Update on Therapies for Idiopathic Pulmonary Fibrosis. Outline

Transcription

1 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

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

3 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

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

5 IPF Clinical Trials PANTHER Prednisone, Azathioprine and N acetylcysteine: A Study That Evaluates Response 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 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 n =133 1 : FVC IPF n = 341 NAC pus P/A n =77* Placebo n = 131 * Stopped early 60 wks 2 : death, acute exacerbation, disease progression IPFnet NEJM 2012;366:1968 and IPFnet NEJM 2014;370:2093 PANTHER Baseline NAC alone (n=133) NAC + P/A (n=77) Placebo (n=131) Age, years Male sex 74% 77% 67% FVC 72% 69% 73% DLCO 45% 42% 46% 6MWT distance Dyspnea(UCSD) QOL (SGRQ) IPFnet NEJM 2012;366:1968 and IPFnet NEJM 2014;370:2093 6

7 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

8 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

9 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 Assessment of Pirfenidone to Confirm Efficacy and 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

10 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) IPF n = 555 King. NEJM 2014;370:2083 Pirfenidone n = 278 Placebo n = wks 1 : FVC 2 : 6MWT distance; PFS; dyspnea; death ASCEND: Subjects Baseline Pirfenidone (n=278) Placebo (n=277) Age, years Male sex 80% 77% FVC 68% 69% DLCO 44% 44% 6MWT distance Dyspnea (UCSD) Definite UIP HRCT 96% 95% King. NEJM 2014;370:

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

12 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:

13 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 = : FVC IPF n = 1066 Placebo n = wks 2 : acute exacerbation; QOL; death Richeldi NEJM 2014;370:

14 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 Richeldi Resp Med 2014;108:1023 Raghu. AJRCCM 2011;183:788 INPULSIS: Subjects Baseline INPULSIS 1 INPULSIS II Nintedanib Placebo Nintedanib placebo N= Age, years Male sex 81% 80% 78% 78% FVC 80% 81% 80% 82% DLCO 48% 48% 47% 46% Oxygen saturation 96% 96% 96% 96% SGRQ score Richeldi NEJM 2014;370:

15 INPULSIS: 1 Endpoint Relative difference = 52% P value < Relative difference = 45% P value < Richeldi NEJM 2014;370:2071 INPULSIS: 1 Endpoint Mean difference (71.3, 148.6) P value < Richeldi NEJM 2014;370:

16 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 * 5.48 Any death POOLED 5.5% 7.8% Respiratory death POOLED 3.8% 5.0% Richeldi NEJM 2014;370:2071 * Statistically significant difference INPULSIS: 2 Endpoints Acute exacerbation Hazard ratio 0.38 (0.19, 0.77) P value = INPULSIS I INPULSIS II Nintedanib Placebo Nintedanib Placebo Change in SGRQ * 5.48 Any death POOLED 5.5% 7.8% Respiratory death POOLED 3.8% 5.0% Richeldi NEJM 2014;370:

17 INPULSIS: Safety and tolerability No difference in SAEs (3x LFT increase 5.1% vs 0.7%) Treatment discontinuation % vs % 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 17

18 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

19 PMH / Meds PMH HTN Seizure disorder Hyperlipidemia Allergies Sulfa Medications Fenofibrate Lamictal Amlodipine Ibuprofen prn Social history Social & Family History ½ ppd x 20 years, quit 15 years ago Denies EtOH, drug use Family history No lung or autoimmune disease 19

20 Exposure History Occupational exposures Works as carpenter Environmental exposures No mold in the home, pets, birds, humidifier or hot tub use, swamp coolers, down Golfs 3x/week Physical Examination Saturation 97% on room air Crackles at bilateral bases R knee is slightly swollen,not warm or tender Otherwise normal exam 20

21 Data CBC, chem 7, LFTs within PFTs normal limits FVC 70% predicted DLCO 40% predicted Walk test in clinic 97% on RA at rest 92% on RA at 3 min FEV (81%) FVC 2.83 (67%) FEV 1 /FVC 0.90 TLC 5.13 (76%) DLco (65%) 21

22 What additional testing would you perform next in this patient? 1. Bronchoalveolar lavage (BAL) 2. BAL and transbronchial biopsy 3. High resolution CT of the chest 4. Surgical lung biopsy 5. No additional testing; diagnosis is clear 22

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26 ANA negative RF = 4 Serological evaluation 26

27 What is the next step for this patient? 1. Bronchoalveolar lavage (BAL) 2. BAL and transbronchial biopsy 3. Surgical lung biopsy 4. No additional testing; diagnosis is clear VATS 27

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29 What is the next step for this patient? 1. No therapy 2. Treat with Prednisone, azathioprine, N acetyl cysteine 3. Treat with pirfenidone 4. Treat with Nintedanib 29