Breaking News in Malattie dell Apparato Respiratorio

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1 COMPROMISSIONE FUNZIONALE RESPIRATORIA E/O COMORBIDITÀ RESPIRATORIE IN PAZIENTI AFFETTI DALLE PRINCIPALI PATOLOGIE CRONICHE Modena 1-3 Ottobre 2015 Breaking News in Malattie dell Apparato Respiratorio Leonardo M. Fabbri, MD, FERS Clinica di Malattie dell Apparato Respiratorio Università degli Studi di Modena e Reggio Emilia

2 BREAKING NEWS IN MALATTIE DELL APPARATO RESPIRATORIO Modena 1 October 2015 CONFLICTS OF INTEREST Il sottoscritto Leonardo FABBRI ai sensi dell art. 3.3 sul Conflitto di Interessi, pag. 17 del Reg. Applicativo dell Accordo Stato-Regione del 5 novembre 2009, dichiara che negli ultimi 2 anni ha avuto rapporti diretti di finanziamento con i seguenti soggetti portatori di interessi commerciali in campo sanitario: Chiesi, GSK, Zambon, AZ, Almirall, BI, Pearl, Menarini, Malesci/Guidotti, Novartis, Takeda, Dompè, Mundipharma

3 MALATTIE DELL APPARATO RESPIRATORIO Leonardo M. Fabbri e Stefania Cerri

4 BREAKING NEWS IN MALATTIE DELL APPARATO RESPIRATORIO Leonardo M. Fabbri COPD Idiopathic Pulmonary Fibrosis Lung Cancer Asthma

5 BREAKING NEWS IN MALATTIE DELL APPARATO RESPIRATORIO Leonardo M. Fabbri COPD Idiopathic Pulmonary Fibrosis Lung Cancer Asthma

6 GOAL OF COPD MANAGEMENT Overall COPD Control achieving Current Control reducing Future Risk defined by defined by Symptoms Reliever use Exacerbations Mortality Activity Lung function Progression of the disease Medication adverse effects www. goldcopd.org 2014

7 Global Strategy for Diagnosis, Management and Prevention of COPD Manage Stable COPD: Pharmacologic Therapy FIRST CHOICE C D GOLD 4 GOLD 3 GOLD 2 GOLD 1 A ICS + LABA or LAMA SAMA prn or SABA prn ICS + LABA or/and LAMA LABA or LAMA B Exacerbations per year mmrc 0-1 CAT < 10 mmrc 2 CAT 10

8 EFFECT OF ROFLUMILAST ON EXACERBATIONS IN PATIENTS WITH SEVERE COPD UNCONTROLLED BY COMBINATION THERAPY Roflumilast 1 2 reduces exacerbations and hospitalisations improves lung function in severe COPD patients with chronic bronchitis who are at risk of frequent and severe exacerbations despite therapy with ICS/LABA or ICS/LABA/LAMA (70%) Martinez FJ et al. Lancet, 2015 Mar 7;385(9971):

9 MEAN RATE OF MODERATE OR SEVERE EXACERBATIONS PER PATIENT PER YEAR Mean rate of COPD exacerbations per patient per year Rate ratio (95% CI) N Two-sided p-value ITT ( ) Placebo Roflumilast PP ( ) Martinez FJ et al. Lancet, 2015 Mar 7;385(9971):

10 POST-BRONCHODILATOR FORCED EXPIRATORY VOLUME IN ONE SECOND (FEV1) IN PATIENTS IN ROFLUMILAST AND PLACEBO GROUPS OVER 52 WEEKS Placebo Roflumilast 1.12 FEV 1 (L) Number at risk Roflumilast Placebo Time (week) Martinez FJ et al. Lancet, 2015 Mar 7;385(9971):

11 Global Strategy for Diagnosis, Management and Prevention of COPD Manage stable COPD: Pharmacologic therapy FIRST CHOICE GOLD 4 GOLD 3 GOLD 2 GOLD 1 C A ICS + LABA or LAMA SAMA prn or SABA prn ICS + LABA +/- LAMA +/- roflumilast LABA or LAMA D B > Exacerbations per year mmrc 0-1 CAT < 10 mmrc > 2 CAT > 10

12 THE STUDY TO UNDERSTAND MORTALITY AND MORBIDITY IN COPD (SUMMIT) STUDY years Participants COPD with moderate airflow limitation: FEV % predicted normal FEV 1 /FVC pack-years smoking history History of CVD or at increased risk of CVD mmrc dyspnoea score 2 n=16,485 R Double-blind treatment period (mean 2 years) FF/VI 100/25 µg OD FF 100 µg OD VI 25 µg OD Placebo All arms on a background of allowed medications Day -4/10 Week 0 Up to 4 years Vestbo J et al. Eur Respir J Sep 27 Vestbo J et al, Press Conference 8 September 2015

13 THE STUDY TO UNDERSTAND MORTALITY AND MORBIDITY IN COPD (SUMMIT) STUDY PROTOCOL MORTALITY AND SECONDARY ENDPOINTS For the primary endpoint of the study, the risk of dying on FF/VI 100/25mcg was 12.2% lower than on placebo* over the study period, which was NOT statistically significant (p=0.137) For the first of two secondary endpoints, FF/VI 100/25mcg reduced the rate of lung function decline (as measured by forced expiratory volume in one second, 'FEV1') by 8mL per year compared with placebo (p=0.019). As the primary endpoint was not met, statistical significance cannot be inferred from this result For the other secondary endpoint, the risk of experiencing an on-treatment cardiovascular (CV) event (CV death, myocardial infarction, stroke, unstable angina and transient ischemic attack [TIA]) at any time was 7.4% lower in patients taking FF/VI 100/25mcg which was NOT statistically significant (p=0.475) Vestbo J et al, Press Release 2015 Sep 8

14 BREAKING NEWS IN MALATTIE DELL APPARATO RESPIRATORIO Leonardo M. Fabbri COPD Idiopathic Pulmonary Fibrosis Lung Cancer Asthma

15 WHO IS MISTER IPF? Male 65 years old Smoker or former smoker Dry cough Dyspnea at exertion Bilateral velcro-type crackles Clubbing Previous different diagnoses Raghu G et al, AJRCCM2011

16 The diagnosis of IPF requires: DIAGNOSIS OF IPF the exclusion of known causes of interstitial lung disease the presence of a definite UIP patternon chest HRCT specific combinations of chest HRCT and SLB patterns Am J Respir Crit Care Med2011; 183:

17 FIBROGENESIS AND MAJOR ORGAN SYSTEMS Rockey DC et al N Engl J Med 2015; 372:

18 ATS/ERS/JRS/ALAT Guidelines; AJRCCM 2015.

19 1. The recommendation against the use of the following agents for the treatment of IPF is strong Anticoagulation (warfarin) Imatinib, a selective tyrosine kinase inhibitor against platelet-derived growth factor (PDGF) Combination prednisone, azahioprine, and N-acetylcysteine Selective endothelin receptor antagonist (ambrisentan) ATS/ERS/JRS/ALAT Guidelines; AJRCCM 2015.

20 Rationale for nintedanibin Idiopathic Pulmonary Fibrosis Nintedanib is a potent intracellular inhibitor of PDGF, FGF and VEGF tyrosine kinase receptors 1 These receptors mediate signalling pathways that are known to be involved in the development of fibrosis 2-4 Nintedanib acts by binding to the intracellular active sites of receptors blocking substrate binding 1 1 Hilberg F et al. Cancer Res2008; 68: Inoue Y et al. Am J RespirCritCare Med 2002; 166: Grimminger F et al. Nat Rev Drug Discov 2010; 9: Selman M et al. Ann InternMed2001; 134:

21 PRIMARY EFFICACY ENDPOINT IN INPULSIS-1 Adjusted annual rate (SE) of decline in FVC (ml/year) ,7-239, ml/year (95% CI: 77.7, 172.8) p< Nintedanib 150 mg bid (n=309) Placebo (n=204) Mean (SE) observed change from baseline in FVC (ml) No. of patients Nintedanib 150 mg bid Placebo Week Nintedanib Placebo Random coefficient regression model including sex, age and height as covariates Missing data were not imputed RicheldiL et al. NEJM 2014; 370:

22 PIRFENIDONE (ESBRIET ) Small molecule, orally available Anti-fibrotic activity with antagonism of TGFβ1 effect (exact mechanism of action unclear) Evaluated for efficacy in patients with mild-tomoderate Idiopathic Pulmonary Fibrosis

23 Primary and key secondary efficacy outcomes during the 52-week study period King TE Jr et al. N EnglJ Med. 2014; 370:

24 BREAKING NEWS IN MALATTIE DELL APPARATO RESPIRATORIO Leonardo M. Fabbri COPD Idiopathic Pulmonary Fibrosis Lung Cancer Asthma

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26 NIVOLUMAB VERSUS DOCETAXEL IN ADVANCED SQUAMOUS-CELL NON SMALL-CELL LUNG CANCER Brahmer J et al. N Engl J Med 2015;373:123-35

27 NIVOLUMAB VERSUS DOCETAXEL IN ADVANCED SQUAMOUS-CELL NON SMALL-CELL LUNG CANCER Among patients with advanced, previously treated squamous-cell NSCLC, overall survival, response rate, and progression-free survival were significantly better with nivolumab than with docetaxel, regardless of PD-L1 expression level Brahmer J et al. N Engl J Med 2015;373:123-35

28 Tumor Immunology in Lung Cancer: Concept of immunoterapy in NSCLC Davies M et al Cancer Management and Research 2014; 6: 63-75

29 BREAKING NEWS IN MALATTIE DELL APPARATO RESPIRATORIO Leonardo M. Fabbri COPD Idiopathic Pulmonary Fibrosis Lung Cancer Asthma

30 THEORETICAL GROUPING OF EMERGING ASTHMA PHENOTYPES BASED ON THE DISTINCTION BETWEEN TH2- HIGH ASTHMA AND NON-TH2 ASTHMA Wenzel S et al, Nat Med. 2012;18(5):716-25

31 THEORETICAL RANGE OF FACTORS THAT MAY BE INVOLVED IN THE DEVELOPMENT OF NON-TH2 ASTHMA Wenzel S et al, Nat Med. 2012;18(5):716-25

32 TH2 IMMUNE PROCESSES IN THE AIRWAYS OF PEOPLE WITH ASTHMA Wenzel S et al, Nat Med. 2012;18(5):716-25

33 MEPOLUZIMB REDUCES SEVERE EXACERBATIONS IN EOSINOPHILIC STEROID RESISTANT SEVERE ASTHMA Pavord I et al, Lancet 2012; 380: Pavord I et al, Lancet 2012; 380:

34 GATA-3 IS CONSIDERED A KEY TRANSCRIPTION FACTOR IN TH2-DRIVEN INFLAMMATORY DISEASES Barnes P, JCI 118 (2008):

35 ALLERGEN-INDUCED ASTHMATIC RESPONSES MODIFIED BY A GATA3- SPECIFIC DNA-ZYME GATA3 is thought to be a critical checkpoint in allergic diathesis A synthetic DNAzyme that catalyzes the inactivation of GATA3 when administered by inhalation attenuated the late asthmatic response in laboratory challenges Krug N et al. N Engl J Med 2015;372:

36 A GATA3-SPECIFIC DNA-ZYME INHIBITS ALLERGEN-INDUCED ASTHMATIC RESPONSES Krug N et al. N Engl J Med 2015;372:

37 ALLERGEN-INDUCED ASTHMATIC RESPONSES MODIFIED BY A GATA3-SPECIFIC DNA-ZYME SB010 significantly attenuates both late and early asthmatic responses after allergen provocation in patients with allergic asthma Biomarker analysis showed an attenuation of Th2-regulated inflammatory responses Krug N et al. N Engl J Med 2015;372:

38 BREAKING NEWS IN MALATTIE DELL APPARATO RESPIRATORIO Leonardo M. Fabbri COPD Idiopathic Pulmonary Fibrosis Lung Cancer Asthma

39 BREAKING NEWS IN MALATTIE DELL APPARATO RESPIRATORIO RINGRAZIAMENTI Mario Bavieri Bianca Beghé Stefania Cerri Enrico Clini Fabrizio Luppi Luigi Zucchi

40 COMPROMISSIONE FUNZIONALE RESPIRATORIA E/O COMORBIDITÀ RESPIRATORIE IN PAZIENTI AFFETTI DALLE PRINCIPALI PATOLOGIE CRONICHE Modena 2-3 Ottobre 2015 Breaking News in Malattie dell Apparato Respiratorio Leonardo M. Fabbri, MD, FERS Clinica di Malattie dell Apparato Respiratorio Università degli Studi di Modena e Reggio Emilia