CLINICAL TRIALS IN THE ERA OF EFFECTIVE THERAPIES

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Presentation transcript:

CLINICAL TRIALS IN THE ERA OF EFFECTIVE THERAPIES LUCA RICHELDI, MD, PhD PATIENT-CENTERED RESEARCH IN PULMONARY FIBROSIS NOVEMBER 14, 2015

SOMEONE ELSE ALREADY MADE THIS POINT Issue 1: which mechanism to target Issue 2: which patients to enrol Issue 3: which end-points to measure ©2015 Pulmonary Fibrosis Foundation. All rights reserved. ERJ 2015; 45: 1218

Issue 1: which mechanism to target Issue 2: which patients to enrol Issue 3: which end-points to measure ©2015 Pulmonary Fibrosis Foundation. All rights reserved.

Point 2: useful hints may derive from biomarker studies MECHANISMS Point 1: mechanisms identified in animal models are not necessarily reliable Point 2: useful hints may derive from biomarker studies Point 3: clearly genetics is emering as a major mechanism ©2015 Pulmonary Fibrosis Foundation. All rights reserved.

MECHANISMS Point 1: mechanisms identified in animal models are not necessarily reliable ©2015 Pulmonary Fibrosis Foundation. All rights reserved.

ANIMAL MODELS The use of alternative and more robust animal models, which better reflect human IPF, is warranted. ©2015 Pulmonary Fibrosis Foundation. All rights reserved. Int J Biochem Cell Biol. 2008; 40: 362

ANIMAL MODELS Eur Respir J. 2015; 45: 1434 ©2015 Pulmonary Fibrosis Foundation. All rights reserved. Eur Respir J. 2015; 45: 1434

ANIMAL MODELS Eur Respir J. 2015; 45: 1434 ©2015 Pulmonary Fibrosis Foundation. All rights reserved. Eur Respir J. 2015; 45: 1434

Point 2: useful hints may derive from biomarker studies MECHANISMS Point 2: useful hints may derive from biomarker studies ©2015 Pulmonary Fibrosis Foundation. All rights reserved.

©2015 Pulmonary Fibrosis Foundation. All rights reserved. Lancet Resp Med 2015; 3: 462

THE PROFILE STUDY Courtesy Toby Maher ©2015 Pulmonary Fibrosis Foundation. All rights reserved. Courtesy Toby Maher

THE PROFILE STUDY Lancet Resp Med 2015; 3: 462 ©2015 Pulmonary Fibrosis Foundation. All rights reserved. Lancet Resp Med 2015; 3: 462

Point 2: useful hints may derive from biomarker studies MECHANISMS Point 1: mechanisms identified in animal models are not necessarily reliable Point 2: useful hints may derive from biomarker studies Point 3: clearly genetics is emering as a major mechanism ©2015 Pulmonary Fibrosis Foundation. All rights reserved.

THE PANTHER TRIAL NEJM 2014; 370: 2093 ©2015 Pulmonary Fibrosis Foundation. All rights reserved. NEJM 2014; 370: 2093

PRIMARY ENDPOINT NEJM 2014; 370: 2093 ©2015 Pulmonary Fibrosis Foundation. All rights reserved. NEJM 2014; 370: 2093

Tollip, muc5b and nac ©2015 Pulmonary Fibrosis Foundation. All rights reserved.

GENETIC STRATIFICATION ©2015 Pulmonary Fibrosis Foundation. All rights reserved.

GWAS STUDIES IN IPF TERC MUC5B TERT 30-33% of the disease risk FAM13A Chromosome -log10(P value) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 X TERC MUC5B TERT 30-33% of the disease risk FAM13A DPP9 ATP11A OBFC1 DSP ©2015 Pulmonary Fibrosis Foundation. All rights reserved. Fingerlin. Nat Genet 2013; 45:613

Issue 1: which mechanism to target Issue 2: which patients to enrol Issue 3: which end-points to measure ©2015 Pulmonary Fibrosis Foundation. All rights reserved.

PATIENTS Point 1: the most recent (successful) trials moved towards centralized review of diagnostic criteria Point 2: there is a risk of narrowing too much the population of patients enrolled in trials Point 3: some recent “deviations” have been explored and can inform future trials ©2015 Pulmonary Fibrosis Foundation. All rights reserved.

PATIENTS Point 1: the most recent (successful) trials moved towards centralized review of diagnostic criteria Point 2: there is a risk of narrowing too much the population of patients enrolled in trials Point 3: some recent “deviations” have been explored and can inform future trials ©2015 Pulmonary Fibrosis Foundation. All rights reserved.

THE INPULSIS TRIALS NEJM 2014; 370: 2071-82 ©2015 Pulmonary Fibrosis Foundation. All rights reserved. NEJM 2014; 370: 2071-82

©2015 Pulmonary Fibrosis Foundation. All rights reserved.

END POINTS Point 1: change in FVC over 1 year has been the basis for recent approvals: challenging in the presence of a comparator arm Point 2: enrichment strategies (particularly in the context of target therapies) might be helpful Point 3: patient-reported outcomes remain an ideal end-point, but a challenging research area ©2015 Pulmonary Fibrosis Foundation. All rights reserved.

END POINTS Point 1: change in FVC over 1 year has been the basis for recent approvals: challenging in the presence of a comparator arm Point 2: enrichment strategies (particularly in the context of target therapies) might be helpful Point 3: patient-reported outcomes remain an ideal end-point, but a challenging research area ©2015 Pulmonary Fibrosis Foundation. All rights reserved.

Enrichment strategies ©2015 Pulmonary Fibrosis Foundation. All rights reserved. Eur Respir J. 2015; 46: 486

avb6 EXPRESSION Eur Respir J. 2015; 46: 486 ©2015 Pulmonary Fibrosis Foundation. All rights reserved. Eur Respir J. 2015; 46: 486

END POINTS Point 1: change in FVC over 1 year has been the basis for recent approvals: challenging in the presence of a comparator arm Point 2: enrichment strategies (particularly in the context of target therapies) might be helpful Point 3: patient-reported outcomes remain an ideal end-point, but a challenging research area ©2015 Pulmonary Fibrosis Foundation. All rights reserved.

END POINTS “It is time to refocus on a patient-centred approach with regards to the co-investigator role, PRO development, and research participants” ©2015 Pulmonary Fibrosis Foundation. All rights reserved. BMC Med 2015; 13: 240

Thank you.