Update on Therapies for Idiopathic Pulmonary Fibrosis Paul Wolters - PDF document

6/2/2015 Update on Therapies for Idiopathic Pulmonary Fibrosis Paul Wolters Associate Professor University of California, San Francisco Outline • Classification of Interstitial lung disease – Clinical classification – Importance of establishing diagnosis of a specific ILD • Review of 3 randomized trials for IPF – PANTHER (prednisone, azathioprine, NAC) – ASCEND (Pirfenidone) – IMPULSIS (Nintedinib) 1

6/2/2015 Clinical Classification Exposure-related: Idiopathic Connective Other: - Occupational interstitial tissue disease: - Sarcoidosis - Environmental pneumonia (IIP) - Scleroderma - Vasculitis/Diffuse alveolar - Avocational - Rheum. arthritis hemorrhage (DAH) - Medication - Sjogrens - Langherhans cell histiocytosis Idiopathic - Desquamative - UCTD (LCH) pulmonary interstitial - Lymphagioleiomyomatosis fibrosis pneumonia (DIP) (LAM) (IPF) - RBILD - Pulmonary alveolar proteinosis (PAP) - Eosinophilic pneumonias Acute interstitial pneumonia - Neurofibromatosis (AIP) - Inherited disorders - Chronic aspiration Cryptogenic organizing - Inflammatory bowel disease pneumonia (COP) Lymphocytic interstitial pneumonia (LIP) Nonspecific interstitial pneumonia (NSIP) Why it is Important to be Aware of IPF 2

6/2/2015 And, the rate of death from pulmonary fibrosis is increasing Olson et al, AJRCCM, 2007 Why This Matters DIP Bjoraker et al, Am J Resp Crit Care Med ‘ 98 /IPF 3

6/2/2015 IPF Treatment: 2010 • “Triple therapy” – Variant of historical RX approach of combined • Prednisone, prednisone and azathioprine and immunomodulator acetylcysteine (azathioprine or cyclophosphamide) Paul Wolters, MD IPF Treatment: 2010 Acetylcysteine with prednisone and azathioprine Rx placebo Demedts NEJM 2005;353:2229 4

6/2/2015 IPF Clinical Trials PANTHER PANTHER • P rednisone, A zathioprine and N ‐ acetylcysteine: A Study Th at E valuates R esponse in IPF • Designed and funded by the NIH IPFnet – Rationale: Test whether the “standard of care” IPF therapy is effective – Address the use of NAC alone and in combination with prednisone/azathioprine against placebo IPFnet NEJM 2012;366:1968 and IPFnet NEJM 2014;370:2093 5

6/2/2015 PANTHER • Enrolled 341 patients with FVC ≥ 50%, DLCO ≥ 30% • Randomized to NAC, NAC plus prednisone/azathioprine, or placebo for 60 weeks • Primary endpoint: Change in FVC NAC alone 1°: FVC n =133 NAC pus P/A IPF 2°: death, acute 60 wks n =77* n = 341 exacerbation, Placebo disease n = 131 progression * Stopped early IPFnet NEJM 2012;366:1968 and IPFnet NEJM 2014;370:2093 PANTHER Baseline NAC alone NAC + P/A Placebo (n=133) (n=77) (n=131) Age, years 68 69 67 Male sex 74% 77% 67% FVC 72% 69% 73% DLCO 45% 42% 46% 6MWT distance 371 362 375 Dyspnea (UCSD) 26 30 27 QOL (SGRQ) 40 39 38 IPFnet NEJM 2012;366:1968 and IPFnet NEJM 2014;370:2093 6

6/2/2015 PANTHER Part A • NAC plus prednisone/azathioprine stopped early for evidence of harm Death or hospitalization IPFnet NEJM 2012;366:1968 PANTHER Part B • No difference in rate of FVC decline with NAC monotherapy • Also no difference in: – Death – Acute exacerbation – Disease progression – Hospitalization – Dyspnea – 6MWT distance – Overall QOL IPFnet NEJM 2014;370:2093 7

6/2/2015 PANTHER: Conclusions • Prednisone/azathioprine/N ‐ acetyl therapy does not slow progression of IPF. – If anything, it may be harmful to patients. • N ‐ acetyl therapy alone does not slow progression of IPF. May 2014 8

6/2/2015 Pirfenidone: Rationale • Pirfenidone limited development of lung fibrosis in animal models. • Reduces production of TGF ‐  • Attenuates the activation of MAP kinases • 2 phase 3 studies in IPF patients had mixed results • One slowed progression of IPF, one did not • Approved in Japan, Canada, Europe ASCEND • As sessment of Pirfenidone to C onfirm E fficacy a nd Safety in Idiopathic Pulmonary Fibrosis – Two previous phase 3 trials had mixed results – Performed in response to an FDA request for an additional trial to support approval – Designed to enrich subjects for disease progression (as measured by change in FVC) King. NEJM 2014;370:2083 9

6/2/2015 ASCEND: Study design • Enrolled 555 highly ‐ selected (1562 screened) patients with IPF • Randomized to pirfenidone or placebo for 52 weeks – Primary endpoint: Change in FVC – Secondary endpoints: 50 meter decline in 6MWT; 20 point increase in UCSD dyspnea score; PFS (10% FVC decline, 50 meter 6MWT decline, or death); death (any cause and related to IPF) Pirfenidone 1°: FVC n = 278 IPF 52 wks 2°: 6MWT n = 555 distance; PFS; Placebo dyspnea; death n = 277 King. NEJM 2014;370:2083 ASCEND: Subjects Baseline Pirfenidone (n=278) Placebo (n=277) Age, years 68 68 Male sex 80% 77% FVC 68% 69% DLCO 44% 44% 6MWT distance 415 421 Dyspnea (UCSD) 34 37 Definite UIP HRCT 96% 95% King. NEJM 2014;370:2083 10

6/2/2015 ASCEND: 1° Endpoint Relative difference = 45% P value < 0.001 King. NEJM 2014;370:2083 ASCEND: 1° Endpoint 10% or greater absolute decline King. NEJM 2014;370:2083 11

6/2/2015 ASCEND: Safety and tolerability • No difference in SAEs (3x LFT increase 2.9% vs 0.7%) • Treatment discontinuation in 14.4% vs 10.8% Adverse event Pirfenidone Placebo Nausea 36.0% 13.4% Rash 28.1% 8.7% Dizziness 17.6% 13.0% Dyspepsia 17.6% 6.1% Anorexia 15.8% 6.5% Vomiting 12.9% 8.7% Decrease in weight 12.6% 7.9% Gastroesophageal reflux 11.9% 6.5% Insomnia 11.2% 6.5% King. NEJM 2014;370:2083 Nintedanib • Intracellular tyrosine kinase inhibitor with multiple targets • Lck • VEGF • PDGF • FGF • Src • Phase 2 study suggested it slowed progression (loss of FVC) of IPF Richeldi. NEJM 2011; 365: 1079 12

6/2/2015 INPULSIS • Rationale: Test whether nintedanib slows progression of IPF. • INPULSIS I and II – Two identical RCTs designed to further develop nintedanib after promising phase II results. – 2 trials are required for approval by FDA. Richeldi NEJM 2014;370:2071 INPULSIS: Study design • Enrolled 1066 patients with IPF/likely IPF • Randomized (3:2) to nintedanib/placebo for 52 wks – Primary endpoint: Change in FVC – Secondary endpoints: time to acute exacerbation; quality of life (SGRQ); categorical change in FVC; death (any cause, respiratory) nintedanib n = 638 1°: FVC IPF 52 wks 2°: acute n = 1066 exacerbation; QOL; death Placebo n = 423 Richeldi NEJM 2014;370:2071 13

6/2/2015 INPULSIS: Study design • Enrolled 1066 patients with IPF/likely IPF HRCT required A/B/C, A/C, or B/C for enrollment: – A. Definite honeycombing, basal/peripheral predominance – B. Reticulation and traction bronchiectasis – C. Atypical features are absent Raghu. AJRCCM 2011;183:788 Richeldi Resp Med 2014;108:1023 INPULSIS: Subjects Baseline INPULSIS 1 INPULSIS II Nintedanib Placebo Nintedanib placebo N= 309 204 329 214 Age, years 67 67 66 67 Male sex 81% 80% 78% 78% FVC 80% 81% 80% 82% DLCO 48% 48% 47% 46% Oxygen saturation 96% 96% 96% 96% SGRQ score 40 40 40 39 Richeldi NEJM 2014;370:2071 14

6/2/2015 INPULSIS: 1° Endpoint Relative difference = 52% Relative difference = 45% P value < 0.001 P value < 0.001 Richeldi NEJM 2014;370:2071 INPULSIS: 1° Endpoint Mean difference 109.9 (71.3, 148.6) P value < 0.001 Richeldi NEJM 2014;370:2071 15

6/2/2015 INPULSIS: 2° Endpoints Acute exacerbation Hazard ratio 1.15 (0.54, 2.42) P value = 0.67 INPULSIS I INPULSIS II Nintedanib Placebo Nintedanib Placebo Change in SGRQ 4.34 4.39 2.80 * 5.48 Any death POOLED 5.5% 7.8% Respiratory death POOLED 3.8% 5.0% * Statistically significant difference Richeldi NEJM 2014;370:2071 INPULSIS: 2° Endpoints Acute exacerbation Hazard ratio 0.38 (0.19, 0.77) P value = 0.005 INPULSIS I INPULSIS II Nintedanib Placebo Nintedanib Placebo Change in SGRQ 4.34 4.39 2.80 * 5.48 Any death POOLED 5.5% 7.8% Respiratory death POOLED 3.8% 5.0% Richeldi NEJM 2014;370:2071 16

6/2/2015 INPULSIS: Safety and tolerability • No difference in SAEs (3x LFT increase 5.1% vs 0.7%) • Treatment discontinuation 23.7 ‐ 25.2% vs 17.6 ‐ 20.1% Adverse event Nintedanib Placebo Diarrhea 62%, 63% 19%, 18% Nausea 23%, 26% 6%, 7% Decreased appetite 8%, 13% 7%, 5% Vomiting 13%, 10% 2%, 3% Weight loss 8%, 11% 6%, 1% Richeldi NEJM 2014;370:2071 October 15, 2014 Pirfenidone = Esbriet Nintedanib = Ofev http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/default.htm 17

6/2/2015 Conclusions • 2 medications are now approved that slow progression of Idiopathic Pulmonary Fibrosis – Pirfenidone: Markets as Esbriet – Nintedinib: Marketed as OFEV • Therapies appear equally efficacious • Select a therapy based on perceived impact of side effect profile for a patient – Pirfenidone: Rash, dyspepsia, fatigue – Nintedinib: Loose stool, rash • Great advance, but improvements are needed…. Meds only slow progression, they do not stop progression or improve lung function. Case • 65 y/o man presents with a 5 ‐ 6 month history of progressive dyspnea on exertion, dry cough • He uses a treadmill regularly – Cut down from 40 to 30 minutes – Decreased speed from 3.6 mph to 2.8 mph • ROS: Right knee pain for many years, otherwise negative 18