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Toronto Neurology Update

Multiple Sclerosis – A Review

Liesly Lee MSc, MD, FRCPC

Associate Professor of Medicine (Neurology) Sunnybrook HSC

University of Toronto

October, 2015

Declaration of Conflicts of Interests

n  Have served on advisory boards, received honoraria, conducted clinical trials with and received research funding from:

u  Allergan u  Biogen Canada u  Serono Canada u  Teva Neurosciences u  Schering (Berlex) u  BioMS u  Bayer Canada u  Novartis, Canada u  Sanofi-Aventis u  Genzyme, Canada

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Learning Objectives n Recognize the clinical features of multiple

sclerosis

n Review the evolving treatment options in multiple sclerosis

n Recognize medical complications of MS and how to treat

n Review community resources available for MS patients

MS

n The most common seriously disabling disease

n  35,000 Canadians n  prevalence rates of 1 in 1000 in North

America

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Environmental factors

Abnormal immunologic response

Genetic predisposition

Infectious agent

MS

Potential Triggers for Multiple Sclerosis

Gilden et al. Lancet Neurol. 2005;4:195; Noseworthy et al. N Engl J Med. 2000;343:938.

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Disease Course in MS Demographics

(N = 3019)

Jacobs et al. Mult Scler. 1999;5:369-376.

Relapsing-remitting 55% Secondary-progressive

30%

Primary- progressive

10%

Progressive- relapsing

5%

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Multiple Sclerosis - Signs

n Optic nerve -decreased visual acuity -colour desaturation -RAPD -pale disc

n Brainstem -INO; dysconjugate EOM’s -nystagmus -pseudo-bulbar (dysarthria)

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7

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Multiple Sclerosis - Signs

n Motor Findings (UMN) -spasticity -weakness -hyperreflexia -extensor plantars -absent abdominal reflexes

Multiple Sclerosis - Signs

n  Sensory -increased vibration sense (esp. legs) -pseudo-athetosis -sensory level (transverse myelitis)

n Coordination -dysmetria -cerebellar tremor/rubral tremor

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Multiple Sclerosis - Signs

n Gait -spastic -wide-based (difficulty with tandem)

n Cognition -dementia -pathological crying -depression

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Implications

n Ability to make diagnosis of clinically definite multiple sclerosis in a patient with one relapse

n NB: needs to have MRI brain with Gad completed +/- MRI spine

Multiple Sclerosis - Natural History

n  50% of patients develop secondary progression after 10 years

n  90% of patients develop secondary progression after 25 years

n  50% of patients become dependent on an assistive device after 15 years

n Only 10% patients accumulate minimal disability or in “benign state”

Weinshenker BG, Brain, 1989

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Phase III trials in R-R MS n  Beta-interferon 1-b (Betaseron) – 1993 n  Beta-interferon 1-a (Avonex) – 1996 n  Beta-interferon 1-a (Rebif) – 1998 n  Glatiramer Acetate (Copaxone) – 1995 n  Natalizumab (Tysabri) – 2007 n  Fingolimod (Gilenya) – 2011

n  BG-12 (Tecfidera)- 2012 n  Teriflunomide (Aubagio) – 2013 n  Alemtuzumab (Lemtrada) - 2014

34% reduced attack frequency

p<0.0001

IFNB Multiple Sclerosis Study Group. Neurology. 1993;43:655-661.

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Interferon beta-1a—time to increased disability by !!1.0 EDSS steps

Adapted from: Jacobs LD et al. Ann Neurol. 1996;39:285-294.

0

10

20

30

40

50

0 26 52 78 104

Placebo

Interferonbeta-1a

Time to sustained progression (weeks)

p = 0.02

Cum

ulat

ive

perc

ent p

rogr

essi

ng

34.9%

21.9%

37% reduction

Burden of Disease with MRI

-6 -4 -2 0 2 4 6 8

10 12

6 months 12 months 18 months 24 months

12 MIU Placebo 6 MIU PRISMS Study Group, Lancet 1998;353:1498-504

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Glatiramer Acetate

n Local skin reactions n  Idiosyncratic chest tightness sensations n Blood work not required

n Costs about $17000-20000/year

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SAM Inhibitors: Implications for MS Therapy

Natalizumab

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Annualized Relapse Rate Pre-specified Primary Endpoint

Ann

ualiz

ed R

elap

se R

ate

(95%

CI)

68%

P<0.0001

Placebo n=315

0.81

Natalizumab n=627

0.26

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

American Academy of Neurology, April 2005

Natalizumab PML Incidence Estimates by Treatment Duration

Inci

denc

e pe

r 100

0 pa

tient

s

*Yousry TA, et al. N Engl J Med. 2006;354:924-933. Observed clinical trial rate in patients who received a mean of 17.9 monthly doses of natalizumab. The post-marketing rate is calculated as the number of PML cases since reintroduction in patients that have had at least 1 dose of natalizumab. Incidence estimates by treatment duration are calculated based on TYSABRI exposure through June 30, 2011 and 145 confirmed cases as of July 5, 2011. The incidence for each time period is calculated as the number of PML cases divided by the number of patients exposed to TYSABRI (e.g. for ≥24 infusions all PML cases diagnosed with exposure of 24 infusions or more divided by the total number of patients exposed to at least 24 infusions). Biogen Idec, data on file.

2.80

1.91

2.84

3.23

3.62

3.13

2.492.74

0.20

1.37

2.04

2.51

1.98

1.241.00

1.62

2.412.73

3.03

2.51

1.88

1.34

2.29

1.85

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Clinica

l Tria

ls*

Post Mark

eting

>=12 I

nfusions

>= 18 I

nfusions

>=24 I

nfusions

>=30 I

nfusions

>=36 I

nfusions

>= 42 I

nfusions

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TRANSFORMS (phase III study) Primary endpoint: annualized relapse rate

0.33

0

0.1

0.2

0.3

0.4

Ann

ualiz

ed re

laps

e ra

te

0.20

Fingolimod 0.5 mg

(n = 429)

0.16

Fingolimod 1.25 mg

(n = 420) IFNβ-1a IM

(n = 431) Modified intention-to-treat population: all patients who underwent randomization and received one dose of a study drug Negative binomial regression model adjusted for study group, country, baseline number of relapses in previous 2 years and baseline disability score. p = 0.16 for fingolimod 0.5 mg vs 1.25 mg

-52% vs IFNβ-1a p < 0.001

-38% vs IFNβ-1a p < 0.001

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Fingolimod revised first-dose monitoring guidance| | Jan 23, 2012| GIL_12_003 l Scientific Internal Use Only 40

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BG-12 (Tecfidera)

0.40

0.22 0.200.29

0

0.1

0.2

0.3

0.4

0.5

0.6

Placebo (n=363)

BG-12 BID (n=359)

BG-12 TID (n=345)

GA (n=350)

0.36

0.17 0.19

0

0.1

0.2

0.3

0.4

0.5

0.6

Placebo (n=408)

BG-12 BID (n=410)

BG-12 TID (n=416)

44% reduction vs placebo p < 0.001

51% reduction vs placebo p < 0.001

*Annualized relapse rate (ARR) calculated with negative binomial regression, with pre-specified adjustment for baseline EDSS score (≤ 2.0 vs > 2.0), baseline age (< 40 vs ≥ 40 years), region, and number of relapses in the 1 year prior to study entry; data after switch to alternative MS therapy were excluded; CI=confidence interval Gold R et al. N Engl J Med 2012; 367:1098-107; Fox R et al. N Engl J Med 2012; 367:1087-97.

29% reduction vs placebo

p=0.01

Annualized Relapse Rate at 2 Years

53% reduction vs placebo p < 0.001

48% reduction vs placebo p < 0.001

Ann

ualiz

ed R

elap

se R

ate*

(95%

CI)

Ann

ualiz

ed R

elap

se R

ate*

(95%

CI)

CONFIRM DEFINE

DMF BID DMF TID DMF BID DMF TID

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Duration of Flushing and GI Events

B. Duration of abdominal pain, nausea/vomiting and diarrhea events reported in the first 3 months of DMF BID treatment

aIncludes abdominal pain upper; bnumber of patients with known start and end dates for the event MeltzerL,etal.AAN2013

Pbo=placebo SheikhSetal.Safety,tolerabilityandPKofBG12administeredwithandwithoutaspirin:keyfindingsfromarandomized,doubleblind,placebo-controlledtrialinhealthyvolunteers”Neurology2012(suppl)

A. Flushing events as measured by Global Flushing Severity Scale (GFSS: 0-10) All groups, n=6

Upper Limit of Mild Flushing

Glo

bal F

lush

ing

Seve

rity

Scal

e

0

1

2

3

4

Day 1 Day 2 Day 3 Day 4 Day 5

Pbo Pbo +ASA 240 mg BID 240 mg BID +ASA Last Dose

0

10

20

30

40

50

60

Even

ts (%

) ≤ 1 > 1-

≤ 2 > 2- ≤ 3

> 3- ≤ 4

> 4- ≤ 5

> 5- ≤ 8

> 8- ≤ 12

> 12- ≤ 24

≥ 24

Duration (weeks)

Diarrhea (n=73b) Nausea/vomiting (n=108b) Abdominal paina (n=110b)

Median duration: Diarrhea = 8 days Nausea/vomiting = 8 days Abdominal pain = 9.5 days

Teriflunomide: Introduction

Teriflunomide is the active metabolite of leflunomide and is responsible for the activity of leflunomide in vivo1

Leflunomide is indicated for the treatment of active rheumatoid arthritis (RA) in adults2,3

Once daily, oral administration May be taken with or without food

1. Claussen M, Korn T. Clin Immunol. 2012;142:49-56; 2. Arava® (leflunomide) Prescribing Information. sanofi-aventis, 2012; 3. Arava (leflunomide) Summary of Product Characteristics, sanofi-aventis, 2013; 4. Aubagio® (teriflunomide) Prescribing Information or Product Information for Respective Countries; 5. Wang L, et al. Eur J Neurol. 2011;18(Suppl 2):268.

Leflunomide Teriflunomide (A77 1726, HMR1726)

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TEMSO: Hair Thinning

n  In most cases, hair thinning occurred early in treatment (within 6 months), was mild to moderate, transient, and recovered without sequelae

n  The probability of onset of hair thinning reduces over time

n  0.5% of patients in the teriflunomide 7-mg group and 1.4% in the teriflunomide 14-mg group discontinued treatment due to hair thinning

AE=adverse event Data on file – CONFIDENTIAL.

Outcomes of patients who developed hair thinning during the TEMSO study (Week 108)

Tota

l AEs

of h

air t

hinn

ing

(%)

100

90

70

40

0 Recovered

without sequelae

50

80

60

30

20

10

Placebo (n=360)

Teriflunomide 7 mg (n=368)

Teriflunomide 14 mg (n=358)

Recovered with

sequelae

Ongoing Worsening in intensity

Unknown

Time course of probability of hair thinning

Highest probability

Lessened risk over time

Placebo (n=360)

Teriflunomide 7 mg (n=368)

Teriflunomide 14 mg (n=358)

Third line treatment

n Alemtuzumab (Lemtrada)….

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Alemtuzumab’s exact mechanism of action is not fully elucidated 1. Fox EJ. Expert Rev Neurother. 2010;10(12):1789-1797; 2. Jones JL, et al. Brain. 2010;133(pt 8):2232-2247; 3. Cox AL, et al. Eur J Immunol. 2005;35(11):3332-3342; 4. Data on file. Cambridge, MA: Genzyme/sanofi.

Alemtuzumab a monoclonal antibody is Thought to Rebalance the Immune System in RRMS

Lab Measurement Rationale Timing

CBC with differential ITP Prior to initiation of treatment and at monthly intervals thereafter until 48 months after the last infusion

Thyroid function tests, such as TSH level Thyroid disorders

Prior to initiation of treatment and at quarterly intervals thereafter until 48 months after the last infusion

Serum creatinine Nephropathies* Prior to initiation of treatment and at monthly intervals thereafter until 48 months after the last infusion

Urinalysis with urine cell counts Nephropathies* Quarterly intervals until 48 months after the last

infusion

Laboratory Monitoring

*Including anti-GBM disease.

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What would I do….Escalation First Line

n  Interferon n Glatiramer Acetate

n Teriflunomide n BG-12

Second Line

n  Fingolimod n Natalizumab Third Line n Alemtuzumab n Clinical Trial/

chemotherapy n  Stem cell

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New Developments

n Minocycline 100mg BID (Clinically Isolated Syndrome) u 6 month conversion to MS – absolute risk

reduction by 27.4% (NNT of 4) u Early or concomitant treatment?

n Ocrelizumab (Primary Progressive MS)

Symptomatic management

n  Fatigue – amantadine, modafinil; Fampyra

n  Spasticity – benzodiazepine, baclofen; tizanidine, dantrolene, Botulinum toxin

n Bladder frequency – oxybutynin, tolterodine, flavoxate, vasopressin, mirabegron

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Symptomatic management

n  Paroxysmal Dystonia – anti-convulsants n Tremor – primidone, propranolol, DBS

n Depression – anti-depressants

n Chronic Pain/Neuropathic Pain – gabapentin, tricyclic, Cymbalta, cannibinoids

For acute relapses

n  Solumedrol 1.0g IV for 3-5 days, followed by oral taper…

n  Prednisone 500mg po BID for 3-5 days – no taper…..

n Rule out underlying infection first (ie UTI)..

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Resources for the family physician

n  CCAC….http://healthcareathome.ca (OT, PT, SW, PSW)

n  Toronto Rehab Institute…www.uhn.ca/torontorehab….416 597-3422

n  Bridgepoint…http://bridgepointhealth.ca/en/index.asp# 416 461-8252

n  West Park Health Care Centre: http://www.westpark.org/

n  MS Society: www.mssociety.ca (support groups, education, local resources) 416 922-6065

Conclusions

n Our understanding of the pathophysiology of MS has evolved…

n Expanding treatment options of MS – potentially progressive types as well?

n  Improved symptomatic management options