IP Library › Granted Patent US 12,336,980
Granted Patent B2
US 12,336,980 · App. 18/046,492 · Granted Jun 24, 2025

Dosing regimen for a selective S1P1 receptor agonist

Inventors: Jasper Dingemanse (Allschwil, CH); Matthias Hoch (Harston, GB); Andreas Krause (Allschwil, CH)
Assignee: Vanda Pharmaceuticals Inc.
A61K31/426A61K9/0053
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,336,980
App. No.
18/046,492
Granted
Jun 24, 2025
Kind
B2
Abstract

The present invention relates to a dosing regimen for (R)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylimmo)-3-o-tolyl-thiazolidin-4-one.

Claims (4)

1. A method of treating a human subject, diagnosed with multiple sclerosis, who has been orally administered once-daily titrating doses, successively over a period of two weeks, of a compound that is (R)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz [Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-thiazolidin-4-one or a pharmaceutically acceptable salt thereof, which successive titrating doses are 2 mg on days 1 and 2; 3 mg of on days 3 and 4; 4 mg on days 5 and 6; 5 mg on day 7; 6 mg on day 8; 7 mg on day 9; 8 mg on day 10; and 9 mg on day 11, and 10 mg on days 12, 13, and 14, comprising:

administering, starting on the day following the last titrating dose, 20 mg of said compound.

2. The method of claim 1 , wherein the multiple sclerosis is relapsing multiple sclerosis.

3. The method of claim 2 , wherein the multiple sclerosis is relapsing-remitting multiple sclerosis.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 29, 2024
From: ACTELION PHARMACEUTICALS LTD
To: VANDA PHARMACEUTICALS INC.
Reel/Frame 066276/0577 →
Priority Claims (2)
WO PCT/EP2014/077469 · Dec 11, 2014 · international
WO PCT/EP2015/058202 · Apr 15, 2015 · international
Continuity (4)
Continuation 17090756 · Nov 5, 2020
Division 16261327 · Jan 29, 2019
Division 15534929
Related Publication 20230131600A1 · Apr 27, 2023
References Cited (181)
US 4959389A · Speiser · 1990 [cited by applicant]
US 7435828B2 · Binkert et al. · 2008 [cited by applicant]
US 7626037B2 · Binkert et al. · 2009 [cited by applicant]
US 7875726B2 · Binkert et al. · 2011 [cited by applicant]
US 7879821B2 · Hauser et al. · 2011 [cited by applicant]
US 8263780B2 · Abele et al. · 2012 [cited by applicant]
US 8273779B2 · Binkert et al. · 2012 [cited by applicant]
US RE43728E · Binkert et al. · 2012 [cited by applicant]
US RE43833E · Binkert et al. · 2012 [cited by applicant]
US 8399514B2 · Lukashev · 2013 [cited by applicant]
US 8492441B2 · Legangneux · 2013 [cited by applicant]
US 8524752B2 · Binkert et al. · 2013 [cited by applicant]
US 8669281B1 · Zeidan · 2014 [cited by applicant]
US 8785484B2 · Brossard et al. · 2014 [cited by applicant]
US RE45174E · Binkert et al. · 2014 [cited by applicant]
US 8912340B2 · Abele et al. · 2014 [cited by applicant]
US 9000018B2 · Binkert et al. · 2015 [cited by applicant]
US 9062014B2 · Bonham et al. · 2015 [cited by applicant]
US 9340518B2 · Herse et al. · 2016 [cited by applicant]
US 20090182047A1 · Joshi · 2009 [cited by applicant]
US 20100048651A1 · Gangakhedkar · 2010 [cited by applicant]
US 20100160259A1 · Schmouder et al. · 2010 [cited by applicant]
US 20100160369A1 · Canne Bannen et al. · 2010 [cited by applicant]
US 20100260755A1 · Gammans · 2010 [cited by applicant]
US 20110112196A1 · Lukashev · 2011 [cited by applicant]
US 20110200557A1 · Grima Poveda · 2011 [cited by applicant]
US 20110257133A1 · Schmouder et al. · 2011 [cited by applicant]
US 20110274657A1 · Aguilar Izquierdo · 2011 [cited by applicant]
US 20110311485A1 · Giulio Matassa · 2011 [cited by applicant]
US 20120034303A1 · Nilsson · 2012 [cited by applicant]
US 20120238028A1 · Reszka · 2012 [cited by applicant]
US 20130259856A1 · Kaye · 2013 [cited by applicant]
US 20130314669A1 · Levin · 2013 [cited by applicant]
US 20130316003A1 · Nilsson · 2013 [cited by applicant]
US 20140056973A1 · Ma · 2014 [cited by applicant]
US 20140057917A1 · Cundy · 2014 [cited by applicant]
US 20140163100A1 · Dawson · 2014 [cited by applicant]
US 20140179778A1 · Mao · 2014 [cited by applicant]
US 20140303217A1 · Brossard et al. · 2014 [cited by applicant]
US 20140315964A1 · Brossard et al. · 2014 [cited by applicant]
US 20140316140A1 · Brossard et al. · 2014 [cited by applicant]
US 20150183741A1 · Guckian · 2015 [cited by applicant]
US 20150203493A1 · Guckian · 2015 [cited by applicant]
US 20150220693A1 · Cadavid · 2015 [cited by applicant]
US 20150238602A1 · Cadavid · 2015 [cited by applicant]
US 20150265580A1 · Brossard et al. · 2015 [cited by applicant]
US 20190091190A1 · Terwey · 2019 [cited by applicant]
US 20190151292A1 · Dingemanse et al. · 2019 [cited by applicant]
AU 752733 · 2002 [cited by applicant]
AU 2013329421A1 · 2015 [cited by applicant]
CA 2834455A1 · 2012 [cited by applicant]
CN 101980704A · 2011 [cited by applicant]
DE 102009008851A1 · 2010 [cited by applicant]
DE 102010048788A1 · 2011 [cited by applicant]
DE 102010026879A1 · 2011 [cited by applicant]
EP 2137537A2 · 2009 [cited by applicant]
EP 2177521A1 · 2010 [cited by applicant]
EP 2202232A1 · 2010 [cited by applicant]
EP 2210890A1 · 2010 [cited by applicant]
EP 2305660A1 · 2011 [cited by applicant]
EP 2316430A1 · 2011 [cited by applicant]
EP 2343287A1 · 2011 [cited by applicant]
EP 2366702A1 · 2011 [cited by applicant]
EP 2390252A1 · 2011 [cited by applicant]
EP 2455080A1 · 2012 [cited by applicant]
EP 2692344A1 · 2014 [cited by applicant]
JP T2005535679 · 2005 [cited by applicant]
JP 2012500285A · 2012 [cited by applicant]
JP 2014515373A · 2014 [cited by applicant]
KR 102427123B1 · 2022 [cited by applicant]
WO 0030622A2 · 2000 [cited by applicant]
WO WO2004010987 · 2004 [cited by applicant]
WO 2005005421A1 · 2005 [cited by applicant]
WO WO2005054215 · 2005 [cited by applicant]
WO 2005082841A1 · 2005 [cited by applicant]
WO WO2006058316 · 2006 [cited by applicant]
WO WO2008062376 · 2008 [cited by applicant]
WO WO2009115954 · 2009 [cited by applicant]
WO 2010022177A2 · 2010 [cited by applicant]
WO WO2010046835 · 2010 [cited by applicant]
WO 2010079222A1 · 2010 [cited by applicant]
WO WO2010072703 · 2010 [cited by applicant]
WO WO2010075239 · 2010 [cited by applicant]
WO 2011035900A1 · 2011 [cited by applicant]
WO 2011067243A1 · 2011 [cited by applicant]
WO 2011069647A1 · 2011 [cited by applicant]
WO 2011113578A1 · 2011 [cited by applicant]
WO 2011144338A1 · 2011 [cited by applicant]
WO 2012162669A1 · 2012 [cited by applicant]
WO 2012164026A1 · 2012 [cited by applicant]
WO 2013119677A1 · 2013 [cited by applicant]
WO 2013148690A1 · 2013 [cited by applicant]
WO 2014018891A1 · 2014 [cited by applicant]
WO 2014020156A1 · 2014 [cited by applicant]
WO 2014028299A1 · 2014 [cited by applicant]
WO 2014031844A1 · 2014 [cited by applicant]
WO 2014031892A1 · 2014 [cited by applicant]
WO WO2014027330 · 2014 [cited by applicant]
WO 2014058875A2 · 2014 [cited by applicant]
WO 2014071371A1 · 2014 [cited by applicant]
WO 2014152494A1 · 2014 [cited by applicant]
WO 2015066515A1 · 2015 [cited by applicant]
WO WO2016092042 · 2016 [cited by applicant]
Brossard, vol. 54, Issue2 Feb. 2014 pp. 179-188 (Year: 2014). [cited by examiner]
Daniele D'Ambrosio, Therapeutic Advances in Chronic Diseasevol. 7, Issue 1, Jan. 2016, pp. 18-33 (Year: 2016). [cited by examiner]
Brossard et al., “Effects of three different up-titration regimens of ponesimod, a selective S1P1 receptor agonist, on heart rate”, ECTRIMS Lyon France, p. 109, (2012). [cited by applicant]
Brossard et al., “Pii-109; Effects of Three Different Up-Titration Regimens of Ponesimod, a Selective S1p1 Receptor Agonist, on Heart Rate”, Nature, vol. 91, p. S92-S93, (2012). [cited by applicant]
Brossard et al., “Pii-111; Ascending Single-Dose Study With Ponesimod, a Selective S1p1 Receptor Agonist: Safety, Pharmacokinetics, Pharmacodynamics, and Modeling”, Nature, vol. 91, p. S93, (2012). [cited by applicant]
Brossard P. et al., “Multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ponesimod, an S1P receptor modulator: Favorable impact of dose up-titration”, J Clin Pharmacol. 2014; vol. 54(2), pp. 179-188. [cited by applicant]
“Actelion's Orally Active Selective S1P1 Receptor Agonist to be Jointly Developed/ Promoted with Roche in Autoimmune Disorders and Transplantation; Deal Potentially Worth well over US$630 Million to Actelion”, USCULO El… [cited by applicant]
Brinkmann, “Sphingosine 1-phosphate receptors in health and disease: Mechanistic insights from gene deletion studies and reverse pharmacology”, Pharmacology & Therapeutics, vol. 115, p. 84-105, (2007). [cited by applicant]
Brossard et al., “Effects on heart rate of three different up-titration regimens of ponesimod, a selective S1P1 receptor modulator, and of re- initiation of treatment in healthy male and female subjects”, ECTRIMS Lyon F… [cited by applicant]
Brossard et al., “Ascending multiple-dose study with ponesimod, a selective S1P1 receptor agonist: tolerability, safety, pharmacokinetics, and pharmacodynamics”, ECTRIMS Lyon France, p. 109, (2012). [cited by applicant]
Brossard et al., “Ascending single-dose study with ponesimod, a selective S1P1 receptor agonist: safety, pharmacokinetics, pharmacodynamics, and modeling”, ECTRIMS Lyon France, p. 111, (2012). [cited by applicant]
Brossard et al., “Pharmacokinetics and pharmacodynamics of ponesimod, a selective S1P1 receptor modulator, in the first-in-human study”, British Journal of Clinical Pharmacology, vol. 76(6), p. 888-896, (2013). [cited by applicant]
Brossard et al., “Effects on heart rate of three different up-titration regimens of ponesimod, a selective S1P1 receptor modulator, and of re- initiation of treatment in healthy male and female subjects”, ECTRIMS Lyon F… [cited by applicant]
Brossard et al., “A randomised, double-blind, ascending multiple-dose study with ponesimod, a selective S1P1 receptor modulator: safety, pharmacokinetics, pharmacodynamics”, ECTRIMS Lyon France, (2012). [cited by applicant]
Brossard et al., “Multiple-Dose Tolerability, Pharmacokinetics, and Pharmacodynamics of Ponesimod, an S1P1 Receptor Modulator: Favorable Impact of Dose Up-Titration”, The Journal of Clinical Pharmacology, p. 1-10, (2013… [cited by applicant]
Brossard et al., “Pii-110; Ascending Multiple-Dose Study With Ponesimod, A Selective S1p1 Receptor Agonist: Tolerability, Safety, Pharmacokinetics, And Pharmacodynamics”, Nature, vol. 91, p. S93, (2012). [cited by applicant]
Bunemann et al., “Activation of Muscarinic K+ Current in Guinea-Pig Atrial Myocytes by sphingosine-1-phosphate”, Journal of Physiology, vol. 489.3, p. 701-707, (1995). [cited by applicant]
Davidov et al., “Chronic nitric oxide synthase blockade desensitizes the heart to the negative metabolic effects of nitric oxide”, Life Sciences, vol. 79, p. 1674-1680, (2006). [cited by applicant]
Fernández et al., “Review of the Novelties Presented at the 28 [cited by applicant]
Frolkis et al., “The Role of Invertors (Intracellular Activators) in Age-Related Changes in Cell Response to Hormones”, Experimental Gerontology, vol. 30(3/4), p. 401-414, (1995). [cited by applicant]
Fujishiro et al., “Use of Sphingosine-1-Phosphate 1 Receptor Agonist, KRP-203, in Combination with a Subtherapeutic Dose of Cyclosporine A for Rat Renal Transplantation”, Transplantation, vol. 82(6), p. 804-812, (2006). [cited by applicant]
Guo et al., “Effects of Sphingosine 1-phosphate on pacemaker activity in rabbit sino-atrial node cells”, European Journal of Physiology, vol. 438, p. 642-648, (1999). [cited by applicant]
Hale et al., “Selecting against S1P3 enhances the acute cardiovascular Tolerability of 3-(N-benzyl) aminopropylphosphonic acid SIP receptor agonists”, Bioorganic & Medicinal Chemistry Letters, vol. 14, p. 3501-3505, (20… [cited by applicant]
Himmel et al., “Evidence for Edg-3 Receptor-Mediated Activation of IK.ACh by Sphingosine-1-Phosphate in Human Atrial Cardiomyocytes”, Molecular Pharmacology, vol. 58, p. 449-454, (2000). [cited by applicant]
Hoch et al., “Effect of Ponesimod, a Selective S1P1 Receptor Modulator, on the QT Interval in Healthy Individuals”, Basic & Clinical Pharmacology & Toxicology, vol. 116, p. 429-437, (2015). [cited by applicant]
Hoch et al., “Oc015—Up-Titration Study With Ponesimod, A Selective S1p1 Receptor Modulator, To Assess Its Maximum Tolerated Dose In Healthy Subjects”, Clinical Therapeutics, vol. 35(8S), p. e6-e7, (2013). [cited by applicant]
Hoch et al., “The Proceedings of the 12th Conference of the European Association for Clinical Pharmacology and Therapeutics”, Clinical Therapeutics, vol. XX(xx), (2015). [cited by applicant]
Hoch et al., “PP162—Thorough QT study with ponesimod, a selective S1P1 receptor modulator”, Clinical Therapeutics, vol. 35(8S), p. e68-e69, (2013). [cited by applicant]
Hoch et al., “Thorough QT study with ponesimod, a selective S1P1 receptor modulator”, EACPT Congress, p. pp. 162, (2013). [cited by applicant]
Hoch et al., “A novel gradual up-titration regimen mitigates the first-dose effects of ponesimod, a selective S1P1 receptor modulator”, 12th European Association for Clinical Pharmacology and Therapeutics (EACPT) Congre… [cited by applicant]
Hoch et al., “A Novel Gradual Up-Titration Regimen Mitigates The First-Dose Effects Of Ponesimod, A Selective S1p1 Receptor Modulator”, Clinical Therapeutics, vol. 37 (8S), e36e37, (2015). [cited by applicant]
Hoch et al., “Clinical pharmacology of ponesimod, a selective S1P1 receptor modulator, after uptitration to supratherapeutic doses in healthy subjects”, European Journal of Pharmaceutical Sciences, vol. 63, p. 147-153, … [cited by applicant]
Huwiler et al., “New players on the center stage: Sphingosine 1-phosphate and its receptors as drug targets”, Biochemical Pharmacology, p. 1-8, (2008). [cited by applicant]
International Search Report of International Application No. PCT/EP2015/079208, mailed on Mar. 4, 2016, 4 pages. [cited by applicant]
Juif et al., “Mitigation of Initial Cardiodynamic Effects of the SIP1 Receptor Modulator Ponesimod Using a Novel Up-Titration Regimen”, The Journal of Clinical Pharmacology, vol. 57(3), p. 401-410, (2017). [cited by applicant]
Kappos et al., “Siponimod (BAF [cited by applicant]
Keller et al., “Immunomodulator FTY720 Induces Myofibroblast Differentiation via the Lysophospholid Receptor S1P3 and Smad3 Signaling”, The American Journal of Pathology, vol. 170, p. 281-292, (2007). [cited by applicant]
Kovarik et al., “A Mechanistic Study to Assess Whether Isoproterenol Can Reverse the Negative Chronotropic Effect of Fingolimod”, Pharmacodynamics, p. 1-8, (2008). [cited by applicant]
Koyrakh et al., “The Heart Rate Decrease Caused by Acute FTY720 Administration is Mediated by the G-Protein-Gated Potassium Channel IKACH”, American Journal of Transplantation, vol. 5, p. 529-536, (2005). [cited by applicant]
Krause et al., “Population modeling of the pharmacokinetics and pharmacodynamics of ponesimod, a selective S1P1 receptor agonist”, University of Auckland, New Zealand, p. 78, (2012). [cited by applicant]
Krause et al., “Population modeling of the pharmacokinetics and pharmacodynamics of ponesimod, a selective S1P1 receptor agonist”, Nature, vol. 91, p. S36-S37, (2012). [cited by applicant]
Krause et al., “Population pharmacokinetics and pharmacodynamics of ponesimod, a selective S1P1 receptor modulator”, Journal of Pharmacokinetics Pharmacodynamics, vol. 41, p. 261-278, (2014). [cited by applicant]
Legangneux et al., “BAF312 Dose-Titration Scheme Significantly Attenuates Initial Heart Rate Reducing Effects in Healthy Subjects”, 63rd American Academy of Neurology Annual Meeting, Honolulu Hawaii, (2011). [cited by applicant]
Legangneux et al., “BAF312 Dose-Titration Scheme Significantly Attenuates Initial Heart Rate Reducing Effects in Healthy Subjects”, British Journal of Clinical Pharmacology, vol. 75(3), p. 831-841, (2012). [cited by applicant]
Lott et al., “Modeling Tolerance Development for the Effect on Heart Rate of the Selective S1P [cited by applicant]
Lott et al., “Tolerance modeling: effects of the selective S [cited by applicant]
Ochi et al., “Sphingosine-1-phosphate Effects on Guinea Pig Atrial Myocytes: Alterations in Action Potentials and K+ Currents”, Cardiovascular Research, vol. 70, p. 88-96, (2006). [cited by applicant]
Olsson et al., “Oral ponesimod in relapsing-remitting multiple sclerosis: a randomised phase II trial”, J Neurol Neurosurg Psychiatry., vol. 85, p. 1198-1208, (2014). [cited by applicant]
Piali et al., “The Selective Sphingosine 1-Phosphate Receptor 1 Agonist Ponesimod Protects against Lymphocyte-Mediated Tissue Inflammation,” The Journal of Pharmacology and Experimental Therapeutics, vol. 337, No. 2, p.… [cited by applicant]
Peters et al., “Sphingosine-1-phosphate signaling in the cardiovascular system”, Current Opinion in Pharmacology, vol. 7, p. 1-7, (2007). [cited by applicant]
Remington, The Science and Practice of Pharmacy, 21st Edition, Part 5, Pharmaceutical Manufacturing; 2005. [cited by applicant]
Rey et al., “Desensitization by Progressive Up-Titration Prevents First-Dose Effects on the Heart: Guinea Pig Study with Ponesimod, a Selective S1P1 Receptor Modulator”, PlosOne, vol. 8(9), p. e74285 (1-7), (2013). [cited by applicant]
Reyes et al., “Effects of ponesimod, a selective S1P1 receptor modulator, on the pharmacokinetics of a hormonal combination contraceptive”, European Journal of Clinical Pharmacology, vol. 70, p. 287-293, (2014). [cited by applicant]
Sanna et al., “Sphingosine 1-Phosphate (S1P) Receptor Subtypes S1P1 and S1P3, Respectively, Regulate Lymphocyte Recirculation and Heart Rate*”, The Journal of Biological Chemistry, vol. 279(4), p. 13839-13848, (2004). [cited by applicant]
Scherz et al., “Three Different Up-Titration Regimens of Ponesimod, an S1P1 Receptor Modulator, in Healthy Subjects”, The Journal of Clinical Pharmacology, p. 1-10, (2015). [cited by applicant]
Schmouder et al., “FTY720: Placebo-Controlled Study of the Effect on Cardiac Rate and Rhythm in Healthy Subjects”, Journal of Clinical Pharmacology, vol. 46, p. 895-904, (2006). [cited by applicant]
Stahl et al., “Handbook of Pharmaceuticals Salts: Properties, Selection, and use”, International Union of Pure and Applied Chemistry, p. 329-350, (2008). [cited by applicant]
Vaclavkova et al., “Oral ponesimod in patients with chronic plaque psoriasis: a randomised, double-blind, placebo-controlled phase 2 trial”, The Lancet, p. 1-10, (2014). [cited by applicant]
Wouters et al., “Pharmaceutical Salts and Cocrystals”, RSC Drug Discovery, p. 1-10, (2012). [cited by applicant]
Basile, “Titration of β-blockers in Heart Failure,” Postgraduate Medicine, vol. 113, No. 3, p. 63-70, (2003). [cited by applicant]
Brossard et al., “Effects on Heart Rate of Three Different Up-titration Regimens of Ponesimod, A Selective S1P1 Receptor Modulator, and of Re-Initiation of Treatment in Healthy Male and Female Subjects,” Multiple Sclero… [cited by applicant]
De Vries et al., “Guide to Good Prescribing: A Practical Manual,” WHO Action Programme on Essential Drugs, 11 pages, (1994). [cited by applicant]
Mccormack et al., “Is Bigger Better? An Argument for Very Low Starting Doses,” CMAJ, vol. 183, No. 1, p. 65-69, (2011). [cited by applicant]
“Abstracts—ACTRIMS Forum 2017”, Multiple Sclerosis Journal, vol. 23, p. 2-90, (2017). [cited by applicant]
De Vries T.P.G.M., Henning R.H., Hogerzeil H.V., Fresle D.A., “Annex 1—Essentials of pharmacology in daily practice”, Guide to Good Prescribing—A practical manual, (Jan. 1, 1998), pp. 98-104, XP055980341. [cited by applicant]
Brennan et al., “Dimethyl Fumarate and Monomethyl Fumarate are Distinguished by Non-Overlapping Pharmacodynamic Effects In Vivo (P1.206)”, Neurology, 2014, vol. 82, Suppl. 10. [cited by applicant]
Brossard et al., “Pharmacokinetics and Pharmacodynamics Of Ponesimod, A Selective S1P1 Receptor Modulator, In the first-in-human study”, British Journal of Clinical Pharmacology, 2013, vol. 76, No. 6, pp. 888-896. [cited by applicant]
Cohen et al., “The Future Of Multiple Sclerosis Treatment”, Journal of the Neurological Sciences, 2009, vol. 277, No. 51, pp. S55-S61. [cited by applicant]
Curtin et al., “Novel Therapeutic Options For Multiple Sclerosis”, Exert Rev. Clin. Pharmacol., 2014, vol. 7, No. 1, pp. 91-104. [cited by applicant]
Ellwardt et al., “Molecular Mechanisms Linking Neuroinflammation and Neurodegeneration in MS,” Experimental Neurology, 2014, vol. 262, pp. 8-17. [cited by applicant]
Fernandez et al., “Combination Therapy In Multiple Sclerosis”, Journal of the Neurological Sciences, 2007, vol. 259, pp. 95-103. [cited by applicant]
Olsson et al., “Oral Ponesimod In Relapsing-Remitting Multiple Sclerosis: A Randomised Phase II Trial”, Journal of Neurology, Neurosurgery and Psychiatry, 2014, vol. 85, pp. 1198-1208. [cited by applicant]
Pitarokoili et al., “Lewis Rat Model of Experimental Autoimmune Encephalomyelitis,” Current Protocols in Neuroscience, 2017, vol. 81, pp. 1-22. [cited by applicant]
Pouzol et al., “Complete Resolution Of Clinical Signs And Synergism Of The Combination Ponesimod-Dimethyl Fumarate In Rat Models Of Multiple Sclerosis”, Actelion Pharmaceuticals Ltd-Poster DMF-ponesimod ACTRIMS, 2017. [cited by applicant]
Shin et al., “Mechanisms of Experimental Autoimmune Encephalomyelitis in Lewis Rats: Recent Insights from Macrophages,” Anat Cell Biol, 2012, vol. 45, pp. 141-148. [cited by applicant]
Shurin et al., “Immune-Mediated Diseases: Where Do We Stand?”, Part Of The Advances In Experimental Medicine And Biology Book Series AEMB, 2007, vol. 601, pp. 1-12. [cited by applicant]
Weaver et al., “An Elevated Matrix Metalloproteinase (MMP) In An Animal Model Of Multiple Sclerosis Is Protective By Affecting Th1/Th2 polarization”, The FASEB Journal, 2005, vol. 19, No. 12, pp. 1668-1670. [cited by applicant]
Wustrow et al., “Comparison of the Efficacy and Tolerability of a Novel Methyl Hydrogenfumarate Prodrug with Dimethyl Fumarate in Rodent EAE and GI Irritation Models”, Neurology, 2011, vol. 76, No. 9, Suppl. 4, pp. A387. [cited by applicant]