Medication Summary
The previous theory regarding the pathogenesis of idiopathic pulmonary fibrosis (IPF) was that generalized inflammation progressed to widespread parenchymal fibrosis. It was believed that an unidentified insult to the alveolar wall initiated a cycle of chronic alveolar inflammatory injury (alveolitis) leading to fibrosis. [80] Based on this pathogenetic concept, anti-inflammatory agents and immune modulators were used to treat idiopathic pulmonary fibrosis.
Depending on available data in the year 2000, a typical regimen of immunosuppression using prednisone and azathioprine was a standard of care; furthermore, a double-blinded clinical trial in 2005 by Demets et al (IFIGENIA Study) on 182 patients with the diagnosis of idiopathic pulmonary fibrosis concluded that a therapy with acetylcysteine at a dose of 600 mg three times daily, added to prednisone and azathioprine, preserves vital capacity and diffusion capacity of carbon monoxide (DLCO) in patients with idiopathic pulmonary fibrosis. [81]
However, in the year 2010, the Prednisolone, Azathioprine, and N-Acetylcysteine: A Study That Evaluates Response (PANTHER) was published and found that patients taking this triple-combination therapy were at increased risk of death and hospitalization compared with patients receiving placebo alone. [82] In addition, when compared with placebo, acetylcysteine in isolation offered no significant benefit with respect to the preservation of forced vital capacity (FVC) in patients with idiopathic pulmonary fibrosis compared with placebo. [83]
These findings have led to a shift away from immunosuppression and antioxidants and left a gap in the years after with no apparent effective options available.
It is currently believed that idiopathic pulmonary fibrosis is an epithelial-fibroblastic disease, in which unknown endogenous or environmental stimuli disrupt the homeostasis of alveolar epithelial cells, resulting in diffuse epithelial cell activation and aberrant epithelial cell repair. [14] The recognition of new factors contributing to the pathogenesis of idiopathic pulmonary fibrosis has led to the development of novel approaches to treat idiopathic pulmonary fibrosis.
This change in understanding the pathogenesis of idiopathic pulmonary fibrosis was translated into the therapeutic options studied in the last two decades, especially with the development of two novel antifibrotic therapies, pirfenidone and nintedanib, that have been developed and approved in the last 8 years, providing treatment options for many patients with idiopathic pulmonary fibrosis.
Tyrosine kinase inhibitors (nintedanib)
Nintedanib is a tyrosine kinase inhibitor that was initially developed as an anti-tumor agent before it was noted to have activity against fibroblasts through inhibition of vascular endothelial growth factor (VEGF) and other profibrotic mediators such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and transforming growth factor (TGF)–β. [84, 85]
In October 2014, the US Food and Drug Administration (FDA) approved nintedanib (Ofev) for treatment of idiopathic pulmonary fibrosis. Approval was based on conducted two replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 and INPULSIS-2). Each trial showed a statistically significant improvement in FVC compared with placebo (P = .001). [86] Nintedanib was associated with the development of diarrhea; however, it led to discontinuation of the medication in less than 5% of the patients. [86]
A 12-month, phase 2 trial, completed by Richeldi and colleagues, assessed the efficacy and safety of four different oral doses of the tyrosine kinase inhibitor nintedanib (formerly BIBF 1120) compared with placebo in patients with idiopathic pulmonary fibrosis. Nintedanib targets PDGF receptors α and β; VEGF receptors 1, 2, and 3; and FGF receptors 1, 2 and 3. The primary endpoint was the annual rate of decline of FVC.
A total of 432 patients were randomly assigned to receive one of four doses of nintedanib (50 mg once a day, 50 mg twice a day, 100 mg twice a day, or 150 mg twice a day) or placebo. In patients receiving 150 mg twice daily, there was a trend toward a reduction in the decline of lung function when compared with placebo. The annual rate of decline in FVC was 0.06 L in those taking 150 mg twice daily compared with 0.19 L in the placebo group (P = .06 with the closed testing for multiplicity).
In regard to secondary endpoints, the incidence of acute exacerbations of idiopathic pulmonary fibrosis was lower in the group receiving nintedanib at 150 mg twice daily compared with placebo (2.4 vs 15.7 per 100 patient-years, P = .02). The highest proportion of patients who discontinued the study medication because of adverse events was those subjects taking 150 mg twice daily. The adverse events most frequently leading to discontinuation included diarrhea, nausea, and vomiting. Overall, the phase 2 study revealed an acceptable safety profile and potential clinical benefits of treatment with nintedanib 150 mg twice daily, thus warranting phase 3 clinical investigations. [87]
It is of note that no mortality benefit was noted with nintedanib treatment in the INPULSIS trials or when the data was pooled with the TOMORROW study. [88] In addition, there was no evidence from pooled data that mortality post exacerbation improved with nintedanib. [89]
Antifibrotic agents (pirfenidone)
Pirfenidone has a number of anti-inflammatory and antifibrotic effects, including inhibition of collagen synthesis, down-regulation of TGF-β and tumor necrosis factor-α, and a reduction in fibroblast proliferation.
The FDA approved pirfenidone (Esbriet) for the treatment of idiopathic pulmonary fibrosis in October 2014. Approval was based on the ACSEND and CAPACITY 1 and 2 trials. Pirfenidone slowed the decline and, in some patients, halted the decline of FVC and improved progression-free survival. [90, 91]
A phase 3 multicenter, double-blind, placebo-controlled, randomized clinical trial in Japan examined the use of pirfenidone. [92] Two-hundred and seventy-five Japanese patients with idiopathic pulmonary fibrosis were randomized to high-dose pirfenidone (n = 108; 1800 mg/d PO), low-dose pirfenidone (n = 55; 1200 mg/d PO), or placebo (n = 104). The primary endpoint was a change in vital capacity from baseline to week 52. Secondary endpoints were progression-free survival time and the change in the lowest SpO2 during a 6-minute steady-state exercise test.
This was followed internationally by the Clinical Studies Assessing Pirfenidone in idiopathic pulmonary fibrosis: Research of Efficacy and Safety Outcomes (CAPACITY) trials (PIPF-004 and PIPF-006), where two concurrent randomized control trials in idiopathic pulmonary fibrosis compared pirfenidone at doses of 2403 mg/day and 1197 mg/day against placebo over 72 weeks.
In study 004, 435 subjects were randomized to a pirfenidone dose of 2403 mg/d (n = 174), a pirfenidone dose of 1197 mg/d (n = 87), or placebo (n = 174). At week 72, a significant reduction in decline of FVC was noted in the group assigned to a pirfenidone dose of 2403 mg/d (-8%) compared with placebo (-12.4%).
In study 006, 344 subjects were randomized to a pirfenidone dose of 2403 mg/d (n = 171) or placebo (n = 173). At week 72, no significant reduction in decline of FVC in the pirfenidone group (-9%) was found compared with placebo (-9.6%). [90]
When data from both studies were pooled together comparing a pirfenidone dose of 2403 mg/d with placebo, a significant reduction in decline of FVC was noted in the pirfenidone group (-8.5%) compared with placebo (-11%). Additionally, in the pooled analysis, pirfenidone prolonged progression-free survival by 26% compared with placebo. Finally, in the pooled analysis, pirfenidone reduced the proportion of patients with a 10% or more decline in FVC by 30% compared with placebo. [90]
In February 2014, InterMune released preliminary data from the phase 3 ASCEND (Assessment of Pirfenidone to Confirm Efficacy and Safety in IPF) trial. [93] The study was a multinational, randomized, double-blind placebo-controlled phase 3 trial to evaluate the safety and efficacy of pirfenidone in patients with idiopathic pulmonary fibrosis and was requested by the FDA because of discrepancies between the two CAPACITY trials in meeting their primary endpoints. Patients (N = 555) were randomly assigned 1:1 to receive oral pirfenidone (2403 mg/day) or placebo and were enrolled at 127 centers in the United States, Australia, Brazil, Croatia, Israel, Mexico, New Zealand, Peru, and Singapore.
The primary endpoint was comparing the proportion of patients in the pirfenidone and placebo groups experiencing either a clinically significant change in FVC or death. At week 52, 16.5% of patients in the pirfenidone group experienced an FVC decline of 10% or more or death, compared with 31.8% in the placebo group. Additionally, at week 52, the data demonstrated that 22.7% of patients in the pirfenidone group experienced no decline in FVC, compared with 9.7% in the placebo group. Pirfenidone alone improved progression-free survival and reduced the decline in the 6-minute walk distance. Gastrointestinal and skin-related adverse events were more common in the pirfenidone group than in the placebo group but rarely led to discontinuation of treatment. [91]
Pooled analysis of the CAPACITY and ASCEND studies found that treatment with pirfenidone at 2403 mg/day reduced the proportion of patients experiencing an FVC of 10% or greater or death by 43.8% [94] In addition, there was a reduction in the relative risk of all-cause and idiopathic pulmonary fibrosis–related mortality at 52 weeks with pirfenidone treatment. [85]
Combination therapy with pirfenidone and nintedanib
To date there is no compelling evidence to support the dual use of pirfenidone and nintedanib for the management of idiopathic pulmonary fibrosis. In 2018, Vancheri et al published a clinical trial investigating the safety, tolerability, and pharmacokinetic and exploratory efficacy endpoints in idiopathic pulmonary fibrosis patients treated with nintedanib at 150 mg twice daily for at least 4 weeks and add-on pirfenidone compared with a group of patients treated with nintedanib alone. [95] While on treatment, gastrointestinal adverse effects were reported in 69.8% of the patients treated with nintedanib with add-on pirfenidone, compared with 52.9% in the patients in the nintedanib arm. The investigators concluded there was a manageable safety and tolerability profile in patients with idiopathic pulmonary fibrosis for the combination therapy.
Similar results were reported in a recent phase 2 study in Japan on 50 idiopathic pulmonary fibrosis patients that assessed combination therapy with both antifibrotics and reported adequate tolerability and no effect for nintedanib on the pharmacokinetics of pirfenidone, with promising secondary efficacy data. [96] Future studies to compare the efficacy of combination therapy with single antifibrotic therapy are warranted.
Tyrosine Kinase Inhibitors
Class Summary
Inhibition of various tyrosine kinases decreases the proliferative activities that lead to fibrosis.
Nintedanib (Ofev)
Nintedanib inhibits multiple tyrosine kinases and targets growth factors, which have been shown to be potentially involved in pulmonary fibrosis (eg, vascular endothelial growth factor receptor [VEGFR], fibroblast growth factor receptor [FGFR], platelet-derived growth factor receptor [PDGF]). It binds competitively to the adenosine triphosphate–binding pocket of these receptors and blocks intracellular signaling, which is crucial for the proliferation, migration, and transformation of fibroblasts, representing essential mechanisms of the idiopathic pulmonary fibrosis pathology.
Antifibrotic Agents
Class Summary
Reduction of fibroblast proliferation may decrease the formation and/or accumulation of fibrotic materials within the lungs.
Pirfenidone (Esbriet)
The precise mechanism by which pirfenidone may work in pulmonary fibrosis has not been established. It inhibits transforming growth factor (TGF)-β, a chemical mediator that controls many cell functions, including proliferation and differentiation. It also inhibits the synthesis of TNF-α, a cytokine that is known to have an active role in inflammation.
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Chest radiograph of a patient with idiopathic pulmonary fibrosis showing bilateral lower lobe reticular opacities (red circles).
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Classic subpleural honeycombing (red circle) in a patient with a diagnosis of idiopathic pulmonary fibrosis.
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A patient with IPF and a confirmed histologic diagnosis of usual interstitial pneumonia. Note the reticular opacities (red circle) distributed in both lung bases and the minimal ground-glass opacities (blue circle).
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A patient with nonspecific interstitial pneumonia. Note the predominance of ground-glass opacities (blue circles) and a few reticular lines (red arrow).
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Patchwork distribution of abnormalities in a classic example of usual interstitial pneumonia (low-magnification photomicrograph; hematoxylin and eosin stain; original magnification, X4). Courtesy of Chad Stone, MD.
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High-resolution CT coronal view showing lower lobe predominant honeycombing (blue arrow) with irregular septal thickening and traction bronchiectasis compatible with typical usual interstitial pneumonia pattern.
Tables
|
Predictor |
Points |
Sex |
Female |
0 |
Male |
1 |
|
Age (years) |
≥60 |
0 |
61-65 |
1 |
|
>65 |
2 |
|
FVC (% predicted) |
>75 |
0 |
50-75 |
1 |
|
< 50 |
2 |
|
DLCO (% predicted) |
>55 |
0 |
36-55 |
1 |
|
≤35 |
2 |
|
Cannot perform |
3 |
Stage |
I |
II |
III |
Points |
0-3 |
4-5 |
6-8 |
Mortality |
|
|
|
1-year |
5.6 |
16.2 |
39.2 |
2-year |
10.9 |
29.9 |
62.1 |
3-year |
16.3 |
42.1 |
76.8 |
