Ronald F. van Vollenhoven Unit for Clinical Therapy Research, Inflammatory Diseases (ClinTRID) The Karolinska Institute Stockholm, Sweden

Transcription

1 Ronald F. van Vollenhoven Unit for Clinical Therapy Research, Inflammatory Diseases (ClinTRID) The Karolinska Institute Stockholm, Sweden

2 Disclosures Research Grants: AbbVie, Amgen, BMS, GSK, Pfizer, Roche, UCB Consultant/Advisor: AbbVie, Biotest, BMS, Celgene, Crescendo, GSK, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, UCB, Vertex Member of steering or advisory committee for or investigator in clinical trials of atacicept, belimumab, epratuzumab, ocrelizumab, tabalumab, and other novel therapeutics

3 The future of the lupus trial 1. What have we learned from trials so far? 2. A strange paradox 3. New ideas

4 The future of the lupus trial 1. What have we learned from trials so far?

5 Prasterone (DHEA) for steroidsparing in SLE Failed primary, but convincing result in plausible subset Petri et al, Arthritis Rheum 46: , 2002

6 Prasterone (DHEA) for steroidsparing in SLE Lesson: Choose the correct (sub-) population for the trial Petri et al, Arthritis Rheum 46: , 2002

7 MMF vs. CyX induction in lupus nephritis The two treatments achieved similar results, but superiority for MMF was not achieved

8 MMF vs. CyX induction in lupus nephritis The two treatments achieved similar results, but superiority for MMF was not achieved but that is clinically a very useful result

9 MMF vs. CyX induction in lupus nephritis Lesson: choose an outcome that makes clinical sense (negotiate with regulators)

10 Rituximab in non-renal lupus P=0.9750* Responders No Clinical Response Partial Clinical Major Clinical Response MCR+PCR Response All early terminations treated as NCR. *p value is based on Wilcoxon Rank sum test stratified by race and baseline assigned prednisone dose. Merrill JT, et al. Arthritis Rheum. 2010;62(1):

11 Rituximab in non-renal lupus P=0.9750* Responders Lesson: The patient population for each drug may have to be more narrowly defined Merrill JT, et al. Arthritis Rheum. 2010;62(1):

12 Rituximab in lupus nephritis: The LUNAR trial Rovin BH, et al. Arthritis Rheum. 2012;64(4):

13 Rituximab in lupus nephritis: The LUNAR trial Lesson: This trial may have been underpowered Rovin BH, et al. Arthritis Rheum. 2012;64(4):

14 Abatacept in non-renal lupus Merrill JT, et al. Arthritis Rheum. 2010;62(10):

15 Abatacept in non-renal lupus Lesson: flare as an outcome may not be sufficiently well defined Merrill JT, et al. Arthritis Rheum. 2010;62(10):

16 Abatacept in renal lupus Furie et al, Arthritis Rheumatol Feb;66(2): doi: /art

17 Wofsy D, et al. Arthritis Rheum. 2012;64(11): Abatacept in renal lupus Lesson: Choice of responder definition must be solidly evidence-based and realistic

18 BLISS-52 Response Rate Over 52 Wks Navarra SV, et al. Lancet. 2011;377(9767):

19 BLISS trials, key learnings Primary outcome for phase III based on phase II Large trial size needed to ensure power ( sledgehammer approach )

20 2. A strange paradox. We know that CyX works for lupus nephritis: But the trial that first showed it had n=65 patients Boumpas et al, Lancet 1992;340:741-5

21 2. A strange paradox. We know that hydroxychloroquine prevents lupus flares: But trial that showed it had n=47 patients New Engl J Med 1991;324:150-4

22 2. A strange paradox. We know that lower dose CyX is effective in LN But the trial that showed it had n=90 patients Houssiau, Arthritis Rheum 2002;46:

23 2. A strange paradox. We know that MMF is equivalent to CyX But the trial that first showed it had n=42 patients Chan et al, N Engl J Med 2000;343:

24 2. A strange paradox. Were there investigators simply lucky? Are clinicians more easy to convince than regulators? Or is it worth doing trials the academic way

25 3. New ideas the succesful lupus trial for the future will have: Different outcomes Organ-specific Corticosteroid-sparing Composite indices too complex, too noisy blur out true efficacy Well-defined outcomes exist for skin (CLASI etc), joints (counts), hematological, and certain small subgroups Corticosteroid-sparing is clinically important and can be used prasterone trial as model

26 3. New ideas the succesful lupus trial for the future will have: Different outcomes Organ-specific Corticosteroid-sparing Focussed patient populations Clinically defined Biomarker-defined Anti-Interferon trials patients defined by signature B-cell signature for some treatments? Efforts underway to redefine SLE (and other CTDs) based on biomarkers

27 3. New ideas the succesful lupus trial for the future will have: Different outcomes Focussed patient populations Different organization Smaller, tighter groups of clinicians who are closely involved with, and invested in, the trial No need for very large numbers of efficacy Future trial models developed in other diseases: Trial embedded in registry Trial done in the learning health care environment

28 Conclusions By learning from trials done in SLE over the past two decades, trials design will improve and future trials in SLE will have a larger chance of succeeding than has so far been the case. More lessons should be drawn from the successful academic trials Novel approaches from both within and outside the SLE field are now being developed