Pirfenidon: Greifbare Hoffnung für Patienten mit IPF?
Treatment for IPF: The changing landscape Prof. Ulrich Costabel Ruhrlandklinik University of Duisburg-Essen Germany Oporto, 11 February 2015 Disclosure Statement Dr. Costabel has served on a Scientific Advisory Board for the following companies: Actelion Boehringer Ingelheim Centocor Gilead InterMune Roche
Wyeth Zambon Background Idiopathic pulmonary fibrosis (IPF): a progressive and fatal lung disease Median survival: 2-5 years Clinical course: insidious decline in pulmonary function, increasingly limiting routine physical activity Progressive deterioration is inevitable - with considerable inter- and intra-patient variability Change in forced vital capacity (FVC): consistently shown to be a strong predictor of mortality Agents that attenuate the decline in FVC may play an important role in the management of patients with IPF Epithelium / fibroblast interaction in lung fibrosis Intrinsic: mutations (SP-A, -D, telomerase, MUC5B) -> ER stress Injury Epithelial cells EMT
Extrinsic: oxidative stress, mechanical stress, GER, viruses PDGF, TGF-b, TNF-a Circulating fibrocytes myofibroblast collagen metalloproteinases: MMP-7 et al MUC5B Promoter Polymorphism and Interstitial Lung Abnormalities General population (n=2633) ILD on CT Correlate: CT with MUC5B 9% 2%
<50 <50 yrs yrs 10 Odds ratio ratio Odds Chest CT MUC5B genotyping % of of patients patients % 10 >50 >50 yrs yrs
MUC5B minor allele 6.3 2.8 ILD ILD definite definite fibrosis fibrosis Hunnninghake GM et al, N Engl J Med 2013;368:2192-2200 Computed Tomographic Images ILD Definite fibrosis Hunninghake GM et al. N Engl J Med 2013;368:2192-2200 Survival in IPF by MUC5B Genotypes INSPIRE cohort (n=438)
Chicago cohort (n=148) Peljto et al, JAMA 2013 IPF: Goals of Treatment Stop disease progression Prolong survival Prevent acute exacerbations Reduce symptoms Treatment of IPF: a dynamic field since 2011 2011: Pirfenidone in Triple therapy out
Anticoagulants out 2014 : Nintedanib, a tyrosine kinase inhibitor of the FGF, PDGF and VEGF receptors, has shown consistent positive effects in 2 phase III trials (INPULSIS trials) Pirfenidone: evidence on efficacy and safety observed in previous studies reinforced (ASCEND trial) NAC monotherapy out (PANTHER trial) 2017: ??? IPF: The Past Treatment Options until 2011 Participation in clinical trials Weak recommendation (BTS ILD guideline 2008): prednisone/azathioprine/NAC If rapid progression: Corticosteroid pulse therapy 500-1000 mg i.v. for 3 days every 2-4 months Lung transplantation: early listing
Acetylcysteine for IPF the IFIGENIA trial Demedts Demedts et al. NEJM 2005 Selected negative IPF trials in the past Trial Drug / (putative MoA) Patients Endpoint Outcome Etanercept (TNFantagonist) 88 FVC, DLFVC, FVC, DLDLCOHB, FVC, DLP(A-a)O2 negative INSPIRE
40 6MWT negative ARTEMISIPF Ambrisentan (endothelin receptor antagonist-ETA) 660 Death or disease progression negative NCT0063869 negative 2011: The Year of Change and Hope
Pirfenidone: The first approved IPF therapy Pirfenidone (Pirespa) was approved for IPF patients in Japan (October 2008). Pirfenidone (Esbriet) was approved for IPF patients in Europe (February 2011). - Therapeutic indications: for mild- to moderate IPF in adults - Pharmaceutical form: 267 mg hard capsules (oral administration) - Recommended dose: 3 x 3 capsules per day after initial titration - Should be initiated and supervised by a physician specialized in treatment of IPF Pirfenidone: Mechanism of Action (Preclinical Studies) PIRFENIDONE INHIBITION OF p38 MITOGEN ACTIVATING PROTEIN KINASE Macrophage TGF-b TNF-a
Fibroblast INHIBITION OF p38 MITOGEN ACTIVATING PROTEIN KINASE PIRFENIDONE INFLAMMATION COLLAGEN DEPOSITION CAPACITY Trials: Pirfenidone in IPF Noble et al, Lancet 2011 Adverse events occuring in >10% of patients in CAPACITY Pirfenidone (n=345) Placebo (n=347) % %
14 4 Photosensitivity 12 2 Anorexia 11 4 17 Noble et al, Lancet 2011 PANTHER-IPF Trial The IPF Clinical Research Network, NEJM 2012; 366: 1968-77 Practical consequences Patients with newly diagnosed IPF:
do not start triple therapy Patients with ongoing triple therapy: withdraw therapy when - disease is progressive - or complications especially infections continue therapy when - disease is stable > 6 months - and well tolerated No concern against NAC mono therapy No change in other ILDs Wells et al, ERJ 2012 Randomized Trial of NAC IPF An explanation for this finding is notin evident. Is NAC for IPF out? Titel
IPF Clinical Network, NEJM 2014 2014: The Year of IPF Breakthrough Therapies 21 Richeldi et al, NEJM 2014;370:2071 TYROSINKINASE INHIBITOR NINTEDANIB* Known mechanism of action An intracellular inhibitor of tyrosine kinases1,2 Targets VEGF, FGF and PDGF receptors1,2 Phase II TOMORROW study 12 months treatment with nintedanib 150 mg bid reduced lung function decline and acute exacerbations in patients with IPF3
INPULSIS trials4 Two replicate 52-week, randomized, doubleblind, Phase III trials Compared the efficacy and safety of nintedanib 150 mg bid with placebo in patients with IPF 1. Hilberg F, et al. Cancer Res 2008;68:477482; 2.Wollin L, et al. J Pharmacol Exp Ther 2014;349:20920; 3. Richeldi L, et al. N Engl J Med 2011;365:107987; 4. Richeldi L, et al. N Engl J Med 2014; published online May 18, 2014 INPULSIS: TWO REPLICATE, RANDOMISED, DOUBLEBLIND, 52-WEEK, PHASE III TRIALS Nintedanib 150 mg bid (n=638) Screening Visit Week 1 R 3:2 ratio Follow-up
Placebo (n=423) 2 3 4 5 6 7 8 9 0 2 4 6 12
24 36 52 Primary endpoint Annual rate of decline in forced vital capacity (FVC) (mL/year) Key secondary endpoints Time to first acute exacerbation (investigator-reported) over 52 weeks Change from baseline in SGRQ total score over 52 weeks Safety Assessed by clinical and laboratory evaluation and adverse events SGRQ, St. Georges Respiratory Questionnaire. 56 KEY INCLUSION CRITERIA Age 40 years Diagnosis of IPF within 5 years of randomization Chest HRCT performed within 12 months of screening HRCT pattern, and, if available, surgical lung biopsy pattern, consistent with diagnosis of IPF as assessed by central review FVC 50% of predicted value
DLCO 3079% of predicted value ELIGIBILITY CRITERIA BASED ON HRCT To qualify to enter the INPULSIS trials if a surgical lung biopsy was not available, criteria A and B and C; or A and C; or B and C had to be met A B Definite honeycomb lung destruction with basal and peripheral predominance Presence of reticular abnormality and traction bronchiectasis consistent with fibrosis with basal and peripheral predominance Atypical features are absent, specifically nodules and consolidation. C Ground glass opacity, if present, is less extensive than reticular opacity pattern 26 BASELINE CHARACTERISTICS INPULSIS-1
81.8 (6.3) 82.4 (5.7) DLCO, % predicted, mean (SD) 47.8 (12.3) 47.5 (11.7) 47.0 (14.5) 46.4 (14.8) SGRQ total score, mean (SD)* 39.6 (17.6) 39.8 (18.5) 39.5 (20.5) 39.4 (18.7) FVC, mL, mean (SD)
*n=298 for nintedanib and n=202 for placebo in INPULSIS-1; n=326 for nintedanib and n=217 for placebo in INPULSIS-2 Primary Endpoint Result Nintedanib* significantly reduced the annual rate of decline in FVC compared with placebo INPULSIS-2 Adjusted annual rate (SE) of decline in FVC (mL/year) INPULSIS-1 125.3 mL/year (95% CI: 77.7, 172.8) p<0.0001 Nintedanib 150 mg bid (n=309) Placebo (n=204) 93.7 mL/year (95% CI: 44.8, 142.7) p=0.0002 Nintedanib 150 mg bid (n=329) Placebo (n=219) Treated set (observed cases); data are adjusted rate (SEM) 1. Richeldi L, et al. N Engl J Med 2014 May; 370(22):2071-82.
*Nintedanib is an investigational compound. Its safety and efficacy have not yet been fully established. TIME TO FIRST ACUTE EXACERBATION (INVESTIGATORREPORTED) IN INPULSIS-1 Nintedanib 150 mg bid Placebo HR 1.15 (95% CI; 0.54, 2.42) p=0.6728 Patients with 1 acute exacerbation, n (%) Nintedanib 150 mg bid (n=309) Placebo (n=204) 19 (6.1) 11 (5.4) TIME TO FIRST ACUTE EXACERBATION (INVESTIGATOR-REPORTED) IN INPULSIS-2 Nintedanib 150 mg bid Placebo HR 0.38
(95% CI; 0.19, 0.77) p=0.0050 Patients with 1 acute exacerbation, n (%) Nintedanib 150 mg bid (n=329) Placebo (n=219) 12 (3.6) 21 (9.6) TIME TO FIRST CONFIRMED OR SUSPECTED ACUTE EXACERBATION PER ADJUDICATION (POOLED DATA) Nintedanib 150 mg bid Placebo HR 0.32 (95% CI; 0.16, 0.65) p=0.0010 Patients with 1 acute exacerbation, n (%) Nintedanib 150 mg bid (n=638)
Placebo (n=423) 12 (1.9) 24 (5.7) ALL-CAUSE MORTALITY: POOLED DATA Nintedanib 150 mg bid Placebo HR 0.70 (95% CI; 0.43, 1.12) p=0.1399 The INPULSIS trials were not powered to show a difference in mortality between nintedanib and placebo SUMMARY OF EFFICACY FINDINGS Nintedanib consistently slows disease progression in IPF by significantly reducing the annual decline in lung function by approximately 50% This clinically relevant effect of nintedanib on disease progression is further supported by: A numerical reduction in all-cause mortality by 30% A numerical reduction in risk of acute exacerbations by 36%
A significantly reduced risk in a pre-specified sensitivity analysis of adjudicated exacerbations by 68% Consistent positive results across a range of lung function endpoints and sensitivity analyses IPF, idiopathic pulmonary fibrosis. 33 Effect of baseline FVC on decline in lung function with nintedanib: results from the INPULSIS trials U Costabel et al Oral presentation Monday, 08 Sept 2014 ANNUAL RATE OF DECLINE IN FVC FVC 70% predicted Adjusted annual rate (SE) of decline in FVC (mL/year) n=207 113.5 mL (95% CI: 51.3,175.7)
FVC >70% predicted n=431 n=154 109.0 mL (95% CI: 68.2, 149.9) Treatment by time by subgroup interaction p=0.9505 Nintedanib 150 mg bid Placebo n=269 TIME TO FIRST ACUTE EXACERBATION (INVESTIGATORREPORTED) FVC 70% predicted nintedanib FVC >70% predicted nintedanib FVC 70% predicted placebo FVC >70% predicted placebo No. of patients FVC 70% predicted nintedanib
256 254 251 250 249 243 235 PROPORTION OF PATIENTS WITH AN ACUTE EXACERBATION AND HR FOR TIME TO FIRST EVENT FVC 70% predicted Nintedanib 150 mg bid (n=207) Patients with 1 acute exacerbation, n (%) 16 (7.7) HR (95% CI)
0.52 (0.28, 0.99) Treatment by subgroup interaction p=0.1747 Placebo (n=154) 23 (14.9) FVC >70% predicted Nintedanib 150 mg bid (n=431) 15 (3.5) 1.00 (0.44, 2.30) Placebo (n=269) 9 (3.3) IPF is a disease Emphysema is a disease
Is the occurrence of two diseases in the same patient a syndrome? What is a Syndrome? A syndrome, in medicine and psychology, is the collection of signs and symptoms that are observed in, and characteristic of, a single condition. Features of CPFE Well preserved lung volumes Dysproportionally reduced gas exchange (DLCO, PaO2) High prevalence of pulmonary hypertension Pulmonary hypertension determines prognosis Cottin et al 2005 A case of CPFE 70 years old patient, exsmoker 60 py COPD Gold III (first diagnosed in 2003) First evidence of lung fibrosis on HRCT 2011 Moderate dyspnoea under effort at presentation (2013) FEV1/FVC 85%, FVC 82% pred, but DLCO 19% pred
CPFE: Distribution as expected Emphysema upper lobes Fibrosis: lower lobes Pathogenetically not related Should treatment be different? Effect of radiologic emphysema on decline in lung function with nintedanib Cottin V et al. Oral presentation at ICLAF 2014. Annual rate of decline in FVC by subgroup No emphysema at baseline n=384 n=257 Emphysema at baseline n=254
n=166 Adjusted annual rate (SE) of decline in FVC (mL/year) 0 -50 -100 -150 -105.1 -118.8 -200 -250 -300 115.4 mL (95% CI: 73.8,157.1) Cottin V, et al. Oral presentation at ICLAF 2014. -234.2
102.0 mL (95% CI: 43.2,160.9) Treatment by time by subgroup interaction P=0.5199 -207.2 Nintedanib 150 mg bid Placebo Effect of FEV1/FVC on decline in lung function with nintedanib Kolb M, et al. Oral presentation at ICLAF 2014. Annual rate of decline in FVC by subgroup FEV1/FVC ratio >0.8 n=401 n=248 FEV1/FVC ratio 0.8
n=237 n=175 Adjusted annual rate (SE) of decline in FVC (mL/year) 0 -50 -100 -88.6 -150 -128.1 -200 95.5 mL (95% CI: 41.9,149.1) -250 -300 126.1 mL
(95% CI: 81.6,170.6) Nintedanib 150 mg bid Placebo Kolb M, et al. Oral presentation at ICLAF 2014. -254.2 Treatment by time by subgroup interaction P=0.0124 -184.0 Adverse events occuring in >10% of patients in INPULSIS Nindetanib (n=638) % Placebo (n=223) % Diarrhea * 62
* Fewer than 5% discontinued due to diarrhea Richeldi et al, NEJM 2014 The ASCEND Study NEJM 2014;370:2083 ASCEND Trial Inclusion criteria ASCEND: FVC 50% and 90% DLco 30% and 90% FEV1/FVC ratio 0.80 Time since IPF diagnosis 6 mo CAPACITY: FVC 50% DLco 35% ratio 0.70 1 year Enrichment of more rapid progressors ASCEND Study Demographics and Baseline Characteristics
Pirfenidone (N=278) Placebo (N=277) Age (years) 69.0 68.0 Male gender (%) 79.9 76.9 U.S. enrollment (%) 67.3 66.4 FVC (% predicted)
68.1 68.0 FEV1/FVC ratio 0.84 0.84 DLco(% predicted) 41.5 43.0 6MWT distance (m) 409.3 423.0 Supplemental O2 use (%) 28.1
27.4 Time since IPF diagnosis (years) 1.4 1.4 Former Smoker (%) 66.2 61.0 HRCT Definite IPF (%) 95.7 94.6 Surgical lung biopsy (%) 30.9 28.5
* Continuous variables expressed as median values Includes patients who had surgical lung biopsy prior to screening that was not mandated by virtue of HRCT diagnosis 54 Primary Efficacy Analysis: Treatment with pirfenidone resulted in a significant between-group difference in the rank ANCOVA analysis (P<0.000001) Proportion of Patients with 10% Decline in FVC or Death (%) Absolute Difference 2.5% 7.9% 12.3% 15.3% Relative Difference 54.0%
58.0% 57.8% 47.9% <0.000001 <0.000001 0.000002 <0.000001 Rank ANCOVA p-value 55 Supportive Analysis of the Primary Endpoint: Treatment group difference at Week 52: a 45% relative reduction in the mean change in FVC Pirfenidone (N=278) Mean change in FVC
(mL) 235 ml Placebo (N=277) Absolute difference, mL Relative difference Rank ANCOVA P-value 428 ml 59.6 111.0 116.7 192.8 62.5% 54.9% 43.9%
45.1% <0.000001 <0.000001 0.000002 <0.000001 56 Supportive Analysis of the primary endpoint: Annual rate of FVC decline at week 52 favored Pirfenidone (Linear Slope Analysis) -164 mL/yr Annual Rate of FVC Change (mL/yr) Figures corrected as per NEJM erratum Aug 2014 Absolute Difference, 116 mL/yr Relative reduction: 41.5%
P<0.0001* * Linear slope analysis: Mixed model with linear time effect adjusted for age, height, and sex 57 6-Minute Walk Distance: Significant between-group difference in the change from baseline to week 52 Proportion of Patients with 50 m Decline or Death (%) Absolute Difference 3.7% 10.9% 10.9% 9.8% Relative Difference
24.1% 39.7% 31.8% 27.5% Rank ANCOVA p-value* 0.401 0.119 0.041 0.036 * Tested for multiple comparisons using the Hochberg procedure 58 Progression-free Survival*: Pirfenidone reduced risk of disease progression or death by 43% 100
273 269 225 192 113 * Time to death or disease progression (confirmed 10% decline in FVC or confirmed 50 m decline in 6MWD) Log-rank test 59 Pooled All-cause Mortality (Week 52): Pirfenidone reduced risk of death by 48% Patients, n (%) Pirfenidone Placebo HR (95% CI)
22 (3.5%) 42 (6.7%) 0.52 (0.310.87) 0.011 HR=hazard ratio; 95% CI=95% confidence interval * Pre-specified secondary endpoint in ASCEND Exploratory analysis in CAPACITY Cox proportional hazards model Log-rank test 60 Pooled All-cause Mortality (Week 52): Treatment group curves diverge early and continue separating throughout the study period 8 Placebo (N=624)
HR 0.52 (95% CI 0.310.87)* P=0.011 6 Cumulative Risk Death (%) of 4 2 Pirfenidone (N=623) 0 0 3 6 Month 9 12
623 624 618 619 609 603 596 586 509 490 Patients at Risk, n Pirfenidone Placebo * Cox proportional hazards model Log-rank test 61 ASCEND Study Summary Treatment with pirfenidone for 52 weeks significantly reduced
disease progression, as measured by Changes in % predicted FVC (p<0.000001) Changes in 6-minute walk distance (p=0.036) Progression-free survival (p<0.001) Treatment with pirfenidone reduced all-cause mortality and treatment emergent IPF-related mortality in pooled analyses at week 52. 62 Pirfenidone: Summary Pirfenidone is the first approved drug for treatment of mild to moderate IPF in Europe. Pirfenidone was tested in 5 randomized placebo-controlled trials including more than 1.600 IPF patients Pirfenidone has a clinically meaningful effect on FVC and exercise tolerance. Pirfenidone reduced disease progression and 1-yearmortality by 50%. The adverse events support a favourable risk-benefit ratio - increased GI und photosensitivity/skin reactions - only few leading to withdrawal IPF Phase III Trials in Comparison ASCEND INPULSIS
70% pts screened enrolled Courtesy of Prof Behr IPF Phase III Trials in Comparison Pirfenidon und Nindetanib have shown efficacy in IPF in reducing annual decline of FVC Differences in study populations preclude direct comparisons of effect size Pirfenidon reduces decline in 6MWD, improves PFS and overall survival, while Nindetanib prolongs time to first acute exacerbation Side effects of both drugs are manageable IPF Trials 2014: Consequences Nintedanib phase III trials (INPULSIS) FDA approval Oct 2014, EMA Jan 2015 Pirfenidone phase III trial (ASCEND) FDA approval Oct 2014
PANTHER trial: NAC monotherapy really a negative tral? The future: IPF therapy 2016? First choice, second choice? Combination therapy? New drugs? PANORAMA: Pirfenidone + NAC MRC-1461 GS-US-322-0207 A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Assess the Efficacy and Safety of GS6624 in Subjects with Idiopathic Pulmonary Fibrosis (RAINIER) GS-6624 Profile GS-6624 Mechanism of action Humanized monoclonal antibody (mAb) with immunoglobulin IgG4 isotype directed against human LOXL2 (lysil oxidase-like 2) Literature indicates LOXL2 is central in the development of
pathologic stroma in fibrotic and oncologic disease: LOXs initiate crosslinking of collagen and elastin, thereby increasing the stiffness of extracellular matrix and tissue Inhibition of LOXL2 enzymatic activity has potential therapeutic activity in disease with fibroblast activity Safety profile Phase 1 safety study ongoing No clinically significant DLTs observed (as of 12 Sep 2012) SAE Grade 4 urosepsis, Grade 2 influenza & chronic renal failure. MRC-1461 Ongoing Phase II / III trials in IPF Trial Drug Status Mechanism End NCT01872689
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