Navigating the High-Efficacy DMT Landscape in MS: Integrating New Data and Real-World Evidence

Jiwon Oh, MD, PhD, FRCPC, discusses multiple sclerosis in this CE activity titled "Navigating the High-Efficacy DMT Landscape in MS: Integrating New Data and Real-World Evidence." For the full presentation, please visit us at www.peervoice.com/QYN870.

1. PeerVoice

Navigating the High-Efficacy DMT Landscape in MS:
Integrating New Data and Real-World Evidence

Learning Objectives

Discuss central nervous system (CNS) penetration of high-efficacy disease-
modifying therapies (DMTs) and potential clinical implications

Summarise the benefits and limitations of high-efficacy DMTs and their
associated outcomes

Evaluate clinical and real-world data regarding high-efficacy DMTs in the
management of people with multiple sclerosis (MS)

Apply evidence-based strategies using high-efficacy DMTs to optimise
outcomes in people with MS

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Part 1 of 4: CNS Penetrance of High-Efficacy D

Jiwon Oh, MD, PhD, FRCPC:

Associate Professor of Medicine

University of Toronto

Medical Director of the Barlo Multiple Sclerosis Centre
St. Michael's Hospital

Toronto, Ontario, Canada

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3. PeerVoice

Jiwon Oh, MD, PhD, FRCPC, has a financial interest/relationship or
affiliation in the form of:

Consultant for Biogen Inc.; Eli Lilly and Company; EMD Serono;

F. Hoffmann-La Roche Ltd. and Novartis AG.

Grant/Research Support from institutional work with Biogen Inc.;
F. Hoffmann-La Roche Ltd; and Idec Pharma.

Advisory Board for Amgen Inc.; Biogen Inc.; Eli Lilly and Company;
EMD Serono; F. Hoffmann-La Roche Ltd.; and Novartis AG.

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Microglia in De- and Remyelination

Apoptotic T cell

>)
Q

an

PDA

PDGF, VEGF, IGF-1,
_MMP12,

MMP14, CXCL1O,
CXCL13, TGF-R1

Phag

à
T cell
Astrocytes
a—
ë | Ree
+ | Microglia

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What Makes a Treatment “High Efficacy”?

A therapeutic effect that can be proven on 21 outcome of inflammation:

Y Substantial decrease of annualised relapse rate and/or

W Substantial decrease of MRI activity (new/enlarging T2-hyperintense lesions and/or
Gd-enhancing lesions)

AND 21 outcome of disease progression:
Substantial decrease of clinical disability progression: Confirmed worsening of EDSS score and its
ar functional system scores, cognitive deterioration, composite scores (eg, MSFC, EDSS worsening plus

220% minimum threshold change for T25FW and 9HPT)

Substantial effect on MRI measures of neurodegeneration: Global or regional brain and spinal cord
atrophy

Substantial effect on body fluid biomarkers: Neurofilament light chain levels

Patient-reported outcomes (PROs)

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Window of Treatment Opportunity

Treatment
initiation
Treatment

ean ;

initiation
| Treat ea with

Treat early with the right product Ñ

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Abbreviations and References

Microglia in De- and Remyelination

Abbreviation(s): BDNF: brain-derived neurotrophic factor; CXCL: interferon gamma-induced protein; IGF-1: insulin-like
growth factor 1; L: interleukin; MHC: major histocompatibility complex; MMP: matrix metalloproteinase;

PD-I: programmed cell death protein 1; PDGF: platelet-derived growth factor; PD-LI: programmed death ligand 1;

TCR: T cell receptor; TGF: transforming growth factor; TNF: tumour necrosis factor; VEGF: vascular endothelial growth
factor.

Reference(s): Zhang X et al. Front Neurol. 2023:14:1157287.

What Makes a Treatment “High Efficacy”?

Abbreviation(s): 9HPT: 9-Hole Peg Test; EDSS: Expanded Disability Status Scale; Gd: gadolinium; MRI: magnetic
resonance imaging; MSFC: Multiple Sclerosis Functional Composite; T25FW: Timed 25-Foot Walk.
Reference(s): Filippi M et al. J Neurol. 2022:269:5382-5394.

Window of Treatment Opportunity

Reference(s): Giovannoni G et al. https://www.msbrainhealth.org/wp-content/uploads/2021/05/brain-health-time-
matters-in-multiple-sclerosis-policy-report.paf. Accessed 25 August 2024.
Wijnands JMA et al. Lancet Neurology. 2017:16:P445-451

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8. PeerVoice

Part 2 of 4: High-Efficacy DMTs in MS: What Can Real-World Evidence
Tell Us About the Patient Experience?

Jiwon Oh, MD, PhD, FRCPC:

Associate Professor of Medicine

University of Toronto

Medical Director of the Barlo Multiple Sclerosis Centre
St. Michael's Hospital

Toronto, Ontario, Canada

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9. PeerVoice

Jiwon Oh, MD, PhD, FRCPC, has a financial interest/relationship or
affiliation in the form of:

Consultant for Biogen Inc.; Eli Lilly and Company; EMD Serono;

F. Hoffmann-La Roche Ltd. and Novartis AG.

Grant/Research Support from institutional work with Biogen Inc.;
F. Hoffmann-La Roche Ltd; and Idec Pharma.

Advisory Board for Amgen Inc.; Biogen Inc.; Eli Lilly and Company;
EMD Serono; F. Hoffmann-La Roche Ltd.; and Novartis AG.

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Two Approaches to Initiation of Therapy for MS

Escalation | |
Initial immunomodulator
therapy

Lateral
switch or
escalate if

tolerability
issues

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11. PeerVoice

Swedish vs Danish Registry: Escalation vs Early HE DMT

Time to Confirmed Disability Progression Time to First Relapse by
by Treatment Strategy Cohort

Treatment Strategy Cohort

e
o £

2 © = E

si 9 11075

ng 075 ge

“6 Sa

ES 32

23 Bs

58 os & B05

$? Sweden: Primary immediate Su Sweden: Primary immediate

ce ie 7 HEDMT strategy E do = HE DMT strategy

550 2 £o:

2 3 Denmark: Primary treatment 5: Denmark: Primary treatment

3 — escalation strategy as —— escalation strategy

25 0 a 0

ae o 1 2 3 4 5 6 o 1 2 3 4 5 6

Time Since Start of First-Line DMT, Years Time Since Start of First-Line DMT, Years

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HE DMT Adherence and Longer-Term Safety Data

+ In longer-term extension

91% studies with ocrelizumab,
cladribine earlier treatment with
treatment ocrelizumab resulted in

persistence greater reductions in

rate

disability progression, with
a favourable long-term
safety profile in people
with relapsing MS and

= Treatment completion people with primary
progressive MS

Insufficient follow-up
= Treatment discontinued

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13. PeerVoice

Additional Data on Long-Term Safety: Selected Studies

Fingolimod

14-year follow-up study of fingolimod showed that annual frequencies of AEs remained low,
and no new safety findings emerged over the long term!

Risk for JC virus (JCV) reactivation and PML development with natalizumab?: Expanded

interval dosing provides additional data on mitigation of the PML risk in patients treated
with natalizumab®

am Cladribine

Long-term observational follow-up programme of patients treated with cladribine did not
detect a higher risk of malignancies*

The safety profiles of HE DMTs vary by

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Patient Preferences for Therapy

Patients showed highest preference for medications that would improve their
symptoms and prevent future disability

Patients were willing to accept a 10% or 30% risk of severe adverse events or death for
medications that prevented progression for 25 or 32 years, respectively

The most important DMT attributes were efficacy, mode and frequency of
administration, and side effect profile; patients showed lower preference for therapies
that require frequent injections

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Abbreviations and References

Two Approaches to Initiation of Therapy for MS

Abbreviation(s): HE: highly effective; IRT: immune reconstitution therapy; MS: multiple sclerosis.
Reference(s): Jiwon Oh, MD, PhD, FRCPC. PeerVoice interview; August 2024.

Swedish vs Danish Registry: Escalation vs Early HE DMT

Abbreviation(s): DMT: disease-modifying treatment/therapy.
Reference(s): Spelman T et al. JAMA Neurol. 2021:78:1197-1204.

HE DMT Adherence and Longer-Term Safety Data
Reference(s): Brownlee W et al. Mult Scler Relat Disord. 202379104951.

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Abbreviations and References (Cont'd)

Additional Data on Long-Term Safety: Selected Studies

Abbreviation(s): AE: adverse event; PML: progressive multifocal leukoencephalopathy.

Reference(s): Cohen JA et al. Ther Adv Neurol Disord. 2019;12:1756286 419878324. doi10.1177/1756286419878324.
Ho P-R et al. Lancet Neurol. 2017;16:925-933.

Ryerson LZ et al. Neurology. 2021:96 (15_Supplement).

Leist T et al. Mult Scler Relat Disord. 2020;46:102572.

Patient Preferences for Therapy

Abbreviation(s): RRMS: relapsing-remitting MS.
Reference(s): Wilson LS et al. Int J MS Care. 2015,17:74-82.

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Part 3 of 4: her-Efficacy DMTs in MS: Further Evidence for Sustained
Long-Term Outcomes That Matter to Patients

Jiwon Oh, MD, PhD, FRCPC:

Associate Professor of Medicine

University of Toronto

Medical Director of the Barlo Multiple Sclerosis Centre
St. Michael's Hospital

Toronto, Ontario, Canada

Copyright © 2010-2024, PeerVoi

18. PeerVoice

Jiwon Oh, MD, PhD, FRCPC, has a financial interest/relationship or
affiliation in the form of:

Consultant for Biogen Inc.; Eli Lilly and Company; EMD Serono;

F. Hoffmann-La Roche Ltd. and Novartis AG.

Grant/Research Support from institutional work with Biogen Inc.;
F. Hoffmann-La Roche Ltd; and Idec Pharma.

Advisory Board for Amgen Inc.; Biogen Inc.; Eli Lilly and Company;
EMD Serono; F. Hoffmann-La Roche Ltd.; and Novartis AG.

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MAGNIFY-MS: Effect of Early Treatment With Cladribine on

MRI-Detectable Disease

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TI Gd+ Lesions

Active T2 Lesions

160% 160% 150%

Screening’ Baseline 7 Month” Month 2” Month 3” Month 6
visit visit visit visit
(n= 254) (n= 258) (n= 252) @- (255) (n=249) (n= 257)

77 1802420

6

5

4

3

É 0102036 oo02=023 0202065

o n
Baseline Month 2 Month 3 Month 6

visit visit visit visit

(n= 256) (n= 253) (n= 246) (n= 248)

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ALITHIOS: Patients at NEDA-3

M Ofatumumab/Continuous ofatumumab

Proportion of Patients, %

Mean exposure (years):

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100

30

60

40

20

OR (95% Cl):
3.53 (276-451),
P<.001
PT

36.7

I Teriflunomide I Newly switched ofatumumab

OR (95% CI
3.89 (3.01-5.02),
P<.001
EA

78.8

n=843 n=855

Core period
16 15

n= 631 n= 630
OLE period Overall
19 19 29 29

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Efficacy Outcomes in CARE-MS Through Year 13

E Alemtuzumab only — Alemtuzumab only
M SC IFNB-Ia (Years 1-2) — SC IFNB-Ia (Years 1-2)
08 M Alemtuzumab (Years 3-11) wid — Alemtuzumab (Years 3-11)
= 0.55 A
5 ole 5 35 so 2 31
o 3 29 30 29
= g 3
E 04 8
< € 25
3
02 = 21 E
Year 0 1 2 3 4 5 6 7 8 9 0 1
6 Core ——— Extension studies
Years 1-2 Years 3-13
No. of
participante 202 435 143 393

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Impact of 10 Years of Ocrelizumab Treatment in MS

No new safety signals were seen in 10-year follow-up data of phase 3
trials (OPERA I/II and ORATORIO) for people with relapsing and primary
progressive MS treated with ocrelizumab

Earlier treatment with ocrelizumab resulted in greater reductions in
disability progression compared to the active comparator (interferon
R-la or placebo), with a favourable long-term safety profile in both
relapsing and primary progressive MS

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Abbreviations and References

MAGNIFY-MS: Effect of Early Treatment With Cladribine on MRI-Detectable Disease

Abbreviation(s): Gd: gadolinium; MRI: magnetic resonance imaging.
Reference(s): de Stefano N et al. Neuro! Neuroimmunol Neuroinflamm. 2022;9:e187.
doi:10.1212/NX.0000000000001187.

ALITHIOS: Patients at NEDA-3

Abbreviation(s): Cl: confidence interval; NEDA: no evidence of disease activity; OLE: open-label extension;

OR: odds ratio.

Reference(s): Hauser SL et al. Mult Scler. 2023;29:1452-1464.

Efficacy Outcomes in CARE-MS Through Year 13

Abbreviation(s): ARR: adjusted response rate; IFN: interferon; SC: subcutaneous.

Reference(s): Coles AJ et al. Ther Adv Neurol Disord. 2023;16:17562864231194823. doi:10.1177/17562864231194823.
Impact of 10 Years of Ocrelizumab Treatment in MS

Abbreviation(s): MS: multiple sclerosis.
Reference(s): Hauser SL et al. American Academy of Neurology 76th Annual Meeting (AAN 2024); Presentation 005.

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Part 4 of 4: High-Efficacy DMTs in MS: Establishing Evidence-Based
Strategies to Optimise Patient Outcomes

Jiwon Oh, MD, PhD, FRCPC.

Associate Professor of Medicine

University of Toronto

Medical Director of the Barlo Multiple Sclerosis Centre
St. Michael's Hospital

Toronto, Ontario, Canada

Copyright © 2010-2024, PeerVoi

25. PeerVoice

Jiwon Oh, MD, PhD, FRCPC, has a financial interest/relationship or
affiliation in the form of:

Consultant for Biogen Inc.; Eli Lilly and Company; EMD Serono;

F. Hoffmann-La Roche Ltd. and Novartis AG.

Grant/Research Support from institutional work with Biogen Inc.;
F. Hoffmann-La Roche Ltd; and Idec Pharma.

Advisory Board for Amgen Inc.; Biogen Inc.; Eli Lilly and Company;
EMD Serono; F. Hoffmann-La Roche Ltd.; and Novartis AG.

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26. PeerVoice

Holistic Approach to MS

MS-specific targets

Therapeutic pyramid

Neurorestoration

E

nation [6 Anti-ageing

— = Brain health

ES] | Physical health
— À

Essential Anti-inflammatory

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Non-MS Targets
Healt

+ Smoking

Alcohol

Exercise (aerobic, HIT)

Diet/metabolic hacking or

‘enhancement (caloric restriction,

intermittent fasting ketogenic diet,

nutriceuticals)

+ Sleep hygiene

+ Comorbidities: Metabolic syndrome,
head injuries, infections (UTIs,
periodontitis, sinusitis, respiratory)

+ Concomitant medications
(anticholinergics)

+ Anti-ageing medications (HRT,
metformin)

+ Social determinants of health (low
levels of education, poverty and

deprivation, social isolation, social

capital, etc.)
Wellness

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Factors Related to DMT Decision-Making

» Preferences

+ Risk tolerance

+ Comorbidities

+ Reproductive
status

À

+ Severity
+ Phenotype

Disease-
related
factors

+ Efficacy Treatment- | System- Financial
+ Safety? related || related coverage
+ Tolerability factors | factors + Access to
+ Monitoring needed services

+ Dosing route and frequency

+ Prognostic signs

® JCV antibody status.

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Which Patients Should Receive HE DMT?

Therapy is based on disease activity:
High activity = HE DMT

Other poor prognostic factors:
Male, obese, older age

Progression or lack of response
to initial therapy

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29. PeerVoice

Platform Therapies Have a Favourable Benefit-to-Risk Profile

Time to First Serious Infection

0.95

080 General population

Any Serious Infection, %

— Fingolimod
Rituximab

Proportion of Patients Without

0.85

o 1 2 3 4 5 6

Time Since Treatment Start, Years

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Abbreviations and References

Holistic Approach to MS

Abbreviation(s): HIT: high-intensity interval training; HRT: hormone replacement therapy; MS: multiple sclerosis;
UTE urinary tract infection.

Reference(s): Giavannoni G et al. Front Neurol. 2024,14:1286122. doi:10.3389/fneur.2023.1286122.

Factors Related to DMT Decision-Making

Abbreviation(s): DMT: disease-modit ying therapy/treatment; JCV: John Cunningham virus.

Reference(s): Farber RS, Sand IK. Ther Adv Neurol Disord. 2015;8:212-232.

Which Patients Should Receive HE DMT?

: highly effective.
on Oh, MD, PhD, FRCPC. PeerVoice interview; August 2024.

Abbreviation(s):
Reference(s):
Platform Therapies Have a Favourable Benefit-to-Risk Profile

Abbreviation(s): GA: glatiramer acetate; IFN: interferon.
Reference(s): Luna G et al. JAMA Neural. 2020,77:184-191.
McGuigan C et al. J Neurol Neurosurg Psychiatry. 2016;87:117-125.

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