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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