Personal View
Combination therapy: the future of management for idiopathic pulmonary fibrosis?

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Summary

Findings from recently published placebo-controlled trials in idiopathic pulmonary fibrosis have established that pirfenidone and nintedanib prevent about 50% of the decline in forced vital capacity typically seen in this disease; future trials are therefore unlikely to use placebo as a control group for ethical reasons. Future clinical assessment will probably include add-on trials in which a new drug is combined with an intervention with established efficacy; this development is in turn likely to herald the use of combination regimens in clinical practice. Personalised medicine (the selection of monotherapies on the basis of individualised biomarker signal) is an intrinsically attractive alternative approach, but is unlikely to be useful in routine management of idiopathic pulmonary fibrosis in the medium-term future because of the complex nature of the disease's pathogenesis. In this Personal View, we review the pleiotropic nature of disease pathogenesis in idiopathic pulmonary disease, the use of combination regimens in other selected chronic lung diseases, and the conceptual basis for combination therapies in interstitial lung disorders other than idiopathic pulmonary fibrosis. On the basis of these considerations, and the emergence of data from add-on trials, we believe that the future of management for idiopathic pulmonary fibrosis lies in the development of combination regimens.

Introduction

Pulmonary fibrosis constitutes the end stage of a broad range of heterogeneous interstitial lung diseases, characterised by the destruction of pulmonary parenchyma, with deposition of extracellular matrix in the interstitial and alveolar spaces. Idiopathic pulmonary fibrosis, the most common fibrotic diffuse disease of the lung parenchyma, is probably not a single disease. As the Spanish philosopher George Santayana observed, “those who cannot remember the past are doomed to repeat it”. Before 2000, the entity of idiopathic pulmonary fibrosis included many patients later believed to have non-specific interstitial pneumonia, a separate disease that was first proposed after reappraisal of histopathological data.1 With increasing knowledge of disease mechanisms (including the study of familial pulmonary fibrosis and other genetic studies), the current entity of idiopathic pulmonary fibrosis can probably be further subclassified, with subgroups of patients no longer viewed as having idiopathic disease and needing very different strategies from those used in the management of idiopathic pulmonary fibrosis. In any discussion of combination therapy in idiopathic pulmonary fibrosis, this caveat needs to be kept in mind.

Clinical management and treatment trials are centred on current diagnostic criteria. The prognosis of idiopathic pulmonary fibrosis is devastating, with 50% of patients dying within 3 years of diagnosis. The course of the disease ranges from relative stability for several years to rapid deterioration to death over months, sometimes punctuated by episodes of rapid decline.2 Until recently, idiopathic pulmonary fibrosis was essentially an untreatable disease. Findings from phase 2 and phase 3 trials were negative, and among those that were positive, confident interpretation of the beneficial effects of pirfenidone on forced vital capacity (FVC) was hampered by the fact that findings from one of the three pirfenidone trials were negative;3 treatment effects from nintedanib (Boehringer Ingelheim, Ingelheim, Germany) and triple therapy on pulmonary function variables were reported in single studies.4, 5 Keenly awaited findings from key phase 3 studies showed that active treatment with pirfenidone or nintedanib was associated with a reduction in FVC decline by roughly 50%.6, 7 Mortality during the trial periods was reduced by about 50% in cohorts pooled from three pirfenidone studies.6 Both drugs had generally acceptable tolerance. Taken in their totality, trials of both drugs have established that clinically important treatment effects are now available in idiopathic pulmonary fibrosis.

However, although these results herald a new era in treatment of idiopathic pulmonary fibrosis, the specialty now faces formidable challenges in moving forward. Paradoxically, the successes of 2014 have greatly complicated the design of future treatment studies. Furthermore, the optimum strategy to harness treatment effects in clinical practice is uncertain. As a European group, we discuss these problems from a European perspective, summarise our understanding of the complex pathogenetic pathways of idiopathic pulmonary fibrosis (with particular reference to current and candidate antifibrotic drugs), and argue the case for major initiatives in the development of combination regimens. We briefly discuss the use of combination therapy in selected respiratory diseases other than interstitial lung disease. Finally, the possible role of combination therapies is underlined in progressive, treatment-resistant pulmonary fibrotic disorders other than definite idiopathic pulmonary fibrosis, including so-called probable idiopathic pulmonary fibrosis, rheumatoid lung, chronic hypersensitivity pneumonitis, and unclassifiable pulmonary fibrosis.

Key messages

  • Because multiple coactivated pathways are involved in the pathogenesis of idiopathic pulmonary fibrosis, targeted therapies are unlikely to work well in isolation

  • An evolution from monotherapy to combination therapy has been the rule in other respiratory diseases

  • In interstitial lung diseases other than idiopathic pulmonary fibrosis, combination therapy is attractive in principle, both to deal with diagnostic uncertainty and to suppress both pro-inflammatory and profibrotic pathways

  • The recent successful treatment trials in idiopathic pulmonary fibrosis have created difficulties in quantification of future smaller incremental reductions in decline in forced vital capacity, the current preferred primary endpoint

  • Personalised medicine and the combination therapy ethos are not mutually exclusive, but personalised medicine should not be assumed to hold the key to major future treatment advances in idiopathic pulmonary fibrosis

Section snippets

Challenges in future trial design

Unless treatments that reverse fibrosis are developed, study design will continue to be based on quantification of the prevention of disease progression. Herein lies a serious difficulty, related to the magnitude of FVC change in idiopathic pulmonary fibrosis. In the placebo groups of reported trials, decline in FVC has averaged 220 mL/year, but this decrease includes the loss of lung function expected from normal ageing. Thus, studies have been powered based on an expected FVC decline due to

Sequential treatment, personalised medicine, and combination therapy

The default option in routine practice in the near future is sequential therapy. In this model, pirfenidone or nintedanib is used as initial therapy until treatment is believed to have failed, on the basis of serial pulmonary function trends, or until the patient finds side-effects to be unacceptable. At this point, a change in treatment is made to the alternative drug. On the basis of available data, no recommendation can be made on the choice of initial drug and optimum time at which therapy

Pathogenesis of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis is characterised by a histopathological pattern of usual interstitial pneumonia, consisting of a heterogeneous mixture of preserved parenchyma and injured regions comprising architectural distortion, honeycombing, fibroblastic foci, sparse cellular inflammation, and hyperplastic or apoptotic alveolar epithelial cells.12 Despite advances in the past decade, understanding of idiopathic pulmonary fibrosis remains largely elusive.13, 14 Historically, the disease was

Drugs with proven treatment effects

Pirfenidone has antifibrotic, anti-inflammatory, and antioxidant properties. It attenuates fibrosis in many animal models, including fibrosis of the lung, liver, heart, and kidney,24 but its exact antifibrotic molecular targets remain elusive.25 Pirfenidone inhibits heat shock protein 47, thus reducing collagen synthesis in transforming growth factor β (TGFβ)-induced lung fibroblasts and subsequent myofibroblast accumulation.26 It suppresses the expression of TNFα, interferon γ, basic

Potential therapeutic targets

In the past decade, several new pathways have been targeted in early-phase clinical trials. The most promising new drugs are anti-LOXL2,33, 34 anti-interleukin 4 and anti-interleukin 13,35, 36 anti-connective tissue growth factor (CTGF),37 anti-αvβ6 integrin,38, 39 and NOX4 inhibitors (table 1).40

All of these drugs are pleiotropic, either through the inhibition of several pathways (pirfenidone and nintedanib) or the inhibition of key upstream pathways that have a multiplicity of effects.

Lung cancer

Platinum-based drugs remain the first-line chemotherapy in non-small-cell lung cancer. However, poor results, non-selectivity for cancer cells, and side-effects associated with the use of these drugs in isolation led to the exploration of drugs targeting pathways involved in cancer growth. Inhibitors of epidermal growth factor receptor (EGFR) are the first targeted drugs to improve progression-free survival in patients with non-small-cell lung cancer who have EGFR mutations. Most recent

Combination therapy in interstitial lung diseases other than idiopathic pulmonary fibrosis

In interstitial lung diseases other than definite idiopathic pulmonary fibrosis, standard therapies do not meet the needs of a large subset of patients with a phenotype of progressive fibrotic disease. In these cases, immune dysregulation can be suppressed by traditional immunomodulatory drugs, but profibrotic pathways remain active. Disease progression despite traditional treatment can be thought of in two frequently encountered clinical scenarios. Combination regimens might be useful when the

Conclusions

In this Personal View, we have argued that combination therapy is an imminent part of drug development in idiopathic pulmonary fibrosis. On the basis of pathogenetic considerations and by analogy with other chronic respiratory diseases, personalised monotherapies specific to individual pathways seem intrinsically unlikely to prove efficacious in idiopathic pulmonary fibrosis in the near future. When other interstitial lung disorders overlapping clinically with idiopathic pulmonary fibrosis are

Search strategy and selection criteria

We searched PubMed with the terms “lung fibrosis” and “treatment”, and “idiopathic pulmonary fibrosis”, “IPF”, “randomised control trial”, and “controlled clinical trial”. All articles identified were English-language, full-text papers. We also identified some articles from the reference lists of publications.

This online publication has been corrected. The corrected version first appeared at thelancet.com/respiratory on January 5, 2015

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