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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.