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

4. 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

5. 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.

6. 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.

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

8. 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

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

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

11. 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.

12. ©2015 Pulmonary Fibrosis Foundation. All rights reserved.
Lancet Resp Med 2015; 3: 462

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

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

15. 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.

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

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

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

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

20. 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

21. 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.

22. 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.

23. 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.

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

25. ©2015 Pulmonary Fibrosis Foundation. All rights reserved.

26. 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.

27. 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.

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

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

30. 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.

31. 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

32. Thank you.