Research Update Marwa Kaisey MD National MS Society

Research Update Marwa Kaisey, MD National MS Society Regional MS Summit September 28 th, 2019

Disclosures • Speaking & Consulting for Biogen, Genentech, and Celgene NEUROLOGY 2

Overview • Diagnostic criteria – what’s new, misdiagnosis • Central vein/new imaging • Neurofilament • New DMTs • Remyelinating treatments • Stem cell treatment 3

How do we diagnose MS? Neurology 4

History of Multiple Sclerosis Diagnostic Criteria Charcot (1868) “La sclerose en plaques disseminees” Marburg (1906) another triad Mc. Donald (2005) Clinical evaluation still important! Mc. Donald (2001) MRI wide -spread Poser (1983) laboratorysupported definite and probable Allison and Millar (1954) “an arbitrary scheme” Mc. Donald (2010) Diagnose with a single MRI Mc. Donald and Halliday (1970 s) evoked potentials NEUROLOGY Broman (1965) dissemination in space and time Mc. Donald (2017) CSF makes a come-back Rose (1976) similar to Schumacher (1965) clinically definite Mc. Alpine (1972) similar to Allison and Millar 5

2017 Mc. Donald Criteria STILL have to prove dissemination in space and dissemination in time of typical symptoms with no alternate diagnosis. • Clinical • MRI • CSF (can now be used to replace dissemination in time) 6

2017 Mc. Donald Criteria NEUROLOGY 7

2017 Mc. Donald Criteria NEUROLOGY 8

2017 Mc. Donald Criteria – The Updates Dissemination in time - new lesion on follow-up MRI OR - simultaneous enhancing* and non-enhancing lesions OR - CSF oligoclonal bands* *new in 2017 Dissemination in space - T 2 hyperintense lesions in 2+ areas: • Periventricular • Juxtacortical or cortical* • Infratentorial • Spinal cord NEUROLOGY 9

So are we now perfect at diagnosing MS? Neurology 10

Misdiagnosis: a big problem in multiple sclerosis “These brain cuttings were popular sessions… On one memorable occasion, we examined the brains of five patients who had been diagnosed in life as having multiple sclerosis. The brain cuttings, however, revealed that all of them had been misdiagnosed. ” – Oliver Sacks, On the Move, 2015. NEUROLOGY 11

Misdiagnosis in multiple sclerosis NEUROLOGY 12

Misdiagnosis in multiple sclerosis NEUROLOGY 13

Misdiagnosis in multiple sclerosis Underdiagnosis Overdiagnosis 14

Misdiagnosis in multiple sclerosis 15

New patients referred to Cedars-Sinai and UCLA neuroimmunology clinics July 2016 -June 2017 UCLA (n=171) Cedars-Sinai (n=193) Firm MS diagnosis 13% Possible MS diagnosis 27% 60% Other neuroimmune diagnosis Firm MS diagnosis 26% Possible MS diagnosis 74% Other neuroimmune diagnosis Kaisey et al, unpublished 16

New patients referred with firm diagnosis of MS July 2016 -June 2017 Cedars-Sinai (n=193) Firm MS diagnosis 17% do not have MS UCLA (n=171) Firm MS diagnosis 19% do not have MS 17

Final diagnosis in misdiagnosed patients Migraine 6 Radiologically Isolated Syndrome 5 Cervical spondylosis with stenosis 3 Peripheral neuropathy 3 Optic neuropathy (without optic neuritis) 3 Neuromyelitis optica spectrum disorder 2 Transverse myelitis, post-infectious 2 Lupus (NMOSD neg) 2 Psoriasis, hypothyroidism, and small vessel ischemic disease 1 Stiff-person syndrome with anti-GAD antibody 1 Pre-syncope and small vessel ischemic disease 1 Bell's palsy 1 Anti-Calcium channel antibody with confluent white matter changes 1 Myasthenia gravis 1 Fibromyalgia with small vessel ischemic disease 1 Encephalitis, infectious 1 Asymptomatic demyelinating changes likely due to TNF alpha inhibitor use 1 Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes 1 Myelopathy, copper deficiency 1 Evaluation ongoing or lost to follow-up (most likely diagnosis listed below) *Cobalt poisoning 1 *Pompe (glycogen storage disease type II) 1 *Hypercoagulable state 1 *Central nervous system vasculitis 1 *Hereditary spastic paraplegia 1 NEUROLOGY Kaisey et al 18

Final diagnosis in misdiagnosed patients Migraine Radiologically Isolated Syndrome Cervical spondylosis with stenosis Peripheral neuropathy Optic neuropathy (without optic neuritis) Neuromyelitis optica spectrum disorder Transverse myelitis, post-infectious NEUROLOGY 6 5 3 3 3 2 2 19

Characteristics of patients with MS misdiagnosis Cedars-Sinai (n=115) p-value Radiologic Red Flags 0. 000 Atypical presentation 0. 000 Radiologic Red Flags 0. 000 Normal exam 0. 039 Atypical presentation 0. 000 Age 0. 075 Normal exam 0. 039 Autoimmune history 0. 099 Had LP 0. 275 Months with diagnosis 0. 293 Family history: neuro 0. 333 Famiy history: autoimmune 0. 453 Working/student 0. 480 Female 0. 536 Migraine history 0. 659 Seen MS doctor 0. 720 Seen neurologist 0. 831 UCLA (n=127) p-value Radiologic Red Flags 0. 000 Atypical presentation 0. 011 0. 000 Radiologic Red Flags Had LP 0. 129 Atypical presentation Migraine history 0. 206 0. 011 Normal exam 0. 320 Autoimmune history 0. 349 Female 0. 440 Age 0. 626 Multiple logistic regression α = 0. 05 20

How do we more accurately diagnose MS?

New MRI techniques NEUROLOGY 22

New MRI techniques: Central vein Absinta, 2016 23

New MRI techniques: Central vein neuropathology-web. org 24

New MRI techniques: Central vein 25

New MRI techniques: Central vein 26

New MRI techniques: Central vein 27

New MRI techniques: Central vein 28

What about new tools to monitor the disease over time?

New serum tools: neurofilament light chains 30

New serum tools: neurofilament light chains Gaetani et al. J Neurology, Neurosurgery & Psychiatry 2019 31

New serum tools: neurofilament light chains Disanto et al, Annals of Neurology, 2017

New serum tools: neurofilament light chains Nfl increases with: -age -other neuordegerative disease -brain injury Disanto et al, Annals of Neurology, 2017

New serum tools: neurofilament light chains How do we more accurately diagnose MS? Barro et al. Brain 2018

New serum tools: neurofilament light chains

New serum tools: neurofilament light chains

How do we know which treatment to pick for which patient?

RRMS Treatment Selection 38

What new treatments are on the horizon?

MS Phenotypes Lublin et al, Neurology 2014 40

MS Phenotypes Courtesy of National MS Society 41

New(ish) MS Treatments • Cladribine – oral – purine analog (/azathioprine) 42

New(ish) MS Treatments • Cladribine – oral – purine analog (/azathioprine) • Siponimod – oral – S 1 P 1 (P 5) receptor mod (/fingolimod) 43

New(ish) MS Treatments 44

New MS Treatments • Novel mechanism: evobrutinib – • Burton’s Tyrosine Kinase (BTK) inhibition 45

New MS Treatments • Novel mechanism: evobrutinib – • Burton’s Tyrosine Kinase (BTK) inhibition • Phase III: evbobrutini BID PO vs interferon beta-1 a IM 46

New MS Treatments • Novel mechanism: evobrutinib – • Burton’s Tyrosine Kinase (BTK) inhibition • Phase III: ebobrutini BID PO vs interferon beta-1 a IM • Target completion in 2023 47

So we’re getting even better at preventing new activity. How about repairing old damage?

Remyelination Strategies • Opicinumab (anti-Lingo 1) 49

Remyelination Strategies • Opicinumab (anti-Lingo 1) –RENEW, Cadavid et al, Lancet Neurology 2017 • Phase II in acute ON • VEP • vs. placebo 50

Remyelination Strategies 51

Remyelination Strategies • Opicinumab (anti-Lingo 1) -RENEW, Cadavid, Lancet Neurology 2017 –SYNERGY • Cavidad et al, Lancet Neurology 2019 • Phase II in RMS • EDSS and MSFC • vs. interferon beta-1 a IM 52

Remyelination Strategies • Opicinumab (anti-Lingo 1) –RENEW, Cadavid, Lancet Neurology 2017 –SYNERGY, Cavidad, Lancet Neurology 2019 –AFFINITY, ongoing • Phase II in RMS • EDSS, 25’ timed walk, 9 -hole peg test • Add-on to DMT 53

Remyelination Strategies • Opicinumab – anti-Lingo antibody • Clemastine – antimuscarinic • Bexarotene – retinoid receptor activator • Liothyronine – synthetic thyroid hormone • ONSTIM - transorbital electrical stimulator 54

“What about stem cells? ”

Stem Cell therapy @selmablair 56

Stem cell therapy How do we more accurately diagnose MS?

Stem Cell therapy eurostemcell. org 58

Stem cell therapy How do we more accurately diagnose MS?

Stem Cell therapy NEUROLOGY 60

Stem Cell therapy NEUROLOGY 61

Stem Cell therapy vector. childrenshospital. org 62

Stem Cell therapy NEUROLOGY 63

Stem Cell therapy NEUROLOGY 64

Stem Cell therapy NEUROLOGY 65

Stem Cell therapy NEUROLOGY 66

Stem Cell therapy NEUROLOGY 67

Thank you Cedars-Sinai Medical Center Nancy Sicotte, MD Zhaoyang Fan, Ph. D UCLA Barbara Giesser, MD University of Vermont Andrew Solomon, MD NEUROLOGY 68

Research Update Marwa Kaisey, MD National MS Society Regional MS Summit September 28 th, 2019