis related biomarker). Phase 3 trials are being considered.70 Targeting senescence Telomere shortening, mitochondrial dysfunction, and epigenetic modifications contribute to cellular senescence, including for alveolar epithelial cells, fibroblasts, and macrophages. Ageing type 2 pneumocytes facilitate macrophage activation, which in turn secrete profibrotic cytokines such as TNF-α, IL-12, IL-1β, IL-6, IL-10, and interferon γ. Raised levels of IL-10 and macrophage migration inhibitory factor, both associated with telomere attrition, have been detected in bronchoalveolar lavage fluid of ageing patients with idiopathic pulmonary fibrosis. Furthermore, senescent fibroblasts show apoptosis resistance, thereby contributing to the development of fibrosis. 3–8 Clinical evaluation of treatments directly targeting cellular ageing are limited, with danazol currently representing the only agent that has been assessed in a randomised clinical trial setting.Phase 2 trials The TELO-SCOPE study ( NCT04638517) explored telomere related fibrosis with danazol, a synthetic steroid, for its potential role in pulmonary fibrosis.71 This 12 month, phase 2 randomised controlled trial included 29 patients with pulmonary fibrosis and telomere length ≤10th centile, of whom 23 (79%) had idiopathic pulmonary fibrosis. This study was ended for futility because of lack of benefit and adverse effects, particularly raised values for liver function tests. Danazol did not preserve telomere length or forced vital capacity, suggesting that danazol is not effective in pulmonary fibrosis with short telomeres.71 Targeting signalling pathways Multiple signalling pathways involved in inflammation, fibroblast activation, and extracellular matrix deposition offer potential therapeutic targets in pulmonary fibrosis. TGF-β is a key cytokine that signals through the kinase SMAD (small mothers against decapentaplegic) pathway to upregulate extracellular matrix protein transcription of collagen and fibronectin, augmenting fibrogenesis. Other downstream mediators of this pathway, such as connective tissue growth factor, are involved in epithelial-mesenchymal transition signalling. 3–8 Several other key signalling pathways contribute to pulmonary fibrosis. The Wnt/β-catenin pathway inhibits glycogen synthase kinase β and prevents the phosphorylation and degradation of β-catenin, a transcription factor that accelerates the expression of profibrotic proteins. The Notch pathway similarly enhances the expression of fibrotic mediators and promotes epithelial-mesenchymal transition. The hedgehog pathway activates GLI transcription factors through ligand-receptor interactions, leading to fibrotic gene expression. Tyrosine kinases and the phosphatidylinositol 3 kinase/protein kinase B pathway are involved in multiple fibrotic signalling cascades and have been extensively investigated as potential therapeutic candidates.3–8 So far, several studies targeting multiple pathways have been unsuccessful, either because of lack of efficacy or intolerable adverse effects in early phase studies.72–78 Phase 3 trials In the 2000s, pathways involving interferon γ1b, a recombinant cytokine with immune modulating effects, were considered. Initial studies showed improvements in forced vital capacity and survival, but subsequent randomised controlled trials showed no survival benefit, indicating limited therapeutic potential. 79 Treprostinil is a prostacyclin analogue that increases intracellular cyclic AMP, inhibiting fibroblast proliferation, and its use in pulmonary hypertension has led to investigation of its direct antifibrotic effect. The INCREASE trial (a phase 3, randomised, double blind, placebo controlled study of inhaled treprostinil in participants with pulmonary hypertension associated with interstitial lung disease) evaluated inhaled treprostinil in 326 patients with interstitial lung disease complicated by pulmonary hypertension.80 Among secondary endpoints, at 16 weeks, patients treated with treprostinil had a mean increase in forced vital capacity of +31 mL compared with a mean decline of −11 mL in the placebo group, resulting in a difference of 44 mL.80 In the open label extension, continued treprostinil treatment was associated with sustained preservation or improvement in forced vital capacity and a reduced risk of clinical deterioration.80 Building on these findings, and to independently assess the role of inhaled treprostinil in the absence of pulmonary hypertension, two replicate phase 3 studies in idiopathic pulmonary fibrosis, TETON-1 and TETON-2 (phase 3, randomised, double blind, placebo controlled study of inhaled treprostinil in participants with idiopathic pulmonary fibrosis) were started in patients with forced vital capacity ≥45% predicted.81 Topline results from TETON-2 in press releases reported significant preservation of forced vital capacity, with superiority over placebo for change in absolute forced vital capacity of 95.6 mL (P<0.001), observed across subgroups and irrespective of background antifibrotic drugs.81 Overall, inhaled treprostinil was well tolerated, with low rates for discontinuing treatment. The most common adverse events were cough, headache, throat irritation, nausea, and dizziness.81 Together, these findings suggest a potential role for inhaled treprostinil as an antifibrotic treatment in idiopathic pulmonary fibrosis.Early clinical trials Tofacitinib, a selective JAK1/3 inhibitor, is currently being evaluated in the first randomised controlled trial, compared with cyclophosphamide and azathioprine, in Sjögren's syndrome associated interstitial lung disease. The primary endpoint is improved forced vital capacity at 52 weeks. 74 Conclusions The landscape of pulmonary fibrosis research is evolving, with many promising treatments under investigation. Despite progress, challenges remain in identifying a safe and efficacious treatment that can not only halt but reverse the fibrotic process. Limited clinical translation, given the encouraging results from phase 2 trials but failure to confirm efficacy in phase 3 trials, highlights ongoing problems.The first difficulty relates to trial designs and patient selection. Biologically, pulmonary fibrosis is a heterogeneous group of diseases, but many trials have enrolled broad patient populations defined mainly by lung function, which can potentially dilute the effects of treatment. This was highlighted with pamrevlumab and PRM-151, where phase 2 benefits were not replicated in larger phase 3 trials.41 53 Also, rates for treatment discontinuation and premature ending of trials were high, which has limited interpretation of several possibly pivotal studies.Another problem is endpoint selection. Forced vital capacity is the dominant primary endpoint across pulmonary fibrosis trials and is clinically relevant because of its association with mortality. Forced vital capacity, however, is relatively insensitive to short term biological change, is subject to variability, and does not adequately capture symptom burden or quality of life. Several trials reviewed here showed discordance between forced vital capacity outcomes and other indicators of disease activity, including quantitative imaging, biomarker modulation, exercise capacity, and symptom trajectories, whereas shorter trials may further limit detection of meaningful therapeutic effects.Also, limited prospective use of biomarkers of target engagement has hindered interpretation of both positive and negative trials. Although post hoc analyses showed associations between imaging, circulating extracellular matrix biomarkers, and decline in lung function, these measures were rarely used to enrich patient populations or confirm biological efficacy. Over reliance on preclinical and animal models has further contributed to translational failure, because pathways effective in experimental fibrosis frequently fail to show durable benefit in human disease.Recent positive data, however, from phase 3 trials with nerandomilast in idiopathic pulmonary fibrosis and progressive pulmonary fibrosis, alongside ongoing late phase studies of inhaled treprostinil, suggest a shift towards improved trial design and broader applicability across fibrotic phenotypes. Parallel efforts to improve drug delivery, tolerability, and pulmonary targeting, such as inhaled and reformulated antifibrotic drugs, represent important contemporary strategies.Overall, evidence from both successful and unsuccessful trials indicates that future progress in pulmonary fibrosis will depend not only on identifying effective molecular targets, but also on optimising trial design, refining patient selection, incorporating complementary endpoints, and validating biomarkers of disease activity and target engagement. Patient involvement is central to advancing pulmonary fibrosis research, as reflected in the testimonials included here, highlighting the value of clinical trial participation for both individual patients and the wider pulmonary fibrosis community.Questions for future research What can we learn from negative phase 2 studies to improve future clinical study design and outcomes?How can we target the pathogenesis of pulmonary fibrosis to halt or reverse the disease?Do different subtypes of interstitial lung disease need distinct therapeutic targets?Can biomarkers predict prognosis and enable earlier treatment, instead of waiting for imaging progression or lung function decline?Patient involvement Patients were not involved in the creation of this article.