www.excemed.org

IMPROVING THE PATIENT’S LIFE THROUGH

MEDICAL EDUCATION

MS Academia: Multiple sclerosis advanced course

13 September 2016 - London, UK

www.excemed.org

IMPROVING THE PATIENT’S LIFE THROUGH

MEDICAL EDUCATION

Assessment of treatment response

Robert J. Fox

Disclosure

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

Dr. Fox has received consulting fees from Actelion, Biogen, Genentech, Mallinckrodt, Novartis, Teva, and Xenoport; and research support from Novartis.

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

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

“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

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

MRI Predictors of Disability

Prosperini et al, Eur J. Neurol. 2009

New MRI lesions are 5-20x more predictive of future disability than relapses

and disability progression

Progressive disability at 5 yrs,

according to disease activity during first year of IFNβ therapy

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

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

NEDA with Natalizumab

No relapse, EDSS progression, or new MRI lesions

p < 0.0001 p < 0.0001 p < 0.0001

% D

ise

as

e A

cti

vit

y F

ree

Havrdova et al. Lancet Neurology 2009;8:254-60

NEDA at 2 years:

Placebo Natalizumab

7% 37%

Fold-Increase 5.3

NEDA with Fingolimod

Kappos et al., AAN 2011

NEDA at 2 years:

Placebo Fingolimod

13% 38%

Fold-Increase 2.9

NEDA with Dimethyl Fumarate

Giovannoni et al., AAN 2012

NEDA at 2 years:

Placebo Tecfidera

15% 28%

Fold-Increase 1.9

NEDA with Teriflunomide

Freedman MS et al. AAN Annual Mtg, 2012; New Orleans, LA. PD05.007

14,3 18,4

22,9

0

20

Placebo Teriflunomide 7 mg Teriflunomide 14 mg

No relapses, MRI activity or EDSS worsening

Pro

po

rtio

n o

f P

atie

nts

(%

)

NEDA at 2 years:

Placebo Teriflunomide

14% 23%

Fold-Increase 1.9

NEDA and MS DMTs

Study Placebo Active Arm Fold

natalizumab (AFFIRM) 7 37 5.3

cladribine (CLARITY) 16 44 2.8

Fingolimod (FREEDOMS) 13 38 2.9

BG-12 (DEFINE) 15 28 1.9

2 years

1 year

Study Placebo Active Arm Fold

natalizumab (AFFIRM) 15 47 3.0

Daclizumab-HYP 11 39 3.5

Pegylated IFNβ1a Q2W 15 34 2.2

Fingolimod vs IFNß-1a IM

Khatri et al. AAN 2012

NEDA at 1 year:

IFNß-1a (IM)

Fingolimod

34%

46%

Fold-Increase 1.4

Dimethyl fumarate vs glatiramer acetate

(*) Glatiramer Acetate in CONFIRM was an active comparator arm

NEDA at 2 years:

BG-12 BID GA

18% 12%

Fold-Increase 1.5

NEDA and MS DMTs

Study Duration Comparator Test Drug Fold

TRANSFORMS IFNß-1a 30 g (IM) vs fingolimod

1 yr 34 46 1.4

CARE MS I IFNß-1a 44 g (SC) vs alemtuzumab

2 yr 27 39 1.4

CARE MS II IFNß-1a 44 g (SC) vs alemtuzumab

2 yr 13.6 32.2 2.4

CONFIRM GA vs BG-12 BID

2 yr 12 20 1.5

NEDA and Improvement

A d ju s t e d h a z a r d r a t i o : 1 . 9 1 8 , 9 5 % C I : ( 1 . 3 7 4 , 2 . 6 7 8 ) ,

p - v a l u e : 0 . 0 0 0 1

NEDA and Patient Reported Outcomes

Bates et al. PS 34- CMSC 2009

NEDA in Clinical Practice

NEDA from general clinical practice cohort

Rotstein et al. JAMA Neurol. 2015;72(2):152-158.

2-year NEDA: positive predictive value of 78% for no progression at 7y

negative predictive value of 41-43%

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

Brain Volume and NEDA

Perez-Miralles et al. Neurol Neuroimmunol Neuroinfl 2015; 21:916-924

1-year brain volume change: -0.86% cut-off yielded sensitivity 71.4% and

specificity 65.5%

Brain Volume and NEDA

Kappos et al, Mult Scler J, 2015

Atrophy estimated from 4 MRIs over 2 years were used to apply cut-offs

for atrophy progression

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

Defining Breakthrough Disease Activity

Sormani and De Stefano, Nature Rev Neurol 2013

Sormani and De Stefano, Nature Rev Neurol 2013

Non-responders behaved similarly to placebo

Defining Breakthrough Disease Activity

Canadian MS Working Group Recommendations

Freedman et al, Can J. Neurol Sci, 2013

Change treatment for:

- 1 High, or

- 2 Moderates, or

- 3 Lows

Limitations:

• Somewhat cumbersome

• Doesn’t integrate transition to progressive MS

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