Imatinib Treatment for Idiopathic Pulmonary Fibrosis Randomized Placebo-controlled Trial Results Caig E. Daniels; Joseph A. Lasky; Andrew H. Limper Kathleen Mieras; Edith Gabor; Darrell R. Schroeder (AJRCCM ; 181 : ) R2 Jang Na-eun Journal conference

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with no known efficacious therapy - demonstrates a progressive reduction in lung volumes, impaired gas exchange, dyspnea, and death with a median survival from diagnosis of 3 to 5 years - no current pharmacologic therapy is known to improve survival or alter the unremitting progression of pulmonary parenchymal fibrosis BACKGROUND BACKGROUND

Many experts believe IPF develops in patients with a specific genetic predisposition after an initial trigger, such as epithelial injury BACKGROUND BACKGROUND The transition of fibroblasts or epithelial myofibroblast and/or recruitment of fibrocytes Deposition of extracellular matrix Multiple factors : oxidative stress growth factors cytokines Application of fibrogenic mechanisms has led to several high- quality clinical trials and identify multiple potential therapeutic targets - Imatinib is a tyrosine kinase inhibitor with potential efficacy to treat fibrotic lung disease

BACKGROUND BACKGROUND Imatinib mesylate (Gleevec) - a tyrosine kinase inhibitor (TK1) with activity against the platelet- derived growth receptors (PDGFR-α,β), discoidin domain receptors (DDR1 and DDR2), c-kit, and c-Abl - initially approved by the FDA in 2001 to treat chronic myelogenous leukemia and proved to be highly efficacious - approved to treat c-kit (+) gastrointestinal stromal cell tumors - investigated as a potential inhibitor of proliferative diseases (other than IPF), such as scleroderma and pulmonary arterial hypertension by the inhibition of PDGFR Imatinib was identified as a potent inhibitor of lung fibroblast- myofibroblast transformation and proliferation as well as extracellular matrix production

OBJECTIVES OBJECTIVES To investigate the safety and clinical effects of imatinib on survival and lung function in patients with carefully diagnosed mild to moderate IPF

METHODS METHODS Research design A randomized, double-blind, placebo-controlled trial of the clinical effect of Gleevec versus placebo in a 1:1 randomization Enrolled in March 2003~ September 2005 completed 96 weeks of double blind therapy in August 2007 Imatinib given orally at a dose of 600mg daily versus placebo over 96 weeks - dose adjustment from 600mg to 400mg daily for perceived drug toxicity Diagnosis of IPF was based on established clinical, radiographic, and pathologic consensus criteria

METHODS METHODS Participants Inclusion criteria - aged 20 to 79 years - no clinical worsening (any one of the following) : greater than 10% decrease in percent predicted FVC : worsening chest radiograph, or worsening dyspnea at rest or on exertion

METHODS METHODS Exclusion criteria - patients with severe disease defined as FVC <55%, DLco< 35%, PaO2<60mmHg - patients with obstructive lung disease on screening - patients with other medical and laboratory conditions : active infection : any condition other than IPF was likely to result in the death of the patient within the next 2 years : history of cardiac or neurologic disease : creatinine >1.5*upper limit of normal (ULN) : hematology (WBC<2500/mm3 or ANC<1500, PLT<100,000/mm3) : liver funtion (TB>2.0*ULN AST or ALT>3*ULN, alb<3.0 mg/dl, ALP>3*ULN)

METHODS METHODS Assessment Laboratory testing - weekly (first 4 wks) -> every 4 wks to complete 16wks -> every 8 wks Adverse events (AEs) and serious adverse events (SAEs) Spirometry, ABG : every 16 wks (first 48 wks) -> every 24 wks A 6 minute walk test: every 48 wks Chest radiograph: every 24 wks

METHODS METHODS Outcomes The primary outcome parameters - a combined measure of disease progression (defined as >10% decline from baseline FVC) or death The secondary outcome parameters - DLco at 96 wks, A-a gradient at 96wks, change in the modified CRP (clinical, radiographic, physiologic) score at 96 wks, overall mortality at 96 wks

RESULTS RESULTS

Over 96 weeks of follow-up, Imatinib had no significance with placebo for the primary endpoint defined as time to disease progression or time to death

RESULTS RESULTS Change in resting PaO2 favored imatinib therapy at 48 weeks (P=0.005) but not at 96 weeks (P=0.074) There was no effect of imatinib therapy on change in FVC at 48, 72, or 96 weeks or change in diffusion capacity of carbon monoxide at 48, 72, or 96 weeks

RESULTS RESULTS During the 96 week trial there were 8 deaths in the imatinib group and 10 deaths in the placebo group (log-rank test P=0.643)

RESULTS RESULTS Overall imatinib-related AEs were common Reported AEs were common in the imatinib-treated group (56 vs. 37, P<0.001) Imatinib was associated with a higher incidence of AD-related drop-out (13 vs. 6, P=0.073) Serious adverse events (SAEs) were not more common in the imatinib group

CONCLUSIONS CONCLUSIONS In a randomized, placebo-controlled trial of patints with mild to moderate IPF followed for 96 weeks, imatinib did not affect survival or lung function There was no benefit of imatinib regarding the primary outcome, time to diseaase progression and no benefit in secondary outcome parameters, including DLco, absolute change in FVC, and a 6- minute walking test

DISCUSSION DISCUSSION This study is the first to rigorously investigate the usefulness of TKIs in the treatment of IPF. - similar to recent well-designed clinical trials investigating treatment of carefully diagnosed mild to moderate IPF with r-interferon, bosentan, and etanercept, imatinib did not demonstrate significant improvement in the primary outcome - although this study demonstrates imatinib was not an effective therapy for IPF, it remains unclear as to whether other TKIs may still warrant study in IPF

DISCUSSION DISCUSSION Limitations - This study performed at 12 centers in the united States and Mexico, so diagnosis was not confirmed at a central ‘core’ by pathology or radiology - Pharmacokinetic and biologic analyses for imatinib activity in treated patients was not performed : the potential impact of circulating a-1 acid glycoprotein(AGP) on the biologic activity of imatinib in this study remains uncertain 1) high levels of AGP in patients with CML resulted in a threefold reduction in serum concentration of imatinib 2) demonstrating half of patients with IPF had circulating levels of AGP high enough to lower imatinib serum levels