Drugs & Aging

https://doi.org/10.1007/s40266-019-00647-y

LEADING ARTICLE

Idiopathic Pulmonary Fibrosis: New and Emerging Treatment Options

Richard J. Hewitt1,2 · Toby M. Maher1,2 

© Springer Nature Switzerland AG 2019

Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating, scarring lung disease with a worse prognosis than some
cancers. The incidence of IPF is increasing and while current antifibrotic therapies slow disease progression, they do not offer
a cure. The pathobiology of IPF is complex and is driven by aging-associated cellular dysfunction, epithelial injury, and an
aberrant wound-healing response characterised by fibroblast activation and extracellular matrix accumulation (ECM) in the
interstitium. As understanding of the underlying mechanisms has evolved, new targets for pharmacotherapy have emerged.
Novel drugs currently in development for pulmonary fibrosis have diverse molecular properties and mechanisms of action,
as well as different routes of administration. A shared primary goal of these agents is reduction of the profibrotic activity of
fibroblasts and limitation of ECM deposition, which hinders gas exchange and ultimately leads to respiratory failure. This
article provides an overview of some promising new therapeutic options for IPF and considers the challenges for future
drug development.

Key Points  1 Introduction

Idiopathic pulmonary fibrosis (IPF) is a devastating lung
disease associated with aging that causes progressive
interstitial scarring, respiratory failure and death.
There are currently only two antifibrotic drugs licensed
for the treatment of IPF in the UK. These drugs slow
disease progression but do not provide a cure.
There is a growing portfolio of novel therapies that target
diverse pathways in the intricate pathobiology of IPF
which have been shown to be safe in early-phase clinical
trials. Many of these drugs aim to reduce the profibrotic
activity of fibroblasts and limit extracellular matrix
deposition.
* Toby M. Maher
t.maher@imperial.ac.uk
1
National Heart and Lung Institute, Imperial College London,
Sir Alexander Fleming Building, London SW7 2AZ, UK
2
Interstitial Lung Disease Unit, Royal Brompton Hospital,
London SW3 6NP, UK
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal
lung disease of unknown cause characterised by relentless
interstitial scarring [1]. The incidence of IPF is estimated
at three to nine cases per 100,000 population per year, and
increases with age [2, 3]. There is interindividual variability
in the disease trajectory, but ultimately prognosis is poorer
than several other types of cancer, with a median survival of
3 years [4, 5]. As normal lung parenchyma is replaced with
scar tissue, there is an irreversible deterioration in lung func-
tion, which has a devastating impact on the quality of life of
sufferers who experience debilitating dyspnoea and cough.
Currently, no pharmacological therapy is available that
can reverse lung fibrosis or cure IPF. There was a paradigm
shift in treatment strategy following the PANTHER-IPF
clinical trial published in 2012 [6], which demonstrated
that patients treated with a combination of prednisolone,
azathioprine and N-acetylcysteine (NAC) had an increased
risk of hospitalisation and death compared with placebo [6].
This led to a reconsideration of the fundamental pathobiol-
ogy of IPF, a move away from conventional immunosup-
pression, and the development of novel antifibrotic agents.
Two orally administered antifibrotic drugs—pirfenidone
and nintedanib—were recommended for the treatment of
IPF in the 2015 ATS/ERS/JRS/ALAT Clinical Practice
Guideline on the basis of clinical trials that demonstrate

Vol.:(0123456789)

they slow disease progression and improve survival [7–10].
Treatment-associated adverse effects (including nausea,
dyspepsia and a photosensitive rash with pirfenidone, and
nausea and diarrhoea with nintedanib), limit tolerability and
lead to drug discontinuation in up to 26% of patients [11].
Although pirfenidone and nintedanib represent a step-change
in the management of IPF, there remains a significant unmet
need for new therapies for this inevitably progressive and
fatal disease. This review aims to highlight promising novel
agents for the treatment of IPF.
2 Idiopathic Pulmonary Fibrosis (IPF)
Pathobiology
Understanding of the mechanisms underlying IPF has
improved significantly over the last 20 years, catalysed in
part by the advent of transcriptomics, which has allowed
unbiased analysis of human samples to identify novel path-
ways [12]. Current evidence supports a pathogenic model
in which alveolar epithelial injury provokes a dysregulated
wound healing response with fibroblast proliferation and
activation, and excess extracellular matrix deposition in the
interstitium (Fig. 1) [13]. This impedes gas exchange, lead-
ing to respiratory failure and ultimately death.
IPF is a complex disease, with a number of potential envi-
ronmental triggers and abnormalities in multiple pathways
driving the disease [14]. Aging-associated cellular distur-
bances, including mitochondrial dysfunction and senes-
cence, with genetic variants, also play a significant role in
Injury
Alveolar space
Epithelium
Mesenchyme
Endothelium
Vascular space
Fig. 1  Schematic overview of the complex pathobiology of IPF and
novel drug candidates. Injury to an aging alveolar epithelium pro-
motes activation of fibroblasts and differentiation to myofibroblasts,
which deposit excess ECM in the interstitium, leading to impaired gas
exchange. Many of the agents listed target more than one aspect of
R. J. Hewitt, T. M. Maher
epithelial vulnerability to injury [13]. It is probable that the
interplay of multiple pathways with inbuilt redundancy is the
reason that many single pathway-targeted drug candidates
have failed in IPF clinical trials.
The histological lesion associated with IPF, usual inter-
stitial pneumonia (UIP), is characterised by spatial and
temporal heterogeneity with normal lung interposed with
active fibrotic foci and honeycombing in a subpleural distri-
bution [1]. It is important to recognise that the development
of fibrosis in IPF is not only associated with the accumula-
tion of collagen and extracellular matrix but is also defined
by architectural destruction of the lung, with abnormal
remodelling of distal airspaces, resulting in loss of the gas
exchange surface area. The nature of this fibrotic destruction
raises the challenge of how best to deliver drugs in IPF, and
shapes treatment aspirations. The loss of lung architecture in
IPF makes it unlikely that even highly effective antifibrotic
drugs will restore normal lung structure and function. As
such, the primary treatment intention in IPF is to stabilise
lung function and prevent further loss rather than, as would
be desirable, to reverse disease.
3 Emerging Targets and Pharmacotherapy
for IPF
3.1 Autotaxin: GLPG1690
Lysophosphatidic acid (LPA), a phospholipid that signals
via G protein-coupled receptors to illicit a range of cellular
Galectin- 3 inhibitor - TD139
Cell- based therapies
• Anti- αVβ6 - BG00011 & GSK3008348
• Anti-CTGF - FG-3019 (Pamrevlumab)
• Autotaxin inhibitor - GLPG1690
• LPA1 receptor antagonist - BMS-
986020
• Pentraxin- 2 - PRM151
• PI3K/mTOR inhibition; GSK2126458
(Omipalisib)
• GPR40 agonist/ GPR84 antagonist –
PB4050
• Anti-IL-13 - Lebrikizumab
the fibrotic cascade, with the common aim of limiting matrix depo-
sition. Adapted from Maher [15]. IPF idiopathic pulmonary fibrosis,
ECM extracellular matrix, CTGF connective tissue growth factor,
LPA lysophosphatidic acid, PI3K/mTOR phosphatidylinositol-3-ki-
nase (PI3K)/mammalian target of rapamycin, IL interleukin
IPF: New and Emerging Treatment Options
responses, including proliferation and migration, is increased
in the bronchoalveolar lavage (BAL) fluid of IPF patients
[16, 17]. In a bleomycin model of fibrosis, LPA, via the
receptor ­LPA1, mediates fibroblast recruitment and increases
vascular permeability following lung injury [17]. Concentra-
tions of autotaxin (ATX; ENPP2), the enzyme responsible
for converting lysophospholipids to LPA, were found to be
increased in IPF lung tissue, prompting further investigation
as a potential therapeutic target [18].
A multicentre, phase IIa randomised placebo-controlled
trial (RCT) of GLPG1690 (Galapagos), an orally adminis-
tered, selective autotaxin inhibitor was published in 2018
[19]. Twenty-three patients with comparable demographics
were enrolled in the trial to take either 600 mg GLPG1690
or placebo once daily for 12 weeks. Treatment-emergent
adverse events of mild to moderate severity were registered
in the placebo and GLP1690 groups in similar proportions.
Two (12%) patients in the GLP1690 group encountered
events directly related to the treatment, but, importantly, no
patients suffered acute exacerbations of IPF or died during
the trial. Measured concentrations of LPA species C18:2
were reduced with a once-daily 600 mg dose of GLP1690
for 12 weeks. The study was not statistically powered to
evaluate efficacy, but spirometry results were encouraging;
mean forced vital capacity (FVC) remained stable in the
GLPG1690 group compared with the placebo group, where
it declined (mean − 70 mls). Parallel phase III trials assess-
ing the safety and efficacy of GLPG1690 with standard med-
ical therapy are now recruiting (ISABELA1, ClinicalTrials.
gov identifier: NCT03711162; and ISABELA2, ClinicalTri-
als.gov identifier: NCT03733444).
3.2 Lysophosphatidic Acid Receptor: BMS‑986020
An alternative strategy for targeting the LPA pathway has
been undertaken using a small molecule inhibitor of recep-
tor ­LPA1, BMS-986020 (Bristol-Myers Squibb), and a
multicentre, phase II, double-blind RCT of BMS-986020
has been completed [20]. A total of 108 IPF patients com-
pleted the 26-week study, in which they were randomized to
receive placebo or BMS-986020 600 mg once or twice daily.
A slower rate of FVC decline was seen in patients treated
with BMS-986020 twice daily compared with placebo.
Furthermore, a dose-related increase in liver enzymes and
three cases of cholecystitis were reported in the treatment
arm and were postulated to be the result of off-target BMS-
986020-induced inhibition of hepatobiliary transporters.
3.3 Pentraxin‑2: PRM‑151
At the centre of the underlying pathobiology of IPF is an
aberrant wound-healing response to alveolar injury. Mono-
cyte-derived alveolar macrophages have been shown to play
a significant role in this process [21]. Pentraxin-2 (PTX-2),
also known as serum amyloid P (SAP), is a blood plasma
pattern recognition receptor synthesised by the liver during
steady state. The pentraxin family also includes pentraxin-1,
more commonly known as C-reactive protein (CRP), and
pentraxin-3. Administration of human SAP inhibits fibro-
sis in a mouse kidney by opsonising apoptotic cell debris
and acting as a ligand for the Fcγ receptor, downregulating
monocyte and macrophage activity [22]. Administration
of recombinant human SAP reduces lung collagen content
in bleomycin challenged and transforming growth factor
(TGF)-β1 overexpressing mice, and is associated with a
reduction in alternatively activated (M2) macrophages [23].
Blood plasma levels of SAP are reduced in IPF patients com-
pared with controls, and correlate with FVC [24].
Intravenous recombinant human pentraxin-2, PRM-151,
was assessed in a small, multiple ascending dose, phase I
RCT in treatment-naive subjects with IPF [25]. It was well
tolerated, with no severe infusion reactions or adverse events
at any dose (1, 5, or 10 mg/kg); however, there was one
episode of treatment-related hypotension. Pharmacokinetic
studies showed, as expected, that pentraxin-2 led to a dose-
dependent increase in PTX-2 levels.
A phase II, double-blind, multicentre RCT of pentraxin-2
administered intravenously (10 mg/kg) every 4 weeks for
24 weeks has now been conducted [26]. Randomisation
was stratified according to background therapy, with sub-
jects being permitted to take concomitant pirfenidone or
nintedanib provided a stable dose was established for at
least 3 months prior to study entry. A total of 111 subjects
completed the trial, in which a significant difference in least
squares mean change in FVC percentage predicted from
baseline to 28 weeks was seen in the pentraxin-2 group
(− 2.5) versus the placebo group (− 4.8); a difference of 2.3
(90% confidence interval [CI] 1.1–3.5; p = 0.001). The most
common adverse event in the pentraxin-2 group was cough,
and although there were four infusion-related reactions, none
were considered by the authors as serious. The authors rec-
ognized the inclusion of subjects with possible UIP and lack
of central review of radiology as limitations of the study.
3.4 Connective Tissue Growth Factor: FG‑3019
(Pamrevlumab)
Key pathways of fibrogenesis, including fibroblast differen-
tiation to and activation of myofibroblasts, ECM deposition
and TGF-β expression, are modulated by the matricellular
protein, connective tissue growth factor (CTGF/CCN2) [27].
CTGF does not appear to act via a unique receptor, thus
complicating the therapeutic targeting of this pathway. How-
ever, an anti-CTGF human monoclonal antibody that binds
CTGF directly with high affinity, FG-3019, also known as
pamrevlumab (FibroGen), was identified as a candidate in

preclinical models of disease [27]. A tenfold increase in
CTGF messenger RNA (mRNA) transcripts was detected in
the BAL fluid of IPF patients compared with controls [28].
In a radiation-induced pulmonary fibrosis mouse model,
FG-3019 attenuates or reverses lung fibrosis, with improve-
ments in lung function and survival, depending on the time
of administration in relation to the initial irradiation injury
[29].
In a phase IIa, open-label, single-arm, multicentre trial,
89 subjects received intravenous pamrevlumab at either
15 or 30 mg/kg every 3 weeks for 45 weeks [30]. Subjects
were allowed to continue prednisolone (≤ 10 mg) and/or
NAC (≤ 1800 mg) provided these had been taken for at
least 4 months prior to study enrolment. Inclusion criteria
included those with a history of disease progression (defined
radiologically or by an FVC decline of ≥ 10%) in the pre-
ceding 12 or 18 months, and ≥ 10% to < 50% whole-lung
fibrosis quantified by high-resolution computed tomography
(HRCT) to allow evaluation of any reversal of lung fibro-
sis, as was suggested in the preclinical studies. The safety
profile was acceptable; treatment-emergent serious adverse
events occurred in 29% of subjects and none of the deaths
that occurred were attributed to the treatment. An average
decline in FVC of 140 mls was seen over the 48-week study
period, with 30% of subjects showing a 0.2–14.1% increase
in FVC. Interestingly, a subset also showed reduced reticular
fibrosis by quantitative HRCT.
Following on from this, a phase II, double-blind, placebo-
controlled trial, ‘PRAISE’, randomised 103 IPF patients to
receive 16 doses of pamrevlumab (30 mg/kg) or placebo
for 48 weeks (ClinicalTrials.gov identifier: NCT03733444).
A late-breaking abstract at the American Thoracic Society
(ATS) 2018 International Conference reported pamrevlumab
slowed progression of fibrosis, as assessed by quantitative
HRCT at weeks 24 and 48 [31]. Although the results of
this study have not yet been published, pamrevlumab has
received fast-track status from the US FDA and is expected
to enter into phase III trials in the near future.
3.5 Galectin‑3: TD139
A pleiotropic, β-galactoside-binding lectin known as galec-
tin-3 (Gal-3) has been implicated in the development of
fibrosis in multiple organs, including the liver and kidney
[32, 33]. Elevated levels of galectin-3 in bronchoalveolar
lavage fluid from IPF subjects have been reported, albeit
inconsistently across studies [34–36]. Interestingly, in the
Framingham Heart Study cohort, higher serum galectin-3
concentrations were associated with lower FVC, reduced
diffusing capacity of the lung for carbon monoxide ­(DLCO)
and interstitial lung abnormalities on CT [37].
Galectin-3 is expressed in numerous cell types, but in the
context of IPF is mainly localized to alveolar macrophages
R. J. Hewitt, T. M. Maher
and type 2 alveolar epithelial cells [35, 36]. Mice with a
genetic deletion of galectin-3 (galectin-3−/−) exhibit less
fibrosis in TGF-β1 and bleomycin murine models [34]. In
response to TFG-β1, alveolar epithelial cells from galec-
tin-3−/− mice show less epithelial–mesenchymal transition
than wild-type, while galectin-3−/− fibroblasts produce less
collagen. Targeting galectin-3 with a small molecule inhibi-
tor, TD-139, instilled directly into the lungs of mice follow-
ing bleomycin, reduced fibrosis [34].
Three different doses (0.3, 3 and 10 mg) of a dry pow-
der inhaler formulation of the galectin-3 inhibitor TD-139
(Galecto Biotech) have been tested in a proof-of-concept,
multicenter, double-blind, phase IIa RCT in 24 subjects
[38]. Galectin-3 was assessed in BAL and plasma predos-
ing and 14 days postdosing. No significant drug-related
adverse effects were reported in the abstract presented at
the ATS 2017 International Conference. There was a high
dose-dependent concentration of TD-139 in BAL pellets,
suggesting inhaled delivery of the drug to the distal air-
space was achieved. TD-139 effectively lowered expression
of galectin-3 in flow-sorted BAL macrophages at the 3 and
10 mg doses. A phase IIb trial is anticipated to start recruit-
ing within the next year.
3.6 αvβ6 Integrin: BG00011 (Formerly STX‑100)
Integrins are transmembrane receptors that modulate cell
adhesion to the extracellular matrix and adjacent cells,
which also interact with the cell cytoskeleton to activate
intracellular signalling [39]. Integrin αvβ6 is strongly
expressed in type I and II alveolar epithelial cells in fibrotic
areas assessed by immunostaining of lung tissue from indi-
viduals with IPF, with higher levels of αvβ6 immunostaining
being associated with an increased risk of death [40, 41].
TGF-β, a key mediator of fibrosis, is secreted in a latent
form coupled with latency-associated protein (LAP). Inte-
grin αvβ6 binds to an arginine-glycine-aspartic (RGD)
sequence on LAP to activate TGF-β1 [42]. Low-dose treat-
ment with a monoclonal antibody to αvβ6 attenuates fibrosis
in a murine bleomycin model [40].
Details of a phase IIa, escalating-dose RCT of BG00011
(formerly STX-100, Biogen), a humanized anti-αvβ6 immu-
noglobulin (Ig) G1 monoclonal antibody, was presented at
the ATS 2018 International Conference [43]. Forty-one
IPF patients received either the drug or placebo by weekly
subcutaneous injection for 8 weeks, in five dose cohorts
(range 0.015–3 mg/kg). Adverse events were reported in
four patients treated with BG00011 but were judged not
to be related to the drug. pSMAD2, a signal transducer
of TGF-β, was reduced in the BAL fluid by BG00011 in
a dose-dependent manner. A phase IIb safety and efficacy
trial over 52 weeks (SPIRIT; ClinicalTrials.gov identifier:
NCT03573505) is now recruiting.
IPF: New and Emerging Treatment Options
A small molecule inhibitor of the αvβ6 integrin,
GSK3008348 (GlaxoSmithKline), has been formulated for
administration as a nebulised solution. In a phase I trial of
29 healthy participants, it was well tolerated at clinically
relevant doses and demonstrated promising pharmacokinet-
ics, with no serious adverse events [44].
3.7 Interleukin‑13: Lebrikizumab
Interleukin (IL)-13 is a T-helper (Th) 2 cytokine that medi-
ates tissue fibrosis and remodelling, in part through TGF-β1
activation [45]. It is increased in lung tissue of bleomycin-
treated mice, and antibody blocking of IL-13 reduces fibro-
sis in this model [46]. Lebrikizumab (Roche) is a human-
ised monoclonal antibody to IL-13. A phase II, randomised,
double-blind, placebo-controlled trial, ‘RIFF’, was under-
taken to assess lebrikizumab (250 mg subcutaneously every
4 weeks) as monotherapy (Cohort A, n = 154) or in combina-
tion with background pirfenidone (Cohort B, n = 351) over
52 weeks (ClinicalTrials.gov identifier: NCT01872689).
Data from this study were presented at the ATS 2018 Inter-
national Conference [47, 48]. Despite an acceptable safety
profile, lebrikizumab was not associated with a benefit in
either the rate of FVC decline or mortality over 52 weeks
in either cohort. To make an informed judgement on the
future potential of lebrikizumab in IPF, we await the fully
published results of the RIFF trial.
3.8 Phosphatidylinositol‑3‑Kinase/AKT
and Mammalian Target of Rapamycin Pathway:
GSK2126458 (Omipalisib)
For over a decade, phosphatidylinositol-3-kinase (PI3K) and
its serine/threonine kinases Akt and mTOR, have garnered
significant traction in the field of oncology as they play a
critical role in cell survival, growth and proliferation [49].
PI3K signalling activity is evident in macrophages, bron-
chial epithelium and fibrotic foci in IPF lung tissue [50]. A
potent small molecule inhibitor of the PI3K/mammalian tar-
get of rapamycin (mTOR) pathway, GSK2126458 (Omipal-
isib), reduces fibroblast proliferation and collagen I synthesis
induced by TGF-β in vitro [50]. In a double-blind, placebo-
controlled, dose-escalation, phase Ib study of omipalisib in
17 IPF patients, the drug had an acceptable safety profile and
[18F]-fluorodeoxyglucose-positron emission tomography
([18F]-FDG-PET)/CT scans confirmed target engagement
in the lungs [51]. Diarrhoea was the most common adverse
event, reported by four participants.
3.9 GPR40 and GPR84: PBI‑4050
PBI-4050, 3-pentylbenzeneacetic acid sodium salt (Prometic
BioSciences Inc.), is a synthetic medium-chain fatty acid
analogue that has been developed as an orally administered
small molecule for the treatment of IPF [52]. It targets the
G-protein-coupled receptors GPR40 and GPR84, where it
acts as an agonist and antagonist, respectively [52]. PBI-
4050 reduced activation and profibrotic gene expression
in human dermal fibroblasts, and histological evidence of
lung fibrosis by 47% in a bleomycin mouse model [52]. In
a phase II, open-label, single-arm study (ClinicalTrials.
gov identifier: NCT02538536), PBI-4050 taken at a dose
of 800 mg daily for 12 weeks was well tolerated and there
was no significant decline in FVC when used alone and in
combination with nintedanib [53]. A drug–drug interaction
with pirfenidone resulted in a significant decline in FVC
over 12 weeks. This was an exploratory study of 41 patients,
therefore an appropriately powered RCT is required to ascer-
tain the effectiveness of this agent.
3.10 Cell‑Based Therapies
At the core of IPF pathogenesis is failed epithelial repair.
Bone marrow-derived mesenchymal stem cells (MSCs)
transplanted into the lungs of mice contributed to the
repair and resolution of injury induced by bleomycin [54].
‘ASTIS’, a phase III trial of autologous haematopoietic stem
cell transplantation in patients with diffuse cutaneous sys-
temic sclerosis (83% of whom had interstitial lung disease
on HRCT), improved lung function [55]. Utilisation of the
regenerative properties of MSCs for the treatment of IPF
is now under investigation in human trials. Eight patients
with moderate–severe IPF received an intravenous infusion
of placenta-derived MSCs from an unrelated donor at a
dose of either 1 × 106 or 2 × 106 MSCs/kg in a single-centre,
phase Ib trial. No significant short-term safety issues were
identified in this study [56]. In accordance with these find-
ings, a phase I trial, ‘AETHER’, administered human bone
marrow-derived MSCs via intravenous infusion to nine IPF
patients with no serious adverse events [57]. In an alternative
approach, three endobronchial infusions of autologous adi-
pose-derived stem cells–stromal vascular fraction (ADSCs-
SVF) at a dose of 0.5 × 106 cells/kg, in a phase Ib study of
14 patients with mild–moderate IPF, was associated with no
adverse events [58]. Up to 5 years of longitudinal data from
this study confirm an acceptable safety profile, but has failed
to demonstrate any alteration in disease course as assessed
by FVC, diffusion capacity of the lungs for carbon monoxide
(DLco), and 6-min walk test (6MWT) [59].
4 Priorities for Future Research
The early-phase trials discussed in this article underscore
the diversity of therapeutic targets currently under investiga-
tion in IPF, a complex disease driven by multiple pathways.

Given the destructive nature of fibrosis in IPF, there is a
need to target the disease at its inception so as to halt the
relentless accumulation of scar tissue. This requires further
research to establish a clearer understanding of the inciting
environmental insults leading to the development of fibrosis,
and to identify individuals at risk of disease or with subclini-
cal fibrosis. To translate potential therapeutic targets from
bench-to-bedside, the preclinical experimental models used
to identify candidate therapies require optimisation and bet-
ter validation [60]. To accelerate the development of new
IPF treatments, there is a pressing need for trial endpoints
that provide an earlier readout of antifibrotic efficacy than
is permitted by FVC. This would allow ineffective treat-
ments to be identified and discarded at an earlier stage in
the development process and would enable prioritisation of
compounds with a greater chance of success in late-phase
trials.
The older age and comorbidities of IPF patients must
be considered when exploiting therapeutic targets that may
impact biological pathways involved in cellular homeostasis
or pose greater risk in association with other health problems
[61]. Targeting the mechanisms of age-associated cellular
dysfunction may prove an effective strategy and has been
reviewed extensively elsewhere [62].
5 Conclusions
Organ fibrosis is a consequence of aging and is a growing
problem across developed countries. IPF is an exemplar
fibrotic disease characterised by progressive destruction
of the lung, with consequent respiratory failure and death.
The successful approval of both pirfenidone and nintedanib
for IPF has proven that the mechanisms driving progressive
fibrosis are therapeutically tractable. The growing portfolio
of novel treatments targeting multiple potential pathways
involved in fibrosis speaks to the molecular complexity of
IPF. Nonetheless, data from early-phase studies provides
hope that a new wave of antifibrotic treatments will reach
the clinic in the near future.
Acknowledgements  Toby M. Maher is supported by a National Insti-
tute for Health Research (NIHR) Clinician Scientist Fellowship (NIHR
Ref: CS-2013-13-017) and a British Lung Foundation Chair in Respira-
tory Research (C17-3).
Compliance with Ethical Standards  monary fibrosis to lung injury by mediating fibroblast recruitment
Conflict of Interest  Richard J. Hewitt has no conflicts of interest. Toby
M. Maher has, via his institution, received industry-academic fund-
ing from GlaxoSmithKline R&D and UCB, and has received consul-
tancy or speakers’ fees from Apellis, AstraZeneca, Bayer, Biogen Idec,
Boehringer Ingelheim, Galapagos, GlaxoSmithKline R&D, Indalo,
Pliant, ProMetic, Roche, Samumed and UCB.
R. J. Hewitt, T. M. Maher
References
1. Daccord C, Maher TM. Recent advances in understanding
idiopathic pulmonary fibrosis. F1000Res. 2016. https​://doi.
org/10.12688​/f1000​resea​rch.8209.1.
2. Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Inci-
dence and prevalence of idiopathic pulmonary fibrosis. Am J
Respir Crit Care Med. 2006;174(7):810–6.
3. Hutchinson J, Fogarty A, Hubbard R, McKeever T. Global inci-
dence and mortality of idiopathic pulmonary fibrosis: a systematic
review. Eur Respir J. 2015;46(3):795–806.
4. Vancheri C, Failla M, Crimi N, Raghu G. Idiopathic pulmonary
fibrosis: a disease with similarities and links to cancer biology.
Eur Respir J. 2010;35(3):496–504.
5. Ley B, Collard HR, King TE Jr. Clinical course and prediction of
survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care
Med. 2011;183(4):431–40.
6. Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ. Pred-
nisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis.
N Engl J Med. 2012;366(21):1968–77.
7. Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK,
Kardatzke D, et al. Pirfenidone in patients with idiopathic pul-
monary fibrosis (CAPACITY): two randomised trials. Lancet.
2011;377(9779):1760–9.
8. King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA,
Glaspole I, Glassberg MK, et al. A phase 3 trial of pirfenidone
in patients with idiopathic pulmonary fibrosis. N Engl J Med.
2014;370(22):2083–92.
9. Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Cos-
tabel U, et al. Efficacy and safety of nintedanib in idiopathic pul-
monary fibrosis. N Engl J Med. 2014;370(22):2071–82.
10. Raghu G, Rochwerg B, Zhang Y, Garcia CA, Azuma A, Behr J,
et al. An Official ATS/ERS/JRS/ALAT Clinical Practice Guide-
line: Treatment of Idiopathic Pulmonary Fibrosis. An Update of
the 2011 Clinical Practice Guideline. Am J Respir Crit Care Med.
2015;192(2):e3–19.
11. Galli JA, Pandya A, Vega-Olivo M, Dass C, Zhao H, Criner GJ.
Pirfenidone and nintedanib for pulmonary fibrosis in clinical
practice: tolerability and adverse drug reactions. Respirology.
2017;22(6):1171–8.
12. Vukmirovic M, Kaminski N. Impact of transcriptomics on our
understanding of pulmonary fibrosis. Front Med (Lausanne).
2018;5:87.
13. Selman M, Pardo A. Revealing the pathogenic and aging-
related mechanisms of the enigmatic idiopathic pulmonary
fibrosis. An integral model. Am J Respir Crit Care Med.
2014;189(10):1161–72.
14. Maher TM, Wells AU, Laurent GJ. Idiopathic pulmonary fibro-
sis: multiple causes and multiple mechanisms? Eur Respir J.
2007;30(5):835–9.
15. Maher TM. Idiopathic pulmonary fibrosis: pathobiology of novel
approaches to treatment. Clin Chest Med. 2012;33(1):69–83.
16. van Meeteren LA, Moolenaar WH. Regulation and bio-
logical activities of the autotaxin-LPA axis. Prog Lipid Res.
2007;46(2):145–60.
17. Tager AM, LaCamera P, Shea BS, Campanella GS, Selman M,
Zhao Z, et al. The lysophosphatidic acid receptor LPA1 links pul-
and vascular leak. Nat Med. 2008;14(1):45–54.
18. Oikonomou N, Mouratis MA, Tzouvelekis A, Kaffe E, Valavanis
C, Vilaras G, et al. Pulmonary autotaxin expression contributes
to the pathogenesis of pulmonary fibrosis. Am J Respir Cell Mol
Biol. 2012;47(5):566–74.
19. Maher TM, van der Aar EM, Van de Steen O, Allamassey L,
Desrivot J, Dupont S, et al. Safety, tolerability, pharmacokinetics,
IPF: New and Emerging Treatment Options
and pharmacodynamics of GLPG1690, a novel autotaxin inhibi-
tor, to treat idiopathic pulmonary fibrosis (FLORA): a phase
2a randomised placebo-controlled trial. Lancet Respir Med.
2018;6(8):627–35.
20. Palmer SM, Snyder L, Todd JL, Soule B, Christian R, Anstrom
K, et al. Randomized, double-blind, placebo-controlled, phase 2
trial of BMS-986020, a lysophosphatidic acid receptor antago-
nist for the treatment of idiopathic pulmonary fibrosis. Chest.
2018;154(5):1061–9.
21. Misharin AV, Morales-Nebreda L, Reyfman PA, Cuda CM, Walter
JM, McQuattie-Pimentel AC, et al. Monocyte-derived alveolar
macrophages drive lung fibrosis and persist in the lung over the
life span. J Exp Med. 2017;214(8):2387–404.
22. Castano AP, Lin SL, Surowy T, Nowlin BT, Turlapati SA, Patel
T, et al. Serum amyloid P inhibits fibrosis through Fc gamma
R-dependent monocyte-macrophage regulation in vivo. Sci Transl
Med. 2009;1(5):5ra13.
23. Murray LA, Rosada R, Moreira AP, Joshi A, Kramer MS, Hesson
DP, et al. Serum amyloid P therapeutically attenuates murine bleo-
mycin-induced pulmonary fibrosis via its effects on macrophages.
PLoS One. 2010;5(3):e9683.
24. Murray LA, Chen Q, Kramer MS, Hesson DP, Argentieri RL,
Peng X, et  al. TGF-beta driven lung fibrosis is macrophage
dependent and blocked by Serum amyloid P. Int J Biochem Cell
Biol. 2011;43(1):154–62.
25. van den Blink B, Dillingh MR, Ginns LC, Morrison LD, Moerland
M, Wijsenbeek M, et al. Recombinant human pentraxin-2 therapy
in patients with idiopathic pulmonary fibrosis: safety, pharmacoki-
netics and exploratory efficacy. Eur Respir J. 2016;47(3):889–97.
26. Raghu G, van den Blink B, Hamblin MJ, Brown AW, Golden
JA, Ho LA, et al. Effect of recombinant human pentraxin 2 vs
placebo on change in forced vital capacity in patients with idi-
opathic pulmonary fibrosis: a randomized clinical trial. JAMA.
2018;319(22):2299–307.
27. Lipson KE, Wong C, Teng Y, Spong S. CTGF is a central media-
tor of tissue remodeling and fibrosis and its inhibition can reverse
the process of fibrosis. Fibrogenesis Tissue Repair. 2012;5(Suppl
1):S24.
28. Allen JT, Knight RA, Bloor CA, Spiteri MA. Enhanced insulin-
like growth factor binding protein-related protein 2 (Connective
tissue growth factor) expression in patients with idiopathic pul-
monary fibrosis and pulmonary sarcoidosis. Am J Respir Cell Mol
Biol. 1999;21(6):693–700.
29. Bickelhaupt S, Erbel C, Timke C, Wirkner U, Dadrich M, Flech-
sig P, Tietz A, Pföhler J, Gross W, Peschke P, Hoeltgen L, Katus
HA, Gröne HJ, Nicolay NH, Saffrich R, Debus J, Sternlicht MD,
Seeley TW, Lipson KE, Huber PE. Effects of CTGF blockade on
attenuation and reversal of radiation-induced pulmonary fibrosis.
J Natl Cancer Inst. 2017. https​://doi.org/10.1093/jnci/djw33​9.
30. Raghu G, Scholand MB, de Andrade J, Lancaster L, Mageto Y,
Goldin J, et al. FG-3019 anti-connective tissue growth factor
monoclonal antibody: results of an open-label clinical trial in idi-
opathic pulmonary fibrosis. Eur Respir J. 2016;47(5):1481–91.
31. Gorina E, Goldin J, Hyun KG, Zhong M, Sekayan T, Yu P, et al.
Lung fibrosis measured by quantitative high resolution computed
tomography (qHRCT) in idiopathic pulmonary fibrosis (IPF)
patients treated with pamrevlumab (FG-3019). Am J Respir Crit
Care Med. 2018;197:A7688.
32. Henderson NC, Mackinnon AC, Farnworth SL, Poirier F,
Russo FP, Iredale JP, et  al. Galectin-3 regulates myofibro-
blast activation and hepatic fibrosis. Proc Natl Acad Sci USA.
2006;103(13):5060–5.
33. Henderson NC, Mackinnon AC, Farnworth SL, Kipari T, Has-
lett C, Iredale JP, et al. Galectin-3 expression and secretion links
macrophages to the promotion of renal fibrosis. Am J Pathol.
2008;172(2):288–98.
34. Mackinnon AC, Gibbons MA, Farnworth SL, Leffler H, Nils-
son UJ, Delaine T, et al. Regulation of transforming growth fac-
tor-beta1-driven lung fibrosis by galectin-3. Am J Respir Crit Care
Med. 2012;185(5):537–46.
35. Nishi Y, Sano H, Kawashima T, Okada T, Kuroda T, Kikkawa K,
et al. Role of galectin-3 in human pulmonary fibrosis. Allergol Int.
2007;56(1):57–65.
36. Cullinane AR, Yeager C, Dorward H, Carmona-Rivera C, Wu
HP, Moss J, et al. Dysregulation of galectin-3. Implications for
Hermansky-Pudlak syndrome pulmonary fibrosis. Am J Respir
Cell Mol Biol. 2014;50(3):605–13.
37. Ho JE, Gao W, Levy D, Santhanakrishnan R, Araki T, Rosas
IO, et al. Galectin-3 is associated with restrictive lung disease
and interstitial lung abnormalities. Am J Respir Crit Care Med.
2016;194(1):77–83.
38. Hirani N, Mackinnon A, Nicol L, Walker J, Ford P, Schambye
H, et al. TD139, A novel inhaled galectin-3 inhibitor for the
treatment of idiopathic pulmonary fibrosis (IPF). Results from
the first in (IPF) patients study. Am J Respir Crit Care Med.
2017;195:A7560.
39. Hynes RO. Integrins: bidirectional, allosteric signaling machines.
Cell. 2002;110(6):673–87.
40. Horan GS, Wood S, Ona V, Li DJ, Lukashev ME, Weinreb PH,
et al. Partial inhibition of integrin alpha(v)beta6 prevents pulmo-
nary fibrosis without exacerbating inflammation. Am J Respir Crit
Care Med. 2008;177(1):56–65.
41. Saini G, Porte J, Weinreb PH, Violette SM, Wallace WA,
McKeever TM, et al. alphavbeta6 integrin may be a potential
prognostic biomarker in interstitial lung disease. Eur Respir J.
2015;46(2):486–94.
42. Munger JS, Huang X, Kawakatsu H, Griffiths MJ, Dalton SL, Wu
J, et al. The integrin alpha v beta 6 binds and activates latent TGF
beta 1: a mechanism for regulating pulmonary inflammation and
fibrosis. Cell. 1999;96(3):319–28.
43. Raghu G, Mouded M, Culver DA, Hamblin MJ, Golden JA,
Veeraraghavan S, et al. Randomized, double-blind, placebo-con-
trolled, multiple dose, dose-escalation study of BG00011 (For-
merly STX-100) in patients with idiopathic pulmonary fibrosis
(IPF). Am J Respir Crit Care Med. 2018;197:A7785.
44. Maden CH, Fairman D, Chalker M, Costa MJ, Fahy WA, Gar-
man N, et  al. Safety, tolerability and pharmacokinetics of
GSK3008348, a novel integrin alphavbeta6 inhibitor, in healthy
participants. Eur J Clin Pharmacol. 2018;74(6):701–9.
45. Lee CG, Homer RJ, Zhu Z, Lanone S, Wang X, Koteliansky V,
et al. Interleukin-13 induces tissue fibrosis by selectively stimulat-
ing and activating transforming growth factor beta [1]. J Exp Med.
2001;194(6):809–21.
46. Belperio JA, Dy M, Burdick MD, Xue YY, Li K, Elias JA, et al.
Interaction of IL-13 and C10 in the pathogenesis of bleomy-
cin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol.
2002;27(4):419–27.
47. Swigris JJ, Ogura T, Scholand MB, Glaspole I, Maher TM, Kar-
datzke D, et al. The RIFF study (Cohort A): A phase II, rand-
omized, double-blind, placebo-controlled trial of lebrikizumab as
monotherapy in patients with idiopathic pulmonary fibrosis. Am
J Respir Crit Care Med. 2018;197:A6167.
48. Maher TM, Kondoh Y, Corte TJ, Glassberg MK, Costabel U,
Lancaster LH, et al. The RIFF Study (Cohort B): a phase II, ran-
domized, double-blind, placebo-controlled trial of lebrikizumab
in combination with pirfenidone in patients with idiopathic pul-
monary fibrosis. Am J Respir Crit Care Med. 2018;197:A6168.
49. Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting
the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug
Discov. 2005;4(12):988–1004.
50. Mercer PF, Woodcock HV, Eley JD, Platé M, Sulikowski MG,
Durrenberger PF, et  al. Exploration of a potent PI3 kinase/

mTOR inhibitor as a novel anti-fibrotic agent in IPF. Thorax.
2016;71(8):701–11.
51. Lukey PT, Harrison SA, Yang S, Man Y, Holman BF, Rashidna-
sab A, Azzopardi G, Grayer M, Simpson JK, Bareille P, Paul L,
Woodcock HV, Toshner R, Saunders P, Molyneaux PL, Thiele-
mans K, Wilson FJ, Mercer PF, Chambers RC, Groves AM, Fahy
WA, Marshall RP, Maher TM. A randomised, placebo-controlled
study of omipalisib (PI3K/mTOR) in idiopathic pulmonary Fibro-
sis. Eur Respir J. 2019. https​://doi.org/10.1183/13993​003.01992​
-2018.
52. Gagnon L, Leduc M, Thibodeau J-F, Zhang M-Z, Grouix B,
Sarra-Bournet F, et al. A newly discovered antifibrotic pathway
regulated by two fatty acid receptors: GPR40 and GPR84. Am J
Pathol. 2018;188(5):1132–48.
53. Khalil N, Manganas H, Ryerson CJ, Shapera S, Cantin AM, Her-
nandez P, Turcotte EE, Parker JM, Moran JE, Albert GR, Sawtell
R, Hagerimana A, Laurin P, Gagnon L, Cesari F, Kolb M. Phase
2 clinical trial of PBI-4050 in patients with idiopathic pulmo-
nary fibrosis. Eur Respir J. 2018. https​://doi.org/10.1183/13993​
003.00663​-2018.
54. Rojas M, Xu J, Woods CR, Mora AL, Spears W, Roman J, et al.
Bone marrow-derived mesenchymal stem cells in repair of the
injured lung. Am J Respir Cell Mol Biol. 2005;33(2):145–52.
55. van Laar JM, Farge D, Sont JK, Naraghi K, Marjanovic Z, Lar-
ghero J, et al. Autologous hematopoietic stem cell transplanta-
tion vs intravenous pulse cyclophosphamide in diffuse cuta-
neous systemic sclerosis: a randomized clinical trial. JAMA.
2014;311(24):2490–8.
R. J. Hewitt, T. M. Maher
56. Chambers DC, Enever D, Ilic N, Sparks L, Whitelaw K, Ayres J,
et al. A phase 1b study of placenta-derived mesenchymal stromal
cells in patients with idiopathic pulmonary fibrosis. Respirology.
2014;19(7):1013–8.
57. Glassberg MK, Minkiewicz J, Toonkel RL, Simonet ES, Rubio
GA, DiFede D, et  al. Allogeneic human mesenchymal stem
cells in patients with idiopathic pulmonary fibrosis via intrave-
nous delivery (AETHER): a phase I safety clinical trial. Chest.
2017;151(5):971–81.
58. Tzouvelekis A, Paspaliaris V, Koliakos G, Ntolios P, Bouros E,
Oikonomou A, et al. A prospective, non-randomized, no placebo-
controlled, phase Ib clinical trial to study the safety of the adipose
derived stromal cells-stromal vascular fraction in idiopathic pul-
monary fibrosis. J Transl Med. 2013;11(1):171.
59. Ntolios P, Manoloudi E, Tzouvelekis A, Bouros E, Steiropoulos P,
Anevlavis S, et al. Longitudinal outcomes of patients enrolled in a
phase Ib clinical trial of the adipose-derived stromal cells-stromal
vascular fraction in idiopathic pulmonary fibrosis. Clin Repir J.
2018;12(6):2084–9.
60. Bonniaud P, Fabre A, Frossard N, Guignabert C, Inman M, Kue-
bler WM, et al. Optimising experimental research in respiratory
diseases: an ERS statement. Eur Respir J. 2018;51(5):1702133.
61. Raghu G, Amatto VC, Behr J, Stowasser S. Comorbidities in idi-
opathic pulmonary fibrosis patients: a systematic literature review.
Eur Respir J. 2015;46(4):1113–30.
62. Mora AL, Rojas M, Pardo A, Selman M. Emerging therapies for
idiopathic pulmonary fibrosis, a progressive age-related disease.
Nat Rev Drug Discov. 2017;16(11):755–72.