Oral Treatment of Multiple
Sclerosis
By: Wen Wang, Brett
Senay, Alex Ko, Aisha
Abo Saada
PHM142 Fall 2014
Coordinator: Dr. Jeffrey Henderson
Instructor: Dr. David Hampson
Introduction:
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MS is a chronic progressive disorder
Acute symptoms of demyelination, axonal
transaction, and progressive neurodegeneration
Results in long term disability
The cause is largely unknown
Pathophysiology:
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CNS inflammation and destruction of myelin
sheath of neuron due to attacks by own immune
system
loss of oligodendrocytes
Lesions in white matter
Breakdown of axon of neurons
Effected Population:
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Second leading cause of disability in young
adults
Females, born/raised far north and south in
latitude, especially Scandinavian and
northern European ethnicity
Mostly females between 20-40, slightly older
in males
Treatment:
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No cure for MS
Long term managed with immuno-modulating med,
limit additions of new symptoms and prevent
worsening
Gilenya (Fingolimod)
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Reduces number of relapses
Slows down physical progression of MS
Dose: 0.5 mg, daily
Cost: $31,000 per year
–
Covered by most private insurance plans
How it Works
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Sphingosine-1-phosphate receptor modulator
on lymphocytes
Fingolimod phosphorylated (activated) by
sphingosine kinase 2
Initially agonist, but results in internalization
of receptors
Receptor regulates the release of
lymphocytes to the blood
Side Effects
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Increased risk of infection
Higher risk of infection from vaccines
Blood pressure increase
Macular edema
Headaches
Tecfidera (dimethyl fumarate)
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First approved by Health Canada in April 2013
Monotherapy for relapsing-remitting MS; reduces frequency of
relapses and delays the progression of disability
Half-life of the active metabolite is short (approx. 1 hour)
May decrease lymphocyte counts
Tecfidera (dimethyl fumarate)
esterase
dimethyl fumarate
(DMF)

monomethyl fumarate
(MMF)
Dimethyl fumarate is metabolized by esterases before
reaching the systemic circulation to its primary active
metabolite, monomethyl fumarate.
Tecfidera (dimethyl fumarate)
Nuclear Erythroid 2-Related Factor 2 (Nrf2) transcriptional
pathway
ARE: antioxidant response element
GCLC: glutamate-cysteine ligase
GSH: glutathione
GstA2: glutathione S-transferase A2;
HO-1: heme-oxygenase-1
Nqo1: NADPH quinone oxidoreductase 1
MMF: monomethyl fumarate
Nrf2: nuclear factor erythroid-derived 2related factor 2
The Nrf2 pathway is involved in the cellular response to oxidative stress.
Laquinimod
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Investigational agent proposed for relapseremitting MS
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Once daily immunomodulator
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Oral administration
Laquinimod – Mechanism of Action
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Same MoA as Fingolimod
Laniquimod is phosphorylated
Modulates lymphocyte S1P (sphingosine-1phosphate)
Prevents deployment of lymphocytes from
lymphoid tissue which prevents autoimmune
attack
Crosses the blood-brain-barrier
Laquinimod – Research
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2 phase III trials (ALLEGRO & BRAVO)
showed promise
ALLEGRO & BRAVO prompted a third phase
III trial (CONCERTO)
Both studies showed a reduction on disability
ALLEGRO showed an improvement in
relapse rates
Summary Slide
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Multiple sclerosis (MS) causes CNS inflammation and destruction of myelin sheath
No cure for MS, treatments only slow down and delay worsening
Fingolimod is phosphorylated by sphingosine kinase 2
– Mechanism of Action: Fingolimod phosphate internalizes the sphingosine-1phosphate receptor that mediates the release of lymphocytes from the lymph
nodes
The therapeutic effects of Tecfidera (dimethyl fumarate):
– Mechanism of Action: appear to be mediated in part through the activation of
the nuclear erythroid 2-related factor 2 (Nrf2) transcriptional pathway, which
results in the upregulation of antioxidant response genes.
Laquinimod – investigational agent similar to fingolimod but not yet approved by
Health Canada, prevents deployment of lymphocytes from lymphoid tissue which
prevents autoimmune attack
References
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Cohen, J. et al. (2010). Oral fingolimod or intramuscular interferon for relapsing multiple
sclerosis. New England Journal of Medicine, 362, 400-415.
Multiple Sclerosis Society of Canada. Gilenya Frequently Asked Questions. Retrieved from
http://mssociety.ca/en/treatments/treatments_updates_fingolimod.htm
Chen H, Assmann JC, Krenz A, Rahman M, Grimm M, Karsten CM, Köhl J, Offermanns S,
Wettschureck N, Schwaninger M. (2014). Hydroxycarboxylic acid receptor 2 mediates
dimethyl fumarate's protective effect in EAE. J Clin Invest. 24(5): 2188-92.
Linker RA. (2011). Fumaric acid esters exert neuroprotective effects in neuroinflammation
via activation of the Nrf2 antioxidant pathway. Brain. 134: 678-92.
Venci JV, Gandhi MA. (2013). Dimethyl fumarate (tecfidera): a new oral agent for multiple
sclerosis. Ann Pharmacother. 47(12): 1697-1702.
Rubin, Susan. (2013). Management of Multiple Sclerosis: An Overview. Disease a Month.
59: 253-260.
Bruck, W., & Wegner, C. (2011). Insight into the mechanism of laquinimod action. Journal
of the Neurological Sciences , 173-179.
Chun, J., & Hartung, H.-P. (2010). Mechanism of Action of Oral Fingolimod (FTY720) in
Multiple Sclerosis. Clinical Neuropharmacology , 91-101.
Jeffery, S. (2012, 08 09). CONCERTO: A Third Phase 3 Trial for Laquinimod in MS
.