Recent advances in ILD and

its management

BY – Dr Radhika
MODERATOR – Dr Amithash M P
Pathogenesis of IPF
Repetitive
alveolar injury

Aberrant wound
healing response

Fibroblastic
proliferation Myofibroblasts
 Diagnosis of IPF (ATS guidelines)
• Exclusion of other known causes of ILD

• Presence of a UIP pattern on HRCT in patients not subjected to

surgical lung biopsy
OR
Specific combinations of HRCT and surgical lung biopsy pattern in
patients subjected to surgical lung biopsy

Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.
Am J Respir Crit Care Med 2011; 183: 788–824.
 Diagnosis of IPF
• New guidelines for IPF diagnosis have been suggested by the
Fleischner Society Paper :

1. Introduction of pretest clinical probability

2. Possible UIP pattern has been upgraded to probable

3. Presence of probable UIP pattern within the clinical context of IPF

obviates the need for tissue based diagnosis

* Lynch DA, Sverzellati N, Travis WD et al. Diagnostic criteria for idiopathic pulmonary fibrosis: a Fleischner Society White Paper. Published online November 15, 2017
http://dx.doi.org/10.1016/ S2213-2600(17)30433-2.
4. A new CT category is introduced - indeterminate for UIP. In these
cases surgical lung biopsy is required for diagnosis

5. Sub-pleural sparing is considered a strong predictor of NSIP

pathology

6. The term “multidisciplinary working diagnosis” is made part of

diagnostic criteria

7. All diagnoses should be reviewed over time to increase confidence

 Treatment of IPF
• Pharmacological Therapies
• Non‐pharmacologic Therapies –
1. LTOT
2. Lung Transplantation
3. Mechanical ventilation
4. Pulmonary Rehabilitation
• Vaccination
• Treatment of complications and
comorbid conditions -
1. Acute Exacerbation
2. Pulmonary hypertension
3. GERD
4. COPD
5. OSA
• Palliative Care
Pharmacological therapies
• Anti-fibrotic agents

• Antioxidants

• Corticosteroids and immunomodulators

• Other drugs – vasodilators, cytokines, anticoagulation

Pirfenidone
• Orally administered pyridine

• Anti-inflammatory, anti-fibrotic, antioxidant properties

• MOA : 1. TGF-β antagonism

2. Direct inhibition of fibroblasts and collagen synthesis

• Dosage : 2403 mg/day, up-titration of dose should be done

Taniguchi trial
• Phase III clinical trial in Japan

• 275 patients randomized into 3 groups

• Significant differences in VC decline between the placebo group (‐0.16

L) and high‐dose group (‐0.09 L)

• Significant differences in progression‐free survival (death or >10%

decline in VC) favoring the pirfenidone group

Eur Respir J 2010; 35: 821–829

CAPACITY trials
(Clinical studies assessing Pirfenidone in IPF : Research of efficacy and safety outcomes)

• Phase 3 clinical trial in mild-moderate IPF cases

• Paul W Noble et al. did two concurrent trials (004 and 006)

• Done for a minimum of 72 weeks in 110 centers in Australia, Europe

and North America

Lancet 2011;377:1760-1769
 Study 004 Study 006

Sample size 435 344

High-dose pirfenidone –8∙0% FVC decline –9∙0%

Placebo –12∙4% –9∙6%
Significance Statistically significant Statistically not significant

• High-dose pirfenidone was associated with fewer deaths (overall and

IPF-related) and higher incidences of adverse effects

• The CAPACITY trial showed that pirfenidone has favorable benefit

risk profile and represents an appropriate treatment option for
patients with IPF
ASCEND trial
• Randomized Phase III trial as per request of US-FDA

• Study period : 52 weeks

• 555 IPF patients

• Mean decline from baseline in FVC was 235 mL in pirfenidone group

and 428 mL in placebo group

• Pirfenidone reduced decline of 6MWD and improved progression-

free survival
 Follow-up study ASCEND and CAPACITY trials :

• 34 subjects on pirfenidone and 68 subjects on placebo with ≥10 %

decline in FVC in the first 3/6 months were assessed again 6 months
later

• Fewer subjects in pirfenidone group experienced further ≥10 %

decline in FVC or death in following 6 months compared with placebo
group#

# Nathan SD, Albera C, Bradford WZ, et al. Effect of continued treatment with pirfenidone following clinically meaningful declines in forced vital capacity: analysis of data from
three phase 3 trials in patients with idiopathic pulmonary fibrosis. Thorax 2016; 71:429
 • Pooled analysis : patients treated with pirfenidone for 1 year were
>40 % less likely to reach the 10% fall in FVC or death and 38 %less
likely to progress at all**

• Systematic review and meta-analysis (2015) : Decrease in mortality,

reduced decline in FVC, reduced A/E’s and improvement in 6MWD*

** Noble PW, Albera C, Bradford WZ, et al. Pirfenidone for idiopathic pulmonary fibrosis: analysis of pooled data from three multinational phase 3 trials. Eur Respir J 2016; 47:243.
*Aravena C, Labarca G, Venegas C, Arenas A, Rada G. Pirfenidone for Idiopathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis. PLoS ONE. 2015;10(8):e0136160.
Summary of pirfenidone
Decreases FVC decline, more pronounced effect in patients with faster FVC decline

Improves progression free survival

Improves exercise capacity

Anorexia is a common side effect, no correlation with disease severity

Other side-effects : photosensitivity and hepatotoxicity

In case of side effects, dose modification better than stopping drug

Nintedanib
• Intracellular inhibitor for multiple tyrosine kinases receptor (PDGF α
and β, VEGF-2 and FGF-1)

• Dose : 150 mg twice daily

• Approved by US Food and Drug Administration in 2014 and by

European Medicines Agency in 2015
TOMORROW trial
• Phase 2 clinical trial

• 52 weeks trial of 150 mg BD nintedanib v/s placebo

• Results : TOMORROW Annual FVC change

Nintedanib −125.4 ml (0.06 L)
Placebo −189.7 ml (0.19 L)

• It improves QOL and a reduction in acute exacerbations of IPF

Richeldi L, Kreuter M, Selman M, Crestani B, Kirsten A-M, Wuyts WA, et al. Long-term treatment of patients with idiopathic pulmonary fibrosis with nintedanib: results
from the TOMORROW trial and its open-label extension. Thorax. 2017 Oct 9;thoraxjnl-2016-209701.
 INPULSIS 1 and 2 trials
• Phase 3 clinical trial
• 52 week
• Sample size : 1066 patients, done in 205 sites in 24 countries
INPULSIS 1 INPULSIS 2

Nintedanib −114.7 ml FVC −113.6 ml

Placebo −239.9 ml −207.3 ml
FVC change statistically significant statistically significant
Increase in time to 1st statistically insignificant statistically significant
acute exacerbation

Increase in SGRQ score statistically insignificant statistically significant

 • No effect on mortality or acute exacerbations

• Most frequent adverse event in the nintedanib groups in both trials

was diarrhea

• Pooled analysis of TOMORROW and INPULSIS trials : Nintedanib

significantly reduced the risk of acute exacerbation*

• Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014; 370:2071
Summary of anti-fibrotic agents
• The positive results from ASCEND and INPULSIS trials have led to
licensing of both drugs by FDA on October 2014, regardless of severity
of IPF

• These novel anti-fibrotic agents have been shown to slow the decline in
forced vital capacity (FVC), they neither halt progression nor reverse
existing fibrosis.

• No direct comparison RCT study between the two drugs has been done
• A systematic review and meta-analysis done demonstrated superior
benefit of nintedanib, on indirect comparison, than pirfenidone, on
forced vital capacity. No difference in mortality was noted*

• Another study showed that nintedanib protected against the risk of

acute exacerbations and not pirfenidone. Nintedanib was superior to
placebo on mortality and no evidence of difference between
pirfenidone and placebo on mortality**

• No evidence of a difference between pirfenidone and nintedanib on

FVC decline noted in another study#

* Loveman E, Copley VR, Scott DA, Colquitt JL, Clegg AJ, O’Reilly KM. Comparing new treatments for idiopathic pulmonary fibrosis – a network meta-analysis. BMC
Pulmonary Medicine. 2015 Apr 18;15:37.
** Rogliani P, Calzetta L, Cavalli F, Matera MG, Cazzola M. Pirfenidone, nintedanib and N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis: a systematic
review and meta-analysis. Pulm Pharmacol Ther. 2016;40(1):95-103.
# Fleetwood K, McCool R, Glanville J, Edwards SC, Gsteiger S, Daigl M, et al. Systematic Review and Network Meta-analysis of Idiopathic Pulmonary Fibrosis
Treatments. JMCP. 2017 Mar 1;23(3-b Suppl):S5–16.
 • Both drugs reduce FVC decline, but neither drug has a clear
advantage on mortality outcomes*

Combination nintedanib plus pirfenidone study : IN-JOURNEY Trial

• Nintedanib with add-on pirfenidone was compared with nintedanib

alone in a series of 104 patients with IPF and at 12 weeks, safety and
tolerability were consistent with profiles of the individual agents

• Slower decline in FVC at week 12 in patients treated with

pirfenidone+nintedanib (−13.3 ml) compared with nintedanib alone
(−40.9 ml)**
*Canestaro, W.J., Forrester, S.H., Raghu, G., Ho, L. & Devine, B.E. Drug treatment of idiopathic pulmonary fibrosis: systematic review and network meta‐analysis. Chest 149, 756–766
(2016).
** Vancheri C, Kreuter M, Richeldi L, Ryerson CJ, Valeyre D, Grutters JC, et al. Nintedanib with Add-on Pirfenidone in Idiopathic Pulmonary Fibrosis. Results of the INJOURNEY Trial.
Am J Respir Crit Care Med. 2017 Sep 10;197(3):356–63.
Corticosteroids
• No randomized controlled trials have been conducted

• Studies have reported no survival benefits

• Substantial morbidity from long‐term corticosteroid therapy

• ATS/ERS/JRS/ALAT Recommendation – Patients with IPF should not be

treated with corticosteroid monotherapy
(strong recommendation, very low‐quality quality evidence)
Anti-oxidants : N-Acetylcysteine (NAC)
• The IFIGENIA Trial : 12‐month decline in vital capacity and DLCO were
significantly less in NAC arm

• PANTHER trail : Combination therapy (prednisone-azathioprine-NAC) was

associated with greater mortality, more hospitalizations and serious
adverse events than placebo

Other drugs :
Strong recommendation against use
Colchicine
Corticosteroid + Immunomodulator
Cyclosporin A
IFN‐ γ
 Non‐pharmacologic Therapies

• Use of oxygen for patients with ILD is encouraged to maintain saturations

>90% both at rest and with exercise (strong recommendation)

• Pulmonary rehabilitation has been shown to improve 6MWD, reduce

dyspnea, anxiety, depression and improves quality of life (weak recommendation)
Comparison of ATS Recommendations
Agent 2015 Guideline 2011 Guideline
Anticoagulation (warfarin) Strong recommendation against Conditional recommendation
use against use
Combination prednisone+ Strong recommendation against Conditional recommendation
azathioprine + NAC use against use
Ambrisentan, Imatinib Strong recommendation against Not addressed
use
macitentan, bosentan Conditional recommendation Strong recommendation against
against use use
Nintedanib Conditional recommendation for Not addressed
use
Pirfenidone Conditional recommendation for Conditional recommendation
use against use
Unchanged ATS recommendations

Agent 2015 Guideline

Antacid therapy Conditional recommendation for use

NAC monotherapy Conditional recommendation against use

PAH treatment No recommendation given

Lung transplantation: single vs. bilateral No recommendation given

 Newer drugs
Pamrevlumab (FG-3019) :
• Mechanism - targets connective tissue growth factor

• Phase 2 trial done showed an acceptable safety profile

• A subset of patients (about one in five) showed some benefit from

treatment

• Unfortunately, none of the patient-related outcome measures showed any

benefit
Raghu G, Scholand MB, de Andrade J, et al. FG-3019 anti-connective tissue growth factor monoclonal antibody: results of an open-label clinical trial in idiopathic pulmonary
fibrosis. Eur Respir J 2016; 47:1481
SUMMARY
• Pathogenesis of IPF - aberrant wound healing leading to fibroblast
proliferation

• All patients with probable UIP pattern on HRCT-thorax with clinical

context of IPF may not require surgical lung biopsy for diagnosis

• No single agent has been strongly recommended in IPF

• Patients with IPF should receive individualized treatment

THANK YOU !