Sequencing in management of Multiple sclerosis

Amr Hassan MD,FEBN
Professor of Neurology - Cairo University
Sequencing in management of MS

Sequencing: What Influences Treatment Choice?

Francois Grand’Maison, Michael Yeung, Sarah A. Morrow, Liesly Lee, FrancoisEmond, Brian J Ward, Pierre Laneuville & Robyn Schecter (2018): Sequencing
of disease-modifying therapies for relapsing-remitting multiple sclerosis: a theoretical approach to optimizingtreatment, Current Medical Research and
Opinion, DOI: 10.1080/03007995.2018.1458023
Sequencing: What Influences Treatment Choice?

DMT
Immune
System
Immune
System
HE
DMT
DMT
Wrestling: when should an action be taken ?

It is common for patients with MS to switch treatments during
the course of the disease
1. Wakeford C et al. Presented at ECTRIMS; October 25–28, 2017; Paris, France. P684; 2. Milliman Report. Multiple Sclerosis: New Perspective on the Patient Journey.
Prepared for Biogen by Milliman, Inc., NY; April 2016.
With the introduction of new DMTs, patients are more willing to switch treatment1
Patient-centric1
• One-third (1/3) of patients are compelled to switch therapies within 2
years of treatment initiation2
• Switching is increasingly driven by reasons other than efficacy1
• Suboptimal response (relapse,
increased disability, MRI lesions)
• Cognitive impairment
• Safety concerns
• Intolerable side effects
• Change in risk tolerance
• Desire for change in quality
of life and/or lifestyle

1. Pardo G, Jones DE. J Neurol. 2017;264:2351-74; 2. Roman C, Menning K. J Am Assoc Nurse Pract. 2017;29:629-38.
Drug properties Patient-centric
• Efficacy
• Safety
• Tolerability
• Duration of immune system impact
• Route of administration
• Time to onset of treatment effect
Disease Characteristics and History
• Disease severity
• Prior treatment
Patient Preferences and Needs
• Adherence behavior
• Lifestyle (e.g., family planning)
• Risk tolerance
Is it common for patients with MS to switch treatments during
the course of the disease

Multiple factors are involved when considering optimal treatment
sequences for relapsing MS (RMS)
Reasons for
switching disease-
modifying therapies
(DMTs)
• Breakthrough disease activity and inadequate response to
therapy
• Intolerability or specific side effects
• Adverse events
• Family planning
• Compliance/adherence issues
• Psychosocial reasons
• Economic/financial reasons
Immunological and pharmacodynamic implications for
treatment sequencing

Immunological and pharmacodynamic implications for
Multiple factors are involved when considering optimal treatment
sequences for relapsing MS (RMS)
Considerations
when switching
from
initial DMT
• There is a lack of data from patient registries concerning
long-term efficacy and safety of treatment sequencing.
• In the absence of data, immunological and
pharmacodynamic information may help inform
clinical reasoning.

Immunological and pharmacodynamic considerations
for forward planning
Duration of immune system effects
Impact on the efficacy and safety of the next DMT
Mechanism of action (MOA)
Effect of DMT on immune cell compartments
Onset of efficacy of next DMT so as to manage
return of disease activity in a timely way

Biogen-42110.
April
2020.
• T cell and then B-cell suppression (or reverse)
• DMF, fingolimod, siponimod, natalizumab and then ocrelizumab or rituximab
(or reverse).
• CD8+ T cells and then CD4+ T cells (or vice versa):
• DMF preferentially reduces CD8+ T cells1; fingolimod preferentially reduces
CD4+ T cells2.
Sequencing DMTs
Sequential lymphocyte suppression
1. Luessi, F, et al. Presented at ECTRIMS 2016, London, Poster P1273; 2. Kowarik MC, et al. Neurology. 2011;76:1214-21.
By choosing a long acting DMT, we may limit our future options,
effectively blocking our next move

Biogen-42110.
April
2020.
• DMTs reduce CNS immune-mediated inflammatory processes, leading to improved
clinical and radiologic outcomes1
• The short- and long-term immunologic impact of each DMT should be considered
when making treatment decisions.1
• Choice of starting DMT should take into account potential future treatment needs by keeping
subsequent treatment options open.1
• Choice of subsequent DMT should take into account the mechanism of action and duration of
immunologic impact of previous DMT, as these can impact efficacy and safety.1
Therapy considerations
1. Pardo G, Jones DE. J Neurol. 2017;264:2351-74.

Considerations for initial treatment decision-making
*Relevant patient and treatment factors determined by the faculty.
Patient
factors*
Treatment
factors*
Prognosis
Willingness to engage
with treatment
Preference for dosing /
monitoring frequency
and route → adherence
Individual
risk profile
Plans for pregnancy
Benefit–risk profile
Long-term safety data
→ defined monitoring
Defined treatment
response → goals
Available risk-
stratification strategy
Mechanism of action →

CD52
CD25
S1P-R
CD20
Oligodendrocyte
B cell Plasma cell
IL-17
IL-4, IL-5
CD4
CD4
Th1
Th2
CD8
CD8
CD8
CD8
Th17
CD4
Dendritic
cell (APC)
Dendritic
cell (APC)
Macrophage
T cell
CD52
CD52
Cytokines
and ROS
VLA-4
NK cell
LA-IL-
2R
VLA-4
VLA-4
CD56bright
• APC, antigen-presenting cell; CD, cluster of differentiation; CNS, central nervous system; IL, interleukin; LA-IL-2R, low-affinity interleukin-2 receptor; NK, natural killer; ROS, reactive oxygen species;
S1P-R, sphingosine-1-phosphate receptor; Th, T-helper cell; VLA, very late antigen-4.
Adapted from Dolati S et al. Biomed Pharmacother. 2017;86:343-353; Bar-Or A et al. Ann Neurol. 2010;67:452-461; Linker RA et al. Trends Pharmacol Sci. 2008;29:558-565; Lisak RP et al. J Neuroimmunol. 2012;246:85-95;
Serafini B et al. Brain Pathol. 2004;14:164-174; Magliozzi R et al. Ann Neurol. 2010;68:477-493; Hunter SF et al. CNS Drugs. 2016;30:135-147.
B cell
CNS
Lymph node Peripheral blood
IL-2

CNS
Lymph node
CD52
CD25
S1P-R
CD20
Oligodendrocyte
B cell Plasma cell
IL-17
IL-4, IL-5
TERI
DMF
DMF
Peripheral blood
CD4
CD4
Th1
Th2
CD8
CD8
CD8
CD8
Th17
CD4
Dendritic
cell (APC)
Dendritic
cell (APC)
Macrophage
T cell
CD52
CD52
Cytokines
and ROS
VLA-4
NK cell
LA-IL-
2R
VLA-4
VLA-4
IL-2
CD56bright
Immuno-
modulator
B cell
DMF, dimethyl fumarate; TERI, teriflunomide.

CNS
Lymph node
CD52
CD25
S1P-R
CD20
Oligodendrocyte
B cell Plasma cell
IL-17
IL-4, IL-5
FINGO
NTZ
Peripheral blood
CD4
CD4
Th1
Th2
CD8
CD8
CD8
CD8
Th17
CD4
Dendritic
cell (APC)
Dendritic
cell (APC)
Macrophage
T cell
CD52
CD52
Cytokines
and ROS
VLA-4
NK cell
LA-IL-
2R
VLA-4
VLA-4
CD56bright
Anti-
migratory
B cell
FINGO, fingolimod; NTZ, natalizumab.
IL-2

CNS
Lymph node
CD52
CD25
S1P-R
CD20
Oligodendrocyte
B cell Plasma cell
IL-17
IL-4, IL-5
OCR
ALEM
CLAD
Peripheral blood
CD4
CD4
Th1
Th2
CD8
CD8
CD8
CD8
Th17
CD4
Dendritic
cell (APC)
Dendritic
cell (APC)
Macrophage
T cell
CD52
CD52
Cytokines
and ROS
VLA-4
NK cell
LA-IL-
2R
VLA-4
VLA-4
CD56bright
Immuno-
depleter
B cell
ALEM, alemtuzumab; 2-CdA, cladribine; OCR, ocrelizumab.
IL-2

PRODUCTION AND
PROLIFERATION
OF LYMPHOCYTES3
•IFNβ therapies*†
•Glatiramer acetate*
•Teriflunomide*▼
•Fingolimod▼
•Natalizumab▼
MIGRATION
OF LYMPHOCYTES3
FUNCTION
OF LYMPHOCYTES3
•IFNβ therapies*†
•Dimethyl fumarate*
•Alemtuzumab▼
•Cladribine*
•Ocrelizumab*▼
DEPLETION
OF LYMPHOCYTES3,4
* This slide deck focuses on the immunological aspects of hypothesised mechanisms of action and the resulting immunological impact and implications; it is not intended to provide an overview of efficacy and safety
and tolerability profiles. The mechanisms of action of IFNβ therapies, glatiramer acetate, teriflunomide, dimethyl fumarate, cladribine and ocrelizumab are not fully elucidated; however, they are thought to act
by modifying immune processes that are currently believed to be involved in the pathogenesis of MS. † Including PLEGRIDY. ▼ This medicinal product is subject to additional monitoring.
MS pathogenesis leads to immunologic imbalances and current DMTs may impact the immune system through four different modalities3,4
•Siponimod▼
•Ozanimod •Ofatumumab
3. Ali R, Nicholas RS, Muraro PA. Drugs in development for relapsing multiple sclerosis. Drugs. 2013;73(7):625-650.
4. Mavenclad (cladribine) Summary of Product Characteristics. August 2017.

Biogen-42110.
April
2020.
Mechanism of action
Short-term effects
(days to weeks)
Medium-term effects
(weeks to months)
Long-term effects
(months to years)
Immunomodulators
Glatiramer acetate
Interferon
Teriflunomide1,*
Dimethyl fumarate2
Teriflunomide1
Antimigratory
treatments
Fingolimod3
Natalizumab4
Immunodepleters
Alemtuzumab5
Cladribine6
Ocrelizumab7
*With rapid elimination.
Adapted from Table 2 in Pardo G et al. J Neurol. 2017;264:2351-2374. 1. Aubagio® (teriflunomide) [summary of product characteristics]. Paris, France: sanofi-aventis groupe; 2017; 2. Pardo G et al. J
Neurol. 2017;264:2351-2374; 3. Gilenya® (fingolimod) [summary of product characteristics]. Horsham, West Sussex, UK: Novartis Europharm Ltd; 2018; 4. Tysabri® (natalizumab) [summary of
product characteristics]. Maidenhead, Berkshire, UK: Biogen Idec Ltd; 2017; 5. Lemtrada® (alemtuzumab) [summary of product characteristics]. Oxford, UK: Genzyme Therapeutics Ltd; 2018; 6.
Mavenclad® (cladribine) [summary of product characteristics]. London, UK: Merck Serono; 2018; 7. Ocrevus® (ocrelizumab) ) [summary of product characteristics] Welwyn Garden City , UK: Roche
Registration Limited ; 2018.

Impact on the efficacy and safety of the next DMT
Onset of efficacy of next DMT so as to manage
return of disease activity in a timely way
Immunological and pharmacodynamic considerations
for forward planning

*This graph is for illustrative purposes only and does not reflect the duration of immune system impact of any particular MS therapy.
Pardo G, Jones DE. J Neurol. 2017;264:2351-2374.
Effects
on
Immune
System*
Days/Weeks to Months
Back to baseline
by days/weeks or months
Duration of Immune
System Impact
Years
Back to baseline
by years
Start
treatment
Baseline
End
treatment
Short-term Long-term
Note that the term “switch flexibility” is intended to be descriptive and NOT prescriptive. Biogen's communications are NOT intended to encourage inappropriate DMT switches.
Treatment decisions should always be left to the discretion of the treating prescriber in consultation with their patient taking into account individual facts and circumstances.

Biogen-42110.
April
2020.
Sequencing DMTs
Temporal effect on immune cell count
Adapted from Table 2 in Pardo G, Jones DE. J Neurol. 2017;264:2351-74 1. Aubagio® (teriflunomide). SmPC. February 2020; 2. Mayzent® (siponimod). SmPC. January 2020;
3. Mavenclad® (cladribine). SmPC. March 2020.
Near term
Days to weeks
Mid term
Weeks to months
Long term
Months to year(s)
• Interferon β-1b
• Interferon β-1a
• Pegylated interferon
• Glatiramer acetate
• Dimethyl fumarate
• Teriflunomide1
(with accelerated
elimination)
• Fingolimod
• Siponimod2
• Natalizumab
• Alemtuzumab
• Cladribine3
• Ocrelizumab
• Mitoxantrone
• Teriflunomide

Biogen-42110.
April
2020.
Sequencing DMTs
DMTs with short-term immune system impact can provide the switch
flexibility needed, within a relatively short time frame of discontinuation
*At ≥2 months after DMF discontinuation, absolute lymphocyte count values were above LLN in 50% of patients7; †average lymphocyte counts were 80% of baseline values after 3
months. 1. Tecfidera® (dimethyl fumarate) SmPC. February 2020; 2. Tysabri® (natalizumab) SmPC. November 2019; 3. Plegridy® (peginterferon beta-1a) SmPC. October 2019; 4.
Aubagio® (teriflunomide) SmPC. February 2020; 5. Gilenya® (fingolimod) SmPC. December 2019; 6. Fox EJ et al. Neurol Clin Pract. 2019;9:53-63; 7. Buckle G et al. Presented at
AAN; April 22–28, 2017; Boston, MA. P5.376.
Lymphocyte counts increase
within 4 weeks*
DMF1
Lymphocytes return to
baseline levels within 4
months
Natalizumab2
Decrease in lymphocytes
similar to placebo
Peginterferon β-1a3
Mild decrease in lymphocyte
counts (<15%)
Teriflunomide4
Lymphocytes return to
normal range within 2
months†
Fingolimod5
Does not affect absolute
lymphocyte counts
GA and IFN6

Biogen-42110.
April
2020.
CD, cluster of differentiation; LLN, lower limit of normal.
1. Lemtrada® (alemtuzumab) US PI; October 2017; 2. Ocrevus® (ocrelizumab) SmPC.January 2019; 3. Mavenclad® (cladribine) SmPC. March 2020.
At 2.5 years, 50% of patients had CD4+ lymphocyte counts
below LLN
Alemtuzumab1
Median time for B-cell counts to return to either baseline or
LLN was 1.5 years
Ocrelizumab2
Lymphocyte counts rose to LLN in >75% of patients within
2 years
Cladribine3
Sequencing DMTs
DMTs with short-term immune system impact can provide the switch
flexibility needed, within a relatively short time frame of discontinuation

The Timing Of Reversibility Of Treatment Effects, In Different Studies, Is Relevant To
Treatment Choice And To Planning Treatment Sequence
Lymphocyte
counts
(×10
9
/L)
±
95%
CI
Time from discontinuation of fingolimod
End of
treatment
Days 1–45 Month 3 Month 6
*
Fingolimod1
n=210
0
0.6
1.4
2.2
1.0
1.8
0.2
0.4
1.2
2.0
0.8
1.6
2.4
2.6
Fingolimod
discontinuation
Natalizumab3
n=106
0
200
400
600
800
1000
1200
1400
0 4 8 12 16 20 24 28
CD4+ T cells
CD19+ B cells
Weeks from natalizumab discontinuation
Natalizumab
discontinuation
0.4
0.8
1.0
1.2
0
0.2
0.6
1.4
*
*
Lymphocyte
counts
(×10
9
/L)
Months after alemtuzumab administration
Alemtuzumab3
n=91
0.8
0 1 3 6
CD4+
lymphocytes
(x
10
9
/L)
9 12 13 15 18 21 24 25 27 30
1.0
1.2
0.6
0.4
0.2
0
CD4+ T cells
Natalizumab2
*Reference lines indicate the mean baseline values for MS patients treated with alemtuzumab and fingolimod. CI, confidence interval; LLN, lower limit of normal; MS, multiple sclerosis.
1 Francis G et al. Mult Scler. 2014;20:471-480; 2. Adapted from Plavina T et al. Neurology. 2017 Oct 10;89(15):1584-1593; 3. Thompson SAJ et al. J Clin Immunol. 2010;30:99-105; 4. Ocrevus® (ocrelizumab) ) [summary of
product characteristics] Welwyn Garden City , UK: Roche Registration Limited ; 2018. 5. Mavenclad (cladribine) [summary of product characteristics}. London, UK: Merck Serono; 2017.
Time for lymphocyte count to return to baseline after last treatment
Ocrelizumab4
n=51
• Median time 72 weeks (range 27–175 weeks)
• Within 2.5 years, B-cell counts rose to either baseline or
LLN in 90% of patients
Cladribine5
n not defined
• Approximately 30 weeks
• At approximately 90 weeks lymphocyte count rose to
LLN in > 75% of patients

Biogen-42110.
April
2020.
Possible relationship between increased
B-cell numbers and development of
secondary autoimmunity in
alemtuzumab-treated patients
Anti-CD20 as sequential treatment for
patients treated with alemtuzumab who
develop secondary autoimmunity?
Sequencing matters – Immunological implications of DMT
treatment sequencing – safety
Baker D, et al. JAMA Neurology. 2017;74:961–9.
CD19 B-cells
Mean
change
from
baseline,
%
Time after ATZ administration, months
Immature B-cells
Mean
change
from
baseline,
% Time after ATZ administration, months
Memory B-cells
Mean
change
from
baseline,
%
Mature B-cells
Mean
change
from
baseline,
%
N=376 N=98
N=98
N=98

Biogen-42110.
April
2020.
• It is now well documented that after withdrawal from Natalizumab and Fingolimod there can be
significant rebound disease activity.1-5
• More recently there have been cases reported with Teriflunomide as well.6-7
• In the case of Natalizumab, multiple studies have attempted to avert this effect
• Ineffective - glatiramer, IFN IM weekly, monthly corticosteroids, azathioprine, fingolimod
• Potentially Effective:
• B-cell depletion may be a viable next step4,5 - 1.8% relapse rate (rituximab)* at 18 months
• Teriflunomide8
• This is not a reason to not use these agents, just plan ahead.
*Rituximab is not licensed for the treatment of MS.
1. Havla JB, et al. Arch Neurol. 2012;69:262-4; 2. Hatcher SE, et al. JAMA Neurol. 2016;73:790-4; 3. Fox RJ, et al. Neurology. 2014;82:1491-8; 4. Lo Re M, et al. Neurol Ther.
2015;4:147-57; 5. Alping P, et al. Ann Neurol. 2016;79:950-8; 6. Yamout BI, et al. J Neurol Sci. 2017:380:79-81; 7. Fuerte-Hortigon A, et al. Mult Scler Relat Disord. 2020;41 [ePub
ahead of print]; 8. Cohan SL, et al. Mult Scler J Exp Transl Clini. 2019;5:1-11.
Sequencing DMTs
Rebound activity

Biogen-42110.
April
2020.
• Rebound disease activity coming off some agents
• Fingolimod1,2 , Natalizumab3-7, Teriflunomide9
• Consider DMT as follow-up treatment - have next treatment in mind
• Following cessation of these agents, there is some evidence for medication with
a B-cell effect to help decrease rebound disease activity.7-8
1. Havla JB, et al. Arch Neurol. 2012;69:262-4; 2. Hatcher SE, et al. JAMA Neurol. 2016;73:790-4; 3. West TW, Cree BAC. Ann Neurol. 2010; 68:395-9; 4. Killestein J, et al. Ann
Neurol. 2010; 68:392-5; 5. Fox RJ, et al. Neurology. 2014;82:1491-8; 6. Lo Re M, et al. Neurol Ther. 2015;4:147-57; 7. Alping P, et al. Ann Neurol. 2016;79:950-8; 8. Cohan SL, et
al. Mult Scler J Exp Transl Clini. 2019;5:1-11; 9. Fuerte-Hortigon A, et al. Mult Scler Relat Disord. 2020;41 [ePub ahead of print].
Sequencing DMTs
Rebound activity

Biogen-42110.
April
2020.
• What about sequential therapy?
• Induction followed by maintenance
• Natalizumab or alemtuzumab followed by ocrelizumab or teriflunomide?
• Cladribine followed by teriflunomide, dimethyl fumarate or interferon?
• Ocrelizumab followed glatiramer acetate or fingolimod?
• At least one small study has deemed this approach plausible1
• Could the highly effective DMT outcome be achieved and then maintained by a
lower risk agent?
• If so, both medications could potentially benefit by a combined increase in efficacy with improved
overall long-term safety
Sequencing matters – Potential opportunities
1. Hausler D, et al. Glatiramer Acetate immune modulates pathogenic B-cell function and maintains clinical benefit after anti-CD20 induction therapy, P666, poster session ECTRIMS London
2016, 9/15/2016.

Biogen-42110.
April
2020.
• PML has been reported with several DMTs
• Natalizumab, Fingolimod, Ocrelizumab, DMF, Alemtuzumab, Teriflunomide
• Some progress has been made to decrease this risk with Natalizumab
• Extended interval dosing (36-42 days)1
• JC virus antibody titer2
1. Zhovtis Ryerson L, et al. Neurology. 2019; 93;e1452-e1462; 2. Gorelik L, et al. Ann Neurol. 2010;68:295-303.
Sequencing DMTs
Carry-over PML

Biogen-42110.
April
2020.
Sequencing DMTs
Carry-over PML Least concern :
Interferon beta, glatiramer acetate
Some concern:
Alemtuzumab (Lemtrada)
Teriflunamide (Aubagio)
Fingolimod (Gilenya)
Dimethyl fumarate (Tecfidera)
High concern:
Natalizumab (Tysabri)

Biogen-42110.
April
2020.
• Before switch from Natalizumab or fingolimod to long lasting B-cell depleting therapies PML
should be thoroughly excluded
• For Natalizumab prior immunosuppression increases future PML risk
• Alemtuzumab, Ocrelizumab, Mitoxantrone, Cladribine
• Off label medications
• Azathioprine, Mycophenolate Mofetil, Cyclophosphamide
• Potential for Fingolimod, Teriflunomide, Dimethyl Fumarate due to lymphopenia
Sequencing DMTs
Carry-over PML

Biogen-42110.
April
2020.
Sequencing DMTs
Carry-over PML

Onset of efficacy for next DMT when determining need to switch:
DMF, ALZ, CLD
Onset of
efficacy in
first 48
weeks
Dimethyl Fumarate1 Cladribine3
• *DMF, delayed-release DMF (also known as
gastro-resistant DMF)
Patients
with
No
Relapse
(%)
No. at Risk
Placebo 437
Cladribine 3.5 mg/kg 433
Cladribine 5.25 mg/kg 456
399
407
425
424
424
447
373
389
404
355
379
388
315
355
363
304
347
350
304
347
350
333
364
375
12
0 24 36 48 60 72 84 96
Weeks
0
25
50
75
100
Patients at risk
Placebo
DMF* BID
Probability
of
relapse
0
0.3
0.4
0.5
0.2
0.1
Placebo=0.437
DMF* BID=0.280
586
598
684
672
525
559
463
527
393
474
334*
422*
367
453
425
495
771
769
667
657
BL 12 24 36 48 60 72 84 96
Week
Alemtuzumab2
0 3 6 9 12 15 18
Follow-up (months)
21 24
Number at risk
Interferon -1a 187 175 156 137 127 118 116 109 101
Alemtuzumab 376 366 358 340 321 313 306 299 287
HR=0.45; P<0.0001
Alemtuzumab 78%
Interferon -1a 59%
P<0.05
Onset of
efficacy:
Week 10
Placebo 61%
Cladribine 3.5 mg/kg 80%
HR=0.44; P<0.001
BL, baseline; BID, twice daily; DMF, delayed-release DMF (also known as gastro-resistant DMF), HR, hazard ratio; ITT, intention-to-treat; MRI, magnetic resonance imaging.
1. Kappos L et al. Eur J Neurol. 2015;664-671; 2. Cohen JA et al. Lancet. 2012;380:1819-1828; 3. Giovannoni G et al. N Engl J Med. 2010;362:416-426.
Onset of
efficacy in
3-6 months

.Gd+, gadolinium-enhancing.
1. Kappos L et al. J Neurol. 2016; 263:354–360; 2. Kappos L et al. New Engl J Med. 2006;355:1124-1140.
Phase 2 Trial: Number of New Gd+ Lesions2
47%
77%
82%
0
P<0.001
Patients
free
from
Gd+
lesions
(%)
40
60
80
100
1 2 3 4 5 6
0
Time (months)
Fingolimod 1.25 mg (n=83)
Fingolimod 5 mg (n=77)
Placebo (n=81)
Pooled FREEDOMS and FREEDOMS-2 Data
Time to First Relapse1
87%
77%
100
Proportion
of
patients
without
confirmed
relapse
(%)
80
60
40
0 60
Fingolimod 0.5 mg
Placebo
120
Time to first relapse (days)
180
783
773
Number of
patients at risk
Fingolimod 0.5 mg
Placebo
712
685
662
628
622
558
Onset of efficacy
at day 48
P≤0.05 (log-rank test)
Fingolimod

*Absolute numbers not available in the publication
1. Kappos L et al. J Neurol. 2013; 260:1388-95; ; 2. Miller DH et al. N Engl J Med. 2003:348:15-23.
†Note: The approved dose of natalizumab is 300 mg IV every 4 weeks.
*P<0.001 vs placebo.
Placebo (n=71)
Natalizumab 3 mg/kg (n=68)†
Natalizumab 6 mg/kg (n=74)†
First
infusion
Month
Cumulative
mean
number
of
lesions
Last
infusion
9.6
1.1*
0.7*
0
2
4
6
8
10
12
1 2 3 4 5 6
0
Phase 2 Trial: Mean Cumulative
Number of New Gd+ Lesions2
Early and Sustained Impact on Relapses1
• A difference in the cumulative probability of relapse from baseline between the
two groups was first observed at day 42 in patients overall, 5.4% for natalizumab
and 9.3% for placebo (HR: 0.56, 95% CI 0.34–0.93; P=0.0238)
Onset of
efficacy at
day 42
Cumulative
probability
of
relapse
134 130
429 422
156
452
183
489
231
544
Number of patients atrisk
Placebo 315
Natalizumab 627
Placebo 55.7%
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Baseline 8 16 24 32 40 48 56 64 72 80 88 96 104
Weeks from baseline
Natalizumab28.7%
Placebo (n = 315)
HR = 0.42, 95% CI 0.34−0.52
P <0.0001
58% decrease relative to placebo
Natalizumab (n = 627)
*
*
Natalizumab

0
1
2
3
4
5
6
7
0 4 8 12 16 20 24
Mean
number
of
T1
Gd+
lesions
Weeks
Placebo (n=54)
Ocrelizumab 600 mg (n=51)
Kappos L et al. Lancet 2011; 378: 1779–87.
Phase 2 Trial: Mean Number of T1 Gd+ Lesions
Onset of efficacy
at 12 weeks
(p<0·0001)
Ocrelizumab

*There are no evidence based data available yet. These recommendations therefore, are based on the proposed waiting times when switching from the existing to
another DMD. DMD,
48
DMD washout periods in real world clinical practice
Prior treatment Recommended usual waiting times in the case of switching to other DMDsa
Glatiramer acetate None, or until remission of treatment-specific effects
Interferon beta None, or until remission of treatment-specific effects
Dimethyl fumarate None, or until remission of treatment-specific effects (ALC>800 x 106)
Teriflunomide ≥4 weeks, or until remission of treatment-specific effects, or 11 days post-elimination
Fingolimod ≥4 weeks, or until remission of treatment-specific effects (ALC>800 x 106)
Natalizumab 4 weeks, and rule out PML by brain MRI and CSF JC virus PCR
Alemtuzumab ≥6–12 months after the last infusion, or until remission of treatment-specific effects
Ocrelizumab/Cladribine ≥6 months after the last infusion, or until remission of treatment-specific effects
The washout period can be shortened based on the severity of disease activity and therefore the urgency of DMD switch

Biogen-42110.
April
2020.
Any consensus on treatment failure?
1. Sormani MP, et al. Mult Scler. 2013:19:605–12; 2. Freedman MS, et al. Can J Neurol Sci. 2013;40:307-23; 3. Bermel R, et al. Ann Neurol. 2013;73:96-103.
Outcomes Modified Rio Score1 Canada Treatment
Optimization2
Bermel Criteria3
Relapses ≥2 relapses (4 years) ≥1 relapses (first year)
≥2 clinical relapses
(2 years)
MRI >4 new T2 lesions
≥3 Gad+ lesions
OR
>3 new T2 lesions
≥2 Gad+ lesions
OR
≥3 new T2 lesions

Pseudo
attacks
No
Rebaselining
No Standard
protocols
Interrater
variability
Unconfirmed
attacks
No Careful
repositioning
Different
machines
Poor
Experience
Poor
Management
of a relapse
Unjustified escalation

Treatment
Initiation Follow up MRI
0 months 6 months 12 month
Rebaselining

PRISMS-15
48%
86%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
PRISMS-15 MIN group
(n=73)
PRISMS-15 MAX group
(n=72)
Cumulative dose analysis:
86%of patients taking sc IFN β-1a consistently over 15 years did not
require a walking aid (equal to an EDSS score ≥6.0)
Patients
with
EDSS
<6.0
(%)
In this post hoc exploratory analysis, cumulative sc IFN β-1a dose exposure was determined and clinical outcomes assessed in the
minimum (lowest quartile, MIN) and maximum (highest quartile, MAX) cumulative dose groups. PRISMS LTFU-15 was a single-visit
follow-up and analyses are exploratory; results should be interpreted with caution. The design of this study does not allow for definitive statements
regarding causality.
CI, confidence interval; EDSS, Expanded Disability Status Scale; LTFU, long-term follow-up; OR, odds ratio.
Kappos L et al. J Neurol Neurosurg Psychiatry 2015;0:1–6
Prevention of Relapses and disability by Interferon beta-1a
Subcutaneously in Multiple Sclerosis – 15 year Follow up

60.7
52.1
31.8
13.9
0
20
40
60
80
100
EDSS ≥4 EDSS ≥6
Patients
(%) MIN group (n=73)
MAX group (n=72)
OR (95% CI):
0.30 (0.15–
0.63)
OR (95% CI):
0.15 (0.07–
0.33)
54
Fewer patients reached EDSS scores ≥4 or ≥6 in the MAX versus MIN group
Patients
(%)
48%
fewer patients
with EDSS
≥4 in MAX
vs MIN group
73%
fewer patients
with EDSS
≥6 in MAX
vs MIN group
In this post hoc exploratory analysis, cumulative sc IFN β-1a dose exposure was determined and clinical outcomes assessed in the
minimum (lowest quartile, MIN) and maximum (highest quartile, MAX) cumulative dose groups. PRISMS LTFU-15 was a single-visit
follow-up and analyses are exploratory; results should be interpreted with caution. The design of this study does not allow for definitive statements
regarding causality.
CI, confidence interval; EDSS, Expanded Disability Status Scale; LTFU, long-term follow-up; OR, odds ratio.
Kappos L et al. J Neurol Neurosurg Psychiatry 2015;0:1–6
PRISMS-15 Prevention of Relapses and disability by Interferon beta-1a

PRISMS-15 Prevention of Relapses and disability by Interferon beta-1a
55
Mean ARR over 15 years was lower in the MAX group than in the MIN group
In this post hoc exploratory analysis, cumulative sc IFN β-1a dose exposure was determined and
clinical outcomes assessed in the minimum (lowest quartile, MIN) and maximum (highest quartile,
MAX) cumulative dose groups. PRISMS LTFU-15 was a single-visit follow-up and analyses are
exploratory; results should be interpreted with caution. The design of this study does not allow for definitive
statements regarding causality.
ARR, annualized relapse rate;
CI, confidence interval; LTFU, long-term follow-up. Kappos L et al. J Neurol Neurosurg Psychiatry
2015;0:1–6
0.50
0.37
0
0.1
0.2
0.3
0.4
0.5
0.6
MIN group (n=73) MAX group (n=72)
Mean
(95%
CI)
ARR
(0.46–0.54)
(0.33–0.40)

NEDA-4/5
Brain atrophy and CSF neurofilament levels
NZ/AZ/Fingo/DAC/Clad
NEDA-3
Focal MRI activity
NZ/AZ
Fanigo/Dac/Clad
IFNBeta/GA/
Teri/DMF
NEDA-1 & 2
Focal MRI activity
NZ/AZ
Fingo/Dac/Clad
IFNBeta/GA/
Teri/DMF
MS Disease
Acitivity
Rapidly-evolving
Severe
Highly-active
Active
Inactive
Conventional
Step-care
Rapid
Escalation
Early
top-down
Flipping the pyramid in MS

• Try to stabilize patient 6 months -1 year prior to trials of
pregnancy (attack free + stable MRI).
• Stop DMDs before conception attempts
59
6
months
1 month
GA
DMF
2
months
3
months
Immuran
Mitoxantrone
Methotrexate:
(either parent)
4
months
Alemutuzumab
12
months
Rituximab
Precautions before pregnancy.
fingolimode
Natalzumab
IFN
Pregnancy plans

DMD washout periods in real world clinical practice before pregnancy

Dobson, Ruth et al. “UK consensus on pregnancy in multiple sclerosis: 'Association of British Neurologists' guidelines.” Practical neurology 19 2 (2019): 106-114.

Revise the disease course
Lublin et al., 2014

Cladribine
Alemtuzumab
Natalizumab
Anti-CD20
Anti S1P
DMF
Teriflunomide
GA
From IFN
IFN
IFN

Note: the original serum-containing formulation of sc IFN β-1a was used in EVIDENCE. EDSS, Expanded Disability Status Scale; IFN, interferon; im, intramuscular; qw, once
weekly; RRMS, relapsing–remitting MS; sc, subcutaneous; tiw, 3 times weekly. Schwid SR et al. Arch Neurol 2005;62:785–92; Schwid SR, Panitch HS. Clin Ther 2007;29:2031–
48
EVIDENCE (EVIDENCE OF INTERFERON DOSE
RESPONSE: EUROPEAN–NORTH AMERICAN
COMPARATIVE EFFICACY)
Time (Weeks; median)
n=272
n=223
n=249
n=190
0 34
Crossover phase
sc IFN β-1a 44 µg tiw
Randomization
N=677
n=339
n=338
0 24 48
Comparative phase
62
im IFN β-1a 30 µg qw
Patients
on
im
IFN
β-1a
30
µg
qw
changed
to
sc
IFN
β-1a
44
µg
tiw

Figure adapted from Schwid SR , 2007,
IFN, interferon; im, intramuscular; qw, once weekly; sc, subcutaneous; tiw, three times weekly
1. Schwid SR et al. Clin Ther 2007;29:2031–48
EVIDENCE study sponsored by Serono Inc.
TRANSITION FROM im IFN β-1a TO sc IFN β-1a
ASSOCIATED WITH REDUCTION IN RELAPSE
RATE
EVIDENCE
Significantly reduces relapse rate
vs im IFN β-1a (EVIDENCE)1
Transitioned from
im IFN β-1a to sc IFN
β-1a
Continued on sc IFN β-1a
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
im IFN β-
1a
sc IFN β-1a sc IFN β-1a sc IFN β-1a
30 μg qw 44 μg tiw 44 μg tiw 44 μg tiw
Annualized
mean
relapse
rate
Comparativ
e phase
Extension
phase
Comparativ
e phase
Extension
phase
0.64
0.32
0.46
0.34
50%
p<0.001 26%
p=0.028

Figure adapted from Schwid SR , 2007,
aCUA lesions defined at new, enlarging, or enhancing lesions on T1-weighted gadolinium-enhanced or T2 scans
IFN, interferon; CUA, combined unique active; im, intramuscular; qw, once weekly; sc, subcutaneous; tiw, three times weekly
1. Schwid SR et al. Clin Ther 2007;29:2031–48
EVIDENCE study sponsored by Serono Inc.
TRANSITION FROM im IFN β-1a TO sc IFN β-1a
ASSOCIATED WITH REDUCTION IN NUMBER OF
CUA LESIONSa EVIDENCE
EVIDENCE1: A
randomized comparison
of low-dose weekly (im
IFN β-1a 30 μg qw vs
high-dose, high-
frequency interferon β-
1a (sc IFN β-1a 44 μg
tiw) for relapsing
multiple sclerosis for 1
to 2 years
Primary endpoint:
Proportion
of patients who
remained free from
relapses
0.0
0.8
1.0
1.2
1.4
1.6
1.8
2.0
Mean
number
of
CUA
lesions
per
patient
scan
0.2
0.4
0.6
1 2 3 4 5 6
im IFN β-1a 30 µg qw
(n=338)
(n=339) (p<0.001)
Months of treatment

Cladribine
Alemtuzumab
Natalizumab
Anti-CD20
Anti S1P
DMF
Teriflunomide
GA
IFN
GA
From GA

Cladribine
Alemtuzumab
Natalizumab
Anti-CD20
Anti S1P
DMF
Teriflunomide
GA
IFN
DMF
From DMF
No washout period,
unless there is severe
infection risk or
markedly low ALC (<
0.2 k/uL),

Cladribine
Alemtuzumab
Natalizumab
Anti-CD20
Anti S1P
DMF
Teriflunomide
GA
IFN
Teriflunomide
From Teriflunomide
rapid elimination
protocol ?

Cladribine
Alemtuzumab
Natalizumab
Anti-CD20
Anti S1P
DMF
Teriflunomide
GA
IFN
Anti-CD20
From anti-CD20 agents
B-cell repopulation
following
discontinuation of
anti-CD20 agents has
been reported as
early as 3-6 months16

Cladribine
Alemtuzumab
Natalizumab
Anti-CD20
Anti S1P
DMF
Teriflunomide
GA
IFN
From Fingolimod
In cases of markedly
low ALC (< 0.2 k/uL),
it is advised to
discontinue the
agent, recheck ALC in
a few weeks
• Confirm recovery or at least trend of rising counts prior to
starting another agent that may also lower ALC (i.e.
dimethyl fumarate, alemtuzumab, cladribine, rituximab,
and ocrelizumab).
• There is also a theoretical concern that lymphocyte
sequestration agents might lower the efficacy of cell
depleting agents.
From Fingolimod

Hassoun, L., Eisele, J., Thomas, K. et al. Hands on Alemtuzumab-experience from clinical practice: whom and how to treat. Mult Scler Demyelinating Disord 1, 10 (2016). https://doi.org/10.1186/s40893-016-0011-1
To Alemtuzumab

From Natalizumab to Alemtuzumab

From Fingolimod to Alemtuzumab

Biogen-42110.
April
2020.
Summary
DMT, disease-modifying treatment; MS, multiple sclerosis.
When making treatment decisions, it is important to:
• Have a plan and always have an exit strategy
• Consider the duration of immune system impact
• Consider long-term/real-world efficacy and safety
• Allow for flexibility in your future DMT options
• Try to minimize the potential impact of overlapping immune effects on your patient
• Sequencing matters

Biogen-42110.
April
2020.
Remember that MS management journey is a
marathon not a sprint

THANK YOU
amrhasanneuro@kasralainy.edu.eg

Biogen-42110.
April
2020.
Exit strategies – a lesson from pilots
Smith, D. Characteristics of Successful Pilots. http://www.cfidarren.com/r-character.htm. Accessed March 2020.
1 Authority – The pilot is the ultimate command authority for the flight... the one responsible for the safe
conduct of that flight
2 Meaningful Self-Evaluation
3 Respect – for others but also the regulations, procedures and process of flight. They never engage in
unsafe behaviors because they respect the equipment they fly and the passengers and cargo held within
4 Recurrent training. Successful pilots don't look at recurrent training as a hassle but as an opportunity to
grow and learn
5 Humility
6 Determination – Experience grows a pilot's skill
7 Planning – Successful pilots are always running the Plan - Do - Check - Analyze cycle in their work.
Successful pilots plan their flight completely before execution
8 Precision – Successful pilots do more than what's good enough
7 Planning – Successful pilots are always running the Plan - Do - Check - Analyze cycle in their work.
Successful pilots plan their flight completely before execution
8 Precision – Successful pilots do more than what's good enough

Biogen-42110.
April
2020.
Exit strategy – Learn to land under difficult circumstances
Chesley Sullenberger is a famous
pilot not because he could take off or
keep the plane in the air, but because
he knew how to land the plane safely
in a very difficult situation
“If you can walk away from a landing,
it's a good landing. If you use the
airplane the next day, it's an
outstanding landing.”
Chuck Yeager

Conclusion
Prospective switching studies, high-quality data collection in patient registries, and robust
analyses of real-world data are still needed to inform treatment sequencing decisions
Long-term efficacy and
safety risks of
sequencing multiple
therapies are still
unknown
• More data are needed from patient registries describing the long-
term efficacy and safety associated with treatment sequencing
• In the absence of data, immunological and pharmacodynamic
information can help to inform clinical reasoning
Logic currently being
applied in treatment
sequencing decisions:
immunological and
pharmacodynamic
factors
• MOA determines which cell types are impacted and the duration of
effects on the immune system
• Shorter half-lives allow for faster washout and earlier initiation of new
treatment
• Longer half-lives require longer washout and the potential for reactivation
of disease activity following drug discontinuation
• Faster onset of activity reduces potential for disease reactivation

Biogen-42110.
April
2020.
Summary
DMT, disease-modifying treatment; MS, multiple sclerosis..
1. Compston A, et al. Lancet. 2002;359:1221-31; 2. Kalincik T, et al. Brain. 2017;140:2426-43; 3. Pardo G, Jones DE. J Neurol. 2017;264:2351-74.
MS is a lifelong disease and it is common for patients to switch treatments during the course of disease
• MS is a chronic, progressive disease, characterized by a high degree of variability in disease course
and response to treatment1,2
• An increasing number of MS treatment options and outcome measures are now in use3
• Switching treatments is not only possible, but common3
DMTs have different durations of immune system impact
• Immunologic effects of DMTs vary widely and can persist from days to years3
• DMTs with long-term immune system impact can limit subsequent options and/or introduce potential
safety risks associated with additive immune effects3
• DMTs with short-term immune system impact in addition can provide flexibility for future options,
within a relatively short time frame of discontinuation3

Biogen-42110.
April
2020.
Subclinical inflammation, demyelination, and neurodegeneration may be present for months or even years before a
patient experiences clinical symptoms
Inflammation, neurodegeneration, cognitive deficits, and
disability in MS over time
Adapted from Fox RJ, Cohen JA. Multiple sclerosis: The importance of early recognition and treatment. Cleve Clin J Med. 2001; 68:157–71.

Biogen-42110.
April
2020.
"Success is not final, failure is not fatal: it is the courage to continue that counts."
— Winston S. Churchill
When to make a change...
What does DMT failure look like?

Biogen-42110.
April
2020.
Think a few moves ahead
Don’t paint yourself
into
a
corner

Biogen-42110.
April
2020.
Treatment sequencing with MS DMTs
DMT selection
Diagnosis of MS
Based on disease activity, disability status and individual preference
Monitor disease activity Monitor the DMT
Safety and tolerability issues
Pregnancy planning
Individual lifestyle leading to non-adherence
Stable disease Sub-optimal response
Continue treatment
DMT, disease-modifying therapy.
Grand’Maison F, et al. Curr Med Res Opin. 2018; 34:1419-30. Reprinted with permission of the publisher Taylor & Francis Ltd, http://www.tandfonline.com
Sequence to another DMT
Don’t limit your options

Pseudo
attacks
NO
Rebaselining
NO
Satandard
protocols
Interrater
variability
Unconfirmed
attacks
NO Careful
repositioning
Different
machines
Poor
Experience
Unjustified escalation
Poor
Management
of a relapse

Treatment
Initiation Follow up MRI
0 months 6 months 12 month
Rebaselining
IFN B,Natalizumab,
DMF,Teriflunomide(3-6m)
GA(9m)
Alemutuzumab(24 m)

Sequencing in management of Multiple sclerosis

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