Taking a Closer Look at Each Patient: Exploring Novel Biomarker and Imaging Strategies in MS

Co-Chairs, Amit Bar-Or, MD, FRCPC, and Jiwon Oh, MD, PhD, FRCPC, discuss multiple sclerosis in this CME/NCPD/CPE/IPCE activity titled “Taking a Closer Look at Each Patient: Exploring Novel Biomarker and Imaging Strategies in MS.” For the full presentation, downloadable Practice Aids, and complete CME/NCPD/CPE/IPCE information, and to apply for credit, please visit us at https://bit.ly/3IyZJQh. CME/NCPD/CPE/IPCE credit will be available until June 29, 2025.

1. Taking a Closer Look at Each Patient
Exploring Novel Biomarker and
Imaging Strategies in MS

Amit Bar-Or, MD, FRCPC Jiwon Oh, MD, PhD, FRCPC
Melissa and Paul Anderson | gg Medical Director, Barlo Multiple Sclerosis Program
Presidents Distinguished Chair e Associate Professor, Division of Neurology
Professor, Department of Neurology = St. Michael's Hospital
Chief, Division of Multiple Sclerosis University of Toronto
and Related Disorders Staff Neurologist Scientist
Director, Centre for Neuroinflammation. Keenan Research Centre
and Experimental Therapeutics of the Li Ka Shing Knowledge Institute
University of Pennsylvania Toronto, Ontario, Canada
Children's Hospital of Philadelphia (CHOP)
Philadelphia, Pennsylvania

Go online to access full CME/NCPD/CPE/PCE information, including faculty disclosures.

Copyright €

2. Our Goals for Today

Help you use guideline-recommended imaging
strategies in MS diagnosis and management

Ensure that you are familiar with the evidence on
new and emerging MS biomarkers

Guide you in taking a team-based approach
to applying imaging and other biomarker findings
in individualizing MS care

2000-2024, PeerView

3. MRI: What’s New With the Tried and True?

Jiwon Oh, MD, PhD, FRCPC
Medical Director, Barlo Multiple Sclerosis Program

Associate Professor, Division of Neurology

St. Michael's Hospital

University of Toronto

Staff Neurologist

Scientist

Keenan Research Centre of the Li Ka Shing Knowledge Institute
Toronto, Ontario, Canada

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4. MRI

+» Has revolutionized the diagnosis and monitoring of patients with MS
— Earlier diagnosis
— Disease monitoring and assessment of treatment response

— Predictive value

s contributed substantially to our understanding of MS pathophysiology

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5. MRI as a Diagnostic Tool: Initial Diagnosis!

03 O) Diagnosis of multiple sclerosis: 2017 revisions of the
McDonald criteria

2010 McDonald MRI Criteria for
Demonstration of DIS?

DIS can be demonstrated by 21 T2 lesions®
in at least 2 of the 4 areas of the CNS

+ Periventricular
+ Juxtacortical
+ Infratentorial
+ Spinal cord?

2010 McDonald MRI Criteria for
Demonstration of DIT*

DIT can be demonstrated by

+ Anew T2 and/or Gd+ lesion(s) on follow-up
MRI, with reference to a baseline scan,
irrespective of the timing of the baseline MRI

+ Simultaneous presence of asymptomatic
'gadolinium-enhancing and nonenhancing
lesions at any time

* Gadolinium enhancement lesions is nat required fr DIS, * a subject has a brainstem or spinal cord syndrome, the symptomatic lesions are excluded trom

the creia and do not contribute to lesion count

1. Thompson AJ et al. Lancet Neural. 2018:17:162-173, 2. Polman CH et al. Ann Neurol. 2011:88:282-302. 3. Swanton JK etal. J Neuro! Nourosurg Psychiat
2006:77.230-839, 4. Swanton JK et al. Lancet Neurol 2007 8:677-686. 5, Montalban X et al, Neurology. 201074:427-434,

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6. From Old to New
Updated Consensus Guidelines for MRI in MS!

12021 MAGNIMS-CMSC-NAIMS consensus recommendations (2% ®
¡on the use of MRI in patients with multiple sclerosis
Cooperative MRI Guidelines crac cc, ee Na a On enge nn ea

Working Group Representing >

MAGNIMS
Magnetic Resonance Imaging in MS

+ Update of 2015 MAGNIMS and 2016
CMSC recommendations for appropriate

csc use of MRI in routine clinical practice
Consortium of Multiple Sclerosis Centers + Update prompted by
— 2017 revisions of McDonald

diagnostic criteria

NAIMS
E) North American Imaging in MS Cooperative — Safety concerns regarding Gd
contrast overuse

— Value of spinal cord MRI

1. Watjes MP et al Lance? Neurol 2021:20:683-670 PeerView.com

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7. Standardized MRI Protocols for MS Diagnosis!

Spinal Cord MRI Protocol

Brain MRI Protocol

id (be or Foe) mac Atleast to of sapital T2-weighed sequences (TSE or FSE)
[ata CENA proto densiy-weighted sequences (TSE of FSE), or STIR CS

Sagital T2-weighted FLAIR (preferably 30; “agita! 30 heavily Ti-weighied sequences (PSIR or

fat suppression is optional) ‘magnetization prepared rapid acquisition of gradient echoes) Optional
Axial T2-weighted FLAIR (unnecessary ia sagital 30 FLAIR with Say St Carl eased
ultplanar reconstruction ls obtained, fat suppression is optonal) Anal T2-weighted (TSE or FSE) or gradientrecaled echo to

corroborate, charactenze, and conter lesions detected on sagital ome
Aa (or 30 sagita) Ti-weighed sequences after contrast Images oro detect lesion in spinal cord segments with high

clinical suspicions of involvement
Dituson-veighted imaging Optional

Sagal Tt-weighted sequences (TSE or FSE) before contrast Optional
Double inversion recovery or PSIR for detecting cortical or ;
ntacorica lesions Spee Sagital Tt-weighted sequences (TSE or FSE) after contrast Recommended
Hof-resohuion Tt-weighted sequences (isotropic 30 acquisition; E

Axial T1-weighted sequences (TSE or FSE) ater contrast Optional

{for quanttatie assessment of brain volume)

Sunceptiy weight imaging EEE

1. Wales MP et al Lance? Neural 202:20:685-670 PeerView.com

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8. MRI: A Useful Tool to Monitor MS Disease Activity!

MRI plays an integral role in monitoring MS

+ MRI lesions develop up to 10-20 times more
frequently than clinical symptoms in patients
with RRMS

Most clinicians generally recommend | 1
an MRI on an annual basis

+ Sometimes more frequently during treatment
initiation/switch

+ There is concern in active, aggressive MS

1. Lubin FD eta. Neurology. 2014:85278-286 PeerView.com

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CT827 Copyright © 2000-2024, PeerView

9. Canadian MS Working Group Recommendations:
Level of Concern Based on Annual MRI Findings’

Recommended Cı for Switching Therapies in RRMS: Time to Effect of Disease-Modifying Therapie:
A Change in DMT Is Indicated for Patients Treatment Response Should be Evaluated
Who Meet Any of the Major Criteria After the Full Clinical Effect Has Been Attained
ne ren re
Relapse + Onerelapseinfirst2 years + 22 relapses in frst year Natalizumab
rate of treatment of treatment
+ IFN-B formulations
+ Mid + Terifunomide
+ No functional impairment + Moderate to severe + Dimethyl fumarate 3mo
(eg, school, work, daily + Functional impairment += Fingolimod
Severity activities) + Motor/cerebellar/brain + Ocrelizumab
+ Nomotorcerebella/brain stemsphincter
‘stem/sphincter involvement + Glatiramer acetate 6mo
involvement
2.y course required for maximal clinical
+ Full recovery at 6 mo + Incomplete recovery + Cladribine effect (benefit reported in pivotal trials
+ No functional impairment + Functional impairment + Alemtuzumab after year 2 dosing, with MRI evaluation
Recovery. EDSS change <1 pointat + EDSS change >1 point at for re-baselining at month 18)
6mo 6mo*

* itbaseline EDSS = 0,>1.5 points. baseline EDSS 555, any EDSS change would be a major concer. >} spinal cor lesions t may warrant a major concern
1. Freedman MS et al. Can J Neurol Sei 2020:47437-455. PeerView.com

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10. Another Approach: The Modified Rio Score!

e
o
©
2
©
©
13
a
E
a

1. Sormani MP etal. Mut Seler. 2013:19:008-612.

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g clinical and MRI monitoring at 1 year to predict prognosis on IFN-$ in next 2 years
2
Mr ev Tzienns | AND | Reses=0 | 13 10
2
MRinew T2lesions <5 | AND | Relapses = 1 El os
£ 10 2
OR 6 3
3 gos
MRinew Tlesons>5 | AND | Relapses=0 | À é
o7 A
E a
3 3 04
MRinew T2lesions <5 | AND | Relapses 22 [4 A
OR zo © 02
5
MRInewT2lesions>5 | AND | Relapses=1 | À
do o
ES 0 1 2 3 4
MRI new T2lesions>5 | AND | Relapses 22 Moi Host

Time, y

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11. Prediction: An Unmet Need in MS Clinical Practice

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12. Prognostic Value of Clinical, MRI, Biological Factor:
Conversion to CDMS"

HR (95% Cl)
Men
Women 1(0.8-1.2)
40-49 y
30-39 y 14 (1-2)
20-29 y 1.8 (1.3-2.5)
0-19 y 19(1.232)
Other
Optic neuritis, 0.9 (0.7-1.2)
OB absent
OB present 130118)
Olesions
1-3 lesions 5.1 (29-89)
4-9 lesions 7.5 (4.3-13.1) =
210 lesions 11.3 (6.7-19.3)
DMT after second attack
DMT before second attack 0.9 (0.64.2)
0
1. Tore Metal rain, 2015:136:1063-114. PeerView.com

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13. Baseline MRI Lesion Load as a Prognostic Factor!

Development of CDMS and an EDSS Score of 3.0 According to the Number of Lesions on the Baseline MRI

Development of CDMS

os

o4

02
O lesions

‘Cumulative Probabi

0m 4 72 98 120 ta 168 102 216 240
Time Since First Attack, mo

1. Tntore Metal. Brain. 2015:138:1963-1874,

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2
2

3

8

eo 210 lesions
£ 49 lesions

3 1-3 lesions
3

‘Cumulative Probability of Developing EDSS3

Reaching EDSS of 23.0

os

os

210 lesions
4-9 lesions

04

02

MM 2 06 10 14 188 192 216 20
Time Since First Attack, mo

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14. Predictive Value of Spinal Cord Lesions Over 15 Years!

+ N=173 patients with CIS followed for 15 years

+ MRl-brain/spine done at baseline, 1 year, and 3 years

+ Baseline spinal cord lesions predictive of SPMS at 15 years
+ New spinal cord lesions predictive of SPMS at 15 years

cis at 15y RRMS at 15 y SPMS at 15 y
Baseline 1y 3y Baseline 1y 3y Baseline 1y 3y
T2-weighted PA > N
brain
Tiaweighted
{post contrast)
brain

T2-weighted
spinal cord

1. Brownlee WJ eta Brain, 2019:142:2276-2207, PeerView.com

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15. Imaging Biomarkers in Development for Use in MS13

Techniques with greatly increased sensitivity and specificity to targeted aspects of MS pathology

Diffusion-tensor imaging + High field MRI
Magnetization-transfer imaging — Cortical lesions

MRS — Deep gray matter
fMRI + Advanced spinal cord MRI

Susceptibility weighted imaging
— Central vein sign (CVS)
— Paramagnetic rim lesions
(PRLs)
Slowly evolving lesions (SELs)
Lesion dynamics

1.FlppiM, Rocca MA. Radiology. 2011:258:850-681, 2. Harison DM et al. JAMA Neurol 2015:72:1004-1012. 3, Wegellet al. Radiology. 2000-217:897-003,

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16. The Central Vein Sign:
A Diagnostic Biomarker of MS?!

‘The central vein sign and its clinical evaluation
forthe diagnosis cf multiple sclerosis: a
consensus statement from the North American
Imagne in Muti Scrosis operative

Previous Lesions, %

Non-MS cisims

MS: a high proportion of WMLs with CVS +
‘Acutoff threshold of 40% has been proposed
to distinguish MS vs non MS

MRI: central vein inside white + More simplified criteria, Select3 and Select6,
matter lesions (WMLs) = available
“central vein sign’ (CVS) + Automated detection methods

MS lesions: perivenular
inflammatory demyelination

1. Sati Petal. Nat Rev Neurol 2016:12:714:722. 2. Popescu Veta. PLOS One. 2016.11:00143042. 3, Mistry N et al Mut Scor2016:22:1289-1206, ñ
4. Talanıye EC etal Neurology. 2011:76'534539, 5. Solomon AJ etal Mut Ser 2018:24750-757. PeerView.com

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17. CVS: Diagnostic Value’

+ Numerous studies show diagnostic utility in differentiating MS vs other WMD
(NMOSD, SLE, migraines, SVD, HCs with/without comorbidities)

+ Also observed in high proportions in RIS
— 90% RIS met > 40% threshold

Tallantyre et al. (2011) 28 MS Dworkin et al. (2018) 40 subjects

Mistry et al. (2013) 29 suspected MS Maggi et al. (2018) 52 RRMS, 31 with inflammatory

Campion et al. (2017) 25 RRMS, 10 SVD CNS vasculopathies
George etal. (2016) 87 subjects Sinnecker etal. (2019) 606 patients

Solomon et al. (2016) 10 RRMS, 10 migraine Suthiphosuwan et al. (2019) 20RIS
Samaraweera et al. (2017) 10 MS, 10 SVD Maggi et al. (2020) 51 suspected MS
Cortese etal. (2018) 18 NMOSD, 18 RRMS 38 patients recruited, 35 received
Solomon et al. (2017) 40 participants (Cake steal: (2020) ‘a clinical diagnosis of MS

1. Chaaban Let al Acta Neuro Scan. 2022:148:279-287.2. Suh CH etal. Sei Rep. 2019:9:18188. PR
3. Gastelano M et al Diagnostics (Base). 2020:10:1025. 4. Suhphosuman Jet al Mut See, 202:27:2199-2208, PeerView.com

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18. CVS: Practical Concerns

Access to appropriate sequences

+ Highest-sensitivity sequence (3D T2*) not accessible without cumbersome research agreements

Mostly evaluated on 3T or 7T platforms

+ 1.5T still most common clinical platform

Optimal threshold

+ Percent cut off works best, but Select3 or Select6 are still pretty good
+ Automated algorithms being developed, but access and incorporation into clinical workflow is still an issue

Level of evidence needed

+ Most studies are cross-sectional; a few are prospective
+ Large prospective studies underway (CAVS-MS, CanProCo)

1. Ontaneda D et al Neuraimage Cin. 2021:32:102834.2. Oh Jet al. BMC Neurol 2021211418 PeerView.com

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19. Paramagnetic Rim Lesions:
A Biomarker of Chronic, Smoldering Inflammation?13

12* GRE Phase GRE

j
Paramagnetic rim lesions: Chronic, “smoldering” inflammation >
and demyelination related to paramagneti of iron-laden 3.

microglia/macrophages at the lesion ex 5 mn

+ Histopathological correlations with chronic, active lesions

Associated with greater physical and cognitive disability

in MS and progressive N
High specificity for MS

Seen across the spectrum of

1. Absinta M et al. J Gin invest 2016;128:2807-2609, 2. Suthiphosuwan S etal. JAMA Neural 2020:77:683-855, 3. Maggi P etal. Ann Neural. 2020,88:1034-1082. PeerView.com

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20. Prognostic Value of PRLs*

Cohort Characteristics of 192 Patients With MS in the Cross-Sectional Cohort

Rim Category No Detected Rims 1-3 Rims 24 Rims ‘Statistical Analysis
‘Demographic and Cinical Data
N(%) 84 (44) 66 (34) 4222) NA
E] Clinical phenotype, n (%)
may, CISIRR 61 (73) 46 (70) 24 (57) Fisher2x 3; P= 2, NS
ee sp 1619) 14(21) 10 (24) 2
Sn PP 7(8) 6(9) 8 (19) =
Ys Women, n (%) 59 (70) 45 (68) 28 (67) Fisher 2x3; P= 9, NS
Id of ‘Age, mean (SD), y 473(145) 4720114) 443(114)

four or more Disease duration, mean (SD), y 13.4(125) 12999) 12283)
PRLs relevant Patients never treated, n (%) 27/84 (32) 11/66 (17) 542(12) Fisher2x3;
10 (12) 12 (18) 10 (24) Fisher 2 x 3,

[EDSS score, median (range)
MSSS score, median (SD) 4925)

lidation required
in prospectiv
He Relationships Between Tests of Memory and Information Processing Speed and PRLS
and Other MRI Measures in Multivariable Regression Models (P Displayed)
CVLT-Total _CVLT-Delayed BVMT-Total BVMT-Delayed_PASAT3 PASAT2 _ SDMT

PASAT score, median (SD) 44.6 (11.9)
‘median (SD)

PRLS, proportion 0.04 0.25 0.47 0.86 0.03 046 0.04
Thalamic fraction 0.29 0.97 0.55 041 0.16 02 04
SubQ lesion count 054 0.82 067 078 089 093 079
a 021 0.06 006 003 021 011 019
“Signiicantvend toward significant P bolded,

1. Suthiphosuwan S eta, JAMA Neurol 2020:77:659-655, 2. ON J et al. Mut Seer, 2021:272199-2208, PeerView.com

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21. SELs as a Marker of MS Progression’

+ SELs are white matter lesions showing linear expansion over time on serial
T1-weighted and T2-weighted scans

+ Proposed as a biomarker of chronic active lesions

+ SELS are seen in all MS phenotypes but are more numerous in PMS and SPMS
vs RRMS

+ Presence of SELs plus PRLs may predict greater clinical progression vs either
in isolation

+» One study showed that the proportion of SELs on MRI at baseline was
associated with poorer EDSS scores and conversion to SPMS at 9-year follow-up

+ Minimal overlap between SELs and PRLs (7%-17%)

1. Perzisa Peta, Neurol Nouroimmuno Newroinfamm. 2022:9.61130. 2. Cali A et al. Mut Soler. 2023:20:352-362. PeerView.com

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22. Case Presentation: Sierra

Sierra, aged 29 years, was diagnosed with RMS at 23 years old
She had two relapses in 18 months and heavy lesion burden early on

Four years after starting ofatumumab, she has not had any relapses, and her MRIs
have been stable on an annual basis

However, she reports that she feels like she’s slowing down over the past 1-2 years

— She used to comfortably tackle 6-8 mile hikes on hilly trails; now she can handle
only 4-5 miles on flat courses

What might this suggest?
What MRI measures might be useful to evaluate her?

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23. Imaging Summary

+ MRI is a useful tool in the diagnosis of MS
- Earlier diagnosis
— Prognosis
— Monitoring of treatment response
- Standardization is important
+ Treatment target guidelines exist for
MRI use in clinical practice and continue
to evolve
+ Better tools are needed in clinical practice
for diagnosis, prognosis, and
disease monitoring

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Advanced, quantitative MRI techniques
have greatly increased sensitivity and
specificity to MS microstructural changes
and are in development as clinical tools
— Diagnosis: CVS, PRLs
— Prognosis/disease monitoring:
PRLs, SELs

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24. Blood, CSF, and Beyond:
Looking at Emerging Biomarker Strategies

Amit Bar-Or, MD, FRCPC
Melissa and Paul Anderson President's Distinguished Chair

Professor, Department of Neurology

Chief, Division of Multiple Sclerosis and Related Disorders

Director, Centre for Neuroinflammation and Experimental Therapeutics
University of Pennsylvania

Children's Hospital of Philadelphia (CHOP)

Philadelphia, Pennsylvania

000-2024, PeerView

25. In Addition to Imaging...

There is a need for additional reliable, clinically useful blood-based,
CSF-based, or other biomarkers to help

+ Establish an MS diagnosis

+ Assess disease status
+ Monitor progression and treatment response

+ Possibly determine prognosis and inform treatment selection

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26. In Addition to Imaging.

Multiple novel biomarkers investigated and/or used as novel endpoints in MS trials
CSF oligoclonal bands
CSF levels of IL-1, IL-2, and
Neurofilament light chain
Kappa free light chains
Glial fibrillary acidic protein
Chitinases (eg, CHISL1)

Contactin-1

Osteopontin

Eye-movement tracking

Digital biomarkers (eg, smartphone/smartwatch-based assessments of gait and balance)

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27. Neurofilament Light Chain (NfL)'

Neuroaxonal Source: NfL Elevations Reflect Neuroaxonal Damage
Structural Cytoskeleton Component (MS, AD, ALS, PD, and Trauma)

3888

3

g

SNfL, pg/mL

* Pearson R = 0.77; P<.001
(95% CI, 0.69-0.83)

100 500 1,000 5.000 10000 25,000
CSF NIL, pg/mL

1. Khai Metal. Nat Rov Neuro. 2018:14577-589, 2. Kuhle Jet al Mut Schr. 201622:1850-1559, 3, Zeteberg Het al. JAMA Neurol 2016.73:60-67,
4. Weyet Pet al Ann Neuro. 201678:152-158. 8, Baciogu M eta. Neuron, 2016;91'56-6. 6, Bergman J eta. Neurol Nouraimmuno Neurointamım. 2016:3:271. —
7, Disato G etal. Ann Neurol. 2017.81:857-970 PeerView.com

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28. Neurofilament Light Chain (NfL)'2

PNS CNS
damage damage
Aging

a Sport
[| Cardiovascular Blood NL lovel Ju, 888
] risk factors permeability

ST)

Increased y
blood volume q

+ Marker of neuroaxonal injury; not MS specific but can have clinical utility in detecting CNS
damage; can be measured in CSF or serum?
— For example, the “Simoa” and “Lumipulse G” assays; both FDA approved

BMI_ Pregnancy

1. Tiensvo AB et al. J Neurol 2021:268:1385-1304, 2. Barr Cet al. Ann Cin Trans! Neurol 2020.72508-2523, PeerView.com

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29. DMT Effect on NfL Levels in MS

DMT can reduce NfL—often
Untreated within first year of initiation

Platform
NfL can act as an early

marker of subclinical
Orals disease activity AND as
HEmAb a real-time indicator of

disease activity

SNfL Z Score

Does not replace MRI's role
in MS therapy monitoring

2 3
Time on Drug or Time Untreated, y

No.of samples o >
‘Untreated 375 1" 101 66 isti
Platform 170 115 92 a ES Important to set realistic
and Le) Bd su 490 358 expectations
HE mad 56 42 292 161 153

1. Benkert Pet al Lancet Neurol 2022:21246-257 PeerView.com

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30. Elevated Levels of sNfL Can Be
Prognostic of MS Relapsing Disease Activity’

In the phase 3 A subgroup n E ghe
ASCLEPIOS | analysis stratified s

and Il trials 1,678 patients by

(ofatumumab vs baseline sNfL n n el
teriflunomide) levels: E
in RMS, baseline ff high: > 9.3 pg/mL;

sNfL levels were low: <9.3 pg/mL

prognostic for gp
on-study lesion y S
formation (as

well as brain Ir RMS disease
volume loss) - ty

1. Cross A etal. Neurology. 2024:102(Suppl 1)P6-6.011, PeerView.com

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31. Thinking Beyond Relapse:
Assessing Risk for PIRA Is a Crucial Unmet Need in MS!

MS increasingly understood not as either relapsing or progressive but as a
disease continuum, with smoldering inflammation present even without relapse

No means, including MRI, yet validated to assess risk
for progression independent of relapse activity (PIRA)

1.0h Jetal. Sei Rep. 2024:14:122, 2. Bar-Or A et al. eBloMed. 2023:93:104882. PeerView.com

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32. Can Elevated Serum NfL Predict Progression?!

NfL levels, a marker of neuroaxonal injury, are higher in patients with confirmed disability worsening
(CDW) with or without relapse than in patients with stable MS

Swiss Multiple Sclerosis Cohort (8,901 visits)

EPIC Study Cohort (3,906 visits)

NfL z-Scores (95%

NfL z-Scores
ci)

(95% Cl)

P=.040 342 -207+56 0.28 (0.18-0.37) P<.001
10.8 13.5 0.09 (0-0.18) P=.056
0.32 0.71 (0.14-0.49) P<.001

CDWt-2] 191 262464 0.23 (0.01-0.45)
CDWumt-1] 191 “122413 0.27 (0.11-0.44) P<.001 342

CDW, 36 -126+14 0.71(0.35-1.07) P<.001 93 -109+3.1

An analysis of longitudinal visits in two cohorts from long-duration studies found higher NfL levels
preceding CDW

+ Nfl z-scores were elevated
— 11 and 13 months before CDW in those with relapse
— 12 and 21 months before CDW in those without relapse (PIRA)

1. Abdelnak At a. JAMA Neurol 2023:80:1317-1325 PeerView.com

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33. NfL Measures in MS Patients on High Efficacy Therapy!

+ Elevated NfL in RMS and PPMS patients on treatment for 48 weeks with anti-CD20 (phase 3
'ORCHESTRA trials) were predictive of nonrelapsing progression (eg, “PIRA”)

OPERA | and II (OCR arm) ORATORIO (OCR arm)

Cumulative Probability,
of CDP24 on EDSS, %

ES ITA 72 ae OW ea VIO O DTT TH O 0 0,
Weeks. Weeks.
lor 893 99 99 8

7457441940849 0 79965 25 208211724 96 WOK TANK OT 6 0 87 EHH wD
on 126126 a 10119 1D 99 OF 08 HL TH 72 eT 0 6 St 35 2 oh 208206 208 200 1415 140 143127 113 03 90 22 7S 00 00 ST m

1. BarOr À et a. BioMed, 2023:93:104862 PeerView.com

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34. PeerView.com/UCT827

Can Combination of Markers Help?
CSF GFAP, NfL, and Neurofilament Heavy Chain!

Leveraged datasets from the open-label anti-CD20 OBOE study, in which
patients underwent pretreatment and post-treatment CSF and blood
sampling + MRI assessment of relapsing and progressive disease

Outcome measures

25 CSF markers, including NfL,
neurofilament heavy chain (NfH),
and GFAP; CDP24; and brain MRI
reflecting focal injury, tissue loss,
and SELs (reflecting nonrelapsing
progressive biology)

1. Gross AH eta, JAMA Neuro, 2024:81:373-383, PeerView.com

Identify biomarkers that distinguish
the two biologies

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35. Can Combination of Markers Help?
CSF GFAP, NfL, and Neurofilament Heavy Chain!

NfL strongly associated with acute inflammatory disease activity
and to some extent with progressive outcomes

NfH and particularly GFAP tracked better with nonrelapsing
progressive outcomes than with acute relapsing disease activity
(better marker of ongoing insidious neuroaxonal injury)

CSF GFAP and NfH may complement NfL in assessing MS

1. Gross AH et al. JAMA Nourol 2024:81:373-383, PeerView.com

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36. GFAP + NfL: Results of EmBioProMS*

Patients followed over a mean of 29.3 months

rn

+ 6-month confirmed
disease progression
was calculated with
combined EDSS,
T25FW, and 9HPT
scores

+ Prospective
multicenter
observational study
followed patients with

PPMS and SPMS

Goal: define the

association between

novel blood
biomarkers and
disease progression
in PMS

High GFAP + low NfL
levels could identify
high progression risk
in patients with
nonactive PMS

1. Abdenak A tal. An Cin Trans Neurol 2028:11477-485 PeerView.com

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37. Integrating Fluid Biomarkers With Other Findings in MS Care:
CMSC Algorithm’

Baseline evaluation

Patient fulfils
IcDonald criteria
for MS diagnosis

<=> <I>

1. Freedman MS et nt J MS Caro. 202123 suppl 1727. PeerView.com

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38. Integrating Fluid Biomarkers With Other Findings in MS Care:
CMSC Algorithm’

Elevated

1. Freedman MS et ant J MS Caro. 202123 suppl 1727. PeerView.com

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39. Integrating Fluid Biomarkers With Other Findings in MS Care:
CMSC Algorithm’

6-12 month monitoring period

+ clinical and/or
MRI

1. Freedman MS et alt J MS Caro. 202123(supph 1)27. PeerView.com

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40. In Addition to Imaging.

Multiple novel biomarkers investigated and/or used as novel endpoints in MS trials
CSF oligoclonal bands
CSF levels of IL-18, IL-2, and IL-6
Kappa free light chains
Chitinases (eg, CHI3L1)
Contactin-1
Osteopontin
Eye-movement tracking

Digital biomarkers (eg, smartphone/smartwatch-based assessments of gait and balance)

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41. In Addition to Imaging.

Multiple novel biomarkers investigated and/or used as novel endpoints in MS trials
CSF oligoclonal bands
CSF levels of IL-18, IL-2, and IL-6
Neurofilament light chain
Kappa free light chains
Glial fibrillary acidic protein
Chitinases (eg, CHI3L1)
Contactin-1
Osteopontin

Eye-movement tracking

Digital biomarkers (eg, smartphone/smartwatcl ised assessments of gait and bal

PeerView.com

024, PeerView

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42. Growing Interest in Digital Biomarkers’

+ Remotely deployable technologies may inform treatment decisions, monitor
patient response to therapy, reduce logistic challenges, and otherwise contribute
to improved MS care

Referencesby Year

+ Asystematic literature search
of studies of digital health
biomarkers for MS found the
strongest focus on gait
assessment, although voice
and cognitive digital
biomarkers are emerging

Numberof Studies

Ouai gai assessment MDigtal voice assessment M Digtal cognitive assessment
=) one) oni)

1.Cobb B eta AAN 2024. P5.013, PeerView.com

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43. Floodlight: A BYOD Approach That Puts Assessments
Into the Hands (Literally) of People With MS!

“You can use Floodlight MS at home and on the go, collecting information that
you can share with your doctor to help inform conversations about your care.

The activities in Floodlight MS provide views of measurements of your
cognition, hand function, and walking ability over time. The app also features
a personal journal that includes daily questions and a symptom tracker
to help you keep a more detailed record of your health.

Unlike many other wellness apps, Floodlight MS was co-designed
with MS experts and people living with MS to create an app that you
can use to share your health data with your doctor.”

906

1. tps play google comvstore/apps/detalsid=comochedsoodightusBizen_USAI=USBpIis1 PeerView.com

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44. Digital Tools: Floodlight App!

Active Tests Passive Monitoring

Test
rience Samplin
ws Experience Sampling
Baty
Mood SYMPIO™ msis-29
‘Question
3
B Fortighty
Sos and Fornghty
g adhoc

Cogi

05%“

somt

Weekly

n | Hand and Arm

Pinching
Test

Daly

Drawa
Shape
Test

Dai

Gait and Posture

Static
Balance
Test

Daly

R

2:Minute
Walk
Test

Daily

» »

Gait Mobility
Behaviour Pattern

Continuous Continuous

1.0h Jetal. Sei Rep. 2024:14:122

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45. Floodlight Open: Global, Open-Access Study

Assessing Use of the Floodlight App!

+ Designed to understand drivers and barriers in real-world use of the app
“N = 1,350 participants with MS; 1,133 without MS (all self-declared)

+ App users self-administer tests of cognition, hand motor function, gait,
postural stability; mobility levels are assessed passively,

+ 38% of users stopped participating after 1 week

— Some persisted as long as >100 weeks ¿a
+ Floodlight Open be
— Demonstrated the feasibility of using E
a BYOD tool to assess performance go
— Highlighted challenges of user engagement 2
and persistence =
o
°
+ Australia (0 = 205) = 54) lay (n= 130)
Belg n= 50) —+ Denmark (n= 34) USA (n= 560)
— canada in = 180) Spann Ñ
1.OnJetal Selop.2024:14:12, PeerView.com

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46. Can Eye Movement Shed Light on Disease
and Cognitive Status in MS?!

Evidence supports a link between anomalies
in eye movement and brain health

In an ongoing longitudinal trial (N = 60 adults with
RRMS or SPMS), gaze-tracking software using the
camera in a tablet (iPad Pro) was used to compare select
eye movements (on fixation, pro- and anti-saccade, and
smooth pursuit visual tasks) with conventional MS
assessments (EDSS, BICAMS, MSFC, SDMT)

Findings from partial least squares regression analyses
suggest that use of mobile, scalable, eye-tracking
technology may provide a noninvasive and sensitive digital
biomarker of progression of cognitive and physical disability

+P <.05.2P<.01. — 7
1. de Vilers-Sidani E et al. Front Neurol. 2023:14:1243504, PeerView.com

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47. Challenges to Using Digital Tools in Clinical Practice

Validation against
existing tools

ition of thresholds
for worsening

Defi

for assessment

+ Must demonstrate ability
to identify clinically
meaningful change

+ Must be validated
against accepted,
existing measures

1. Torous Jet
4. Weite T

PeerView.com/UCT827

+ Need to define thresholds
for clinical worsening
based on digital monitoring

+ Once established, these
measures can be used to aid
clinical decision-making

+ Must account for possible
practice effects over time

Trans Psychiatry 2017:T:01083, 2. Torous J etal. NPJ Schizophr. 2018:48, 3. Sneha S, Varshney U. Decision Support Systems 2009;46:606-619,
J Med Intemet Ros. 2021:23:030394,

+ Need to establish optimal
measurement protocol
which will likely differ
between assessments
(eg, active vs passive
outcome monitoring)

Copyright © 2000-2024, PeerView

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48. Back to the Case Presentation: Sierra

Sierra, aged 29 years, was diagnosed with RMS at 23 years old

She had two relapses in 18 months and heavy lesion burden early on

Four years after starting ofatumumab, she has not had any relapses, and her MRIs
have been stable on an annual basis

However, she reports that she feels like she’s slowing down over the past 1-2 years

— She used to comfortably tackle 6-8 mile hikes on hilly trails; now she can handle
only 4-5 miles on flat courses

What biomarkers—alone or in combination—would provide
further insight on Sierra’s current condition?
What would be prognostic?
How might the expanding range of biomarkers affect team-based MS care?

PeerVie

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49. Conclusions

+ Biomarkers can help guide treatment decisions over time

Leverage biomarkers are currently available—such as MRI—to guide
treatment decisions with patients

+ Await guidance on biomarkers that are up and coming—such as NfL,
GFAP—to guide therapy in the future

Digital tools may become useful in clinical practice following
substantial validation

+ Use biomarkers to individualize patient treatment decisions and
therapy goals

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