MS Academia: Multiple sclerosis advanced course

Transcription

1 6 October Barcelona, Spain MS Academia: Multiple sclerosis advanced course IMPROVING THE PATIENT S LIFE THROUGH MEDICAL EDUCATION

2 Mark S. Freedman University of Ottawa and the Ottawa Hospital Research Institute Ottawa, Ontario, Canada Receipt of research or educational grants: None Receipt of honoraria or consultation fees: BayerHealthcare, BiogenIdec, Chugai, EMD Canada, Genzyme, Novartis, Opexa, Roche, Sanofi-Aventis, Teva Canada Innovation Member of a company advisory board, board of directors or other similar group: Actelion, BiogenIdec, Chugai, Genzyme, Merck Serono, Novartis, Opexa, Sanofi-Aventis Participation in a company sponsored speaker s bureau: Genzyme 2

3 6 October Barcelona, Spain Efficacy profile of existing treatments M.S. Freedman IMPROVING THE PATIENT S LIFE THROUGH MEDICAL EDUCATION

4 Patient Profiles for Treatment Newly diagnosed, treatment naïve 1 Patients considering other DMTs because of tolerability issues or ongoing side effects 1,2 Patients who discontinued other DMTs because of dosing or adherence difficulties 1,2 Patients who discontinued other DMTs because of lack of efficacy Considered together Would these different patients warrant a different efficacy profile? 1. Wingerchuk DM, Carter JL. Mayo Clin Proc. 2014;89: Devonshire V et al. Eur J Neurol. 2011;18:69-77.

5 Goals of MS Therapy 1. Treatments. Accessed May 16, 2013

6 Goals of Treatment The best option is one that hits consistently on all outcome measures Slowing EDSS Progression Reducing Relapses Reducing MRI Activity

7 Current MS Therapies Injectables: Interferon- 1a, Interferon- 1b Glatiramer acetate Monoclonal antibodies: Natalizumab Alemtuzumab Oral treatments Fingolimod Dimethyl fumarate Teriflunomide

8 Emerging MS Therapies Oral treatments: Other S-1-P receptor agonists Ponesimod, Siponimod, Ceralifimod Laquinimod Monoclonal antibodies: Daclizumab Ocrelizumab, Ofatumumab Secukinumab Cell-based treatments Abilit-T autologous T cell vaccination treatment (SPMS) BMT & autologous stem cell transplantation Mesenchymal stem cell transplantation

9 Choosing a Therapy for a Patient Treatment is for the long term Balancing benefits vs. risks Source of data: Clinical trials + extension Registries Real world Ultimate goal: to use group data to try and predict the response of a single patient over time

10 Responders vs. Non-Responders How do you distinguish between these? True Responders NEDA due to treatment effect These can easily be defined as they are having the events (relapse, MRI or progression) False Responders NEDA due to natural history Non- Responders Continued disease activity despite treatment

11 Response to Treatment Clinical trial data produces group means and 95% confidence intervals but where does the individual patient lie? Placebo % CI: mg % CI: % 6% Reduction 14 mg % CI: Annualized relapse rate N Engl J Med 2012;365:

12 Comparing Efficacy Across Trials: Which to Use? Absolute (ARR) vs. Relative Risk Reduction (RRR) If all populations are at the same risk of having a relapse then RRR should be constant If high risk patients are selected for trials but their risk for relapse is lower then can you reliably use RRR? In such cases, using the ARR and NNT may be a more accurate comparator When event rates become very low, even absolute differences start to lose meaning as they must take into account efficacy and the infrequency of the event

13 Clinical Trial Outcome Measures Why can t we simply compare outcome measures across trials to know which is better? Trial designs differ Outcome definitions (relapse, progression) Frequency of clinical exams or MRI Statistical analysis Reference population (placebo) differ Which outcome measure do we use? Relative reduction to a placebo group Absolute reduction (expected irrespective of a placebo group)

14 Annualized Relapse Rate Absolute vs. Relative Risk Reduction 1,6 1,4 1,2 1 0,8 0,6 0,4 0,2 0 NNT = % Relative =.75 Absolute NNT = 2 Placebo Treatment 50% Relative =.5 Absolute NNT = 4 50% Relative =.25 Absolute Drug X Drug Y Drug Z Which drug is shows showing the most the greatest convincing efficacy? effect? NNT, number needed to treat = (1/absolute reduction)

15 Annualized Relapse Rate Absolute vs. Relative Risk Reduction NNT 2 for both drugs % Relative =.41 Absolute Placebo Treatment % Relative =.5 Absolute IFNDrug -1a sc X Natalizumab Drug Z NNT, number needed to treat = (1/absolute reduction)

16 Annualized Relapse Rate Absolute vs. Relative Risk Reduction NNT = 5 for both drugs 0,6 0,5 36% Relative =.2 Absolute Placebo Treatment 0,4 0,3 50% Relative =.2 Absolute 0,2 0,1 0 Teriflunomide Drug X Dimethyl Drug Fumarate Y NNT, number needed to treat = (1/absolute reduction)

17 Clinical Trial Outcome Measures Primary outcome: relapses Protocol defined, severity not specified Usually reported as annualized rate Does not differentiate among patients with 1 or >1 relapses Secondary outcomes: All independent of relapses EDSS progression MRI PRO (QoL) Duration: 2 years What happens after 2 years?

18 Study Agent Comparison of Main Outcome Measures in Established Treatments IFN -1b IFN -1a IFN 1a Glatiramer 250 g 30 g im qw 44 g sc tiw Acetate ARRR 34% 18% 32% 29% Absolute RRR Relative Reduction in new T2 & Gd+ MRI Activity Relative Reduction in EDSS Progression Absolute Reduction in Proportion Progressing 83% 52% 78% 30% 29%* 37% 30% 12%* 8%* 13% 11% 3%* *p= ns

19 Comparison of Main Outcome Measures in More Recent Treatments Study Agent Natalizumab Fingolimod Teriflunomide Dimethyl Fumarate ARRR 68% 54% 31% 53% Absolute RRR Relative Reduction in new T2 & Gd+ MRI Activity Relative Reduction in EDSS Progression Absolute Reduction in Proportion Progressing 83% 92% 74% 82% 67% 85%* 90%* 42% 30% 30% 38% 12% 6.4% 7.1% 11% *MRI studies performed on 43% of patients

20 Effect of BP Lowering Agents ACE inhibitor trial of BP reduction Mean BP change between treated & placebo groups = 3 mm Hg This has little clinical meaning in and of itself Kaplan Meier Estimates of the Composite Outcome of Myocardial Infarction, Stroke, or Death from Cardiovascular Causes in the ACE treated Group and the Placebo Group N Engl J Med 2000;342:

21 EDSS Progression In Pivotal Trials Agent Study Control Statistically Significant Benefit? p values GA COP-1 Placebo NO p=0.11 sc IFN -1a PRISMS Placebo YES p<0.05 im IFN -1a MSCRG Placebo YES p=0.02 IFN -1b IFNB-1a Placebo NO p=0.161 Alemtuzumab CARE MS-I s.c. IFN-β1a NO p=0.22 CARE MS-II s.c. IFN-β1a YES p=0.008 BG-12 DEFINE Placebo YES p=0.005 CONFIRM Placebo NO p=0.25 Fingolimod FREEDOMS I Placebo YES p=0.02 FREEDOMS II Placebo NO p=0.25 Natalizumab AFFIRM Placebo YES p<0.001 Teriflunomide TEMSO Placebo YES p=0.03 (14 mg) TOWER Placebo YES P=0.04

22 What is the Key Goal of All Therapies? Restricted to wheelchair Bedridden Death Need for walking assistance Normal Neurologic exam Some limitation in walking ability Minimal disability EDSS

23 What is the Key Goal of All Therapies? Preventing or delaying disability How good are short term measures of relapse or MRI activity predictive of longer term benefit? So much depends then on the quality of the relapse or the MRI change Similarly, short term EDSS progression can be qualitatively different depending on where on the scale the progression takes place

24 Is There Evidence for Treatment of Relapses & MRI Changing the Course of Progressive MS? How much does a treatment effect on relapses predict an effect on EDSS progression? The equation predicts for instance, if there is a 50% relative reduction in ARR one can expect a 30% relative reduction in the risk of EDSS worsening How much does a treatment effect on MRI predict an effect on EDSS progression? The equation predicts for instance, if there is a 50% relative reduction in MRI markers one can expect a 5% relative reduction in the risk of EDSS worsening Sormani M et al. Neurology 2010;75:

25 Cumulative probability Long-term benefit of treatment with IFN-β Cumulative probability Propensity scores for important progression milestones Untreated group Treatment group p< p< Time to SPMS Time to EDSS 6 (years) Trojano M et al. Ann Neurol 2007;61:300 6

26 Relapse Events in MS: What are Their Meaning? Are they all the same? Do they all contribute equally to disease? Is there a surrogate for severity? Steroid use Hospitalization Change in EDSS, SNRS, ADL, or other scale Are those with complete recovery different from those without? How significant is a reduction in relapse rate of <0.2 per annum? (1 attack every 5 years)

27 MRI Events in MS MRI Activity measures New or persistent CEL New or enlarging T2 Burden of disease T2 T1 black holes Atrophy MTR/MRS/DTI (exploratory outcomes)

28 MRI Events in MS: What are their meaning? Baseline burden/activity: A small increase over a small baseline vs. small increase over a high baseline does it matter Timing, overall volume, Gd+ or # of lesions: New lesion rate, large vs. small lesions, Gd+ vs. Gd-, or # of new lesions and their location does it matter? Scan Frequency: The more MRI scans performed, the more lesions there are to count - does it matter?

29 PRO Events in MS: What are their meaning? Quality of Life: Different scales, populations, subjective Employment Ability to maintain gainful employment Family Care of children Able to participate in family events Maintenance of the home

30 Events in MS: What are their meaning? Are they all inter-related? Is an attack associated with new MRI activity different from one without MRI change? Do attacks associated with MRI activity but no change in EDSS count for anything? Is time a factor? How often they occur/time? How quickly they occur?

31 Current MS Disease Measures Efficacy currently determined based on independent effects on relapse, MRI or EDSS Would a relapse associated with both MRI and EDSS change be more significant? Likely to be extremely few in current trials, since it would be driven by the event with lowest frequency (i.e. EDSS) What if efficacy was based on preventing events? What is the meaning of being free of a relapse? Relapse-free would have to also imply no activity in other measures (MRI or EDSS progression)

32 No Evidence of Disease Activity (NEDA): A New Metric Given our inability to distinguish meaning among the current MS metrics the simplest way to equalize them is to acknowledge that: they re all bad - but they may not be or more accurately: they can t be good so being free of them is probably a good thing But being free of one but not the others would make no sense (i.e. someone who is free of relapses but had significant EDSS change is counter-intuitive)

33 Striving for NEDA NEDA = no evidence of disease activity No relapse, progression or MRI activity Does not take into account patient factors such as fatigue, cognition, depression NEDA 3 vs. NEDA 4 Concept that MRI atrophy might add something but not widely accepted or available Laudable goal, but hard to achieve over time Important goal especially in the short term

34 NEDA patients (%) NEDA Data from Clinical Trials: 2 year 80 AFFIRM (2001) 60 TEMSO (2004) FREEDOMS (2006) CARE-MS I (2007)* 40 CARE-MS II (2007)* DEFINE (2007) ADVANCE (2009) 20 0 Placebo teriflunomide 14 mg DMF 240 mg bid fingolimod 0.5 mg Peg IFNβ-1a Q2W natalizumab sc IFN β-1a 44 µg tiw alemtuzumab *Data from CARE MS I and II trials present the percentage of patients who achieved NEDA between Year 1 and Year 2, all other trials present the cumulative percentage of NEDA patients over 2 years

35 *Trial data are not comparable owing to different definitions of relapse or EDSS progression and frequency or type of MRI Treatment Increases Odds of Achieving NEDA over 2 Years* Alemtuzumab 2.4* *DAF vs IFN -1 sc Teriflunomide 1,6 Additive effect to that of IFN -1 sc? IFNb1a sc 3,41 Fingolimod 2,54 Cladribine 2,91 Natalizumab 5, Increase Odds of NEDA of Treatment over Placebo

36 Sustaining NEDA: CLIMB Study 215 patients with CIS/RMS followed for at least 7 years with annual MRI & bi-annual clinical assessment NEDA at 2 years had a positive predictive value of 78.3% for no progression ( EDSS 0.5) at 7 years Rotstein DL et al. JAMA Neurol :

37 NEDA: A Potentially Better Outcome Measure? What sort of relative or absolute difference in NEDA would be meaningful in a clinical trial? How do we insure meaningfulness of change? All disease activity cannot be dominated by MRI? If events in populations are becoming less meaningful (due in part to earlier identification and change in diagnostic criteria), is being free of these less meaningful events more meaningful?

38 Conclusions Changing MS population Steady reduction in outcome measures of disease activity so difficult to determine efficacy based on clinical event rates Effective treatments are becoming mainstream obviating the ability to use a placebo comparator Is it now a reasonable goal for clinicians to strive for a state of no evidence of disease activity (NEDA)? A NEDA composite should be considered as a primary outcome measure for forthcoming trials, especially if using active comparators

39 Treatment Challenges: Benefit vs. Risk M o A Historical Therapies Some advantages might be worth the risks Emerging Therapies

40 6 October Barcelona, Spain MS Academia: Multiple sclerosis advanced course IMPROVING THE PATIENT S LIFE THROUGH MEDICAL EDUCATION