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This webinar is organised and funded by Teva Pharmaceuticals Europe B.V. Date of Preparation: December 2018 | HQ/MTCNS/18/0009a

Thank you for joining. The webinar will begin shortly

This webinar is organised and funded by Teva Pharmaceuticals Europe B.V. Date of Preparation: November 2018 | HQ/MTCNS/18/0009a

Welcome and Introduction

• Prof. Sven Schippling

Faculty

• Prof. Sven Schippling, Moderator

Deputy Head of the Department of Neuroimmunology and Clinical Multiple Sclerosis Research (nims) at the University Hospital Zürich, Switzerland

• Prof. Gavin Giovannoni

Chair of Neurology, Blizard Institute, Barts and The London School of Medicine and Dentistry, UK

Agenda

Time (CET) Title Speaker 11:00–11:05 Welcome and introduction Sven Schippling 11:05–11:10 Understanding EDSS Sven Schippling 11:10–11:20 EDSS: Is it fit for purpose? Gavin Giovannoni 11:20–11:25 Ask the audience All 11:25–11:30 Beyond EDSS: How else can we evaluate disability progression? Sven Schippling 11:30–11:40 Exploring other clinical measures of disability: A discussion Gavin Giovannoni 11:40–11:45 Ask the audience All 11:45–11:55 How best to assess disability progression in everyday life? A patient’s perspective Patient contributor 11:55–12:00 Future perspectives Sven Schippling

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Understanding EDSS

• Prof. Sven Schippling

Disclosures

• Sven Schippling is supported by the Swiss National Science Foundation (SNF), the Swiss Multiple Sclerosis

Society, the Betty and David Koetser Foundation for Brain Research and the Myelin Repair Foundation (USA).

• He is the Co-Director of the Clinical Research Priority Program for Multiple Sclerosis (CRPPMS) supported by the

University of Zurich.

• He is a member of the International Clinical Consortium of the Guthy Jacksson NMO Charitable Foundation,

California, USA.

• He sits on the Steering committees of the OCTIMS, PASSOS, BENEFIT, REFINE, EMPIRE, ENSEMBLE and CLARIFY-

MS trials, the MS in the 21st Century and the ParadigMS initiatives.

• He is a founding member of the Neuromyelitis Optica Study Group (NEMOS), Germany, and the Drug

Development Network (DDNZ), Zurich, Switzerland.

• He received travel support as well as speaker´s fees from Actelion, Almirall, Bayer Healthcare, Biogen,

Sanofi/Genzyme, Merck, Novartis, Roche, Santen, TEVA.

• Results based on a survey

sent to 13,186 patients in 9 countries

• The proportion of patients

employed or on long-term sick leave is calculated as a percentage of patients 65 years of age or younger

• In a Danish cohort study, the

median time to early pension was 10 years for patients and 24 years for controls2

Spain Sweden Switzerland UK Netherlands Italy Germany Belgium Austria ~10 years2

10 20 30 40 50 60 70 80 90 0.0/1.0 2.0 3.0 4.0 5.0 6.0 6.5 7.0 8.0/9.0

EDSS score Proportion of patients ≤ 65 years of age working (%)

Adapted from 1. Kobelt G, et al. J Neurol Neurosurg Psych 2006;77:918–26; 2. Pfleger CC, et al. Mult Scler. 2010;16:878–82.

A consequence of increasing disability in MS: Early loss of employment1

EDSS=Expanded Disability Status Scale

What is EDSS?

• Method of quantifying and monitoring

disability in MS over time

• The EDSS scale ranges from 0–10 in

0.5 unit increments

• EDSS 1.0–4.5 refers to people with MS

who are able to walk without any aid and is based on measures of impairment in 8 functional systems

• EDSS steps 5.0–9.5 are defined by the

impairment to walking

Pyramidal Cerebellar Brainstem Sensory

Bowel and bladder function

Visual function Cerebral function Other

EDSS functional systems

Adapted from https://www.mstrust.org.uk/a-z/expanded-disability-status-scale-edss; Accessed November 2018.

The Expanded Disability Status Scale (EDSS)

Adapted from Kurtzke JF. Neurology 1983;33:1444–52. 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0

10.0

Normal neurological examination No disability Minimal disability Moderate disability Relatively severe disability Disability precludes full daily activities Assistance required to walk Restricted to a wheelchair Restricted to bed

• r chair

Confined to bed Death

EDSS

EDSS: Is it fit for purpose?

• Prof. Gavin Giovannoni

Disclosures

• In the last 5 years, Gavin Giovannoni has received compensation for serving as a

consultant or speaker for, or has received research support from:

• AbbVie, Actelion, Atara Bio, Biogen, Canbex, Celgene, Sanofi-Genzyme,

Genentech, GlaxoSmithKline, Merck-Serono, Novartis, Roche, Synthon BV and Teva

EDSS: Is it fit for purpose?

What are the strengths of EDSS? What are the weaknesses of EDSS? What do your patients think of the EDSS? What is your experience of using EDSS? Are there any challenges associated with performing EDSS in the clinic?

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Beyond EDSS: How else can we evaluate disease progression?

• Prof. Sven Schippling

Importance of bodily functions as rated by patients with MS

Adapted from Heesen C, et al. Multiple Sclerosis 2008;14:988–91.

Optical coherence tomography (OCT) allows:

• Rapid, non-invasive quantification
• f retinal nerve fibre layer

thickness and macular volume by low coherent near infrared light

• In vivo imaging of the retinal

pathology

Adapted from Frohman EM, et al. Nat Clin Pract Neurol. 2008;4:664–75.

Optical coherence tomography

Detector A Transmitted light B Reflected light Detector Semitransparent mirror splits light beam Mirror #2 Infrared light 800nm wavelengths Mirror #2 Infrared light 800nm wavelengths Retina same distance as mirror #2

Adapted from Oberwahrenbrock T, et al. Mult Scler Int. 2012;2012:530305.

OCT findings in MS patients with a history of optic neuritis

Significant difference between the groups ***: p<0.001 HC=healthy control RRMS=relapsing-remitting MS SPMS=secondary progressive MS ON=optic neuritis

Significant difference between the groups: * p<0.05; **p<0.01;***p<0.001 HC=healthy control RRMS=relapsing-remitting MS SPMS=secondary progressive MS PPMS=primary progressive MS NON=No optic neuritis

OCT findings in MS patients without a history of

• ptic neuritis

Adapted from Oberwahrenbrock T, et al. Mult Scler Int. 2012;2012:530305.

Structural retinal, functional visual damage and visual QoL

Walter SD, et al. Ophthalmology 2012; Brandt AU et al. Akt Neurologie 2017

100 80 60 40 20 60 70 80 90 100 Thickness of GCL+IPL (microns) r=0.49, P<0.0001 r=0.31, P=0.0006 NEI-VFQ-25 composite (best QoL=100 points) Low-contrast 2.5% (number of letters identified correctly) 95% confidence interval from SE of Prediction for fitted line GCL+IPL

Photo courtesy of James Fujimoto, PhD

Macular RNFL OPL+PRL OPL+INL

Adapted from Martinez-Lapiscina EH, et al. Lancet Neurol. 2016;15:574–84.

• Patients with a pRNFL of

≤87 μm (Spectralis) or ≤88 μm (Cirrus) had double the risk of disability worsening at any time after the first and up to the 3rd year of follow up

• Risk increased almost four

times after the 3rd year and up to the 5th year of follow up

Retinal thickness is associated with worsening of MS

pRNFL=peripapillary

100 80 60 40 20 Cumulative % Follow-up (years) 2 3 4 5 1

175 179 206 89 96 123 29 35 45 15 22 24 278 268 272 297 290 292 Lowest pRNFL Intermediate pRNFL Highes pRNFL Number at risk Lowest vs highest tertile HR=1.65, 95% CI 1.23-2.21, p=0.001 Intermediate vs highest tertile HR=1.00, 95% CI 0.72-1.38, p=0.982 pRNFL thickness Lowest Intermediate Highest

Amato MP, et al. J Neurol. 2006;253:1054–9.

How ‘benign’ is benign MS?

Benign MS: Cognitive psychological and social aspects in a clinical cohort

• 163 patients with ‘benign’ MS (disease duration ≥15 years and EDSS score ≤3.0):

– Cognitive impairment 45% – Fatigue 49% – Depression 54%

Patients failing ≥ 2 cognitive tests (%)

p<0.0001

• Deficits were found

mainly in memory, speed of information processing, attention and executive functions

Adapted from Feuillet L, et al. Mult Scler. 2007;13:124–7.

The hidden symptoms of MS: Cognitive functioning in clinically isolated syndrome

Adapted from Calabrese M, et al. Arch Neurol. 2009;66:1144–50.

Cognitive impairment and grey matter volumes

NCV=normalised neocortical grey matter volume

Cognitive parameters:

• Memory task
• Information

processing speed

• Attention
• Verbal fluency

Exploring other clinical measures of disability: A discussion

• Prof. Gavin Giovannoni

Disability assessment

Mobility tests (timed 25 foot walk) EDSS vs MSFC Coordination tests, e.g. 9-hole peg test Visual acuity tests Cognitive testing Smart phone tests Tests in clinical practice vs clinical trials

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How best to assess disability progression in everyday life? A patient’s perspective

Krish Chohan

Disability progression in everyday life

Which symptom(s) are you most concerned about? Which symptom has the biggest impact on your quality of life? What are your thoughts

• n EDSS?

What are your thoughts

• n the timed 25 foot

walk test? Which symptom has gotten progressively worse with time? What is the impact of symptoms that are less obvious/visible on your quality of life?

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Future perspectives

• Prof. Sven Schippling

Future perspectives

• Technical measurements (MRI, OCT, etc) should be explored further to help

deliver personalised treatment

• Standardisation of these measures will be key
• Listen to your patients to uncover hidden symptoms of disease, such as fatigue,

depression and pain

• Patient-reported outcomes (PRO) should be an integral part of both clinical

practice and trials

Personal communication of the speaker.

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