Emerging therapeutic strategies
Research into improved treatment options for patients with IPF continues. Several studies investigated combination therapy using nintedanib and pirfenidone. A multicentre prospective study in Japan (N = 50) observed an increase in reports of nausea and vomiting when patients receiving pirfenidone were treated with nintedanib, compared with patients receiving pirfenidone alone [
118]. The addition of nintedanib to pirfenidone was not associated with any additional safety signals in a prospective international study of patients (N = 89) on a stable dose of pirfenidone [
119]. In the INJOURNEY clinical trial (N = 104), the addition of pirfenidone to nintedanib was associated with an increase in gastrointestinal AEs, compared with nintedanib alone. However, 34 patients (64%) who received combination therapy completed the trial, suggesting that combination treatment is feasible in a large proportion of patients. Exploratory efficacy analysis suggested that combination therapy reduced FVC decline to a greater extent than nintedanib alone [
8]. A smaller study (N = 37) observed no pharmacokinetic interactions between the two drugs [
10]. Data from large, prospective studies are, however, absent.
No safety signals associated with switching from pirfenidone to nintedanib are evident from real-world data [
66,
85,
120]. No difference in efficacy was observed between patients who initiated nintedanib after discontinuing pirfenidone and those who were pirfenidone-naïve. A common reason for pirfenidone discontinuation was disease progression; the efficacy of nintedanib in these patients suggests that patients who experience disease progression under pirfenidone could still benefit from treatment with nintedanib [
85,
110]. In a small number of patients (n = 4) who transitioned from nintedanib to pirfenidone, no new safety signals were observed [
66].
The aforementioned clinical trial INSTAGE assessed the effect of sildenafil and nintedanib on QoL, compared with nintedanib alone, in patients with advanced lung function impairment. While the addition of sildenafil gave only a numerical improvement in QoL, the results of this trial suggested that sildenafil might confer additional benefit in lowering the risk of disease progression in these patients [
11]. Furthermore, the benefit of combination therapy on QoL may not have reached the threshold for significance because the study was underpowered, as the INSTAGE trial was powered under the assumption that the effect of sildenafil on QoL would not be affected by nintedanib therapy. The trial design did not account for the possibility of a more pronounced treatment effect of nintedanib on QoL in patients with lower FVC, as observed in subgroup analyses of the INPULSIS trials [
11,
40]. Future clinical trials in patients with IPF and a greater degree of lung function impairment should take these potential design limitations into consideration. The effect of combination therapy was consistent irrespective of the presence of right heart dysfunction at baseline [
64]. The treatment guidelines for IPF give a conditional recommendation against sildenafil for the treatment of IPF, but make no recommendation regarding the treatment of patients with PH and IPF [
35].
GERD is a common comorbidity in IPF; however, data on the use of anti-acid therapies are conflicting. While prespecified analysis of placebo cohorts from the IPFnet programme suggested positive effects [
121], a
post-hoc analysis of data from the placebo arms of the CAPACITY and ASCEND trials suggested that the use of anti-acid therapies does not affect disease course in patients with IPF, and international guidelines give a conditional recommendation for these therapies in patients with IPF and GERD [
35,
121,
122]. A
post-hoc analysis of the INPULSIS trials found that use of anti-acid therapies (proton pump inhibitors (PPIs) and histamine-2 receptor agonists) at baseline did not affect the treatment benefit of nintedanib [
123]. The treatment of GERD with PPIs might be associated with an increased risk of enteric bacterial infection [
124], and data suggest that patients with IPF and FVC < 70% pred who receive anti-acid therapies are at greater risk of infections (general and pulmonary) than those who do not [
122].
In addition to clinical research using existing therapies, novel pharmacotherapies are in development [
125]. As nintedanib and pirfenidone are now considered standard of care in IPF, several trials of novel therapeutics (including GLPG1690 [
126], PRM-151 [
127], PBI-4050 [
128] and pamrevlumab [
129]) allowed concomitant therapy with nintedanib or pirfenidone in both treatment and placebo arms [
125‐
129]. During a Phase II trial of PBI-4050, an inhibitor of differentiation of fibroblasts into myofibroblasts, an apparent interaction with pirfenidone was observed. Change in mean FVC from baseline to week 12 was numerically superior in the PBI-4050 plus nintedanib group (+0.06% pred) than in either the PBI-4050 alone (−1.11%) or the PBI-4050 plus pirfenidone (−2.69%) groups [
128]. Future combination regimens will, therefore, be dependent on the pharmacokinetic and safety profiles of both agents.
Non-pharmacological interventions are also being explored. A systematic review found that pulmonary rehabilitation can improve exercise capacity and QoL in patients with ILD, including IPF, albeit in the short term [
130]. In the SPRINT-IPF trial (NCT03717012), pulmonary rehabilitation in combination with nintedanib will be tested against nintedanib alone in patients with IPF (N = 290, planned). The primary endpoint is the change in 6-minute walk distance [
131].
Other progressive fibrosing ILDs
Progressive pulmonary fibrosis is the hallmark of IPF, but this phenotype occurs in other ILDs [
13,
133‐
136]. In general, treatment for these diseases involves off-label use of corticosteroids and immunosuppressive agents [
135]. Due to mechanistic similarities between IPF and progressive fibrosing ILD, nintedanib therapy is under investigation in SSc-ILD and in other progressive fibrosing ILDs [
9,
13,
104].
Systemic sclerosis is a rare autoimmune disease characterized by fibrosis of the skin and internal organs. ILD is one of the leading causes of morbidity and mortality in SSc [
9,
104,
137]. SSc-ILD has an estimated prevalence of 1.7–4.2 per 100,000 individuals in Europe [
138]. The SENSCIS trial investigated the use of nintedanib in patients with SSc-ILD. The primary endpoint was the annual rate of FVC decline, which was −52.4 mL per year in patients receiving nintedanib (n = 288) and −93.3 mL per year in patients receiving placebo (n = 288) [
104]. These rates are lower than those in the INPULSIS trials (−113.6 and −223.5 mL per year in the nintedanib and placebo arms, respectively), probably because FVC decline in SSc-ILD follows a more heterogeneous course than the irreversible progressive decline observed in patients with IPF [
2,
6,
139‐
141]. Furthermore, the SENSCIS trial included a heterogeneous patient population, and 48% of patients were receiving continuing treatment with mycophenolate mofetil [
104]. The relative reduction in FVC decline associated with nintedanib versus placebo in SENSCIS (44%) was similar to that observed in the INPULSIS trials (49%) [
2,
104]. The AE profile of nintedanib in patients with SSc-ILD was similar to that observed in patients with IPF, although a higher proportion of patients reported diarrhoea (76% and 32% in the nintedanib and placebo arms, respectively) in the SENSCIS trial than in the INPULSIS trials (62% and 18% in the nintedanib and placebo arms, respectively). potentially arising from the underlying systemic disease [
2,
104].
Nintedanib has also been investigated in patients with ILDs that have developed a progressive fibrosing phenotype. The disease in these patients is characterized by decline in lung function, increasing extent of fibrosis by HRCT, or worsening of respiratory symptoms, despite treatment with immunomodulatory therapies [
13,
134]. The INBUILD trial assessed the efficacy and safety of nintedanib in patients with fibrosing ILDs and a progressive phenotype, excluding IPF [
13,
142]. The primary endpoint was the annual rate of FVC decline, which was −80.8 mL in patients treated with nintedanib (n = 332), compared with −187.8 mL in patients treated with placebo (n = 331). Inclusion was based on extent of fibrosis by HRCT (≥ 10%) and a common underlying progressive phenotype rather than diagnoses of any particular ILD, and INBUILD therefore included patients with ILDs such as: hypersensitivity pneumonitis (n = 173, 26%); autoimmune-associated ILDs (n = 170, 26%), such as rheumatoid arthritis-associated ILD (n = 89, 13%) and SSc-ILD (n = 39, 6%); idiopathic non-specific interstitial pneumonia (n = 125, 19%); and unclassifiable idiopathic interstitial pneumonia (n = 114, 17%). Patients were stratified by the presence or absence of a UIP-like pattern by HRCT. The annual rates of FVC decline in patients with UIP-like pattern were −82.9 mL and −211.1 mL in patients treated with nintedanib and placebo, respectively. In patients with other HRCT patterns these were −79.0 mL and −154.2 mL, respectively. The most common AE was diarrhoea, which occurred in 67% and 25% of patients receiving nintedanib and placebo, respectively. The efficacy of nintedanib in these patients could suggest common pathobiological mechanisms in fibrosing ILDs, irrespective of clinical diagnosis [
142,
143]. A real-world study of patients (N = 11) with fibrosing ILDs that had developed a progressive phenotype who were treated with either pirfenidone (n = 10) or nintedanib (n = 1) observed that antifibrotic therapy was associated with stabilization of FVC, further indicating that this approach might be a valuable treatment option [
144].