MS Academia: Multiple sclerosis advanced course

Transcription

1 13 September London, UK MS Academia: Multiple sclerosis advanced course IMPROVING THE PATIENT S LIFE THROUGH MEDICAL EDUCATION

2 Robert J. Fox Assessment of treatment response IMPROVING THE PATIENT S LIFE THROUGH MEDICAL EDUCATION

3 Robert J. Fox, MD Staff Neurologist, Mellen Center for Multiple Sclerosis Vice-Chair for Research, Neurological Institute Professor, Cleveland Clinic Learner College of Medicine Cleveland Clinic, Cleveland, OH, USA Disclosure Dr. Fox has received consulting fees from Actelion, Biogen, Genentech, Mallinckrodt, Novartis, Teva, and Xenoport; and research support from Novartis.

4 Objectives 1. Understand the concept of No Evidence of Disease Activity (NEDA) 2. Apply this NEDA to current MS disease modifying therapies 3. Recognize breakthrough disease activity in clinical practice

5 Nomenclature Disease-Free Status is commonly used, but is discouraged, because we lack methodology to fully evaluate ongoing pathology Disease-Activity Free Status (DAF) is better, but we lack methodology to assert that we have eliminated all disease activity (e.g. triple-dose gadolinium?) No Evident Disease Activity (NEDA) is a reasonable term for this concept. It implies that the neurologist has monitored the patient for disease activity

6 Disease-Free Status in AFFIRM The First Report of the Concept Our aim was to develop composite measures that can be applied in clinical practice and used as a measure of disease remission in clinical studies. Therefore, relapses, progression of disability (sustained for 12 weeks), Gad+ lesions, and new or enlarging T2-hyperintense lesions were taken into account. Havrdova et al. Lancet Neurology 2009;8:254-60

7 Definition from Clinical Trials No new or enlarging T2 lesions No new Gad+ lesions No relapses No confirmed disability worsening Atrophy not included in definition

8 MRI Predictors of Disability Progressive disability at 5 yrs, according to disease activity during first year of IFNβ therapy New MRI lesions are 5-20x more predictive of future disability than relapses and disability progression Prosperini et al, Eur J. Neurol. 2009

9 Definition from Clinical Trials No new or enlarging T2 lesions No new Gad+ lesions No relapses No confirmed disability worsening Atrophy not included in definition

10 Disability Worsening 2 contributors: New inflammation (relapses, new lesions) Degeneration from previous injury Driver of progressive MS Little impact of current therapies on degeneration component Disability worsening may be suboptimal metric for current anti-inflammatory therapies

11 % Disease Activity Free NEDA with Natalizumab No relapse, EDSS progression, or new MRI lesions p < p < p < NEDA at 2 years: Placebo Natalizumab 7% 37% Fold-Increase 5.3 Havrdova et al. Lancet Neurology 2009;8:254-60

12 NEDA with Fingolimod NEDA at 2 years: Placebo Fingolimod 13% 38% Fold-Increase 2.9 Kappos et al., AAN 2011

13 NEDA with Dimethyl Fumarate NEDA at 2 years: Placebo Tecfidera 15% 28% Fold-Increase 1.9 Giovannoni et al., AAN 2012

14 Proportion of Patients (%) NEDA with Teriflunomide No relapses, MRI activity or EDSS worsening 20 14,3 18,4 22,9 NEDA at 2 years: Placebo Teriflunomide 14% 23% Fold-Increase Placebo Teriflunomide 7 mg Teriflunomide 14 mg Freedman MS et al. AAN Annual Mtg, 2012; New Orleans, LA. PD05.007

15 NEDA and MS DMTs 1 year Study Placebo Active Arm Fold natalizumab (AFFIRM) Daclizumab-HYP Pegylated IFNβ1a Q2W years Study Placebo Active Arm Fold natalizumab (AFFIRM) cladribine (CLARITY) Fingolimod (FREEDOMS) BG-12 (DEFINE)

16 Fingolimod vs IFNß-1a IM NEDA at 1 year: IFNß-1a (IM) Fingolimod 34% 46% Fold-Increase 1.4 Khatri et al. AAN 2012

17 Dimethyl fumarate vs glatiramer acetate NEDA at 2 years: BG-12 BID GA 18% 12% Fold-Increase 1.5 (*) Glatiramer Acetate in CONFIRM was an active comparator arm

18 NEDA and MS DMTs Study Duration Comparator Test Drug Fold TRANSFORMS IFNß-1a 30 g (IM) vs fingolimod CARE MS I IFNß-1a 44 g (SC) vs alemtuzumab CARE MS II IFNß-1a 44 g (SC) vs alemtuzumab CONFIRM GA vs BG-12 BID 1 yr yr yr yr

19 NEDA and Improvement A d j u s t e d h a z a r d r a t i o : , 9 5 % C I : ( , ), p - v a l u e :

20 NEDA and Patient Reported Outcomes Bates et al. PS 34- CMSC 2009

21 NEDA in Clinical Practice NEDA from general clinical practice cohort 2-year NEDA: positive predictive value of 78% for no progression at 7y negative predictive value of 41-43% Rotstein et al. JAMA Neurol. 2015;72(2):

22 Definition from Clinical Trials No new or enlarging T2 lesions No new Gad+ lesions No relapses No confirmed disability worsening Atrophy not included in definition

23 Brain Volume and NEDA 1-year brain volume change: -0.86% cut-off yielded sensitivity 71.4% and specificity 65.5% Perez-Miralles et al. Neurol Neuroimmunol Neuroinfl 2015; 21:

24 Brain Volume and NEDA Atrophy estimated from 4 MRIs over 2 years were used to apply cut-offs for atrophy progression Kappos et al, Mult Scler J, 2015

25 Brain Volume and NEDA Caveats: Published studies are from very controlled image acquisitions do not replicate clinical practice Published studies followed patients for 1-2 years. Individual patients have significant biologic variability in atrophy estimates Application of atrophy to routine clinical practice is not ready. Courtesy Kunio Nakamura, PhD, Cleveland Clinic

26 Defining Breakthrough Disease Activity Sormani and De Stefano, Nature Rev Neurol 2013

27 Defining Breakthrough Disease Activity Non-responders behaved similarly to placebo Sormani and De Stefano, Nature Rev Neurol 2013

28 Canadian MS Working Group Recommendations Change treatment for: - 1 High, or - 2 Moderates, or - 3 Lows Limitations: Somewhat cumbersome Doesn t integrate transition to progressive MS Freedman et al, Can J. Neurol Sci, 2013

29 Take-home Message Goal of MS therapy: No evidence of disease activity (NEDA) NEDA is achievable in some patients: Up to 40% NEDA in 2- years with available drugs Disability progression may be confounded by previous injury Treating to Target in the Office: Requires individualized planning with each patient Baseline MRI, follow-up MRI;? New baseline after 3-6 mos? Many modifiers: relapse severity and recovery; lesion characteristics Recognize transition to progressive MS Unresolved issues: Optimal definition, incomplete assessment; integration with treatment risks