Treating progressive MS, MS Research Day, Stornoway 14 Apr 2018

1. Klaus Schmierer, MB BS PhD FRCP
Reader in Clinical Neurology & Consultant Neurologist
@KlausSchmierer
Stornoway, 14 Apr 2018
Can we prevent or slow down
progressive MS?

2. Disclosures (~acknowledgements)
PI of trials sponsored by Novartis, Roche, Teva, Medday.
Involved in trials sponsored by Biogen, Genzyme, BIAL, Cytokinetics,
Canbex.
Speaking honoraria from, and/or served in an advisory role for, Biogen,
Merck, Merck Inc., Novartis, Roche, Teva.
Remuneration for teaching activities from EXCEMED & MS Academy.
Supported for attendance of meetings by Genzyme, Merck, Novartis, and
Roche.
Research grant support from Biogen, Lipomed, Novartis, MS Society of
Great Britain & Northern Ireland, National MS Society (US), Royal College
of Radiologists, and Barts Charity.

3. Why are we talking about
progressive MS as if it were a
separate thing from relapsing MS?

4. Symptoms
e.g.
Limping,
Weak bladder,
Optic neuritis,
…
No symptoms No symptoms
Relapsing remitting MS (Hollywood)

5. Remission is often incomplete – stepwise progression
Relapse Remission Relapse Remission Relapse
RemissionRelapseRelapse RemissionRemission?Etc.
No symptoms
Relapsing remitting MS (Reality)

6. Some problems due to MS are insidious, often
not even considered part of MS (“I’m getting old”)
Fatigue
Forgetfulness
Declining cognitive speed/ability to multi-task
Depression
Sexual dysfunction
Temperature sensitivity

7. 57%
7%
-20%
0%
20%
40%
60%
Focus on cognition
CIS Patients
n = 40
Healthy Controls
n = 30
p < 0.0001
Deficits in memory, speed
of information processing,
attention and executive
functioning
Patients failing
≥ 2 cognitive
tests
Feuillet L et al. Mult Scler 2007;13:124–7

8. • MS affects everyone differently, however it remains one disease
• Disease progression – the continuous decline of function due to
accelerated brain & spinal cord tissue loss – is part of MS even at
the relapsing stage
• Conversely, elements of relapsing MS are clearly evident in many
people with a diagnosis of progressive MS
• These elements include tissue loss due to inflammation in the brain
& spinal cord – there is no such thing as “early inflammatory”
(relapsing) versus “late degenerative” (progressive) MS
• Differences between RMS and PMS are determined by:
• the degree of tissue loss that has taken place,
• the amount of lost/retained “brain reserve”, and
• neuroanatomy and length-dependency of nerve fibre function
RMS and PMS: Similarities and differences

9. 8 y 20 y 30 y
The EDSS
Current limit in DMT trials

10. #ThinkHand#ThinkHand#ThinkHand
Dubuisson, et al. Mult Scler 2017;14:1956-7.

11. Neuroanatomy
55% of cortico-
spinal tract
axons terminate
at the cervical
level.
Patestas MA & Gartner LP, 2016. Schieber MH. J Neurophysiol 2001;86:2125–43.

12. MS lesions can hit long tracts in more places than short ones,
legs/bladder/bowel functions are therefore at higher risk than arms!
Kurtzke JF. Mult Scler Relat Disord 2015;4:95–103.
Mult Scler Relat Disord 2017;12:70-78.

13. www.ms-res.org
@BartsMSBlog
@BartsMS_Charity
www.ms-res.org
@BartsMSBlog
@BartsMS_Charity

14. Expectations must be realistic

15. Nerve fibre loss in the spinal cord
D Carassiti
F Scaravilli
N Petrova
Petrova, et al. Brain Pathol 2017

16. - 60%
Petrova, et al. Brain Pathol 2017
Nerve fibre loss in the spinal cord

17. What to expect from a DMT in progressive MS?
Delayed worsening Stabilised
Improved function Recovered function
✓ ✓?

18. Therapies for advanced/progressive MS
(until very recently)
• Ocrelizumab: licensed in Europe, North America, and
elsewhere
• Simvastatin: now in phase III trial
• Biotin: still in phase III trial
• Sodium-channel blockers (Phenytoin, Lamotrigine):
phase II trials positive (brain volume, nerve fibre layer of eye)
• #ChariotMS

19. • Symptoms of primary progressive MS since 2007
• Back pain, leg stiffness, from 2010 sensory level,
sensory loss in dominant right hand
• Enrolled in ORATORIO 2012
• EDSS= 5.5 (2012)
• EDSS= 6.0 (2017)
Craig, 50

20. #ChariotMS
https://www.slideshare.net/KlausSchmierer/chariot-ms-4mssocietyfeb20184slsh
EDSS 6.5 – 8.5

21. Use a drug that is…
• Effective in RMS (phase III evidence)1,2
• Effective in PMS (phase II evidence)3-5
• Convenient: s.c. immune reconstitution therapy, rapid elimination,
no drug-drug interactions, drug free pregnancy6
• CNS penetrant: kills non-/dividing lymphocytes7,8
• Safe: risk of infections mitigated by personalized dosing6; cancer
risk no different compared to licensed DMT9; no secondary
autoimmunity10; oral version licensed (for relapsing MS)11
1Giovannoni, et al. NEJM 2010; 2Leist, et al. Lancet Neurol 2014; 3Sipe, et al. Lancet 1994; 4Beutler, et al. Proc Nat Acad Sci USA 1996; 5Rice,
et al. Neurology 2000; 6Mao, et al. JNNP 2017; 7Santana, et al. Blood 1994; 8Kearns Cancer Res 1994; 9Pakpoor, et al. Neurol Neuroimmunol
Neuroinflamm 2015; 10Baker, et al. JAMA Neurol 2017. 11http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-
_Initial_authorisation/human/004230/WC500229786.pdf
#ChariotMS

22. #ChariotMS

24. @KlausSchmierer
www.ms-res.org David Baker
Ben M Jacobs
Bryan Ceronie
Cristo Albor
Cesar Alvarez-Gonzalez
Daniele Carassiti
Dayo Afolabi
Francesco Scaravilli
Gareth Pryce
Gavin Giovannoni
Monica Marta
Natalia Petrova
Samuel Herrod
Sharmilee Gnanapavan
Stefania de Trane
Zhifeng Mao
#ChariotMS