Abstract
Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease associated with significant morbidity and mortality. Historically, IPF has been managed using combination immunosuppressive therapy; however, this has been shown to be associated with increased mortality. Over the past 5 years, 2 disease-modifying agents have been licensed for use in IPF. Pirfenidone is a novel therapy with antifibrotic and anti-inflammatory properties. Evidence from a number of randomised control trials has shown that pirfenidone slows the progression of decline in forced vital capacity in IPF. Nintedanib is a tyrosine kinase inhibitor with antifibrotic properties which has also been shown to significantly reduce disease progression. As head-to-head comparison data are lacking, treatment selection is based on patient and clinician preference and tolerability of side effects. In the future, combination therapy with pirfenidone and nintedanib or with additional therapies may further improve lung function preservation.
Introduction
Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease associated with significant morbidity and mortality. Historically, management of IPF primarily involved immunosuppression which was at best ineffective1,2 and at worst harmful. 3 Over the past 5 years, the introduction of novel antifibrotic agents in the form of pirfenidone and nintedanib has changed the landscape of IPF and provided hope of improving disease outcomes. In this review, we will discuss the evidence for each medication and the important clinical issues to consider when initiating therapy.
Disease Context
Idiopathic pulmonary fibrosis is the most common form of interstitial lung disease (ILD). 4 It typically presents in patients in their sixth and seventh decades with symptoms of progressive breathlessness and cough. It is associated with a restrictive pattern on pulmonary function testing. The diagnosis should be made by a multidisciplinary team involving chest physicians, radiologists, and histopathologists. Idiopathic pulmonary fibrosis requires exclusion of other forms of ILD caused by occupational and environmental exposures, connective tissue disease, and drugs. 5 It is associated with a pattern of usual interstitial pneumonia (UIP) on high-resolution computed tomography (HRCT) or surgical lung biopsy. The precise cause is unknown but is believed to be multifactorial. There is evidence of genetic susceptibility and environmental influence with a higher proportion of patients suffering from IPF being smokers.6,7 The global incidence of IPF is reported between 2.8 and 9.3 per 100 000 and appears to be rising. 8 The prognosis of IPF is extremely poor with a median survival of 3 to 5 years. 9
Historical Treatment
Traditionally, immunosuppressive therapy was the cornerstone of treatment for IPF. This was primarily achieved with corticosteroids and azathioprine. In 2005, the Idiopathic Pulmonary Fibrosis International Group Exploring N-Acetylcysteine I Annual (IFIGENIA) study was published which suggested that the addition of N-acetylcysteine (NAC) to this combination slowed progression of decline in lung function. 10 Triple therapy with prednisolone, azathioprine, and NAC became a treatment of choice for patients with IPF. 11 This treatment regimen was challenged by the publication of the Prednisolone, Azathioprine, and N-Acetylcysteine: A Study That Evaluates Response (PANTHER) study in 2012 which showed that triple therapy with prednisolone, azathioprine, and NAC was associated with increased mortality when compared with placebo. 3 The same study also showed that NAC alone showed no benefit in comparison with placebo at slowing decline in lung function. Publication of the PANTHER study led to a sea change in pharmacological management of IPF. Clinicians moved away from immunosuppressive therapy, and for a period, there appeared to be little hope for effective therapeutic agents in preventing decline in IPF. However, the arrival of disease-modifying agents in the form of pirfenidone and nintedanib has changed the outlook and provided credible options in the management of this deadly disease.
Pirfenidone
Pirfenidone is an immunosuppressant therapy specifically designed for use in IPF. The pharmacodynamic action of pirfenidone is not well understood. It exhibits both anti-inflammatory and antifibrotic properties when tested in in vitro and animal models. It is thought that actions include the suppression of fibroblast proliferation, inhibition of profibrotic cytokines, such as platelet-derived growth factor (PDGF) and transforming growth factor β (TGF-β), reduction in collagen production, and inhibition of pro-inflammatory cytokines.12,13
Much of the initial work into pirfenidone took place in Japan. A phase 2 double-blind placebo-controlled trial (SP2) showed significant reduction in decline in vital capacity (VC) in the pirfenidone group as one of its secondary outcomes, although the primary end point of change in baseline from lowest Sp
There were some concerns regarding the methodology of the SP3 trial, so further work was conducted by way of the Clinical Studies Assessing Pirfenidone in idiopathic pulmonary fibrosis: Research of Efficacy and Safety Outcomes (CAPACITY) programme. 16 These comprised 2 multicentre, multinational randomised-controlled trials (RCTs) (PIPF-004 and PIPF-006) comparing pirfenidone against placebo at reducing decline in forced VC (FVC) in patients with mild-to-moderate IPF (FVC > 50% at baseline). PIPF-004 enrolled 435 patients who were randomly assigned to receive pirfenidone at a dose of either 2403 mg daily or 1197 mg daily or placebo. PIPF-006 enrolled 344 patients who received either 2403 mg daily of pirfenidone or placebo. In the pooled analysis of the 2 studies, patients taking pirfenidone had less decline in their FVC at 72 weeks (8.5% predicted vs 11% predicted for placebo) and significantly fewer patients reached a decline of 10% predicted FVC, considered a prognostic marker in IPF. Pirfenidone did improve progression-free survival; however, there was no significant reduction in mortality. Following publication of these data, pirfenidone received approval by the European Medicines Agency in December 2010. The National Institute for Health and Clinical Excellence (NICE) approved pirfenidone for use in the United Kingdom in April 2013 under a Patient Access Scheme and only in patients with an FVC of 50% to 80%. 17 Lung function must be closely monitored and pirfenidone discontinued if the percent-predicted FVC falls by 10% or more within a year.
The United States Food and Drug Administration (FDA) was presented with the data from the CAPACITY programme in 2010 and felt that the evidence was insufficient and requested a further phase 3 trial. The Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) study published in 2014 randomised patients to receive either 2403 mg daily of pirfenidone (n = 278) or placebo (n = 277) for 52 weeks. 18 In this study, the use of pirfenidone was associated with a significant reduction in FVC decline. The proportion of patients suffering a 10% drop in predicted FVC was 47.9% lower in the pirfenidone group compared with placebo, and significantly more patients saw no decline in FVC. As with the CAPACITY study, the ASCEND study failed to show a reduction in mortality associated with pirfenidone; however, a recently published pooled analysis of the data from all 3 phase 3 RCTs suggests that pirfenidone does convey a mortality benefit in comparison with placebo. 19 The additional evidence provided by the ASCEND study led to pirfenidone receiving FDA approval in October 2014. It has subsequently received approval for use in Australia and New Zealand in 2016.
Pirfenidone is manufactured as 267-mg capsules with 3 capsules taken, 3 times a day to provide a total daily dose of 2403 mg. On initiation of therapy, the dose is titrated up over the course of 14 days. Initially, one 267-mg capsule is taken 3 times daily for the first week followed by 2 capsules 3 times daily for the second week and maximum dose from then onwards. A photosensitivity rash is a commonly reported side effect, and so, it is generally recommended that patients wear protective clothing or sunscreen when out in sunlight. Other commonly reported side effects include nausea, diarrhoea, fatigue, and dyspepsia. Pirfenidone can cause clinically significant elevation in liver enzymes, so liver function tests should be checked prior to starting on the treatment and monitored throughout. Pirfenidone is metabolised by cytochrome P450 1A2 (CYP1A2) and therefore may interact with other drugs which use this pathway. Concomitant use with strong inhibitors of CYP1A2 such as fluvoxamine is not recommended. In addition, cigarette smoke can potentiate the metabolism of pirfenidone by CYP1A2, and it is recommended that patients cease smoking on initiation of treatment. Pirfenidone is contraindicated in patients with a creatinine clearance of less than 30 mL/min. 20
Nintedanib
Nintedanib is a tyrosine kinase inhibitor licensed for use in advanced non–small-cell lung cancer and IPF. Its mechanism of action is believed to be through inhibition of PDGF, fibroblast growth factor, vascular endothelial growth factor, and TGF-β leading to suppression of fibrosis. 21 The evidence for the use of nintedanib in IPF comes primarily from 2 phase 3 double-blind placebo-controlled RCTs, the INPULSIS 1 and INPULSIS 2 trials. 22 Both trials included patients aged 40 years or older, with an HRCT or biopsy-proven diagnosis of IPF and an FVC% predicted of 50% or greater. The primary end point for both the studies was annual rate of decline of FVC. A total of 1066 patients entered into the 2 trials and were randomised to receive nintedanib 150 mg twice daily or placebo and were followed up over the course of a year. Both trials demonstrated a significant reduction in the rate of decline in FVC with the prespecified pooled analysis showing the annual rate of decline to be approximately half in the nintedanib group (113.6 vs 223.5 mL placebo). Subanalysis using a definition of a decline in FVC% predicted of less than 10% as a ‘response’ to therapy found that a significantly greater proportion of patients taking nintedanib (70.1%) responded to treatment compared with placebo (60.5%). Although a trend was noted towards a reduction in mortality associated with the use of nintedanib, this was not significant. In addition, the results failed to show a consistent reduction in the number of acute exacerbations with nintedanib; however, the study was insufficiently powered to detect this. Based on the INPULSIS trial and supportive evidence from the phase 2 TOMORROW (To Improve Pulmonary Fibrosis with BIBF 1120) trial, 23 nintedanib received approval from the US FDA in October 2014, on the same day as pirfenidone, and approval from the European Medicines Agency in November 2014. Nintedanib received approval for use in the United Kingdom by NICE following a technology appraisal in January 2016. 24 As with pirfenidone, NICE recommended that nintedanib should be restricted to patients with an FVC of 50% to 80% predicted and be discontinued if percent-predicted FVC declines by 10% or more in a 12-month period. This logic has been questioned with post hoc analysis suggesting that nintedanib is equally effective in patients with preserved lung function (FVC > 90% predicted at baseline). 25
Nintedanib is supplied as 150-mg capsules taken twice a day. A reduced dose of 100 mg twice a day can be used for patients intolerant of the higher strength. Diarrhoea is a common adverse effect of nintedanib and was reported in 62.4% of patients receiving the medication in the INPULSIS trials. 18 Nausea is also commonly reported. Nintedanib is also associated with a rise in liver enzymes which require monitoring. Patients taking nintedanib in the INPULSIS trial were noted to have a slightly higher risk of bleeding events, and so, it is recommended that patients taking full-dose anticoagulation should avoid using nintedanib. In addition, 17 patients (2.7%) receiving nintedanib in the INPULSIS trial reported a myocardial infarction during treatment in comparison with 5 patients (1.2%) in the placebo arm. For this reason, the manufacturer recommends caution when considering treating patients with a history of coronary artery disease. 26
Current and Future Therapeutic Considerations
Recent international guidelines on the management of IPF recommend the use of both pirfenidone and nintedanib. 27 There have not been any head-to-head comparison studies between the 2 drugs; therefore, choice between the 2 should be guided by individual patient preference. It is important to screen for factors which may influence therapy choice when assessing patients with IPF, for example, frequent outdoor hobbies (photosensitivity rash associated with pirfenidone) or history of gastrointestinal upset (nintedanib). Pirfenidone is taken as 9 separate capsules per day. The dose was divided to reduce the size of the capsule to make it easier for elderly patients to take the total dose; however, this represents a relatively high pill burden for some patients. Similarly, the fact that most of the patients who suffer from IPF are elderly means that common comorbidities such as ischaemic heart disease can limit the use of nintedanib. Both treatments are similarly priced but costly. In the United States, the cost is just under US$100 000 per year for treatment, whereas in the United Kingdom, NICE has placed limits on prescription based on lung function following their analysis of cost-effectiveness.17,24
The development of disease-modifying agents in IPF has been a major breakthrough after years of ineffective treatment. Clinicians now have 2 evidence-based therapies to choose from allowing a patient-centred approach to be taken and providing an alternative if initial treatment is not tolerated. Current research is investigating how to optimise and improve antifibrotic therapy. One theory is the use of combination therapy. There have been case studies in which pirfenidone and nintedanib have been used together to treat IPF. 28 In a German study, the addition of nintedanib in a patient with declining lung function on pirfenidone monotherapy led to stabilisation of lung function. 29 However, as there have not been any clinical trials evaluating the safety or efficacy of combining pirfenidone and nintedanib, there is currently insufficient evidence to adopt this approach in clinical practice. Two studies have evaluated the combination of NAC and pirfenidone in IPF. A Japanese case-control study combined pirfenidone with inhaled NAC in patients with IPF and a decline in FVC of ≥10% in the preceding 6 months. 30 They compared this combination with pirfenidone alone and found that annual rate of decline in FVC was significantly lower in the group taking pirfenidone and NAC (−610 vs −1320 mL). However, a phase 2 double-blind placebo-controlled trial evaluating the addition of oral NAC to pirfenidone found that combination therapy was not associated with improved clinical outcomes in IPF, although the study was primarily looking at the safety and tolerability of combination therapy. 31 Alternative therapies investigated as potential disease-modifying agents in IPF include proton-pump inhibitors and co-trimoxazole.32,33 Initial phase 2 studies have been conducted on 2 monoclonal antibodies predicted to have disease-modifying activity in IPF. Simtuzumab is a monoclonal antibody with activity against lysyl oxidase–like 2 (LOXL2), an enzyme involved in collagen deposition in IPF. 34 Unfortunately, results from a double-blind RCT failed to show any improvement in progression-free survival associated with simtuzumab. Another monoclonal antibody, FG-3019, with activity against connective tissue growth factor, has completed initial open-label trials and is undergoing placebo-controlled investigation. 35
In conclusion, 2 efficacious disease-modifying agents, pirfenidone and nintedanib, are now available for the management of IPF, providing patients and clinicians with optimism for a brighter future in treating this debilitating condition.
Footnotes
Peer review:
Five peer reviewers contributed to the peer review report. Reviewers’ reports totalled 811 words, excluding any confidential comments to the academic editor.
Funding:
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests:
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Author Contributions
CH wrote the first draft of the manuscript. NC reviewed and edited the manuscript. All authors approved the final version of the manuscript.