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Relapsing-remitting multiple sclerosis

Disease ID:1197
Name:Relapsing-remitting multiple sclerosis
Associated with:1 target
1 immuno-relevant target
12 immuno-relevant ligands
Synonyms
Relapsing-remitting MS | RRMS
Description
A multiple sclerosis characterized by periods of relapse followed by remission. Symptoms may vary from mild to severe, and relapses and remissions may last for days or months.
Database Links
Disease Ontology: DOID:2378

Targets

CD20 (membrane-spanning 4-domains, subfamily A, member 1)
Comments:  CD20 is the molecular target of the RRMS therapeutic ocrelizumab.
Ligand interactions: 
Ligand Comments
ocrelizumab
Ocrelizumab is approved to treat RRMS.

Ligands

Key to terms and symbols Click ligand name to view ligand summary Click column headers to sort
Ligand References Clinical and Disease comments
amiselimod
Immuno Disease Comments: Phase 2 clinical candidate for RRMS.
Clinical Use: Amiselimod (MT-1303) has completed Phase 2 dose-finding clinical trials in patients with relapsing-remitting multiple sclerosis (NCT01742052) and moderate to severe chronic plaque psoriasis (NCT01987843). Phase 2 trials in Crohn's disease patients are underway. | View clinical data
Bioactivity Comments: In vivo (in mice) amiselimod (MT-1303) hydrochloride decreases peripheral blood lymphocyte count with an ED50 value of 0.04mg/kg body weight [11]. Affinity for S1P receptors is not provided in the patent. Note that bioactivity is attributed to the active metabolite [15], the prodrug is almost completely inactive at S1P1R. | View biological activity
ASP4058 21
Immuno Disease Comments: ASP4058 ameliorates rodent experimental autoimmune encephalomyelitis (EAE), a model of human MS.
Clinical Use: ASP4058 has completed a Phase 1 clinical trial (NCT01998646) in healthy subjects. | View clinical data
Bioactivity Comments: ASP4058 has a wider safety margin than the non-selective S1P agonist, , for bradycardia and bronchoconstriction in rodents [21]. It is proposed that the selectivity profile of ASP4058 should minimise the risk of adverse effects thought to be mediated by S1P3 activation [4,18]. | View biological activity
evobrutinib
Immuno Disease Comments: Phase 2 clinical candidate for RR-MS- see NCT02975349
Clinical Use: Evobrutinib is being evaluated in Phase 2 clinical trials for rheumatoid arthritis, systemic lupus erythematosus and relapsing-remitting multiple sclerosis. A full list of evobrutinib trials registered with ClinicalTrials.gov is available by clicking here. | View clinical data
fingolimod
Immuno Disease Comments: Approved drug for RR-MS.
Clinical Use: Used in the treatment of relapsing-remitting multiple sclerosis (MS) [7]. In May 2018, the FDA approved the use of fingolimod as a treatment for relapsing MS in pediatric patients. This is the first drug to be approved for treating MS in this patient group. | View clinical data
Bioactivity Comments: Note that most of the bioactivity maps to the active metabolite .
FTY720 exhibits no measurable agonist activity at human S1P2, S1P3 and S1P4 receptor subtypes, compared to S1P1 and S1P5 [6]. | View biological activity
alemtuzumab
Immuno Disease Comments: Approved drug for RR-MS, and controlled access for B-cell chronic lymphocytic leukemia (CLL) and transplant indications.
Clinical Use: Alemtuzumab is primarily used for the treament of relapsing-remitting multiple sclerosis (RRMS). Based on results from clinical trials, the UK National Institute for Health and Care Excellence (NICE) approved use of this drug for RRMS in May 2014. In November 2014, the US FDA approved alemtuzumab for RRMS. A list of clinical trials for this drug in MS patients is available using this link to ClinicalTrials.gov.

Alemtuzumab can also be used in B-cell chronic lymphocytic leukemia (CLL) therapy and in transplant indications, but access for these indications is controlled through a patient access programme (in the UK).

Results from Phase 3 trial NCT00548405, suggest that treating RRMS patients with alemtuzumab earlier can actually improve preexisiting disability, rather than just slowing disease progression (with caveats around risk-benefit, and the serious side-effects of alemtuzumab therapy; side-effects such as infusion associated reactions, infections, and development of other autoimmune diseases) [5]. | View clinical data
Bioactivity Comments: The necleotide sequences for the CAMPATH-1 antibody were originally identified by Crowe et al. (1992) [3], and this article reports the ADCC effector function of the antibody against K422B lymphoma cells. The reported nucleotide sequences were used to generate an antibody with swapped anti-CAMPATH domains, described in patent US7923538 [13]. The constructed antibodies exhibited improved complement-dependent cytotoxic activity (CDC) and antibody-dependent cell-mediated cytotoxic activity (ADCC) compared to Campath1H-IgG. Affinity data for the interaction between the antibody and the CAMPATH-1 antigen is not provided in either the original article or in patent US7923538 [14]. | View biological activity
teriflunomide
Immuno Disease Comments: A RR-MS treatment initiated under specialist supervision.
Clinical Use: Used to reduce flare-ups in patients with relapsing multiple sclerosis (MS). | View clinical data
daclizumab
Immuno Disease Comments: Approval covers use of the daclizumab beta form of the drug to treat RRMS.
Clinical Use: Originally approved to abrogate renal allograft rejection. Zenapax® was withdrawn from use, at the request of the marketing authorisation holder (Roche) for commercial reasons.
A Phase II clinical trial NCT01468311 investigating the use of radio-labelled daclizumab as part of the immunosuppressive conditioning regimen in preparation for stem cell transplant in Hodgkin's lymphoma patients was suspended before completion.

Daclizumab beta (BIIB019, produced in a high yield process) is being evaluated in Phase III clinical trial for relapsing-remitting multiple sclerosis (MS). Click here to view these Phase III trials at ClinicalTrials.gov. Pharmacokinetics of daclizumab beta are published in [17]. In May 2016, the US FDA approved the once-monthly daclizumab injection, Zinbryta® (which contains daclizumab beta) for the treatment of patients with relapsing forms of MS, but is only to be used for patients who have had an inadequate response to two or more MS drugs. | View clinical data
Bioactivity Comments: Peptide sequence analysis of the heavy chain variable region of daclizumab provides a match with patented sequence from US5693761 [12]. | View biological activity
ocrelizumab
Immuno Disease Comments: Ocrelizumab is approved to treat RRMS.
Clinical Use: The US FDA had granted breakthrough therapy designation for ocrelizumab for the treatment of primary progressive multiple sclerosis which converted to full FDA approval for the treatment of relapsing and primary progressive types of multiple sclerosis in March 2017. Phase III clinical trials eg NCT01194570 and NCT01247324 were used to evaluate ocrelizumab clinical potential.

Development of this antibody as a treatment for other inflammatory disorders, such as rheumatoid arthritis and systemic lupus erythematosus, and B-cell malignancies has been suspended [8-9]. | View clinical data
Bioactivity Comments: Ocrelizumab depletes CD20+ B cells in the blood and lymphoid tissues of cynomolgus monkeys (Macaca fascicularis) [19]. B cell numbers recover to normal levels after one or two treatments [19]. Affinity data for clone 2H7.v16 is presented below. Clone 2H7.v31 exhibited 20-fold higher antibody-dependent cell-mediated cytotoxicity (ADCC) than the approved anti-CD20 monoclonal . | View biological activity
peginterferon beta-1a
Immuno Disease Comments: Approved drug for RR-MS.
Clinical Use: Approved for the treatment of relapsing-remitting multiple sclerosis. See Calabresi et al (2014) [1] for the reults of the phase III ADVANCE clinical trial. (NCT00906399). | View clinical data
MK-0812
Immuno Disease Comments: Phase 2 trial NCT00239655 in RRMS was terminated.
Clinical Use: MK-0812 has completed a Phase II efficacy, tolerability and safety clinical trial in patients with rheumatoid arthritis (NCT00542022), and a Phase II trial in patients with relapsing-remitting multiple sclerosis (NCT00239655). | View clinical data
Bioactivity Comments: MK-0812 blocks all MCP-1-driven CCR2 activation in vitro and inhibits migration of rhesus monkey monocytes to the skin in an experimental hypersensitivity reaction in vivo [20]. | View biological activity
ozanimod 2
Immuno Disease Comments: Phase 3 clinical candidate for relapsing MS (see NCT02576717). Perliminary efficacy is reported in Celgene's Press release of Apr 24, 2018, but has yet to be confirmed.
Clinical Use: Ozanimod has reached Phase III clinical trial for its potential antiinflammatory effects in relapsing multiple sclerosis and ulcerative colitis. | View clinical data
Bioactivity Comments: Ozanimod is metabolized to , a compound which retains an activity profile indistinguishable from its parent [16]. | View biological activity
briakinumab
Immuno Disease Comments: Clinical development for RRMS has been terminated.
Clinical Use: Results from a Phase 2 clinical trial (NCT00292396) evaluating briakinumab in patients with moderate to severe chronic plaque psoriasis are reported in [10]. Several Phase 3 trials comparing briakinumab against placebo, and (two approved anti-psoriatic drugs) for moderate to severe chronic plaque psoriasis (link here to a list of these trials on ClinicalTrials.gov) have been completed. Clinical development of briakinumab for rheumatoid arthritis, Crohn's disease and multiple sclerosis has been terminated. As of May 2017, there are no active clinical trials evaluating this antibody. | View clinical data

References

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1. Calabresi PA, Kieseier BC, Arnold DL, Balcer LJ, Boyko A, Pelletier J, Liu S, Zhu Y, Seddighzadeh A, Hung S et al.. (2014) Pegylated interferon β-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study. Lancet Neurol, 13 (7): 657-65. [PMID:24794721]

2. Celgene. New Analyses from Pivotal Phase III Trials of Oral Ozanimod in Relapsing Multiple Sclerosis To Be Presented at the 2018 American Academy of Neurology Annual Meeting. Accessed on 26/04/2018. Modified on 26/04/2018. celgene.com, http://ir.celgene.com/releasedetail.cfm?ReleaseID=1064723

3. Crowe JS, Hall VS, Smith MA, Cooper HJ, Tite JP. (1992) Humanized monoclonal antibody CAMPATH-1H: myeloma cell expression of genomic constructs, nucleotide sequence of cDNA constructs and comparison of effector mechanisms of myeloma and Chinese hamster ovary cell-derived material. Clin. Exp. Immunol., 87 (1): 105-10. [PMID:1339322]

4. Forrest M, Sun SY, Hajdu R, Bergstrom J, Card D, Doherty G, Hale J, Keohane C, Meyers C, Milligan J et al.. (2004) Immune cell regulation and cardiovascular effects of sphingosine 1-phosphate receptor agonists in rodents are mediated via distinct receptor subtypes. J. Pharmacol. Exp. Ther., 309 (2): 758-68. [PMID:14747617]

5. Giovannoni G, Cohen JA, Coles AJ, Hartung HP, Havrdova E, Selmaj KW, Margolin DH, Lake SL, Kaup SM, Panzara MA et al.. (2016) Alemtuzumab improves preexisting disability in active relapsing-remitting MS patients. Neurology, 87 (19): 1985-1992. [PMID:27733571]

6. Hale JJ, Lynch CL, Neway W, Mills SG, Hajdu R, Keohane CA, Rosenbach MJ, Milligan JA, Shei GJ, Parent SA et al.. (2004) A rational utilization of high-throughput screening affords selective, orally bioavailable 1-benzyl-3-carboxyazetidine sphingosine-1-phosphate-1 receptor agonists. J. Med. Chem., 47 (27): 6662-5. [PMID:15615513]

7. Horga A, Montalban X. (2008) FTY720 (fingolimod) for relapsing multiple sclerosis. Expert Rev Neurother, 8 (5): 699-714. [PMID:18457527]

8. Hutas G. (2008) Ocrelizumab, a humanized monoclonal antibody against CD20 for inflammatory disorders and B-cell malignancies. Curr Opin Investig Drugs, 9 (11): 1206-15. [PMID:18951300]

9. Kausar F, Mustafa K, Sweis G, Sawaqed R, Alawneh K, Salloum R, Badaracco M, Niewold TB, Sweiss NJ. (2009) Ocrelizumab: a step forward in the evolution of B-cell therapy. Expert Opin Biol Ther, 9 (7): 889-95. [PMID:19463076]

10. Kimball AB, Gordon KB, Langley RG, Menter A, Chartash EK, Valdes J, ABT-874 Psoriasis Study Investigators. (2008) Safety and efficacy of ABT-874, a fully human interleukin 12/23 monoclonal antibody, in the treatment of moderate to severe chronic plaque psoriasis: results of a randomized, placebo-controlled, phase 2 trial. Arch Dermatol, 144 (2): 200-7. [PMID:18283176]

11. Kiuchi M, Marukawa K, Kobayashi N, Sugahara K. (2009) Amine Compound and Use Thereof for Medical Purposes. Patent number: US20090137530. Assignee: Mitsubishi Tanabe Pharma Corporation. Priority date: 15/12/2005. Publication date: 28/05/2009.

12. Queen CL, Schneider WP, Selick HE. (1997) Genetic engineering; complementarity zones. Patent number: US5693761. Assignee: Protein Design Labs, Inc.. Priority date: 28/12/1988. Publication date: 02/12/1997.

13. Shitara K, Niwa R, Natsume A. (2011) Recombinant antibody composition. Patent number: US7923538. Assignee: Kyowa Hakko Kirin Co., Ltd. Priority date: 22/07/2005. Publication date: 12/04/2011.

14. Shitara K, Niwa R, Natsume A. (2011) Recombinant antibody composition. Patent number: US7923538 B2. Assignee: Kyowa Hakko Kirin Co., Ltd. Priority date: 22/07/2005. Publication date: 12/04/2011.

15. Sugahara K, Maeda Y, Shimano K, Mogami A, Kataoka H, Ogawa K, Hikida K, Kumagai H, Asayama M, Yamamoto T et al.. (2017) Amiselimod, a novel sphingosine 1-phosphate receptor-1 modulator, has potent therapeutic efficacy for autoimmune diseases, with low bradycardia risk. Br. J. Pharmacol., 174 (1): 15-27. [PMID:27714763]

16. Taylor Meadows KR, Steinberg MW, Clemons B, Stokes ME, Opiteck GJ, Peach R, Scott FL. (2018) Ozanimod (RPC1063), a selective S1PR1 and S1PR5 modulator, reduces chronic inflammation and alleviates kidney pathology in murine systemic lupus erythematosus. PLoS ONE, 13 (4): e0193236. [PMID:29608575]

17. Tran JQ, Othman AA, Mikulskis A, Wolstencroft P, Elkins J. (2016) Pharmacokinetics of daclizumab high-yield process with repeated administration of the clinical subcutaneous regimen in patients with relapsing-remitting multiple sclerosis. Clin Pharmacol, 8: 9-13. [PMID:26929672]

18. Trifilieff A, Fozard JR. (2012) Sphingosine-1-phosphate-induced airway hyper-reactivity in rodents is mediated by the sphingosine-1-phosphate type 3 receptor. J. Pharmacol. Exp. Ther., 342 (2): 399-406. [PMID:22570366]

19. Vugmeyster Y, Beyer J, Howell K, Combs D, Fielder P, Yang J, Qureshi F, Sandlund B, Kawaguchi L, Dummer W et al.. (2005) Depletion of B cells by a humanized anti-CD20 antibody PRO70769 in Macaca fascicularis. J. Immunother., 28 (3): 212-9. [PMID:15838377]

20. Wisniewski T, Bayne E, Flanagan J, Shao Q, Wnek R, Matheravidathu S, Fischer P, Forrest MJ, Peterson L, Song X et al.. (2010) Assessment of chemokine receptor function on monocytes in whole blood: In vitro and ex vivo evaluations of a CCR2 antagonist. J. Immunol. Methods, 352 (1-2): 101-10. [PMID:19913021]

21. Yamamoto R, Okada Y, Hirose J, Koshika T, Kawato Y, Maeda M, Saito R, Hattori K, Harada H, Nagasaka Y et al.. (2014) ASP4058, a novel agonist for sphingosine 1-phosphate receptors 1 and 5, ameliorates rodent experimental autoimmune encephalomyelitis with a favorable safety profile. PLoS ONE, 9 (10): e110819. [PMID:25347187]