Precision medicine in idiopathic pulmonary fibrosis

Introduction

Most diseases, idiopathic pulmonary fibrosis (IPF) included, are heterogeneous entities which exhibit varying manifestations in different individuals. Despite this, most pharmacological therapies are administered uniformly based on diagnosis and with little regard to inter-individual differences. The emergence of precision medicine (also referred to as personalised or stratified medicine) has been driven by the recognition that, with advances in biological understanding, a one-size-fits-all approach to medical therapy is increasingly inappropriate.¹ It is anticipated that the introduction of tailored therapy will improve treatment outcomes, reduce side effects, prevent unnecessary exposure to ineffective therapies and save money through more efficient use of healthcare resources. Such is the current enthusiasm for personalised medicine that, in the United States, President Obama is spearheading a $300 million Precision Medicine Initiative.²

Factors determining an individual’s response to a specific pharmacotherapy can be separated in to those which are patient-specific and those which are disease-specific. The pharmacokinetics of many drugs are influenced by a variety of patient-specific factors including age, gender, ethnicity, weight, body fat composition and co-morbid conditions (especially renal or hepatic disease). The growing field of pharmacogenomics has led to the discovery of genetic factors which determine individual variability in absorption, metabolism and clearance of drugs. Differences in hepatic enzymes such at the cytochromes can result in vastly different drug exposures between individuals given identical doses of the same drug. An example of pharmacogenomics entering routine clinical practice is the measurement of thiopurine methyltransferase (TMPT) levels prior to administration of thiopurine drugs such as azathioprine.³

The major driving force in the development of precision medicine has, however, been the recognition of disease-specific factors which influence treatment outcomes. This recognition has, in turn, been driven by the advent of modern high-throughput molecular biology techniques which have led to the discovery that apparently identical disease processes can arise through different molecular abnormalities. The field of precision medicine is most advanced in oncology where it has been demonstrated that specific molecular phenotypes (e.g. oestrogen receptor positivity and tamoxifen sensitivity in breast cancer and epidermal growth factor receptor (EGFR) receptor positivity and responsiveness to EGFR inhibitors in non-small cell lung cancer) determine treatment outcomes.⁴ However, it is not just malignant diseases which are amenable to personalised therapy. Recently introduced biological therapies for asthma have been approved for very specific subgroups of patients.⁵ The observation that there are inherent differences between individuals with the same disease has led to the coining of the term endotype; a subtype of a condition defined by a distinct pathophysiological mechanism.⁶

Can precision medicine be applied to IPF?

IPF shares may of the characteristics of malignancy.⁷ Importantly it is a complex multi-pathway disease which arises through abnormalities in many of the processes involved in the normal wound healing response.⁸ Genetic studies already point to several distinct genetic polymorphisms which determine susceptibility to fibrosis and which in turn influence the rate of disease progression.⁹ Furthermore, early evidence suggests that some of these polymorphisms may underpin response to specific pharmacotherapies.¹⁰ Measurement of specific proteins, such as periostin, matrix metalloproteinase (MMP)-3 and CXCL13, identifies separate populations of individuals with IPF who have activation of different disease pathways and differing prognosis.^11,12 Similarly, autoantibodies to heat shock protein 70 and type V collagen have been identified in sub-groups of IPF subjects.^13,14 In the case of type V collagen autoantibodies this observation has led to clinical trials of an oral immunotherapy targeting this specific endotype.¹⁴

The two approved therapies for IPF, pirfenidone and nintedanib, have pleotropic effects and block multiple disease pathways.¹⁵ More targeted therapies e.g. interferon gamma, endothelin antagonists, anti-IL13 antibodies, CCL2 antagonists and lysl oxidase-like (LOXL)-2 blocking antibodies have, to date, proved disappointing when used in unselected populations of IPF patients despite compelling pre-clinical evidence of these compounds being anti-fibrotic.¹⁵ It is interesting to speculate that, like mepolizumab in asthma,¹⁶ these drugs could be effective if the appropriate disease endotype could be reliably identified. An important goal of precision medicine is to ensure that treatments which benefit small subgroups are not dismissed because efficacy signals are overlooked in unselected cohorts. If precision medicine can be delivered effectively to IPF then there may be value in re-examining some of the drugs which have previously failed in large scale clinical trials conducted in unstratified IPF cohorts.

What is needed to bring precision medicine to IPF?

Although the concept of precision medicine is deceptively simple the steps required to move from current practice to targeted therapy are challenging and are the same as those encountered in other areas of healthcare (Figure 1).¹⁷ An initial prerequisite are large, prospective, longitudinal, collaborative studies in which diagnosis, monitoring and sample collection are performed according to rigorously applied shared operating procedures and standards. A number of such studies (e.g. PROFILE¹⁸, COMET¹², the European IPF network registry¹⁹) are currently well advanced. The next step is to identify candidate biomarkers and pathways. This can be achieved through both hypothesis-driven research based on existing disease knowledge or via unbiased analysis of large scale -omic data derived from disease specific biological samples. Both approaches have the potential to identify novel, disease-relevant biomarkers which can be used to inform diagnosis, prognosis, treatment stratification and/or therapeutic response.^18,20 Robust biomarker identification requires both discovery and (ideally, multiple) validation cohorts—a point which emphasises the necessity of large national and international collaborative networks in the development of precision treatments.

Figure 1.

Pathway to precision medicine.

Availability of target-specific therapies is an important component of an effective precision medicine strategy. Fortunately, IPF is an area of active drug discovery and so the potential for targeted treatment is large. The successful application of personalised medicine requires appropriately designed randomised controlled trials; initially in unselected patient populations (but usually with biomarker-driven stratification) and later in defined disease endotypes. In the ideal situation the identification of the sub-group of patients most likely to respond to treatment should precede clinical trial development. However, personalised approaches to treatment can be developed post-regulatory approval. For such trials to be undertaken in IPF there is an urgent need for end-points which permit the design of smaller and shorter efficacy studies.²⁰ Furthermore, given the challenges inherent in delivering precision medicine it is vitally important that there is full engagement of all potential stakeholders including; patient groups, academic institutions, the pharmaceutical industry, diagnostics companies and funding bodies.

Conclusion

The advent of anti-fibrotic therapy has brought new hope to those suffering with IPF. However, as current treatments only slow disease progression there remains major unmet need for those suffering with this devastating condition. The complex multi-pathway pathogenesis of IPF makes precision medicine highly attractive. Some of the important building blocks for developing a personalised approach to IPF therapy (such as candidate targeted drugs, longitudinal cohort studies, putative stratification biomarkers and identifiable genetic sub-types) are already in place. Nonetheless, a lot remains to be done before precision medicine can be delivered to IPF patients in day-to-day clinical practice. For the field to move forward it is vitally important that all stakeholders work collaboratively with the shared goal of making precision IPF medicine a reality.

Funding

Dr Toby Maher is supported by an NIHR Clinician Scientist Fellowship (NIHR Ref: CS-2013-13-017).

Conflict of interest: T.M.M. has no declarations directly related to this manuscript. He has, however, received industry-academic research funding from GlaxoSmithKline R&D, UCB and Novartis and has received consultancy or speakers fees from Astra Zeneca, Bayer, Biogen Idec, Boehringer Ingelheim, Cipla, Dosa, Galapagos, GlaxoSmithKline R&D, ProMetic, Roche (and previously InterMune), Sanofi-Aventis, Takeda and UCB.