1. Dr Chris. Halfpenny Consultant Neurologist, Southampton & Portsmouth
Multiple Sclerosis
Dr Chris. Halfpenny
Consultant Neurologist,
Southampton & Portsmouth

2. The Talk The basics - a little revision
The state of play regarding disease modifying therapies
What are they?
What do they do?
Who would benefit?

3. The Basics - Revision A central nervous system disease.
Episodes affecting different parts of the central nervous system at different times.
Inflammation, leading to demyelination and temporary conduction block, symptomatic only if it occurs in an eloquent area

4. Some Definitions A Relapse:- Clinically Isolated Syndrome:-
Onset of new neurological symptoms, or a substantial deterioration of previous symptoms, lasting more than 24 hours, not explicable on the basis of infection or other process
Clinically Isolated Syndrome:-
Single neurological episode without clinical evidence of previous episodes, with a normal MRI scan has a ~20% chance of progressing to MS, with and abnormal scan fulfilling certain criteria has an 85% chance of developing MS

5. Some more definitions
Relapsing Remitting :- disease characterised by relapses with substantial regression of symptoms afterwards – 70% start like this
Primary Progressive :- gradual progressive disease from onset without relapses. ~15% of MS cases
Secondary Progressive :- progressive disease following period or relapsing remitting disease

6. Relapsing
Remitting
Progressive
Phase
Disability
Clinical
Course
Axon Loss
Clinical Threshold
White Matter Lesions
Grey Matter Lesions
Disability Accrued from Relapses
“Inflammation”

7. ? Oligodendrocyte Damage Acute Relapse Apoptotic Myelin Membranes
Macrophages phagocytose
Myelin sheaths
Acute
Inflammation
Denuded Axons
Conduction Block
Remyelination
Chronic Demyelinated Axons
Axon
Protected
Slow, Insecure
Conduction
Accumulating
axon loss
Transient Symptoms
Progressive Disability
Chronic Inflammation
within BBB

8. Recognising the disease
Time course is key
Onset over hours to days, recover over weeks
Typical relapses
Optic neuritis
Spinal relapse (ascending sensory disturbance, tight band sensations, urgency, tripping over cracks in pavement)
Trigeminal neuralgia in young women
Vertigo+, “Bell’s Palsy”+, diplopia (eg INO) etc
Uhthoff’s and Lhermitte’s

9. The acute relapse Acute Relapse Clinic
Can the patient cope at home with help?
No - admit
Yes
Is there evidence of infection?
Check Chest, MSU, FBC & CRP
await results…
Yes – treat No
Are they significantly disabled by the relapse
and not showing signs of improvement?
Eg –unable to work, care for themselves etc
Yes
Consider high dose steroids
Oral Methylpred 500mg/day x5days
Or IVMP 1g/day x3days No
Physio/OT if needed

10. Steroids in Acute Relapses
Speed recovery from an acute relapse
Possibly by only a few days
Do not alter the outcome at 6 months
If relapse severe + not improving in a few days
Exclude infection
Need adequate doses (>60mg)
IV methyl pred 1g 3/7 or 500mg po for 5/7
Gastric protection if a risk factors
Avoid oral tail-off unless prev. bad withdrawal
Avoid long term steroids
Counsel about long term side effects (inc weakness, avascular necrosis)

11. Disease Modifying Treatments
When to treat?
Who to treat?

12. Who Is Most At Risk?
Frequency of relapses in the first year(s) appear(s) to predict long-term disability
Weinshenker et al Brain ‘89 112(6)
Scalfari et al Brain ‘10 133(7)
Frequent relapses in established disease correlate poorly with later disability
Confavreux et al Brain ’03 126(4)
MRI activity early has some predictive value
Brex et al NEJM ‘02 346(3)

13. When to treat?
Potent immune modulation (alemtuzumab) given early in the disease appears not just to stop relapses but to halt progression in the medium term (~5 years)
Coles et al NEJM ‘08 359(17)
The same treatment in patients with established secondary progression stops relapses but fails to halt progression
Coles et al Annals Neurol. ‘99 46

14. Overview of Treatments
Drug
Relapse Rate Reduction
Safety Issues
Side effects/ Convenience
Availability
Beta-Interferon
30%
(LFTs)
‘flu’ & inj. sites
Widely
Glatiramer
Injection sites
Mitoxantrone
~65%
Leakaemia,
cardiotoxicity
Infusions
Unlicensed
Natalizumab
68%
PML 0.1%/yr
Mthly infusions
Widely ‘07
Alemtuzumab
80%+
Autoimmunity
2 courses infus.
Cladribine
55%
Infections VZV ?cancers+
Oral - courses
Rejected by EMA
Fingolomod
Infections, ophth, HT
Daily oral (?I/P)
? Late 2011

15. IFN & Glatiramer
Relapsing Remitting (or early progression with dominant relapses)
2 significant relapses in 2 years
Reduce relapse rate by ~30%
Safe, but ‘flu-like side effects troublesome
Effect on progression remains unproven
Pointers towards some effect if treatment commenced early
New ABN guidelines?

16. Natalizumab Tysabri Integrin α4 blockade
Stops circulating lymphocytes entering the CNS
Well tolerated monthly infusions
Effective relapse suppression (68% cf placebo)
Risk of PML appears to increase with time on treatment:-
Very low in first year
By 2 years around 1 in 1000 per year of treatment
Stratifying risk based on PML serology(40% negative)
Risk of rebound disease activity when stopped

17. Mitoxantrone
Originally suggested for highly active RRMS and possibly early progression
50% reduction in relapse rate
Cardiotoxicity, less common with newer regimes
Risk of Leukaemia – particularly Promyelocytic leukaemia ?0.3%++

18. Alemtuzumab Campath Anti CD52 monoclonal depletes all lymphocytes,
Prolonged immunomodulation
2+ courses of infusions, with long-term control
Highly effective relapse reduction (78% cf IFNβ1a)
Stops progressive disability when given early
30% risk of Autoimmunity
ITP
Thyroid
Phase 3 trials (vs IFN-β1a) due FDA “fast track”

19. Campath (Alemtuzumab)
Unlicensed, and cheap! (at present)
“resets” the immune system
No effect on establishes progression
Marked reduction in relapse rate for those with highly active disease – 74% cf IFN
Most convincing effect on progression of any drug, when started early enough
25% occurrence of other autoimmune disease (Graves, ITP etc)

20. FREEDOMS
TRANSFORMS
Placebo
0.40 /yr
0.5 mg Fingolimod
0.18 /yr
0.16 /yr
1.25 mg Fingolimod
0.20 /yr
IFN-β1a (Avonex)
0.33 /yr
Fingolimod
Sphingosine analogue – stops lymphocytes leaving lymph nodes, and thus accessing CNS
Daily oral tablet, first dose given in hospital due to potential for bradycardia and AV block
Relapse reduction 55% (0.18 cf 0.4 relapse/yr)
Macular oedema (?high dose only)
Hypertension
2 deaths from HSV/ZVZ encephalitis
Approved by FDA – NICE review after July ‘11

21. Cladribine Purine analogue, preferentially depleting lymphocytes,
CLARITY
Placebo
0.33 /yr
Cladribine 3.5 mg/kg
0.14 /yr
Cladribine 5.25 mg/kg
0.15 /yr
Cladribine
Purine analogue, preferentially depleting lymphocytes,
Leads to prolonged immune modulation
Short oral course at yearly intervals
Relapse reduction 58% (0.14 cf 0.34)
Infections – zoster
Tumours – uterine fibroids, ?cancers
Rejected by European Medicines Agency
“Risks outweigh benefits”

22. Future Prospects Drug Mode of Action Phase III Studies Completion Date
Teriflunomide
DiHydroOrotate
Dehydrog. inhibitor
↓Dividing Cells
TEMSO: v placebo
TOWER: v placebo
TENERE: add-on IFN
TOPIC: in CIS
ECTRIMS next wk
September 2011
BG-12
Dimethyl fumarate
Nrf2 transcriptional activator
?neuroprotection
DEFINE: v placebo
CONFIRM: v glatir.
December 2010
April 2011
Laquinimod
Cytokine modulator
↓L’cytes into CNS
ALLEGRO: v placebo
BRAVO: v IFNβ1a
February 2011
November 2011
Rituximab
Depletes B cells
Ann Neurol 66(4)
Published ‘09
Daclizumab
IL-2 blocking mAb ↑NK cells
SELECT: v placebo
DECIDE: v IFNβ1a
January 2014