A Phase 3 Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis N ENGL J MED. May 18, /NEJMoa Talmadge E. King, Jr., M.D., Williamson Z. Bradford, M.D., Ph.D., Socorro Castro-Bernardini, M.D., Elizabeth A. Fagan, M.D., Ian Glaspole, M.B., B.S., Ph.D., Marilyn K. Glassberg, M.D., Eduard Gorina, M.D., Peter M. Hopkins, M.D., David Kardatzke, Ph.D., Lisa Lancaster, M.D., David J. Lederer, M.D., Steven D. Nathan, M.D., Carlos A. Pereira, M.D., Steven A. Sahn, M.D., Robert Sussman, M.D., Jeffrey J. Swigris, D.O., and Paul W. Noble, M.D., for the ASCEND Study Group* 내과 R3 박소영

BACKGROUND Idiopathic pulmonary fibrosis (IPF) –Chronic, progressive, and fatal lung disease –Characterized by irreversible loss of lung function –Poor prognosis Pirfenidone –The 1st anti-fibrotic drug approved for the treatment of IPF –An orally available pyridone analog

Pirfenidone –Anti-fibrotic, anti-inflammatory, and antioxidant activities reduces fibroblast proliferation inhibits TGF-β stimulated collagen production reduces the production of fibrogenic mediators such as TGF- β reduce production of inflammatory mediators such as TNF-α and IL-1β BACKGROUND

The ASCEND (Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis) trial To confirm the effect of pirfenidone on disease progression in patients with idiopathic pulmonary fibrosis a randomized, double-blind, placebo-controlled trial Design modification with respect to the CAPACITY trial –The implementation of centralized procedures for diagnosis, spirometry, and adjudication of deaths –Eligibility criteria to allow enrollment of patients with an increased risk of disease progression

METHODS Study Sites and Patients –At 127 sites in 9 countries –Eligible criteria between the ages of 40 and 80 years Centrally confirmed diagnosis of IPF based on chest HRCT –Definite UIP –Possible UIP → Confirmed on surgical lung biopsy Predicted FVC: 50~90% Predicted DL CO : 30~90% FEV1/FVC: ≥ 80% 6MWD: ≥ 150 m

Study Design and Assessments –Oral pirfenidone (2403 mg per day) or placebo for 52 weeks –Physical examination and clinical laboratory assessments at baseline and at weeks 2, 4, 8, 13, 26, 39, and 52 –Pulmonary function, exercise tolerance, and dyspnea at baseline and at weeks 13, 26, 39, and 52 Statistical Analysis –The primary efficacy end point The change in predicted FVC% (from baseline to week 52) –An absolute decline of 10 percentage points in the percentage of the predicted FVC or death –No decline in the percentage of the predicted FVC –The secondary end points The change in the 6-minute walk distance Progression-free survival Change in dyspnea The rate of death from any cause The rate of death from IPF

RESULTS Study Patients –July 2011 ~ January 2013 –A total of 555 patients

Primary Efficacy Analysis

-235mL -428mL Primary Efficacy Analysis

Prespecified Secondary Efficacy Analyses

Analysis of UCSD SOBQ scores: no significant between-group difference in dyspnea at week 52

DISCUSSION The high rates of study completion and treatment adherence and the consistent magnitude of treatment effect across the primary and secondary end points. Limitations –Enrolled patients with mild-to-moderate physiological impairment –Required central confirmation of the diagnosis of idiopathic pulmonary fibrosis on the basis of criteria from recent diagnostic guidelines The general similarity in outcomes at 1 year between our study and the CAPACITY studies –militates against any limitation that this requirement might impose on the generalizability of our results.

DISCUSSION The high rates of study completion and treatment adherence and the consistent magnitude of treatment effect across the primary and secondary end points. Limitations –Enrolled patients with mild-to-moderate physiological impairment –Required central confirmation of the diagnosis of idiopathic pulmonary fibrosis on the basis of criteria from recent diagnostic guidelines The general similarity in outcomes at 1 year between our study and the CAPACITY studies –militates against any limitation that this requirement might impose on the generalizability of our results.

CONCLUSION Pirfenidone as compared with placebo reduced disease progression in patients with idiopathic pulmonary fibrosis. Treatment was generally safe, had an acceptable side- effect profile, and was associated with fewer deaths.