new treatment options

1. A New Hope for Idiopathic
Pulmonary Fibrosis

2. Idiopathic pulmonary fibrosis (IPF)
• IPF is an irreversible and ultimately fatal disease characterized
by progressive loss of lung function due to fibrosis
• Predominantly affects older patients and has a death rate
worse than that of many cancers , including breast, ovarian
and colorectal cancers. (3-year survival, 50%).
• 40,000 people will die from IPF this year in USA, the same
number that is claimed by breast cancer.
• However, in contrast to most cancers, there has been limited,
and sometimes conflicting evidence that any drug could alter
the course of this disease.

3.  believed to arise from an aberrant proliferation of
fibrous tissue and tissue remodeling due to the
abnormal function and signaling of alveolar
epithelial cells and interstitial fibroblasts.
 The activation of cell-signaling pathways through
tyrosine kinases such as vascular endothelial
growth factor (VEGF), fibroblast growth factor
(FGF), and platelet-derived growth factor (PDGF)
has been implicated in the pathogenesis of the
disease

7. About Pirfenidone
 Developed by Intermune
 orally active
 Anti-fibrotic agent that inhibits the synthesis of TGF-beta
 Also inhibits the synthesis of TNF-alpha
 On February 28, 2011,the European Commission (EC)
granted marketing authorization for Esbriet® (pirfenidone)
 The approval authorized marketing of Esbriet in all 28 EU
member states.
 On October 1, 2012, Health Canada approved Esbriet for the
treatment of mild to moderate IPF in adult patients.
 Pirfenidone is not approved for sale in the United States

9. About CAPACITY
• The CAPACITY program consisted of two concurrent 72-week trials, which enrolled
a total of 779 patients.
• Both trials were multinational, randomized, double-blind, and placebo-controlled.
• The studies were designed to evaluate the safety and efficacy of pirfenidone in IPF
patients with mild to moderate impairment in lung function.
• The primary endpoint in both studies was the change from Baseline to Week 72 in
percent predicted FVC.
• This endpoint was met with statistical significance in CAPACITY 2 (p=0.001). The
secondary endpoints of PFS and categorical change in FVC also achieved statistical
significance (p<0.05).
• Although the primary endpoint was not met in CAPACITY 1 (p=0.501), supportive
evidence of a pirfenidone treatment effect was observed on a number of measures,
including percent predicted FVC at weeks 24, 36 and 48, and on 6MWD.
• Pirfenidone demonstrated a favorable safety profile and was generally well
tolerated in both CAPACITY studies.

11. ASCEND
 ASCEND (Assessment of Pirfenidone to Confirm Efficacy
and Safety in IPF)
 A multinational, randomized, double-blind, placebo-
controlled Phase 3 trial designed to evaluate the safety
and efficacy of pirfenidone in patients with IPF.
 Patients (N=555) were randomly assigned 1:1 to
receive oral pirfenidone (2403 mg/day) or placebo and
were enrolled at 127 centers in the United
States,Australia, Brazil, Croatia, Israel, Mexico, New
Zealand, Peru and Singapore.

12.  In ASCEND, pirfenidone significantly reduced decline in lung function as
measured by change in percent predicted forced vital capacity (FVC) from
Baseline to Week 52 (rank ANCOVA p<0.000001).
 Additionally, significant treatment effects were demonstrated on both of
the key secondary endpoints of change in six-minute walk distance
(6MWD) (p=0.0360) and progression-free survival (PFS) (p=0.0001).
 The secondary endpoint of dyspnea (shortness of breath) was not met.
 In ASCEND, treatment with pirfenidone was associated with fewer deaths
although the study was not powered for and did not reach statistical
significance on mortality.
 A pre-specified analysis of the pooled population from ASCEND and the
two Phase 3 CAPACITY studies showed that the risk of all-cause mortality
was reduced by 48% at Week 52 in the pirfenidone group compared to the
placebo group (Hazard Ratio [HR] 0.52, log rank p=0.0107).
 In ASCEND, treatment with pirfenidone showed a favorable safety profile
and was generally well tolerated.

13. Exploratory Week 72 Pooled Analyses
 Analyses of the following clinical outcomes were performed
on the pooled data from the ASCEND and CAPACITY studies
through 72 weeks (the CAPACITY endpoint).
 These analyses showed a magnitude of treatment effect of
pirfenidone in the range of 43% to 57% and were statistically
significant favoring pirfenidone:
 FVC decline >/= 10% or death
 Progression-free survival
 All-cause mortality
 Treatment-emergent all-cause mortality
 IPF-related mortality
 Treatment-emergent IPF-related mortality

14. Pooled Phase 3 Safety Analyses
In the pooled Phase 3 data set of ASCEND and
CAPACITY, the profiles of adverse events (AEs)
(treatment-emergent, Grade 3 or 4), serious
adverse events (SAEs) and AEs leading to
discontinuation were similar to those
observed in ASCEND.

15. Long-term Pirfenidone Safety Data Published
in Respirology
• "Our long-term safety analysis is extremely
robust given the large study population and
overall duration of treatment exposure, which
is unique for novel agents for orphan
diseases,“
Dominique Valeyre M.D., of the Hôpital Avicenne, Bobigny, France,
and lead author of the Respirology paper.
"These data provide further evidence to support
the long-term clinical use of pirfenidone in
patients with idiopathic pulmonary fibrosis."

18. • Our own experience

20. About Nintedanib
 Nintedanib is an intracellular tyrosine kinase
inhibitor (TKI) in development by Boehringer
Ingelheim
 It targets growth factors, which have been
shown to be potentially involved in pulmonary
fibrosis -- the vascular endothelial growth
factor receptor (VEGFR), fibroblast growth
factor receptor (FGFR), and platelet-derived
growth factor receptor (PDGFR).

21. The INPULSIS™ trials
• The INPULSIS™ data presented at the 2014 American Thoracic
Society (ATS) International Conference in a joint NEJM/Journal
of American Medical Association (JAMA) session on May 18
and as a late-breaking oral presentation on May 20.
• Performed at 205 sites in 24 countries in the America, Europe,
Asia, and Australia.

22. The INPULSIS™ trials
 Two replicate 52-week, randomized, double-blind, phase 3
trials (INPULSIS-1 and INPULSIS-2) to evaluate the efficacy and
safety of 150 mg of nintedanib twice daily as compared with
placebo
 The primary end point was the annual rate of decline in
forced vital capacity (FVC).
 Key secondary end points were the time to the first acute
exacerbation and the change from baseline in the total score
on the St. George’s Respiratory Questionnaire, both assessed
over a 52-week period.

23. The St. George’s Respiratory Questionnaire
• Disease-specific instrument designed to measure impact on
overall health, daily life, and perceived well-being in patients
with obstructive airways disease.
• 50 items
• 2 parts (3 components)
• Part I (Symptoms): several scales; Part II (Activity and
Impacts): dichotomous (true/false) except last question (4-
point Likert scale)
• Scores range from 0 to 100, with higher scores indicating
more limitations.

24.  A total of 1066 patients were randomly assigned in a 3:2 ratio to receive
nintedanib or placebo.
 The adjusted annual rate of change in FVC was −114.7 ml with nintedanib
versus −239.9 ml with placebo (difference, 125.3 ml; 95% confidence
interval [CI], 77.7 to 172.8; P<0.001) in INPULSIS-1 and −113.6 ml with
nintedanib versus −207.3 ml with placebo (difference, 93.7 ml per year;
95% CI, 44.8 to 142.7; P<0.001) in INPULSIS-2.
 In INPULSIS-1, there was no significant difference between the nintedanib
and placebo groups in the time to the first acute exacerbation (hazard ratio
with nintedanib, 1.15; 95% CI, 0.54 to 2.42; P = 0.67);In INPULSIS-2, there
was a significant benefit with nintedanib versus placebo (hazard ratio, 0.38;
95% CI, 0.19 to 0.77;P = 0.005).
 The most frequent adverse event in the nintedanib groups was diarrhea,
with rates of 61.5% and 18.6% in the nintedanib and placebo groups,
respectively, in INPULSIS-1 and 63.2% and 18.3% in the two groups,
respectively, in INPULSIS-2.

25. In Conclusion
• In patients with idiopathic pulmonary fibrosis,
Nintedanib reduced the decline in FVC, which
is consistent with a slowing of disease
progression;
• Nintedanib was frequently associated with
diarrhea, which led to discontinuation of the
study medication in less than 5% of patients.

27. Acknowledgement
 Dr. W.Kodikara Arachchi.
 Dr. Arosha Dissanayaka.
 Dr. S. Muhunthan.