1. Practical Perspectives on Clinical Controversies in MS A Case-Based Approach
Thursday, May 31, 2018
MODERATOR
Stephen Krieger, MD
Associate Professor of Neurology
Director
Neurology Residency Program
Icahn School of Medicine at Mount Sinai
New York, New York
MS = multiple sclerosis

2. Program Agenda Welcome, Instructions, and Introductions
Stephen Krieger, MD
Treatment Decisions in Clinically Isolated Syndrome: Impact of the 2017 Updated McDonald Criteria
Management Considerations for Highly Active RRMS
Anne Cross, MD
Pregnancy in MS: Strategies for Care
Maria Houtchens, MD, MMS
Review of High-Efficacy Therapies in Development
Thomas Leist, MD, PhD
Questions & Answers
All Faculty 

3. Treatment Decisions in Clinically Isolated Syndrome Impact of the 2017 Updated McDonald Criteria
MODERATOR
Stephen Krieger, MD
Associate Professor of Neurology
Director
Neurology Residency Program
Icahn School of Medicine at Mount Sinai
New York, New York

4. Emily 26 years old Recent experience of eye pain and blurred vision
New patient visit

5. The CIS Describes a first episode of neurologic symptoms that
Lasts at least 24 hours
Is caused by inflammation and demyelination in ≥ 1 or sites in the CNS
Can be either monofocal or multifocal
Common synonyms
First attack
Initial demyelinating event
"Singular sclerosis"
Miller DH, et al. Lancet Neurol. 2012;11:

6. Monofocal vs Multifocal
1 neurologic sign or symptom
1 lesion
Optic neuritis
Multifocal
> 1 sign or symptom
Lesion in > 1 place
Optic neuritis + weakness
Miller DH, et al. Lancet Neurol. 2012;11:

7. CIS as the Outset of MS
Up to 85% of patients with MS present with a single isolated episode of demyelination
Thus, identifying these patients when they present with earliest MS is crucial to prevention of accumulation of burden of disease and, therefore, disability
Although little head-to-head data exist, many therapeutic agents do show benefit in delaying conversion from CIS to CDMS
Miller DH, et al. Lancet Neurol. 2012;11:

8. Symptoms of CIS Brainstem Syndromes Spinal Cord Syndromes
Transverse myelitis
Asymmetric limb weakness
Sphincter symptoms
Optic Neuritis
Pain on eye movement Reduced visual acuity
Afferent pupillary defect
Brainstem Syndromes
Internuclear ophthalmoplegia
Sixth nerve palsy
Vertigo
Facial sensory loss
Miller DH, et al. Lancet Neurol. 2012;11:

9. The Differential Diagnosis of CIS
Idiopathic demyelinating diseases
ADEM, NMO, CRION
Inflammatory nonidiopathic diseases
Sarcoidosis, Behçets, vasculitis, SLE, Susac syndrome
Noninflammatory CNS diseases
Stroke (ischemic optic neuropathy), metabolic disorders (B12 deficiency), structural disorders (compressive myelopathy)
Nonpathological disorders
Complex migraine
Nonneurologic disorders
Psychogenic, somatoform, conversion, anxiety

10. IMAGE NO LONGER AVAILABLE
MS MRI Diagnostic Criteria Specificity for Dissemination in Space and Time
IMAGE NO LONGER AVAILABLE
*On either baseline or follow-up MRI.
a. McDonald WI, et al. Ann Neurol. 2001;50: ; b. Polman CH, et al. Ann Neurol. 2005;58: ; c. Montalban X, et al. Neurology. 2010;74: 10

11. Multiple Sclerosis Misdiagnosis
Contributors to MS Misdiagnosis[a]
Yes n (%)
Inappropriate application to MS diagnostic criteria of neurologic symptoms atypical for a demyelinating attack
72 (65)
Inappropriate application to diagnostic criteria of a historical episode of neurologic dysfunction without corroborating objective evidence of a lesion (on neurologic examination, evoked potentials, or imaging)
53 (48)
Overreliance on the presence of MRI abnormalities meeting DIS to confirm a diagnosis of MS in a patient with "nonspecific neurologic symptoms"
66 (60)
Nature Reviews Neurology
The Tension Between Early Diagnosis and Misdiagnosis of Multiple Sclerosis[b]
Andrew J. Solomon; John R. Corboy
a. Solomon AJ, et al. Neurology. 2016;87: ; b. Solomon AJ, et al. Nat Rev Neurol. 2017;13:

12. Rationale for McDonald 2017 Revision
Several reasons behind the current revision
Recognition that MS is frequently misdiagnosed
Noting the McDonald criteria were not designed to differentiate MS from its mimics
New data on the relationship between MS and NMOSD
Recently revised criteria from MAGNIMS
Removes the distinction between asymptomatic and asymptomatic enhancing lesions
New data showing use of CSF in diagnosis and the need to emphasize its value
Need for better performance of the criteria in special populations
Pediatric
Asian persons
Latin American persons
Identification of subsets of patients with a high likelihood of MS but in whom the criteria are not diagnostic – Increased Sensitivity
Thompson AJ, et al. Lancet Neurol. 2018;17:

13. 2017 McDonald Criteria Revisions
5/14/2019 8:25 AM
2017 McDonald Criteria Revisions
DIS
2 attacks, or ≥ 1 T2 lesion in ≥ 2 locations (periventricular, cortical/juxtacortical, infratentorial, spinal cord)
Symptomatic and asymptomatic lesions can count
DIT
2 attacks, or simultaneous Gd+ and Gd- lesions, or new lesion on follow-up MRI
Symptomatic and asymptomatic lesions can count
With typical CIS meeting DIS,
CSF with OCBs allows diagnosis -- substitutes for DIT
Thompson AJ, et al. Lancet Neurol. 2018;17:
© 2007 Microsoft Corporation. All rights reserved. Microsoft, Windows, Windows Vista and other product names are or may be registered trademarks and/or trademarks in the U.S. and/or other countries.
The information herein is for informational purposes only and represents the current view of Microsoft Corporation as of the date of this presentation. Because Microsoft must respond to changing market conditions, it should not be interpreted to be a commitment on the part of Microsoft, and Microsoft cannot guarantee the accuracy of any information provided after the date of this presentation. MICROSOFT MAKES NO WARRANTIES, EXPRESS, IMPLIED OR STATUTORY, AS TO THE INFORMATION IN THIS PRESENTATION.

14. Archetypal MS IMAGE NO LONGER AVAILABLE Periventricular lesion
Ovoid, radiating, "Dawson fingers," right angle to ventricle, inferior callosal involvement
Images courtesy of Stephen Krieger, MD.
Bakshi R, et al. Neurology. 2004;63(suppl):S3.

15. McDonald 2017 Cortical and Juxtacortical Lesions
Images courtesy of Matilde Inglese, MD, PhD.

16. MS Classic Spinal Cord Lesion
Image courtesy of Maxim Bester, MD.

17. IMAGE NO LONGER AVAILABLE
Effect of Presence of Spinal Cord Lesions on Time to Conversion From CIS to CDMS: Survival Curves
IMAGE NO LONGER AVAILABLE
Reproduced from Sombekke MH, et al. Neurology. 2013;80:69-75.

18. Predictive Markers of Disease Evolution After CIS
Presence of OCBs in CSF -- can be diagnostic for MS in some circumstances
Multifocal presentation
Spinal cord lesions
High T2 burden of disease on MRI
More infratentorial lesions on baseline MRI (brainstem, cerebellum)
Pyramidal and cerebellar symptoms
Younger age of onset, < 30 years of age

19. Emily 26-y-old woman presenting with left optic neuritis
Does she need a spinal tap to diagnose MS?
In this case no, though it may be beneficial to have such additional information
T2W Images
Post-Gd T1W Image
MRI images courtesy of Matilde Inglese, MD, PhD.

20. CIS Treatment Delays Onset of CDMS
Using older iterations of the McDonald criteria for CIS/MS, trials have shown benefit with
IFN-β1a (CHAMPS, REFLEX, ETOMS)[a]
IFN-β1b (BENEFIT)[a]
Glatiramer acetate (PreCISe)[a]
Teriflunomide (TOPIC)[b]
Cladribine (ORACLE)[c]*
*Not FDA-approved for the treatment of MS.
a. Freedman MS, et al. Mult Scler Relat Disord. 2014;3: ; b. Miller AE, et al. Lancet Neurol. 2014;13: ; c. Freedman MS, et al. Mult Scler J Exp Transl Clin. 2017;3:

21. Management Considerations for Highly Active MS
Anne Cross, MD
Professor of Neurology
Washington University School of Medicine
St Louis, Missouri

22. Maria
27 years old
Onset of MS at age 19
Has tried multiple MS drugs

23. What Is HAMS?
No universally accepted definition but generally refers to patients with relapsing MS and involves
CLINICAL[a]
Frequent relapses
Severe relapses, often multifocal
Incomplete recovery from relapses
Accrual of disability (physical or cognitive)
IMAGING[a]
High burden of MRI lesions
Frequent Gd+ lesions
Early brain atrophy
Continued Gd+ lesions despite MS therapy
Increasing T2w lesion burden despite MS therapy
Another published HAMS definition: ≥ 2 disabling relapses in 1 year AND MRI activity[b]
HAMS implies significant inflammatory activity[a]
Rapidly progressive MS without relapses or acquisition of new MRI lesions is not HAMS
a. Freedman MS, et al. Continuum ;22: ; b. Menon S, et al. J Neurol Neursurg Psychiatry. 2013;84:

24. Who Is at Higher Risk of Having HAMS?
African American people[a]
Children[b]
Hispanic people (?)*
Men > women[c]
*Hispanic -- not 100% clear; study results differ.
a. Cree BA, et al. Neurology. 2004;63:
b. Bigi S, et al. J Child Neurol. 2012;27:
c. Menon S, et al. J Neurol Neurosurg Psych. 2013;84:

25. Treatment Considerations for HAMS
Weigh benefits of proposed therapies against their risks
Many MS specialists think the treatment algorithm should be adjusted for HAMS toward using more aggressive, but typically also riskier, DMTs

26. What Characteristics in a DMT Are Needed for HAMS Treatment?
Clinical*
Rapid onset of action (preferably < 2 months)
Reduces relapse rate > 50% vs placebo
Slows accumulation of neurologic disability
Good data for prolonged NEDA
Imaging*
Reduces new lesion/Gd+ lesion formation on MRI
Reduces "persistent black hole" development
Slows brain and spinal cord atrophy
*These are not evidence-based; taken from consensus papers, conferences, and my own opinion.

27. Caveats on the Tables to Follow
The studies reported in these tables are not strictly comparable
Different times
Different diagnostic criteria for MS
In different geographic locations
With differing inclusion and exclusion criteria
Different trial methodologies
Different endpoints
Different MRI scanner technologies
NEDA is controversial and may not be predictive of long-term response
This is an attempt to compare the agents specifically for the patient with HAMS

28. Effects on ARR (Relative and Absolute) of the Main DMTs
Agent
Trials/Duration
ARR ↓ vs Placebo
Absolute ↓
IFN-β1b 250 μg qod SC
1993/3 years[a]
34%↓
0.43 (1.27 vs 0.84 at 3 y)
IFN-β1a 30 μg/wk
1996/2 years-stopped early[b]
18%-21%↓
0.15 (0.82, 0.67 all; 0.9, 0.61, 104-wk subset)
IFN-β1a 44 μg SC tiw
PRISMS/1998/2 years[c]
33%↓
Not found
IFN-β1a 125 μg q2w
ADVANCE/2014/48 weeks[d]
35%↓
0.141 ↓ (48 wk)
Glatiramer acetate 20 mg
1995/2 years[e]
29%↓
0.25 ↓ (0.84 vs 0.59)
Glatiramer 40 mg tiw
GALA/2013/1 years[f]
34%
0.174 ↓ (0.51 vs 0.33)
Natalizumab
AFFIRM/2006/2 years[g]
68%↓
0.5 ↓ (0.73, 0.23 at 2 y)
Alemtuzumab 12 mg/d or 24 mg/d
CARE MS I and II/2012/2 years both[h,i]
55% ↓, 49% ↓ vs IFN-β1a 44 ug SC tiw
0.26 ↓ CARE II
Ocrelizumab (vs IFN-β1a 44 μg)
OPERA I and II/2017/96 weeks[j]
46% and 47% ↓ vs IFN-β1a
0.13, 0.13 ↓
Fingolimod 5 mg
FREEDOMS/2010/2 years[k] FREEDOMS II/ 2014/2 years[l]
TRANSFORMS/ 2010/1 years[m]
54%, 48% (52% vs IFN-β1a IM)
0.22 ↓
Teriflunomide 14 mg po/d
TOWER/2014/variable, ≥ 48 weeks; TEMSO/2011/108 weeks[n,o]
36% ↓, 31% ↓ (TOWER, TEMSO)
0.18, 0.17↓ (TOWER, TEMSO)
Dimethyl fumarate
DEFINE, CONFIRM/2012/2 years both[p,q]
49%, 44% ↓ (DEFINE, CONFIRM)
0.19 ↓ (DEFINE)
Future? Cladribine 3.5 mg/kg*
CLARITY/2010/96 weeks[r]
57.6% ↓
0 .19 ↓ (0.33 vs 0.14)
*Not FDA approved for the treatment of MS Bold: >50% reduction vs placebo/comparator.
a. The IFNB Multiple Sclerosis Study Group 1993; b. Jacobs 1996; c. PRISMS study group 1998; d. Calabresi 2014; e. Johnson 1995; f. Davis 2017; g. Polman 2006; h. Cohen 2012; i. Coles 2012; j. Hauser 2017; k. Kappos 2010; l. Calabresi 2014 ADVANCE; m. Cohen 2010; n. Confavreux 2014; o. O'Connor 2011; p. Gold 2012; q. Fox 2012; r .Giovannoni

29. Time to Onset of Benefits for the Main DMTs
Agent
Trials/Duration
Onset of Effect
IFN-β1b 250 μg qod sc
1993/3 years[a]
3 wk (in MRI study of 8 subjects), 60 d in pivotal trial by clinical separation and by MRI effect[a]
IFN-β1a 30 μg/wk
1996/2 years-stopped early[b]
< 26 wk (progression on Kaplan-Meier curve)
IFN-β1a 44 μg SC tiw
PRISMS/1998/2 years[c]
≤ 2 mo, (monthly MRI subgroup)
IFN-β1a 125 μg q2w
ADVANCE/2014/48 weeks[d]
≤ 12 wk (Kaplan-Meier extrapolation)
Glatiramer acetate 20 mg
1995/2 years[e]
No data
Glatiramer 40 mg tiw
GALA/2013/1 year[f]
≤ 6 mo (↓ cumulative # T1W & T2W lesions)
Natalizumab
AFFIRM/2006/2 y[earsg]
≤ 4 wk by MRI activity
Alemtuzumab 12 mg/d or 24 mg/d
CARE MS I & II/2012/2 years both[h,i]
≤ 3 mo (based on ARR, CARE I, disability, CARE II; monthly MRI study where 3/7 patients had new lesions up to 3 mo)
Ocrelizumab (vs IFN-β1a 44 μg)
OPERA I & II/2017/96 weeks[j]
≤ 8 wk (full effect, some effect at 4 wk on MRI, Kappos Ph 2)
Fingolimod
FREEDOMS/2010/2 years; FREEDOMS II/2014/ 2 years[k,l,]
≤60 d (phase 2 relapse, MRI)
Teriflunomide 14 mg po/d
TOWER/2014/variable, ≥48 weeks; TEMSO/2010/108 weeks[m,n]
≤12 wk (TOWER disability on Kaplan-Meier)
Dimethyl fumarate
DEFINE, CONFIRM/2012/2 years both[o,p]
≤ 6 mo (based on ARR in DEFINE)
Future? Cladribine 3.5 m/kg*
CLARITY/2010/96 weeks[q]
≤12 wk (relapse on Kaplan-Meier)
*Not FDA approved for the treatment of MS. Bold: ≤2 months onset of efficacy on MRI or relapse rate.
a. The IFNB Multiple Sclerosis Study Group 1993; b. Jacobs 1996; c. PRISMS Study Group 1998; d. Calabresi 2014; e. Johnson 1995; f. Davis 2017; g. Polman 2006; h. Cohen 2012; i. Coles 2012; j. Hauser 2017; k. Kappos 2010; l. Calabresi. 2014; m. Confavreux 2014; n. O'Connor 2011; o. Gold 2012; p. Fox 2012; q .Giovannoni 2010.

30. IMAGE NO LONGER AVAILABLE
Cumulative Mean Number of New Gd-Enhancing Lesions on MRI in Each Group During Treatment
IMAGE NO LONGER AVAILABLE
From Miller DH. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2003;348: Copyright © Massachusetts Medical Society. Reprinted with permission from Massachusetts
Medical Society.

31. NEDA, NEDA-3, NEDA-4
NEDA: may be useful measure for assessing relative therapeutic efficacy
NEDA-3: no relapses, no progression, no MRI activity (new or Gd+)
NEDA-4: includes brain volume
FREEDOMS and FREEDOMS extension (N > 900)[a]
NEDA-3 at 1 year best at predicting time to first relapse, occurrence of first relapse, new T2W lesions
NEDA-4 better at predicting disability progression, risk for EDSS 6 or worse
NEDA-3 in Brigham and Women's 7-y cohort (n = 219; CIS or RRMS)[b]
NEDA-3 at 2 years had a positive predictive value of 78.3% for no progression (EDSS by 0.5) at 7 years
NEDA UCSF cohort (n = 517; 366 RRMS)[c]
Proportion of patients meeting NEDA definition declined substantially over time
NEDA at year 2 was not associated with statistically significant EDSS outcomes at year 10
The NEDA group showed a trend toward more, rather than less, worsening in EDSS score over the long term
Many patients meeting NEDA criteria at 2 years subsequently developed significant disability
a. Kappos L, et al. Mult Sclerosis 2016;22: ; b. Rotstein D et al. JAMA Neurol. 2015;72: ; c. University of California, San Francisco MS‐EPIC Team, et al. Ann Neurol ;80:

32. NEDA Rates With the Main DMTs
Agent
NEDA vs placebo*
Timeframe of NEDA
IFN-β1b NA
IFN-β1a 30 μg IM wk
21%[a]
at 3 years in COMBI Rx
IFN-β1a 44 μg SC tiw
27.1% (no placebo control)[b]
~2 years (OPERA)
IFN-β1a 125 μg SC q2w
33.9% vs 15.1%[c]
48 weeks
Glatiramer acetate
19%[a]
Natalizumab
37% vs 7%[d]
2 years (post hoc of AFFIRM)
Alemtuzumab
CARE-MS I: 39% vs 27% (vs IFN-β1a)[e]
CARE MS II: 32% vs 14% (vs IFN-β1b)[f]
~ 40% for next 3 y; no controls[g]
2-year study
5 y (2-y study + next 3 y)
Fingolimod
31% vs 9.9% NEDA-3
19.7% vs 5.3% NEDA-4 (includes BV)[h]
2 years
Dimethyl fumarate
26% vs 12%[i]
2 years
Teriflunomide 14 mg
28.1% vs 14.3%[j]
Month 6 to month 24
Ocrelizumab
47.7% vs 27.1% (IFN-β1a )[b]
~ 2 years
Future? Cladribine†
41.7% vs 15.1% [k]
96 week (combined CLARITY and ONWARD)
*Unless otherwise noted.
†Not FDA approved for the treatment of MS.
a. Rotstein 2015; b. Havrdova 2018; c. Arnold 2014; d. Havrdova 2009; e. Cohen 2012; f. Coles 2012; g. Havrdova. 2017; h. Kappos 2016; i. Havrdova 2017; j. Chan 2016; k. Giovannoni

33. Hierarchical Effects on Relative Risk for Relapse at 2 Years in RRMS per AAN Guideline Subcommittee
Agent (Risk Ratio) [a]
AAN Confidence [a]
Alemtuzumab (0.43)
High*
Rituximab (0.51, extrapolate to ocrelizumab?)
Moderate
Cladribine (0.53)†
Natalizumab (0.56)
Fingolimod (0.57)
IFN-β1a 125 μg q2w (pegylated) (0.62)
High
Dimethyl fumarate (0.64)
IFN-β1a 30 μg IM/week (0.79)
Glatiramer acetate/IFN-β1b 250 μg qod (0.82)
Both moderate
IFN-β1a 44 μg tiw (0.84)
Teriflunomide (0.88)
*Clinicians should prescribe 1 of these 3 agents for people with HAMS — Level B recommendation.[b]
†Not FDA-approved for the treatment of MS.
a. Rae-Grant A, et al. Neurology. 2018;90:
b. Rae-Grant A, et al. Neurology. 2018;90:

34. Effects on Disability and Level of Confidence Assigned by AAN Guideline Subcommittee
Agent
Disability vs Placebo*
AAN Confidence for Disability[a] ↓
IFN-β1b
29% ↓ pivotal trial (NS)[b]
Very low
IFN-β1a 30 μg IM/wk
37% ↓[c]
High
IFN-β1a 44 μg SC tiw
38% ↓ (2 year)[d]
IFN-β1a 125 μg SC q2wk (48-wk trial)
38% ↓[e]
Glatiramer acetate (3 y)
28% ↓ (pivotal trial)[f]
Low
Natalizumab
42%↓ (AFFIRM)[g]
Alemtuzumab
(CARE-MS I); 42% ↓ CARE-MS II vs IFN-β1a[h,j]
High vs comparator
Fingolimod
32% ↓ (FREEDOMS)[j]
Dimethyl fumarate (2 y)
38% ↓ DEFINE; 21% ↓ (CONFIRM)[k,l]
Teriflunomide 14 mg
32%, 30% ↓TOWER, TEMSO[m,n]
Ocrelizumab
40% ↓ vs IFN-β1a[o]
Future? Cladribine†
33% ↓ in CLARITY[p]
Moderate
*Unless otherwise noted; †Not FDA approved for the treatment of MS.
a. Rae-Grant 2018; b. The IFNβ Multiple Sclerosis Study Group 1993; c. Jacobs 1996; d. PRISMS Study Group 1998; e. Calabresi 2014; f. Johnson 1995; g. Polman 2006; h. Havrdova 2017; i. Coles 2012; j. Kappos 2010; k. Gold 2012; l. Fox 2012; m. Confavreux 2014; n. O'Connor 2011; o. Hauser 2017; p. Giovannoni 2010.

35. Imaging Benefits for the Main DMTs
Agent
Trial Name
MRI vs Placebo*
IFN-β1b (3 y)
None — pivotal trial[a]
Median 80% ↓ active scans; 75% ↓ in new lesion formation in q6w subgroup
IFN-β1a 30 ug IM wk
None[b]
51% ↓ Gd+ lesions at 2 years
IFN-β1a 44 ug SC tiw
PRISMS[c]
Median 78% ↓ in active scans
IFN-β1a 125 ug SC q2w
ADVANCE[d]
Mean 67% ↓ at 48 wk new/enlarging lesions
Glatiramer acetate 20 mg/d
None — pivotal trial
Glatiramer acetate 40 mg tiw
GALA[e]
6 mo: 38% ↓ Gd+ lesions; 24.2% ↓ new/enlarging lesions
12 mo: 52.5% ↓ Gd+ lesions; 47.3% ↓ new/enlarging lesions
Natalizumab (2 y)
AFFIRM[f]
92% ↓ Gd+; 83% ↓ new/enlarging
Alemtuzumab (2 y)
CARE-MS I and II (vs IFN-β)[g]
37%, 39% ↓ Gd+ (CARE I, II); 40% ↓, 24% ↓ BVL (CARE-I, II) NOTE: vs BIFN1a. Both almost 90% activity-free in years 1, 2
Fingolimod
FREEDOMS[h]
79% ↓ Gd+; 36% ↓ BVL
Teriflunomide
TEMSO[i]
67% ↓ lesion volume vs placebo
Dimethyl fumarate (2 y both)
DEFINE[j], CONFIRM[k]
85% ↓; 71% ↓ new/enlarging DEFINE, CONFIRM
Ocrelizumab
OPERA I and II (vs IFN-β1a)[l]
94%-95% ↓ Gd+; 77%-83% ↓ new/enlarging (vs IFN-β1a)
Future? Cladribine (96 wk) †
CLARITY [m]
85.7% ↓ Gd+; 73.4% ↓ active T2W lesions
*Unless otherwise noted; †Not FDA-approved for the treatment of MS.
a. Paty 1993; b. Jacobs 1996; c. Manfredonia 2008; d. Calabresi 2014; e. Davis 2017; f. Polman 2006; g. Coles 2012; h. Kappos 2010; i. O'Connor 2013; j. Gold 2016; k. Fox 2012; l. Hauser 2017; m. Giovannoni 2010.

36. Characteristics Needed for HAMS Treatment Which DMTs Do Best?
Clinical
Rapid onset of benefit (preferably < 2 months)
IFN-β, natalizumab, alemtuzumab, fingolimod, ocrelizumab (maybe others)
Reduces relapse rate > 50% vs placebo
Natalizumab, fingolimod, ocrelizumab, cladribine* (dimethyl fumarate borderline)
> 90% reduction Gd+ lesions
Natalizumab, ocrelizumab
> 80% reduction Gd+ lesions
Natalizumab, ocrelizumab, cladribine,* fingolimod, dimethyl fumarate, fingolimod, alemtuzumab (IFN-β1a almost)
Slows accumulation of neurologic disability > 40% vs comparator
Alemtuzumab, ocrelizumab
> 30% 2-year NEDA
Natalizumab, alemtuzumab, fingolimod, ocrelizumab, cladribine*
Subgroup analyses in patients with HAMS of alemtuzumab, natalizumab, fingolimod, and cladribine* showed benefit
*Not FDA-approved for the treatment of MS.

37. Summary Thoughts and Recommendations
HAMS means significant relapse activity and acquisition of new lesions on MRI
HAMS represents highly inflammatory pathology
Relapses affect quality of life and can lead to accumulation of permanent neurologic impairment
Rapid onset of benefit seen with natalizumab, ocrelizumab, fingolimod, and the IFN-βs
5 DMTs (natalizumab, alemtuzumab, fingolimod, ocrelizumab, and cladribine*) show best results, while acknowledging the caveats that go along with between-trial comparisons
*Not FDA-approved for the treatment of MS.

38. Pregnancy in MS Strategies for Care
Maria Houtchens, MD, MSSc
Assistant Professor of Neurology
Brigham and Women's Hospital
Boston, Massachusetts

39. Rachel
32 years old
Considering pregnancy

40. Epidemiology of MS in Women
MS prevalence in United States: /100,000[a]
899,624 in 2010
947,484 in 2017
Almost 200,000 are women between 18 and 44 years old[a]
A significant number of patients are women who have either been pregnant after MS diagnosis or will become pregnant after MS diagnosis[b]
Prevalence of MS in Women Aged 18 to 44 years in 2010
IMAGE NO LONGER AVAILABLE
a. Wallin MT, et al. ECTRIMS Poster P344.

41. Individualized Reproductive Counseling
Patient
Younger, reproductive years
Older, menopausal transition
Reproductive plan
Not ready or no desire for a family
Planning for pregnancy
No family planning needs
Appropriate counseling
Newly-diagnosed young adults may not be ready to plan for a family, and must be counseled on contraception1
MS patient who plan on becoming a mother will need to discuss
How MS might affect fertility, pregnancy, childbirth, and breast-feeding1
Multidisciplinary and personalized approaches can help optimize reproductive outcomes2
Heredity of MS: While first degree relatives (siblings, parent, children) of MS patients have an increased relative risk of MS compared with the age-adjusted background population, the likelihood of not getting the disease in children of MS patients is approximately 98%3
How to cope with parenting4
The uncertainty of MS and the possibility of future disability, with the accompanying impact on finances, family roles, the physical ability to care for a child and the heredity of MS1,5
MS patients reaching menopausal transition age may benefit from discussion on perimenopausal changes that may exacerbate MS symptoms, overlap between menopause and MS-related symptoms and co-morbidities6
1. Giesser B et Benedetto-Anzai MT. Talking about Reproductive Issues. Prof Resource Center National MS Society; 2. Borisow N et al. The EPMA Journal 2012; 3:1-10; 3. Compston A, Coles AJ. Lancet 2008;372: ; 4. Prunty M et al. Mult Scler 2008;14:701-4; 5. Alwan S et al. MSJ. 2013; 19: ; 6. Bove et al. J Neurol 201;261:
Reliable contraception
Sexual dysfunction
Fertility/conception
Pregnancy/childbirth
Postpartum, breastfeeding, coping with parenting
DMT discussion
Amato MP, et al. Neurol Sci. 2017;38:

42. How Do We Choose the Safest Time to Attempt Conception?
Personal decision (availability of a spouse or a partner, financial security, social support system, and health status of future parent[s])
Significant correlation between prepregnancy ARR × 12 mo preceding conception and postpregnancy relapse rate (untreated MS cohort)[a]
Need to consider potentially extended time off DMTs while attempting pregnancy
Probably helpful to stabilize an active patient with more effective therapies for 6 to 12 mo prior to attempting conception
Establish prepregnancy clinical and radiographic disease baseline
a. Vukusic S, et al. Brain. 2004;127:

43. Effects of Pregnancy on the Course of MS
PRIMS
First prospective study of 254 women with MS[a]
269 pregnancies[a]
Followed for up to 2 years after delivery
Results:
Relapse rate/y
Prepregnancy: 0.7[a,b]
Third trimester: 0.2 (~ 70% reduction)[a,b]
First 3 mo postpartum: 1.2; 72% of women did not experience any relapses[b]
ARR for the 21-month postpartum period did not differ significantly from the prepregnancy rate
Breastfeeding was not predictive of a subsequent relapse or of disability progression
From Confavreux C, et al. Rate of pregnancy-related relapse in multiple sclerosis. N Engl J Med. 1998;339: Copyright ©1998 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
a. Confavreux C, et al. N Engl J Med. 1998;339: ; b. Vukusic S et al. Brain. 2004;127:

44. Prepregnancy Support and Counseling
Individualized reproductive counseling
Psychological impact of pregnancy on MS
Pregnancy rates in patients with MS
Fertility and infertility in MS
Contraceptive options in MS
Family planning and optimizing conception attempts and timing
Preconception care and pregnancy testing

45. Infertility
Inability to conceive after 12 months of regular intercourse and optimal timing of conception attempts[a]
WHO definition now acknowledges this definition of infertility[a]
Delaying conception until the end of schooling/attainment of steady job -- overall increase in maternal age before the first conception in the Western world[b]
a. WHO website.
b. Balasch J, et al. Fetal Diagnos Therap. 2011;26:

46. Fertility in MS Study results mixed for ovarian reserve
Serum AMH levels[a]
Patients with MS (n = 76): ± ng/mL
Controls (n = 58): 3.34 ± ng/mL
No difference[b]
25 patients
25 control participants
Patients with MS more likely to employ artificial insemination to conceive[c]
MS: 4.9% (n = 3/61)
General population: 0.9% (n = 55,547)
Greater prevalence of factors related to decreased infertility in patients with MS
Endometriosis[d]
Sexual dysfunction (50% to 90%)[e]
Thyroid autoimmunity[f]
Treatment-related temporary amenorrhea or premature ovarian failure[g]
a. Thöne J, et al. Mult Scler. 2015;21:41-47; b. Sepulveda M, et al. Mult Scler. 2016;22: ; c. Jalkanen A, et al. Mult Scler. 2010;16: ; d. Katiyar A, et al. Front Genet. 2018;9:42; e. Houtchens MK, et al. Semin Neurol. 2017;37: ; f. Perga S, et al. Front Immunol 2018;9:311; g. Alroughani R. Mult Scler. 2014;20:

47. Prevalence of Infertility and Infertility Treatments in MS
Objective
To compare the prevalence of infertility and infertility treatments administered to women with and without MS, based on a US retrospective commercial claims analysis
Study Population
US women with MS ICD-9-CM: 340.xx
Aged 18 to 55 years
≥ 1 y of continuous insurance eligibility
Sample selection
117,041 women with MS
Comparator group: 1,422,836 women without MS
Variable
Women With MS, n (%)
Women Without MS, n (%)
P Value
Infertility diagnosis
8254 (8.5)
7837 (8.1)
.0006
Fertility treatment
979 (1.0)
1150 (1.2)
.0002
Live birth
4843 (5.0)
6865 (7.1)
< .0001
Houtchens MK, et al. ECTRIMS Poster P356.

48. MS and Pregnancy Outcomes
Babies born to mothers with MS are slightly smaller for gestational age by weight (OR = 1.45)
No difference in Apgar scores in babies of mothers with MS
Increased rate of cesarean deliveries*
No increase in
Birth defects
Perinatal mortality
Other adverse fetal outcomes
*Primarily result of increase in rate of planned and not emergency deliveries.
Dahl J, et al. Neurology. 2005;65:

49. Preconception Care
Daily standard prenatal vitamins with 0.4 mg to 1 mg of folate[a]
Smoking and alcohol cessation
Improved sleep hygiene
Vitamin D3 supplementation: low levels are associated with[b]
Adverse pregnancy outcomes
Poorer clinical and radiologic MS course
Increased MS susceptibility in offspring
a. Bove R. Semin Neurol. 2016;36:
b. Jalkanen A, et al. Acta Neurol Scand. 2015;131:64-67.

50. Labor and Delivery
Method of labor and delivery does not affect the postpartum course of MS
Cesarean section to be considered in a woman with paraplegia, pelvic floor weakness, decreased or absent pelvic floor sensation
Epidural anesthesia or general anesthesia, if required, has no effect on postpartum course of MS
Consider stress-dose steroids for a woman with extended exposure to corticosteroids in pregnancy or prepartum

51. New FDA Pregnancy Disclosures
FDA goal: to support healthcare providers' understanding of drug product risks and benefits and to facilitate informed prescribing decisions and patient counseling
FDA website.

52. Former FDA Pregnancy Categories
New slide
Slide
Table
Ref1, FDA HHS Labeling
Pg30832/col2/S Pregnancy category A through pg30833/col1/S Pregnancy Category X
Ref 2, FDA CHEMM
Pg1/all
Pregnancy Category
Description
Category A
Adequate and well-controlled human studies have failed to demonstrate a risk to the fetus during the first trimester
No evidence of risk in later trimesters
Category B
No adequate and well-controlled studies in pregnant women
Animal studies have not demonstrated a risk
Category C
Animal studies have shown an adverse effect on the fetus
Potential benefits may warrant use of the drug in pregnant women despite potential risks
Category D
Studies in humans have demonstrated adverse reactions leading to human fetal risks
Category X
Studies in animals or humans have demonstrated adverse reactions leading to fetal abnormalities
Risks involved in the use of the drug in pregnant women clearly outweigh potential benefits
Speaker Notes
Bullet 1
The FDA requires...
Ref 1, FDA HHS Labeling
Pg30832/col2/P2/ln1-11
Bullet 2 and sub 1
Unless a drug... Ref 1, FDA HHS Labeling
Pg30832/col2/P2/all
Ref 2, FDA CHEMM
Pg1/all
HHS website.
Bullet 3
A discussion... Ref 1, FDA HHS Labeling
Pg30831/col2/P1/ln14-19
Bullet 4
Lactation categories... Ref 1, FDA HHS Labeling
Pg30833/col2/P2/ln8-17
Bullet 4, sub
For example... Ref 1, FDA HHS Labeling
Pg30833/col2/P3/all

53. MS DMTs and Former FDA Pregnancy Risk Categories
Category
MS Therapy
Category A NA
Category B
Glatiramer acetate[a]
Category C
Alemtuzumab[b]
Dimethyl fumarate[c]
Fingolimod[d]
IFN-βs[e-h]
IVIg*[i]
Natalizumab[j]
Ocrelizumab[k]
Rituximab*[l]
Category D
Azathioprine*[m]
Cyclophosphamide*[n]
Mitoxantrone[o]
Category X
Methotrexate*[p]
Teriflunomide[q]
*Not FDA-approved for the treatment of MS.
a. Copaxone PI 2018; b. Lemtrada PI 2017; c. Tecfidera PI 2017; d. Gilenya PI 2018; e. Avonex® PI 2016; f. Betaseron® PI 2016; g. Extavia® PI 2016; h. Rebif® PI 2015; i. Gammaplex PI 2015; j. Tysabri® PI 2018; k. OcrevusTM PI 2017; l. Rituxan® PI 2018; m. Imuran® PI 2011; n. EndoxanTM PI 2013; o. Novantrone® PI 2012; p. Methotrexate PI 2016; q. Aubagio® PI 2016.

54. Natalizumab Risk in Pregnancies
Animal studies[a]
Not teratogenic
Increased risk for miscarriage in 1 of several studies
Human studies
Preliminary data show no increased risk (birth weight, malformation, abortion)[b]
During the second quarter, transplacental transport of antibodies observed[c]
Caveat: if given during the last quarter of pregnancy, hematologic screening of the newborn is necessary[d]
40% of natalizumab-treated women have relapses during pregnancy if it is discontinued before pregnancy onset[c]
Natalizumab crosses into breast milk[e]
a. Tysabri® PI 2004; b. Portaccio E, et al. Neurology. 2018;90:e823-e831; c. Portaccio E, et al. Neurology. 2018;90:e832-e839; d. Haghikia A, et al. JAMA Neurol. 2014;71: ; e. Proschmann U, et al. Mult Scler. 2017:

55. Long-Term Exposure to Natalizumab During Pregnancy
Data source
German MS and Pregnancy Registry
Prospectively collected
Standardized interview every 3 months throughout pregnancy and following 24 months
Analysis of natalizumab exposure
Observation
Exposure to Natalizumab, Weeks
< 24 (n = 6)
< 30 (n = 21)
> 30 (n = 13)
Newborn
Total 3 18 11
With HA 1 7
Relapse, no
During pregnancy
Postpartum 5
Kumpfel T, Thiel S, Meinl I, et al. Long-term exposure to natalizumab during pregnancy - a prospective case series from the German Multiple Sclerosis and Pregnancy Registry. Presented at: 7th Joint ECTRIMS-ACTRIMS Meeting; October 25-28, 2017; Paris, France. Abstract 204.
Kumpfel T, et al. ECTRIMS Abstract 204.

56. Fingolimod Risk in Pregnancies
Teratogenic in animal studies
Fertility is not reduced
No interaction with EE-LNG oral contraceptive
Worldwide pregnancy registries
280 pregnancies
Healthy newborns: 65
SA: 27
Elective termination: 49
Major congenital anomaly: 6
Recommendations
2 mo after last intake, sufficient contraception for women
Breastfeeding is contraindicated
Houtchens personal communication.

57. Disease Activity During Pregnancy After Fingolimod Withdrawal in Women With MS
Up to one-third of women on fingolimod treatment before pregnancy will experience an intrapartum relapse
Risk of intrapartum relapse is associated with duration of time off fingolimod before pregnancy
6% to 8% of this group of patients will have a significant increase of EDSS up to 6 mo postpartum
Hemat S, et al. AAN Abstract P5.032.

58. Rituximab and Ocrelizumab in Oncology and Rheumatologic Conditions
Patients
RA, NHL, SLE, ITP, transplants
Several cases of B-cell + NHL either relapsed or diagnosed in the first trimester of pregnancy and treated with 375 mg weekly for 4 doses
253 pregnancy cases identified; 153 with known outcomes
Live birth: 60%
Full-term delivery: 78%
< 37-week gestation: 24%
First-trimester SA: 21%
Elective termination 18%
Fetal demise*: n = 1
*22 weeks from nuchal cord.
Houtchens M. Personal communication.

59. Rituximab in MS and NMOSD
Retrospective single-center case series
11 pregnancies in 10 women treated with rituximab within 6 mo of conception
Pregnancy ongoing: 1
Live term birth: n = 9
Status unknown: 1
Time from rituximab infusion to conception: 1 to 6 months
Relapses
During pregnancy: 0
Postpartum: 1
Das G, et al. Neurol Neuroimmunol Neuroinflamm. 2018;5:e453.

60. Pregnancy Outcomes With Alemtuzumab Background
Alemtuzumab is approved in > 60 countries for the treatment of RRMS
It is undetectable in serum within 30 days of IV administration
Women of childbearing potential are advised to use effective contraception for 4 mo after treatment
Analysis of pregnancy data from clinical trials* of alemtuzumab
972 women treated with alemtuzumab
248 pregnancies among 156 women
9 pregnancies within 4 mo of alemtuzumab dosing
*CAMMS223, CARE-MS I and II, CAMMS503409, and TOPAZ trials.
Rog D, et al. ECTRIMS Poster P742.

61. Pregnancy Outcomes With Alemtuzumab Results
Parameter
Results
Age at conception, y
32.5 ± 4.4
Time from last alemtuzumab dose to conception, months
34.4 ± 22.7
Outcomes among 248 pregnancies, no.
Ongoing 14
Unknown 16
Completed
218
Live births with no congenital abnormalities or birth defects, (%)
147 (67)
SA, (%)
48 (22)
Elective termination, (%)
22 (10)
Stillbirth: nuchal cord, (%)
1 (0.5)
Rog D, et al. ECTRIMS Poster P742.

62. Pregnancy Outcomes With Cladribine Background
Women of childbearing potential are advised to use effective contraception for 6 mo after treatment
Based on theoretical considerations, the time from the first dose of active treatment with cladribine* to within 6 months after the last dose is considered to be the potential period during which patients may be exposed to any teratogenic effects of treatment
Analysis of pregnancy data from clinical trials of cladribine tablets
Patients treated
1976 with cladribine*
802 with placebo
Total exposure time in patient years
8650 with cladribine*
2361 with placebo
*Not FDA-approved for the treatment of MS.
John V, et al. ECTRIMS Poster P1874.

63. Pregnancy Outcomes With Cladribine Results
Placebo
(n = 20)
Cladribine†
(n = 44)
During the Cladribine† Risk Period (n = 16)
Among Partners of Men Taking Cladribine (n = 10)
Live birth‡
9 (45)
18 (41) 3 9 SA
5 (25)
9 (20) 2
Elective termination
Personal choice
4 (20)
14 (32) 10
Medically indicated
1 (5)
3 (7) 1
Unknown
*Data are presented as n (%).
†Not FDA-approved for the treatment of MS .
‡No congenital malformations.
John V, et al. ECTRIMS Poster P1874.

64. Optimal Characteristics of a DMT for a Patient With MS Considering Pregnancy
High-efficacy
Easy-to-manage administration
No teratogenic effects
Redosing needed only once or twice a year

65. Review of High-Efficacy Therapies in Development
Thomas Leist, MD, PhD
Professor of Neurology
Thomas Jefferson University
Philadelphia, Pennsylvania

66. Universal Treatment Goals in MS
Prevent relapses
Halt disability progression
Prevent brain lesions
Reduce the rate of brain atrophy
Long-term disease management and safety
Stringency
Free of apparent clinical disease activity
Free of apparent MRI disease activity
Rotstein DL et al. JAMA Neurol. 2015;72:

67. Evolving Outcome Measures in MS
Measurement
Conventional Disability
Composite Disability
NEDA 3
No Evidence of Disease Progression and Disease Activity
Expanded No Disability Progression and Disease Activity
Assessment of disability progression
EDSS score ✔
T25-FW
9-HPT
SDMT/cognitive measure
Assessment of disease activity
Relapses
MRI activity
Atrophy/adv measure

68. Additional Outcome Measures
Symbol Digit Modalities Test
Cognition
Symbols are paired with digits 1 to 9; patient provides the corresponding digit for a given symbol. Tests attention, visuoperceptual processing, working memory, and psychomotor speed
Low-Contrast Visual Acuity
Visual Acuity
Tests how well eyes function in low light and how well objects from similarly colored or shaded backgrounds can be distinguished; more sensitive than high-contrast letter charts

69. MS Treatment Landscape
CONFIDENTIAL - DO NOT DISTRIBUTE
MS Treatment Landscape
Cladribine†
Siponimod†
Ozanimod†
Ofatumumab†
1994
1996
2000
1998
2002
2004
2006
2008
2010
2012
2014
IFN-β1bSC
IFN-β1a IM
IFN-β1aSC
Natalizumab
Glatiramer
acetate
Fingolimod
Alemtuzumab
Teriflunomide
2016
Daclizumab*
Ocrelizumab
2018
DMF
2020
2022
DMF = dimethyl fumarate 
*Withdrawn.
†In development, not FDA-approved.

70. MS Treatment Landscape (cont)
CONFIDENTIAL - DO NOT DISTRIBUTE
MS Treatment Landscape (cont)
Presumed Mechanism of Action
Protein/peptide-based
Small molecular entities
Other
Presumed Mechanism of Action
Glatirameroids
Blocking
mAbs
(natalizumab)
Interferons
Modulating
(daclizumab –
withdrawn)
Depleting
(ocrelizumab,
rituximab
alemtuzumab)
Protein/peptide-based = parenteral medication
Immune
modulators
(teriflunomide;
S1P antagonists;
fumaric
acid esters)
Antimetabolite
agents
(cladribine*)
mAb = monoclonal antibody
MOA = mechanism of action
Small molecular entity =
oral dosing possible
Hematopoietic
stem cell
transplant*
*Not FDA-approved for the treatment of MS.

71. Novel S1P Receptor Agonists
Siponimod*
Ozanimod*
Ponesimod*
Fingolimod
Main active compound
Siponimod
CC112273
Ponesimod
P-fingolimod
Receptor
S1P1; S1P5
S1P1
S1P1 to S1P5
Half-life
30 h
19 h
6 to 9 d
Phase 3 trials
SPMS
RRMS
Siponimod/ placebo
Ozanimod/ IFN-β1a qw
Ponesimod/ teriflunomide
Fingolimod/ placebo
Ponesimod/ DMF
Fingolimod/ IFN-β1a qw
*Not FDA-approved for the treatment of MS.

72. S1P Agonists in Development: Phase 3 Trials
Siponimod* EXPAND Trial (Siponimod/placebo)[a]
Reduced 6-month CDP 26% (P = .0058)
Reduced brain volume loss by 23% (12 and 24 months; P = .0002)
Reduced increase of T2 lesion volume by 80% (12 and 24 months; P < .0001)
Reduced ARR by 55% (P < .0001)
No difference in the T25-FW test and MS Walking Scale
Ozanimod* SUNBEAM, RADIANCE Trial (Ozanimod 0.5 mg/1 mg/placebo)
3-mo CDP not significant in pooled analysis
Reduced brain volume loss[b]
SUNBEAM 12% (0.5 mg; P = .06); 33% (1 mg; P < .0001) vs IFN-β1a
RADIANCE 25% (0.5 mg; P < .0001); 27% (1 mg; P < .0001) vs IFN-β1a
Reduced increase of T2 lesion volume
SUNBEAM[c] 25% (0.5 mg; P < ); 48% (1 mg; P < .0001) vs IFN-β1a
RADIANCE[d] 34% (0.5 mg; P < ); 42% (1 mg; P < .0001) vs IFN-β1a
ARR
SUNBEAM[c] 0.24 (0.5 mg; P = .0013); (1 mg; P < .0001); 0.35 (IFN-β1a)
RADIANCE[d] 0.22 (0.5 mg; P = .0167); (1 mg; P <. 0001); 0.28 (IFN-β1a)
*Not FDA-approved for the treatment of MS.
a. Kappos L, et al. Lancet. 2018;391: ; b. Arnold D, et al. ECTRIMS Poster P1857; c. Comi G, et al. ECTRIMS Abstract 232; d. Cohen JA, et al. ECTRIMS Abstract 280.

73. Ofatumumab
90% reduction of new Gd+ lesions with depletion to 32 CD19+ cells/mL
Repletion to LLM CD19+ by about study week 48
MIRROR Study[a]
3 mg
q12w
30 mg
60 mg
q4w
Placebo
Number 34 32 64 67
Cumulative new Gd+ lesions 0-12 wk 33 30 63
Mean cumulative new enlarging T2 lesions 4-12 wk
0.36
0.11
0.09
0.08
0.83
Ofatumumab* Phase 3 Development[b]
ASCLEPIOS I (NCT ), ASCLEPIOS II (NCT )
Identical design: randomized, double-blind/double-dummy, parallel trial
20 mg ofatumumab SC q4w
Active-control (teriflunomide 14 mg oral)
Primary endpoint: ARR
900 patients with RRMS aged 18 to 55 y
*Not FDA-approved for the treatment of MS.
a. Bar-Or A, et al. Neurology. 2018;90:e1805-e1814; b. Hauser SL, et al. AAN Abstract S

74. Oral Cladribine Trials and Extensions
2 y
4 y
8 y
PREMIERE registry[c]
ONWARD (Phase 2)[e] (3.5 mg/kg * + IFN-β)
ORACLE-MS[d] (3.5 and 5.25 mg/kg)*
CLARITY[a] (3.5 and 5.25 mg/kg)*
CLARITY EXT[b] (3.5, 5.25, 7.0, and 8.75 mg/kg)*
ClinicalTrials.gov. Prospective observational long-term safety registry of multiple sclerosis patients who have participated in cladribine clinical trials (PREMIERE). Accessed June 10, 2018.
Montalban X, Cohen B, Leist T, et al. Efficacy of cladribine tablets as add-on to IFN-beta therapy in patients with active relapsing MS: final results from the phase II ONWARD study. Poster presented at: 68th Annual American Academy of Neurology Meeting; April 15-21, 2016; Vancouver, BC, Canada. Poster P3.029.
*Not FDA approved for the treatment of MS.
a. Giovannoni G, et al. N Engl J Med. 2010;362: b. Giovannoni G, et al. Mult Scler. 2017: c. ClinicalTrials.gov. NCT d. Leist TP, et al. Lancet Neurol. 2014;13: e. Montalban X, et al. AAN Abstract P3.029.

75. Cladribine Phase 3 Trials
ORACLE[a]
Cladribine* 3.5 mg/kg (n = 206)
Placebo
(n = 206)
Risk Reduction
Conversion to CDMS, % 14 38
67†
Conversion to McDonald 2005, % 54 82
50†
CLARITY
Cladribine* 3.5 mg/kg (n = 433)
Placebo
(n = 437) ‡
Risk Reduction, %
Odds Ratio
ARR[b]
0.14 (0.12, 0.17)
0.33 (0.29, 0.38)
58¶
T2 lesions[b]
0.38
1.43
73.4¶
Proportion relapse-free, %[b]
79.7
60.9
2.53
Disease activity-free, %[c]**
46.8
17.4
4.25
No 3-mo SDP,[b] %
85.7
79.4
1.55
*Not FDA-approved for the treatment of MS.
‡Data are presented as mean (95% CI).
†P < .0001; ¶ P < .001; **n = 382 in the placebo group and 404 in the 3.5-mg cladribine group.
a. Leist TP, et al. Lancet Neurol. 2014;13: ; b. Giovannoni G, et al. N Engl J Med. 2010;362: ; c. Giovannoni G, et al. Lancet Neurol. 2011;10:

76. Cladribine Phase 3 Extension Trial
IMAGE NO LONGER AVAILABLE
*Not FDA-approved for the treatment of MS.
Giovannoni G, et al. Mult Scler J. 2017:

77. Concept of Repopulation in MS Treatment
Multiple Sclerosis
Multiple Sclerosis
Reduction of Pathogenic Immune Repertoire
Expansion Naive Immune Cells Antigenic Reexperience
Enhanced Immune Regulation
"Retolarized"
Immune Repertoire
Reductive Conditioning
(eg, CD4+ Th1/Th17; CD8+ CD161+)
Treg; Breg; NKreg
Enduring Biologic Effect
Time/ Repopulation

78. Oral Cladribine Safety
Lymphopenia was the most frequent AE[a]
Infections occurred at similar frequency in the cladribine* tablets 3.5 mg/kg group compared with the placebo cohort, with the exception of a small increase of herpes zoster reactivations mainly during grade 3 and 4 lymphopenia[a]
No statistically significant or clinically relevant increase in malignancy risk was observed with cladribine* tablets[b]
*Not FDA-approved for the treatment of MS.
a. Cook S, et al. ECTRIMS Poster P1142; b. John V, et al. ECTRIMS Poster P1878.

79. Thank you for participating in this activity.
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