Efficacy of Pirfenidone and Nintedanib in Interstitial Lung Diseases Other than Idiopathic Pulmonary Fibrosis: A Systematic Review

Pirfenidone and nintedanib are antifibrotic medications approved for idiopathic pulmonary fibrosis treatment by regulatory agencies and available for clinical use worldwide. These drugs have been shown to reduce the rate of decline in forced vital capacity and the risk of acute exacerbation among patients with idiopathic pulmonary fibrosis. Recent data suggest that different interstitial lung diseases with a progressive pulmonary fibrosis phenotype can share similar pathogenetic and biological pathways and could be amenable to antifibrotic therapies. Indeed, historical management strategies in interstitial lung disease have failed to identify potential treatments once progression has occurred despite available drugs. In this systematic review, we summarized data on the efficacy of pirfenidone and nintedanib in interstitial lung diseases other than idiopathic pulmonary fibrosis as well as ongoing and upcoming clinical trials. We identify two well-designed trials regarding nintedanib demonstrating the efficacy of this drug in slowing disease progression in patients with interstitial lung diseases other than idiopathic pulmonary fibrosis. On the other hand, results on the use of pirfenidone in interstitial lung diseases other than idiopathic pulmonary fibrosis should be interpreted with more caution on the basis of trial limitations. Several randomized control trials are underway to improve the quality of evidence in the interstitial lung disease field.


Introduction
Interstitial lung diseases (ILDs) represent a heterogeneous group of more than 200 entities of either known or unknown etiology [1]. Idiopathic pulmonary fibrosis (IPF) is the most common cause of idiopathic ILDs, and it is characterized by progressive fibrosis of the lungs with a poor prognosis [2]. Pirfenidone and nintedanib are antifibrotic medications approved for IPF treatment by regulatory agencies and available for clinical use worldwide [3]. These drugs have been shown to reduce the rate of decline in forced vital capacity (FVC) and the risk of acute exacerbation among patients with IPF [4,5]. Other ILDs may also show a progressive pulmonary fibrosis (PPF) phenotype [6]. Recent data suggest that different ILDs with a PPF phenotype can share similar pathogenetic and biological pathways and could be amenable to the same treatment [7,8]. Thus, it is biologically reasonable that pharmacological agents with antifibrotic properties, such as pirfenidone and nintedanib, may be efficacious in non-IPF PPF and fibrotic ILD [8]. Recent well-designed randomized control trials (RCTs) have confirmed this hypothesis [9,10]. In this review, we summarized data on the efficacy of pirfenidone and nintedanib in ILDs other than IPF as well as ongoing and upcoming clinical trials for these drugs in ILDs.

Summary of the Main Results
In total, 1724 publications were identified in the PubMed searches ( Figure 1). Screening of titles and abstracts resulted in 1626 being excluded, leaving 98 publications. A manual search of the references of these selected articles found no additional publications that met the inclusion criteria and were not identified in the PubMed search. The majority of the studies were rejected because they either included IPF patients (n = 71), had multiple publications for the same study (n = 8), had study designs, comments, or case series (n = 5), or were pharmacokinetic or safety profile studies (n = 4). A final pool of 10 studies was included in the systematic review, with a total of 1990 patients enrolled (Table 1) [9,10,[13][14][15][16][17][18][19][20]. Eight studies reported data on patients treated with pirfenidone, while two studies reported data on patients treated with nintedanib. Selected papers were published from 2002 to 2022, with a high frequency in the period 2019-2022 (8/10, 80%) [9,10,[13][14][15][16][17][18]. The majority had a randomized, double-blind, placebo-controlled design (8/10, 80%) [9,10,13,[15][16][17]19,20]. All papers considered FVC as the primary outcome: eight as the only primary outcome and two in combination with other parameters as a composite outcome. FVC was evaluated at 6 months in three papers, at 1 year in six papers, and at different time endpoints in one paper. A consensus on quality assessment was achieved. Only two studies, both on nintedanib, were evaluated as "high" using the GRADE scale. All other studies were rated as "low" or "very low" using the GRADE scale. A final pool of 10 studies was included in the systematic review, with a total of 1990 patients enrolled (Table 1) [9,10,[13][14][15][16][17][18][19][20]. Eight studies reported data on patients treated with pirfenidone, while two studies reported data on patients treated with nintedanib. Selected papers were published from 2002 to 2022, with a high frequency in the period 2019-2022 (8/10, 80%) [9,10,[13][14][15][16][17][18]. The majority had a randomized, double-blind, placebocontrolled design (8/10, 80%) [9,10,13,[15][16][17]19,20]. All papers considered FVC as the primary outcome: eight as the only primary outcome and two in combination with other parameters as a composite outcome. FVC was evaluated at 6 months in three papers, at 1 year in six papers, and at different time endpoints in one paper. A consensus on quality assessment was achieved. Only two studies, both on nintedanib, were evaluated as "high" using the GRADE scale. All other studies were rated as "low" or "very low" using the GRADE scale.

Efficacy of Ninitedanib
Data on nintedanib efficacy in ILD patients other than IPF comes from two large trials, INBUILD and SENSCIS [9,10].
The INBUILD trial enrolled 663 subjects with chronic fibrosing ILDs other than IPF meeting criteria for ILD progression. Patients were randomly assigned (1:1) to receive 150 mg of oral nintedanib twice daily or a placebo for at least 52 weeks. [9]. The term "progressive fibrosing ILDs" (PF-ILDs) refers to a spectrum of lung disorders other than IPF that share a progressive clinical phenotype that is characterized by an increasing extent of fibrosis on high-resolution CT, a decline in lung function, and worsening of symptoms despite management deemed appropriate in clinical practice [6]. The result of the trial showed that the FVC decline was −187.8 mL per year with placebo and −80.8 mL per year with nintedanib (p < 0.001), resulting in a difference of 107 mL. The reduction in annual FVC decline was similar to the rate observed in IPF nintedanib trials (125.3 mL in INPULSIS-1 and 93.7 mL in INPULSIS-2), suggesting a similar biological effect [4,9]. In the INBUILD trial, glucocorticoids were taken by over half the patients at baseline, while 15.2% were taking immunomodulatory therapies [9]. The effect of nintedanib on reducing FVC decline was not influenced by the use of glucocorticoids and immunomodulatory therapies [21]. Several different types of ILD (other than IPF) were included in INBUILD and classified into five subgroups: hypersensitivity pneumonitis, idiopathic non-specific interstitial pneumonia, unclassifiable ILD, autoimmune disease-related ILD, and "other" fibrosing ILDs. In a post-hoc analysis, no significant differences in efficacy between disease subgroups were observed [22].
The SENSCIS trial was a randomized, double-blind, placebo-controlled trial in which 576 patients with systemic sclerosis (SSc)-ILD were randomly assigned (1:1) to receive 150 mg of oral nintedanib twice daily or a placebo for at least 52 weeks [10]. SENSCIS enrolled adults fulfilling the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for SSc with the onset of the first non-Raynaud's symptom within the 7 years prior to screening. SSc-ILD was confirmed by a high-resolution computed tomography (HRCT) scan performed within the 12 months prior to screening, which showed fibrotic ILD to affect ≥10% of the lungs, as assessed by central review. The observed FVC decline was 52.4 mL per year in the nintedanib group and −93.3 mL per year in the placebo group (p = 0.04).
The largest trial that has been published so far on pirfenidone efficacy is the UILD study [16]. In this randomized, double-blind, placebo-controlled, 1:1, phase 2 trial, 253 patients with a progressive, fibrosing, unclassifiable ILD (uILD) were randomized to pirfenidone 2403 mg daily or placebo. The mean predicted change in FVC from baseline over 24 weeks was −87.7 mL in the pirfenidone group versus −157.1 mL in the placebo group (p = 0.002). Notably, the subgroup analysis suggests that pirfenidone may be less effective in uILD patients receiving mycophenolate at randomization, whereas a beneficial treatment effect for pirfenidone on FVC change was observed in patients not receiving MMF at randomization, regardless of previous corticosteroid use [23]. Since uILD represents a diagnosis of exclusion, a post-hoc analysis of data from the pirfenidone in the UILD trial was performed based on the surgical lung biopsy (SLB) status [24]. The study revealed that pirfenidone may be an effective option regardless of SLB status.
The RELIEF study was conducted in ILD patients with progressive functional decline despite conventional therapy [15]. In this randomized, double-blind, placebo-controlled, parallel Phase 2b trial, 127 patients were randomized to receive pirfenidone 2403 mg daily or a placebo. The absolute change in percentage of FVC% predicted from baseline to week 48 in the intention-to-treat population was evaluated as the primary outcome. Pirfenidone-treated patients had a significantly lower decline in FVC% predicted compared with placebo-treated ones (p = 0.043). However, due to the premature trial termination due to slow recruitment and the subsequent issue related to underpowering, interpreting FVC trends in the RELIEF study should be done with caution.
TRAIL1 was a randomized, double-blind, placebo-controlled, multicenter phase 2 trial conducted in patients with RA-ILD [13]. Patients were randomly assigned (1:1) to receive 2403 mg oral pirfenidone (pirfenidone group) or placebo (placebo group) daily. The primary endpoint was the incidence of the composite endpoint of a decline from baseline in predicted forced vital capacity (FVC%) of 10% or more or death during a 52-week treatment period. The difference in the proportion of patients who met the composite primary endpoint between the two groups was not significant (11% patients in the pirfenidone group vs. 15% in the placebo group; OR 0.67 [95% CI 0.22 to 2.03]; p = 0.48). However, the trial was stopped early due to slow recruitment and the COVID-19 pandemic.
A double-blind, randomized, placebo-controlled pilot study has been conducted in SSc-ILD by Acharya et al. [17]. Patients were randomized to receive either pirfenidone or a placebo for 6 months. The primary outcome was the proportion of subjects with either stabilization or improvement in FVC at 6 months. In this study, stabilization/improvement in FVC was seen in 16 (94.1%) and 13 (76.5%) subjects in the pirfenidone and placebo groups, respectively (p = 0.33). However, the small sample size and the short follow-up period limit the interpretability of the results.
Recently, a prospective, controlled cohort, single-center study was conducted in patients with CTD-ILD [14]. Physicians recommended whether to add pirfenidone to background therapy (glucocorticoids and/or immunosuppressive therapy) and solicited the opinions of patients according to the inclusion criteria. The primary endpoint of the study was the change in FVC and DLCO after 24 weeks of treatment according to the 4 CTD-ILD groups. The authors found a significant improvement in FVC% in the pirfenidone group in the case of SSc-ILD, or inflammatory myopathy-ILD. The DLCO% was significantly improved in RA-ILD patients treated with pirfenidone compared to the control case. However, the study suffers from several methodology limitations (single-center study; limited sample size of each distinct CTD-ILD group; lack of randomized control arms; short duration of follow-up) that underpower the results.
An open-label, proof-of-concept, randomized, single-center study was conducted in CHP patients to evaluate the efficacy of pirfenidone added to immunosuppressive drugs [18]. The primary outcome was the change in predicted FVC value in % and ml after 12 months. The results showed that the inclusion of pirfenidone was not associated with a significant improvement in the predicted value of FVC (% and ml). However, results should be interpreted with caution due to the small sample size.
Finally, two small, randomized, double-blind, placebo-controlled trials have been conducted in Hermansky-Pudlak syndrome, a rare, genetic, multisystem disorder characterized by oculocutaneous albinism, bleeding diathesis, immunodeficiency, granulomatous colitis, and pulmonary fibrosis with a similar presentation to IPF [19,20,25]. Both trials assessed the rate of change in FVC between the placebo and pirfenidone groups as the primary outcome. The timing of the FVC assessment varied depending on the trial. Notably, in only one of the two trials, a statistically significant difference was observed [20].

Discussion
The use of antifibrotic agents in ILD has been a topic of worldwide interest in the last few years. In this systematic review, we gathered data regarding the efficacy of pirfenidone and nintedanib in ILD other than IPF. Data on nintedanib efficacy in ILD patients other than IPF comes from two high-quality trials, INBUILD and SENSCIS [9,10]. Both trials have shown that nintedanib is efficacious in attenuating disease progression in patients with non-IPF ILD, despite management and regardless of the radiographic pattern of fibrosis.
However, the five major diagnostic subgroups identified in the INBUILD trial are underpowered, and FVC treatment effects lie immediately above "statistical significance." Thus, results on specific subgroups in the INBUILD trial should be interpreted with caution. In the SENSCIS trial, treatment with nintedanib slowed down the annual loss of FVC by 40 mL/year compared to placebo, apparently unimpressive compared to the INBUILD trial [9,10]. However, the rate of decline in the placebo arm was also lower compared to the INBUILD trial (−93.3 mL versus 187.8 mL). This mirrors the heterogeneous disease behavior of SSc-ILD, which has a variable course and only becomes progressive in some patients and is characterized by both an increase in fibrotic abnormalities on high-resolution CT and a decline in FVC. Notably, 43% of progression was prevented compared with FVC decline in the placebo arm, leading to rapid regulatory approval for nintedanib in SSc-ILD. Notably, in both SENESCIS and INBUILD trials, curves for FVC change from baseline separated by week 12 and continued to diverge since the end of the study, similarly to nintedanib trials in IPF [4,9,10]. Moreover, the benefit of nintedanib on FVC decline was observed regardless of fibrotic pattern or lung fibrosis extent on HRCT. These considerations are consistent with the overlapping pathophysiology of progressive fibrotic ILDs, irrespective of ILD diagnosis. Conclusions on pirfenidone's efficacy in ILD other than IPF are more guarded, on the basis of trial limitations. The largest study on pirfenidone in ILD other than IPF, the UILD study, suffers from several limitations. The primary endpoint was assessed with serial home spirometry, which provided less meaningful data compared to the previous published trials on pirfenidone in IPF. Subgroup analysis of the UILD study suggests that pirfenidone may be less effective in UILD patients receiving mycophenolate at randomization, whereas a beneficial treatment effect for pirfenidone on FVC change was observed in patients not receiving MMF at randomization, regardless of previous corticosteroid use [22]. However, the subgroup analysis has been limited by the small sample size. Moreover, uILD represents a diagnosis of exclusion; indeed, patients generally receive a uILD diagnosis when all other ILDs have been ruled out. Centers may apply varying intensities of diagnostic investigations or different diagnostic thresholds when evaluating a patient, leading to heterogeneity in the uILD definition [23]. This is a relevant consideration since uILD patients were identified by investigators at each site and not by a central reading in the UILD trial. Moreover, other limitations in pirfenidone studies should be acknowledged. Interpreting FVC trends in the RELIEF study should be done with caution due to the premature trial termination due to slow recruitment and the consequent issue related to underpowering [15]. Notably, some of the trials concerning pirfenidone were stopped early due to slow recruitment and the COVID-19 pandemic [15,17,18]. The small sample size and the short follow-up period undercut the results of the majority of pirfenidone trials [13,14,[17][18][19][20].
Other respiratory and extra-respiratory parameters have been evaluated as secondary outcomes in the studies analyzed. Concerning lung function, there was a significantly lower decline in diffusing lung capacity for carbon monoxide (DLCO) in the group receiving pirfenidone compared to the placebo group, suggesting a beneficial treatment effect of pirfenidone [15,18,19]. However, this was not a consistent finding [16]. Of note, symptoms and quality of life measured by the Saint George Respiratory Questionnaire (SGRQ) were not significantly improved by antifibrotic treatment [9,10,17,19,20]. Likewise, nintedanib did not improve fibrosis-related skin involvement as measured by the modified Rodnan skin score [10].

Ongoing Clinical Trials
Several interventional clinical trials are underway to explore the use of antifibrotic therapies in both fibrosing ILDs and PF-ILD.

Ongoing Clinical Trials on Nintedanib
Several interventional trials are evaluating the use of the drug and its efficacy in fibrotic ILDs, while no studies are evaluating its use in non-fibrotic ILDs to prevent subsequent fibrosis, except for one trial on COVID-19 sequelae (    Two clinical trials are evaluating the efficacy of nintedanib in patients with pneumoconiosis (NCT05067517, NCT04161014) [27,33].
The NCT05335278 is evaluating the use of nintedanib in patients with myositis (dermatomyositis, polymyositis, overlap myositis, or anti-synthetase syndrome)-related ILD [28]. It is important to note that only patients with PPF-ILD can be included in the trial.
Bronchiolitis obliterans syndrome (BOS) is a severe complication after transplant, and nintedanib has been proposed as a possible therapeutic agent due to its antifibrotic properties. The NINBOST2018 trial (NCT03805477) is enrolling patients with BOS after allogeneic hematopoietic cell transplantation to evaluate safety and tolerability, while the INFINITx-BOS trial (NCT03283007) is a phase III trial assessing the efficacy of nintedanib in reducing the rate of decline of FEV1 in patients with BOS after lung transplant [34,35].
Although not properly a fibrotic ILD, the efficacy of nintedanib is under study in patients with lymphangioleiomyomatosis (LAM) (NCT03062943) [36]. Because of its antityrosine kinase receptor inhibition on platelet-derived growth factor receptor (PDGFR), nintedanib has been shown to inhibit mTOR activation. Moreover, the inhibition of vascularendothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) signaling pathways reduces tumor angiogenesis in the lung and consequently could potentially contribute to the reduction of LAM cell dissemination and the progression of the disease [38,39].
One clinical trial (NCT04193592) is assessing the efficacy of pirfenidone in pulmonary fibrosis related to Hermansky-Pudlak syndrome [50].
The STOP-BOS trial (NCT03315741) is evaluating the safety and tolerability of pirfenidone in patients with BOS after hematopoietic cell transplant, while the EPOS study (NCT02262299) is assessing its efficacy in lung transplant recipients with BOS [55,59].
Regarding CTD-ILD, the NCT05505409 trial is recruiting patients with CTDs and ILD unresponsive to treatment, while the NCT04928586 trial is recruiting patients with CTD-ILD to evaluate the efficacy of pirfenidone associated with disease-modifying antirheumatic drugs (DMARDs) against DMARDs alone [41,46]. Interestingly, both trials are including not only patients with definite CTDs but also those with undifferentiated connective tissue disease (UCTD)/ interstitial pneumonia with autoimmune features (IPAF). Note that both studies do not require progressive pulmonary fibrosis as an inclusion criterion.
Regarding specific CTDs, the NCT03857854 trial has enrolled patients affected by dermatomyositis, including patients with fibrotic and non-fibrotic ILD [52]. The SLS III trial (NCT03221257) is the only trial evaluating the efficacy of mycophenolate in association with pirfenidone against a placebo [56].
The PIONEER trial (NCT05075161) is evaluating the use of pirfenidone to prevent pulmonary fibrosis in patients admitted to an intensive care unit due to acute respiratory distress syndrome (ARDS) [45]. Only patients with moderate or severe ARDS and an inflammatory phenotype can be included in the study.
One trial (NCT03902509) is evaluating the efficacy of pirfenidone in the treatment of grade 2-3 pulmonary radiation injury [51].

Conclusions
This systematic review focused on consolidating findings from the literature on the effects of pirfenidone and nintedanib on patients with non-IPF ILDs. Regarding pirfenidone, the quality of the evidence ranges from very low to low. Results of the included studies suggest that pirfenidone may have a beneficial impact on lung function in patients with non-IPF ILD. In particular, the unclassifiable ILD patients might benefit from pirfenidone treatment. Regarding nintedanib, the quality of the evidence is considered high according to the GRADE criteria, although only 2 studies have assessed efficacy in non-IPF ILD. The overall findings suggest that nintedanib may have a beneficial impact on disease progression in patients with non-IPF ILD. However, results on both drugs should be interpreted with caution because of limitations in the available evidence. Moreover, there are several controversial points that should be clarified with further studies and evidence. Examples of challenges that need to be addressed in the future are the timing of therapy initiation and the strategies that should be adopted for overlap or combination with existing immunosuppressive therapies and potential drug interactions. Several RCTs are underway to improve the quality of evidence in the ILD field.