Download New Oral Treatments for Multiple Sclerosis

New Oral Treatments for
Multiple Sclerosis
Alexander Jesso, Linda Mangera, Sophie Rusnock,
Morgan Walmsley
PHM142 Fall 2016
Coordinator: Dr. Jeffrey Henderson
Instructor: Dr. David Hampson
Multiple Sclerosis
•
Multiple sclerosis (MS) is a central nervous system (CNS) disease characterized by damage to the
myelin sheath of neurons
•
Myelin is essential for saltatory conduction of action potentials in nerve cells
•
Because the disease affects the CNS, there is a large range of symptoms
Moyes, C.D., and Schulte, P.M.
(2015). Principles of Animal
Physiology, 3rd ed. Pearson:
Ontario, Canada.
Multiple Sclerosis
•
There are 4 patterns of progression:
•
Relapsing remitting (RRMS)
•
This is the most common type
of MS, characterized by
unpredictable periods of
relapse and remission
•
Secondary progressive (SPMS)
•
Primary progressive (PPMS)
•
Progressive relapsing (PRMS)
Hvizdos, A.J., and Mosler, C.R. (2016). Current
Perspectives on Multiple Sclerosis. US Pharmacist,
41(1): 22 - 26.
Multiple
Sclerosis
See the next slide for text description.
Steinman, L., and Zamvil, S. (2003).
Transcriptional analysis of targets in
multiple sclerosis. Nature Reviews
Immunology, 3: 483 - 492.
Multiple Sclerosis
•
MS is considered an autoimmune disease
•
B cells, T cells, and antigen presenting cells (APCs) enter the CNS using the surface
receptor alpha 4 integrin
•
Once in the CNS, they secrete cytokines that damage oligodendrocytes (which
produce myelin)
•
T cells and macrophages release osteopontin (OPN), interleukin 23 (IL 23) IFN
gamma, and tumour necrosis factor (TNF), which all damage myelin
•
OPN attracts T helper 1 cells
•
B cells produce myelin specific antibodies that activate the complement cascade and
further damage oligodendrocytes
Gilenya (fingolimod)
•
First oral MS drug approved by FDA (2010)
•
Adult dose: 0.5mg po daily
•
Used to delay progression of relapsing-remitting MS
•
Drug action: immunomodulation
•
Fingolimod HCl
Sphingosine 1-phosphate (S1P) receptor modulator
•
Fingolimod-phosphate blocks the ability of lymphocytes to egress from lymph
nodes, thereby reducing the number of lymphocytes available to migrate to the
CNS
•
In phase 2 and phase 3 clinical trials, fingolimod-treated patients saw reduced
disease activity clinically and in MRI results
Gilenya: Mechanism of Action
sphingosine kinase
Fingolimod
Fingolimod-phosphate
(active metabolite)
● Sphingosine 1-phosphate: extracellular ligand for S1P1 receptors (GPCRs)
● Fingolimod-phosphate binds to high-affinity S1P receptors 1, 3, 4, 5
expressed on lymphocytes
● Binding causes receptors to internalize or degrade from cell surface
● Down-regulation: S1P signal that controls proliferation and migration
becomes blocked, preventing lymphocytes from exiting lymph nodes
● This reduces overall lymphocyte count in the bloodstream, thereby reducing
the number of lymphocytes infiltrating the CNS
● Also has a direct anti-inflammatory effect in astrocytes (neuroprotection)
Chun, J. and
Hartung, H.
(2010).
Mechanism of
action of oral
fingolimod
(FTY720) in
multiple sclerosis.
Clin.
Neuropharmacol.,
33(2): 91-101.
Aubagio (Teriflunomide)
● Approved in Canada in 2013
● Adult dose: 14mg/day
● Active metabolite of leflunomide, a drug used for rheumatoid arthritis
● Immunomodulator that works by inhibiting the proliferation of lymphocytes
(and other rapidly proliferating cells)
● In clinical trials, reduced both the active relapse rate and the progression of
disability
● Adverse effects: Vulnerability to infection, nausea, hair loss, fetal harm
Aubagio: Mechanism of Action
● Inhibits the enzyme dihydroorotate
dehydrogenase (DHODH)
○ Enzyme function: oxidizes dihydroorotate
to orotate
○ Binds in the hydrophobic tunnel leading
to the active site
● DHODH is essential for de novo
pyrimidine synthesis
○ De novo synthesis is not the only way to
obtain pyrimidines, but it is the method
favoured by rapidly-growing cells
Image: Meunier-Lehmann, H., Vidalain, P. O., Tangy, F. & Janin,
Y. L. (2013). On Dihydroorotate Dehydrogenases and Their
Inhibitors and Uses. J. Med. Chem., 56(8), 3148-3167. doi:
10.1021/jm301848w
Tecfidera (dimethyl fumarate)
• First line therapy for MS
• Reduces inflammation caused when the immune system attacks myelin. A
study but Munster attributes this to a change in the balance between T-cells.
• Tecfidera has anti-oxidant properties by activating NRF2 pathway which
ultimately protects nerves from ROS
• Clinical Trials: DEFINE and CONFIRM both showed great efficacy with low
safety concerns
NRF2 Pathway
• Neutralize Free radicals that
cause oxidative stress
• DNA transcription factor
• Encode Leucine Zipper (bZIP)
transcription factors.
• NRF2 has two mechanisms
whether in oxidative or
constitutive conditions.
Nrf2 Antioxidant Stress Response | Cayman
Chemical. (n.d.). Retrieved November 14,
2016, from
https://www.caymanchem.com/article/2168
Summary
• MS is an autoimmune disease characterized by damage to the myelin sheath
• Fingolimod phosphate binds to S1P receptors, thereby blocking the ability of
lymphocytes to egress from lymph nodes. This reduces overall lymphocyte
count meaning less are available to migrate to the CNS.
• Teriflunomide (Aubagio) works by inhibiting de novo pyrimidine synthesis at
the DHODH step, thus blocking the ability of lymphocytes to proliferate
• Tecfidera reduces inflammation by altering the balance between TH1 and
TH2 cells. It also reduces oxidative stress caused by the immune system by
activating the NRF2 pathway.
References
Bridel, C. & Lalive, P. H. (2014). Updates on multiple sclerosis treatments. Swiss Med Wkly., 144(w14012), . doi: 10.4414/smw.2014.14012
Canadian Pharmacists Association. eCPS. [Internet]. Ottawa: The Association; 2016. Aubagio; [revised 2015 Sep; cited 2016 Nov 14]. Available from: http://www.etherapeutics.ca.myaccess.library.utoronto.ca/ with authorized username and password.
Chun, J. & Hartung, H. (2010). Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin. Neuropharmacol., 33(2), 91-101.
doi:10.1097/WNF.0b013e3181cbf825
Frohman, E. M., Racke, M. K., & Raine, C. S. (2006). Multiple Sclerosis — The Plaque and Its Pathogenesis. New England Journal of Medicine, 354(9), 942-955.
doi:10.1056/nejmra052130
Hvizdos, A.J., and Mosler, C.R. (2016). Current Perspectives on Multiple Sclerosis. US Pharmacist, 41(1): 22 - 26.
Mehling, M., Kappos, L. & Derfuss, T. (2011). Fingolimod for multiple sclerosis: mechanism of action, clinical outcomes, and future directions. Curr. Neurol. Neurosci.
Rep., 11, 492. doi:10.1007/s11910-011-0216-9
May, O. L. (2012, February 01). Nrf2 Antioxidant Stress Response | Cayman Chemical. Retrieved November 14, 2016, from
https://www.caymanchem.com/article/2168
Meunier-Lehmann, H., Vidalain, P. O., Tangy, F. & Janin, Y. L. (2013). On Dihydroorotate Dehydrogenases and Their Inhibitors and Uses. J. Med. Chem., 56(8),
3148-3167. doi: 10.1021/jm301848w
Moyes, C.D., and Schulte, P.M. (2015). Principles of Animal Physiology, 3rd ed. Pearson: Ontario, Canada.
Steinman, L., and Zamvil, S. (2003). Transcriptional analysis of targets in multiple sclerosis. Nature Reviews Immunology, 3: 483 - 492.