Presentation delivered on 30 Nov 2017 at the 25th European Charcot Foundation meeting in Baveno. Emphasis on risk in disease modifying treatment.

2. 2
High efficacy treatments
in the management of patients with MS
Klaus Schmierer
United Kingdom

3. 3
Klaus Schmierer, PhD FRCP
Blizard Institute
Queen Mary University of London
London, UK
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, Cinnagen, Merck, Merck Inc., Novartis,
Roche, Teva.
Supported for attendance of meetings by Genzyme, Merck-Serono, Novartis.
Research grant support from Novartis, Biogen, National MS Society (US), MS Society of Great Britain & Northern
Ireland, Royal College of Radiologists, and Barts Charity.

4. Objective
 Discuss the risks of high efficacy therapies for MS

5. Immunotherapies for relapsing MS
https://www.mstrust.org.uk/understanding-ms/ms-symptoms-and-treatments/ms-decisions/decision-aid
Highly effective
?
Highly effective

7. http://msbrainhealth.org/perch/resources/time-matters-in-ms-report-may16.pdf
“Treat early”

8. Maintenance / escalation vs. immunosuppression/reconstitution
Maintenance / escalation therapies
• Continuous treatment
• Low to high efficacy
• Reversible
• Perceived to be lower risk
• Cumulative, or increased, risk with
time
• Examples
• GA, IFNβ, teriflunomide, BG12,
fingolimod, natalizumab, daclizumab,
(anti-CD20)
• Breakthrough disease
• Suboptimal or failure to respond
• NEDA reliable metric for efficacy
• Rebound activity
• Likely
• Can be life-threatening
Immunosuppression/reconstitution
• Short-courses (pulsed therapy)
• High efficacy
• “Irreversible”
• Perceived to be higher risk
• Early / late risks
• Examples
• Non-selective: Mitoxantrone,
alemtuzumab, HSCT- BMT
• Selective: cladribine
• Breakthrough disease
• Commonly considered indication of need
to retreat
• Rebound activity
• Less likely
• Unlikely to be life-threatening
• Pregnancy
• Potentially “curative”?
• 15–20-year experiment
Not licensed for MS in Europe: HSCT-BMT; Licensed in some European countries only: Mitoxantrone

9. Define personality
Worrier vs risk taker
Escalation Induction
A treatment algorithm?
Patient? Patient?
Doctor? Doctor?

10. What is an immunosuppressant?
Definition: Immunosuppression is a reduction of the activation or
efficacy of the immune system.
This definition refers to short-term/intermittent (induction) and
long-term persistent immunosuppression (maintenance).
For a drug to be considered an immunosuppressant it should:
1) cause significant lymphopaenia
2) be associated with opportunistic infections
3) reduce the antibody response to vaccines
4) be associated with secondary malignancies

11. Continuous (e.g. fingolimod)
1. Persistent immunosuppression
2. Risk increases with time (cumulative)
a. Increase risk of PML (complex
pathogenesis)
b. Increased risk of other opportunistic
infections
c. Increased risk of secondary
malignancy
3. Live vaccines contraindicated
4. High-risk of exotic infections
a. Dengue
b. Zika
c. Etc.
5. Pregnancy not recommended
6. Long-term burden of
pharmacovigilance
Short-term (e.g. alemtuzumab)
1. Short-term immunosuppression
2. Risk short-term (front-loaded)
a. Low risk of PML
b. Low risk of other opportunistic
infections
c. Low risk of secondary malignancy
3. Live vaccines not necessarily
contraindicated
4. Low-risk of exotic infections if travel
occurs after immune reconstitution
5. Pregnancy safe post immune
reconstitution
6. Less of a pharmacovigilance burden
Immunosupppression

12. PML
Herpes encephalitis
Rebound on withdrawal
1. Selective adhesion molecule blocker
2. Infusion reactions
a. Anaphylactoid
b. Associated with anti-drug antibodies
3. Blocks CNS immune surveillance
a. PML
b. CNS infections
c. Possible link with CNS lymphomas
4. Rebound activity post-washoutwww.clinicspeak.org Khatri et al. Neurology 2009;72:402–409.
Natalizumab

13. Natalizumab
Ann Clin Transl Neurol 2014;1:755-64.

14. APC
Lymph
node
S1P-R
T
Gliosis
S1P-R
Fingolimod
Fingolimod
CNS / Immune
and Neural
system
Periphery /
Immune
system
Oligo’s
VZV - Chickenpox & Zoster TB
Cryptococcosis HistoplasmosisKaposi’s PML Basal Cell Ca
etc…...
Rebound on withdrawal
PRES and other vascular complications
Macular
oedema
Conduction Block
Lymphopaenia
1. SIP modulator
a. Lymphopaenia (prolonged)
b. Bradycardia/Conduction block
c. Vascular complications (macular
oedema, hypertension, PRES)
d. Bronchoconstriction
2. Immunosuppression
a. Opportunistic infections
b. Secondary malignancies
c. Blunted vaccine response
Fingolimod

15. Francis et al. MSJ 2013
Giovannoni et al. Pract Neurol. 2016 Oct;16(5):389-93.
Fingolimod

16. VZV TB Listeria Nocardia
Molluscum HPVCMV EBV
PCP
Etc...
Thomas et al. Neurol Neuroimmunol Neuroinflamm 2016;3:e228;
AVN
AAN 2017, Boston
1. Non-selective leukocyte depletion
a. Leukopaenia (neutrophils &
monocytes)
b. Lymphopaenia (prolonged)
c. Infusion reactions (moderate to
severe)
d. Complications of corticosteroids
2. Immunosuppression
a. Opportunistic infections
i. Acute bacterial, e.g. Listeriosis
ii. Typical opportunistic, e.g. CMV
3. Aberrant immune reconstitution
a. Secondary autoimmunity
b. Anti-drug antibodies
Innate
Immunity
Adaptive
Immunity
AVN = avsacular necrosis, HPV = human papiloma virus, PCP = Pneumocystis carinii pneumonia, VZV =
varicalle zoster virus
Alemtuzumab hits both innate and adaptive immunity

17. 17

18. Identified Risk
Rate in
Alemtuzumab-
Treated Patients Notes
ITP
Auto-
immune Events
~1% (1 fatality prior
to implementation of
monitoring program)1
• Onset generally occurred 14-36 mo after first exposure1
• Most cases responded to first-line medical therapy1
0.3%
(anti-GBM n=2)1
• Generally occurred within 39 mo after last administration1
• Responded to timely medical treatment and did not develop permanent kidney
failure2
Nephropa-
this
Thyroid
disorders
(Hypo/hyper)
~36%a
(serious, 1%)1
• Onset occurred 6-61 mo after first Alemtuzumab exposure;
peaked in year 3 and declined thereafter3
• Most mild to moderate, most managed with conventional medical therapy,
however, some patients required surgical intervention1
• Higher incidence in patients with history of thyroid disorders1
IARs
>90%
(serious, 3%)1
• Occurred within 24 h of Alemtuzumab administration1
• Most mild to moderate; rarely led to treatment discontinuation1
• May be caused by cytokine release following mAb-mediated
cell lysis1
Infections
71%
(serious, 2.7%)1
• Incidence highest during first mo after infusion; rate decreased over time2
• More common with Alemtuzumab; mostly mild to moderate1
• Generally of typical duration; resolved following conventional medical treatment1
aThrough 48 mo after first exposure. ITP, immune thrombocytopenia; GBM, glomerular basement membrane; mAb, monoclonal antibody.
1. Alemtuzumab Summary of Product Characteristics. Oxford, UK: Genzyme Therapeutics, Ltd; 2013; 2. Wynn D, et al. Presented at: European Committee for Treatment and Research in Multiple
Sclerosis; 2013; Copenhagen; P597;
3. Coles AJ, et al. Neurology. 2012;78:1069-1078. 4. Willis et al. 2016 Aug;22(9):1215-23.
.
Haemolytic
anaemia
Goodpasture’s Syn.ITP Bullous
Pemphigoid
Immune neutropeniaGrave’s orbitopathy Neonatal hyperthyroidism
Acquired
Haemophilia
Pernicious Anaemia
Etc... Cervical dysplasia4 MGUS4
+
10% pre/malignant 6.1 yrs FUp
Alemtuzumab risks identified in clinical trials

19. 45% Reduction
(95% CI: 35.5%, 53.1%)
p<0.0001
(n=922) (n=919)
ARR
Adapted from: Amaravadi L, et al. Poster presentation at AAN 2015;P1.149;
IL-2
Daclizumab blocks high-affinity IL-2 receptor
signalling, resulting in higher levels of IL-2
available for signalling through intermediate-
affinity IL-2 receptor
IL-2 intermediate-affinity (βγ) receptor
IL-2 high-affinity (βαγ) receptor
Daclizumab
Activation
CD4+
TactCD4+
cell
CD4+
Tact cell
CD56brig
ht
Bielekova B, et al. Arch Neurol. 2009;66:483–89.
Autoimmune hepatitisHypersensitivity skin rash Glomerulonephritis IBD
Infections
Daclizumab

20. * One of the kinases is deoxycitidine kinase (DCK).
The phosphatase is 5’-nucleotidase.
Leist TP, Weissert R. Clin Neuropharmacol 2011;34:28–35.
deoxyadenosine cladribine
Pakpoor J et al. Neurol Neuroimmunol Neuroinflamm 2015;2:e158
VZV TB
Giovannoni G et al. N Engl J Med 2010;362:416–26.
Cladribine

21. 1. Crawford A, et al. J Immunol 2006;176(6):3498–506. 2. Bar-Or A, et al. Ann Neurol 2010;67(4):452–61. 3. Lisak RP, et al. J Neuroimmunol
2012;246(1-2):85–95. 4. Weber MS, et al. Biochim Biophys Acta 2011;1812(2):239–45. 5. Serafini B, et al. Brain Pathol 2004;14(2):164–74.
6. Magliozzi R, et al. Ann Neurol 2010;68(4):477–93.
Antigen
presentatio
n1,2
Autoantibody
production4
Ectopic lymphoid
follicle-like
aggregates5,6
Cytokine
production2,3
PML Breast Ca VZV & herpes
Ocrelizumab

22. Immunomodulation ▪ ▪ ▪ ▪ Immunosuppression
E.g. interferon-ß, GA E.g. fingolimod, ocrelizumab
MET that results in
continuous
immunomodulation
MET that results in
continuous
immunosuppression
Chronic therapy that is maintained and/or escalated
over time resulting in changes in immune function
only during active treatment
Maintenance/Escalation (MET) Immunosuppression/reconstitution
Short course therapy resulting in long-term
qualitative changes in immune function
E.g. cladribine E.g. alemtuzumab
IRT that affects both the
innate & adaptive
immune systems
IRT that selectively
affects the adaptive
immune system
Non-Selective IRT
(NIRT)
Selective IRT
(SIRT)
Derisked MET
E.g. Natalizumab, DMF,
Teriflunomide, Daclizumab
A new classification of DMT for MS?

23. Baseline
1. FBC - Leukocytes /
platelets
2. LFTs, U&E, Urine
3. Pregnancy tests
4. Immunoglobulin levels
5. Serum protein
electrophoresis
6. Serology
a. HIV1&2
b. Hepatitis B&C
c. VZV
d. Syphilis
e. TB
Elispot/Quantiferon
assay
7. Cervical smear
8. Vaccinations
9. MRI
10. LP (CSF analysis)
11. Listeria prophylaxis
Infusion-DMTs & IRTS
1. Infusion reactions
a. Corticosteroids
b. Anti-histamines
c. Anti-pyretics
2. Infections
a. Herpes prophylaxis
b. Listeria/PCP
prophylaxis
Monitoring
1. Bloods
a. FBC - leukopaenia
b. TFTs
c. LFTs
d. U&E
2. Urine
a. Autoimmune
b. Renal dysfunction
3. MRI
a. Disease activity
b. PML
4. Infection
a. Serology
b. CSF
5. Disease activity
6. Pregnancy
7. Malignancy
a. Skin
b. Cervical
c. Breast
d. Etc.
Derisking immunosuppression

24. aTotal number of administrations over the first 12 months of treatment. b3.5 mg/kg. 5 days of treatment separated by 1 month; total number of tablets dependent on weight. c These
agents are under clinical investigation and have not been proven to be safe and effective. There is no guarantee they will be approved in the sought-after indication. IFN, interferon;
sc, subcutaneous; SmPC, Summary of Product Characteristics. 1. Rebif® EU SmPC; 2. Copaxone® SPC; 3. Aubagio® EU SmPC; 4. Tecfidera® EU SmPC; 5. Tysabri® EU SmPC; 6.
Gilenya® EU SmPC; 7. Lemtrada® EU SmPC; 8. Zinbryta® EU SmPC; 9. Giovannoni G, et al. N Engl J Med 2010;362:416–26; 10. Kappos L et al. Lancet 2011;378:1779–87; 11.
Katsarava Z et al. BMC Neurol 2015;15:170; 12. Kruk ME, Schwalbe N. Clin Ther 2006;28:1989–95; 13. Devonshire V et al. Eur J Neurol 2011;18:69–77
Treatment burden

25. Numbers indicate the number of blood tests. ECG, electrocardiogram; hypersens., hypersensitivity; SmPC, Summary of Product Characteristics. 1. Rebif® EU SmPC; 2. Copaxone®
UK PI; 3. Aubagio® EU
4. Tecfidera EU SmPC; 5. Tysabri® EU SmPC; 6. Gilenya® EU SmPC; 7. Lemtrada® EU SmPC; 8. Zinbryta® EU SmPC. 9. Mavenclad EU SmPC.
NB. Screening for latent infections in particular TB & Hep B, C must be performed prior to initiation of cladribine in year 1 & 2.
Monitoring burden

26. 26
Take-home message: have your cake and eat it?

27. 27
High efficacy treatments
in the management of patients with MS
Klaus Schmierer
United Kingdom