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

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?

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

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

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

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

? 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

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

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

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)

Disease Modifying Treatments When to treat? Who to treat?

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)

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

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

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?

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

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%++

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 2012. FDA “fast track”

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)

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

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”

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