A New Hope for Idiopathic Pulmonary Fibrosis

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.

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

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

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.

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.

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.

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

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.

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."

• Our own experience

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).

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.

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.

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.

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.

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.

Acknowledgement

Dr. W.Kodikara Arachchi. Dr. Arosha Dissanayaka. Dr. S. Muhunthan.