Idiopathic Pulmonary Fibrosis Medication

Updated: Dec 07, 2017
  • Author: Amanda M K Godfrey, MD; Chief Editor: Guy W Soo Hoo, MD, MPH  more...
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Medication

Medication SummaryAntioxidantsBiological response modulatorsEndothelin receptor antagonistsPhosphodiesterase inhibitorsTyrosine kinase inhibitorsAntifibrotic agentsColchicine

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. [53] Based on this pathogenetic concept, anti-inflammatory agents and immune modulators were used to treat idiopathic pulmonary fibrosis. However, 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. [13] 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.

The optimal medical therapy for the treatment of idiopathic pulmonary fibrosis has yet to be identified. Therefore, in selecting patients for treatment, careful consideration should be paid to the risk-to-benefit ratio. Patients should understand the risk of adverse effects from treatment along with any potential merits of therapy before deciding on a course of action. Pros, cons, risks, benefits, and alternatives must be discussed in a comprehensive fashion.

Corticosteroids have not been evaluated in a randomized, placebo-controlled trial to determine their benefit in treating patients with idiopathic pulmonary fibrosis. [54] Retrospective uncontrolled studies have reported no survival benefits.

An oxidant-antioxidant imbalance may contribute to the pathogenesis of idiopathic pulmonary fibrosis. Therefore, a double-blind, randomized, placebo-controlled trial in 155 subjects with idiopathic pulmonary fibrosis was completed to test the hypothesis that high dose (600 mg PO tid) N -acetylcysteine (NAC), administered over a period of 1 year in addition to prednisone and azathioprine, would slow functional deterioration in patients with idiopathic pulmonary fibrosis. [55] No true placebo group was included in that subjects in the placebo group received prednisone and azathioprine. The study showed that NAC, added to prednisone and azathioprine, significantly slowed the rate of deterioration of vital capacity and DLCO at 12 months. However, this did not translate into a survival benefit . Additionally, a significantly lower rate of myelotoxic effects was noted in the group taking NAC. [55]

The PANTHER-IPF trial was initiated by the Idiopathic Pulmonary Fibrosis Network. This blinded, randomized, placebo-controlled trial was designed to determine whether azathioprine and oral corticosteroids and/or NAC slow the rate of disease progression in idiopathic pulmonary fibrosis. [2] Patients with mild-to-moderate lung function impairment were assigned to 1 of 3 groups, receiving a combination of prednisone, azathioprine, and NAC; NAC alone; or placebo alone in a 1:1:1 ratio. [56]

In October 2011, when approximately 50% of the data had been collected, an announcement was made that 1 of the 3 arms was stopped. This arm was comparing triple-drug therapy (azathioprine, prednisone, NAC) to placebo. The interim results showed that compared with placebo, those assigned to triple-drug therapy had greater mortality (11% vs 1%), more hospitalizations (29% vs 8%), more serious adverse events (31% vs 9%), and remained on the assigned treatment at a much lower rate (78% vs 98%). [56] The other 2 study arms, comparing NAC alone to placebo alone, have continued. [57]

Evidence-based guidelines recommend that the majority of patients with IPF should not be treated with N-acetylcysteine monotherapy, [43, 44] however, this therapy may be a reasonable choice in a minority of patients.

Elevated levels of tumor necrosis factor (TNF)–α, a cytokine with inflammatory and fibrogenic properties, have been detected in the lungs of animals in experimental models of pulmonary fibrosis and in patients with idiopathic pulmonary fibrosis. [58] Etanercept is a recombinant soluble human TNF receptor that binds to TNF and neutralizes its activity.

To investigate the potential efficacy of etanercept as therapy for idiopathic pulmonary fibrosis, a multicenter, double-blind, randomized, placebo-controlled trial was conducted. Patients with idiopathic pulmonary fibrosis were randomized to receive subcutaneous etanercept (25 mg twice weekly) or placebo as their sole treatment for idiopathic pulmonary fibrosis.

At the conclusion of the 48-week trial, no differences were noted in the predefined endpoints between the etanercept group and the placebo group. [59] Therefore, it was a negative study. An explanation for the negative results could simply be due to the small sample size (88 patients) and inadequate power of the trial to detect a significant difference. Evidence-based guidelines recommend that patients with idiopathic pulmonary fibrosis should not be treated with etanercept. [1]

Interferon-γ is an endogenously produced cytokine with diverse properties, including antifibrotic, antiinfective, antiproliferative, and immunomodulatory effects. In vitro, exogenous interferon-γ therapy inhibits the expression of profibrotic cytokines, enhances the activation of macrophages and killing of ingested bacteria, shifts the T-cell response toward a macrophage-dominated inflammatory response, and up-regulates the expression of antimicrobial peptides by alveolar macrophages and monocytes. [58] It was hypothesized that interferon-γ1b therapy may influence the course of idiopathic pulmonary fibrosis through antifibrotic, anti-inflammatory, or antiinfective effects.

In 2004, the results of a double-blind, randomized, placebo-controlled trial that assigned 330 patients with idiopathic pulmonary fibrosis unresponsive to corticosteroid therapy to receive subcutaneous interferon-γ1b (200 µg 3 times per wk) or placebo, were reported. Over a median of 58 weeks, interferon-γ1b therapy did not significantly affect progression-free survival, pulmonary function, or quality of life. [58] However, a trend toward enhanced survival was noted in all randomized patients who were treated with interferon-γ1b, which was more pronounced in patients who adhered to treatment. [58]

In 2009, the results of a multicenter, double-blind, randomized, placebo-controlled trial, which was designed to assess the effect of interferon-γ1b on survival in patients with idiopathic pulmonary fibrosis and mild-to-moderate impairment in baseline pulmonary function, were reported. [60] Eligible patients were aged 40-79 years, had been diagnosed in the past 48 months, had a forced vital capacity of 55-90% of the predicted value, and DLCO of 35-90% of the predicted value. Patients were randomly assigned to receive 200 µg interferon-γ1b (n = 551) or equivalent placebo (n = 275) subcutaneously 3 times per week. [60]

At the second interim analysis (median treatment duration of 64 wk), 15% of patients on interferon-γ1b and 13% of patients on placebo had died. Interferon-γ1b did not improve survival in patients with mild-to-moderate idiopathic pulmonary fibrosis. [60] Therefore, treatment of idiopathic pulmonary fibrosis with interferon-γ1b is not currently recommended. [1]

Endothelin-1 is a potent, endogenous vasoconstrictor that is implicated in the pathophysiology of pulmonary arterial hypertension. Additionally, endothelin-1 is a profibrotic molecule that can modulate matrix production and turnover, resulting in increased collagen synthesis and decreased collagenase production. [61] Bosentan, an endothelin receptor A and B antagonist is approved for the treatment of pulmonary hypertension. Bosentan has been shown to have antifibrotic effects in an animal model of pulmonary fibrosis. [2]

The BUILD-1 trial, a randomized, placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis, was designed to evaluate the efficacy, safety, and tolerability of bosentan in patients with idiopathic pulmonary fibrosis. The primary objective was to evaluate the effect of bosentan on 6-minute walk distance. [61] Patients with idiopathic pulmonary fibrosis were randomized to receive bosentan (n = 74) at 62.5 mg twice daily for 4 weeks, increased to 125 mg twice daily thereafter, or placebo (n = 84), for 12 months or longer. [61]

Bosentan showed no superiority over placebo in 6-minute walk distance up to month 12. In analyzing secondary endpoints, a trend was noted that favored the bosentan group in terms of time to disease progression, dyspnea assessments, and quality-of-life assessments. These benefits were more pronounced in the subgroup of patients that underwent surgical lung biopsy. [61]

Based on these results, investigators pursued a follow-up phase III study (BUILD-3) of greater power, with the primary objective to demonstrate that bosentan delays disease worsening or death in patients with idiopathic pulmonary fibrosis. [2] The study included 616 patients with a proven diagnosis of idiopathic pulmonary fibrosis , of less than 3 years duration, who underwent a surgical lung biopsy. The primary end-point was not met. Currently, evidence-based guidelines recommend that patients with idiopathic pulmonary fibrosis should not be treated with bosentan. [1, 43, 44]

Sildenafil, a phosphodiesterase-5 inhibitor, leads to pulmonary vasodilatation by stabilizing cyclic guanosine monophosphate, the second messenger of nitric oxide. It is hypothesized that sildenafil, through pulmonary vasodilation, would improve ventilation-perfusion matching and thus gas exchange in patients with idiopathic pulmonary fibrosis.

To assess the potential efficacy of sildenafil in the treatment of idiopathic pulmonary fibrosis, a multicenter, double-blind, randomized, placebo-controlled trial was conducted. One hundred and eighty patients were enrolled in the study. [62] Patients with advanced idiopathic pulmonary fibrosis (diffusing capacity less than 35% of predicted value) were randomly assigned to receive sildenafil (20 mg tid) or matched placebo over 12 weeks. The primary outcome was the presence or absence of an improvement of at least 20% in the 6MWT at 12 weeks, as compared with baseline.

At the conclusion of the 12-week study period, no significant difference was noted in the proportion of patients with an improvement of 20% or more in the 6MWT in patients taking sildenafil compared with those taking placebo. However, statistically significant differences in the change in dyspnea, PaO2, diffusing capacity, and quality of life favoring sildenafil were noted. The presence of these positive secondary outcomes may stimulate further research. [62]

However, Guidelines on idiopathic pulmonary fibrosis by the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Association conditionally recommend against the use of sildenafil. [43, 44]

In October 2014, the FDA approved nintedanib (Ofev) for treatment of idiopathic pulmonary fibrosis. Approval was based on conducted 2 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 = 0.001). [63] Nintedanib was associated with the development of diarrhea; however, it led to discontinuation of the medication in less than 5% of the patients. [63]

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 to placebo in patients with IPF. Nintedanib targets platelet-derived growth factor receptors α and β, vascular endothelial growth factor receptors 1, 2, and 3, and fibroblast growth factor receptors 1, 2 and 3. The primary end point 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 to placebo. The annual rate of decline in FVC was 0.06 liters in those taking 150 mg twice daily compared to 0.19 liters in the placebo group (P = 0.06 with the closed testing for multiplicity).

In regards to secondary end points the incidence of acute exacerbations of IPF was lower in the group receiving nintedanib at 150 mg twice daily compared to placebo (2.4 versus 15.7 per 100 patient years, P = 0.02). 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 include 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. [64]

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. [65, 66]

Experimental models of idiopathic pulmonary fibrosis revealed that pirfenidone, a novel compound with combined anti-inflammatory, antioxidant, and antifibrotic effects, had potential therapeutic benefits for idiopathic pulmonary fibrosis. [67] A randomized, double-blind, placebo-controlled trial of 10 patients with idiopathic pulmonary fibrosis evaluated the efficacy of pirfenidone. Patients were randomized to pirfenidone (n = 72) at 1800 mg orally per day or placebo (n = 35).

The primary endpoint was defined as the change in the lowest SpO2 during a 6-minute steady-state exercise test. The secondary endpoints were changes in resting pulmonary function test results, disease progression by HRCT patterns, episodes of acute exacerbations of idiopathic pulmonary fibrosis, change in serum markers of pneumocyte damage, and changes in quality-of-life measurements. [67] No significant treatment effect in the primary endpoint was noted. Positive treatment effects were demonstrated in the secondary endpoints of change in vital capacity measurement at 9 months and acute exacerbations of idiopathic pulmonary fibrosis occurring exclusively in the placebo group during 9 months. [67] This study prompted additional studies to evaluate the efficacy and safety of pirfenidone in idiopathic pulmonary fibrosis.

A phase III clinical trial in Japan, which was a multicentered, double-blind, placebo-controlled, randomized trial that examined the use of pirfenidone. [68] 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. [68]

Significant differences were observed in the decline of vital capacity between the placebo group (-0.16 L) and the high-dose pirfenidone group (-0.09 L). Additionally, a significant improvement was noted in progression-free survival time in the high-dose pirfenidone group compared with the placebo group. [68] The results of this study led to regulatory approval of pirfenidone in Japan for the treatment of IPF.

The Clinical Studies Assessing Pirfenidone in IPF: Research of Efficacy and Safety Outcomes (CAPACITY) program conducted 2 multinational trials to evaluate the change in percentage predicted FVC at week 72. [65] All patients enrolled in both studies had mild to moderate IPF. 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 to 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%). [65]

When data from both studies were pooled together comparing a pirfenidone dose of 2403 mg/d to 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. [65]

In February 2014, InterMune released preliminary data from the Phase 3 ASCEND (Assessment of Pirfenidone to Confirm Efficacy and Safety in IPF) trial. [69] The study was a multinational, randomized, double-blind placebo-controlled Phase 3 trial to evaluate the safety and efficacy of pirfenidone in patients with IPF. 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 alos 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. [66]

Currently, evidence-based guidelines recommend that most patients with idiopathic pulmonary fibrosis should not be treated with pirfenidone and that this therapy may be a reasonable choice in a minority of patients. [1] However, with the new data available from the CAPACITY program trials and the ASCEND trial, pirfenidone has a favorable benefit-risk profile and now represents a treatment option for patients with IPF which has been approved by the FDA. [65]

Colchicine has been shown to inhibit fibroblast proliferation and collagen synthesis in vitro. Several prospective clinical trials have compared colchicine with various treatment regimens showing no difference in clinical outcomes. Evidence-based guidelines recommend that patients with idiopathic pulmonary fibrosis should not be treated with colchicine. [1]

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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 (ATP)-binding pocket of these receptors and blocks the intracellular signaling, which is crucial for the proliferation, migration, and transformation of fibroblasts, representing essential mechanisms of the idiopathic pulmonary fibrosis pathology.

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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)-beta, a chemical mediator that controls many cell functions including proliferation and differentiation. It also inhibits the synthesis of TNF-alpha, a cytokine that is known to have an active role in inflammation.

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Corticosteroid, Systemic

Class Summary

In some older observational studies, in which the definition of idiopathic pulmonary fibrosis was less specific, corticosteroids alone had positive effects on spirometry and gas exchange in approximately 15-30% of patients. Many investigators believe that this subgroup of responders did not have idiopathic pulmonary fibrosis, but instead had nonspecific interstitial pneumonia.

Corticosteroids have not been evaluated in a randomized, placebo-controlled trial to determine their benefit in treating patients with idiopathic pulmonary fibrosis. Retrospective uncontrolled studies have reported no survival benefits. Latent tuberculosis should be excluded before patients are started on corticosteroid therapy.

Evidence-based guidelines recommend that patients with idiopathic pulmonary fibrosis should not be treated with corticosteroid monotherapy.

Prednisone (Sterapred)

Prednisone is metabolized in the liver to its active form, prednisolone. Corticosteroids, including prednisone, prevent or suppress inflammation and immune responses when administered at pharmacological doses. At a molecular level, unbound corticosteroids readily cross cell membranes and bind with high affinity to specific cytoplasmic receptors. This binding induces a response by modifying transcription and, ultimately, protein synthesis, to achieve the steroid's intended action. Such actions may include inhibition of leukocyte infiltration at the site of inflammation, interference in the function of mediators of the inflammatory response, and suppression of humoral immune responses.

The initial response should occur within 3 months of initiating corticosteroid therapy. Improvement in objective parameters such as HRCT imaging, pulmonary function tests, 6MWT, and/or dyspnea scores should be monitored when deciding if additional therapy with prednisone is warranted.

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Immunosuppressant Agent

Class Summary

Corticosteroids and immunomodulator agents (azathioprine or cyclophosphamide) had not been previously evaluated in randomized, placebo-controlled trials to determine their benefit in treating patients with idiopathic pulmonary fibrosis.

The PANTHER-IPF trial was initiated by the Idiopathic Pulmonary Fibrosis Network. This blinded, randomized, placebo-controlled trial was designed to determine whether azathioprine and oral corticosteroids and/or NAC slow the rate of disease progression in IPF. Patients with mild-to-moderate lung function impairment were assigned to one of three groups, receiving a combination of prednisone, azathioprine, and NAC; NAC alone; or placebo alone in a 1:1:1 ratio.

In October 2011, when approximately 50% of the data had been collected, an announcement was made that one of the three arms was stopped. This arm was comparing triple-drug therapy (azathioprine, prednisone, NAC) to placebo. The interim results showed that compared with placebo, those assigned to triple-drug therapy had greater mortality (11% vs 1%), more hospitalizations (29% vs 8%), more serious adverse events (31% vs 9%), and remained on the assigned treatment at a much lower rate (78% vs 98%). The other two study arms, comparing NAC alone to placebo alone, have continued.

Azathioprine (Imuran)

Azathioprine decreases the metabolism of purines and may also inhibit DNA and RNA synthesis. It also may integrate into nucleic acids, resulting in chromosome breakage, nucleic acid malfunction, or synthesis of faulty proteins. Azathioprine may interfere with coenzyme functioning, thereby decreasing cellular metabolism, and may inhibit mitosis. Its effects may decrease the proliferation of immune cells and result in lower autoimmune activity.

Cyclophosphamide (Cytoxan)

Cyclophosphamide is a prodrug that requires hepatic activation in order to be cytotoxic. Phosphoramide mustard and acrolein are formed following hepatic and cellular activation. Phosphoramide mustard is the active alkylating moiety responsible for the cytotoxic effects. As with other bifunctional alkylating agents, phosphoramide mustard forms intrastrand and interstrand DNA-DNA cross-links, which are responsible for the inactivation of DNA. Cyclophosphamide also has immunosuppressant effects. It causes lymphopenia (both B and T cells) and selective suppression of B-lymphocyte activity.

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