Emerging multiple sclerosis disease-modifying therapies

Current Opinion in Neurology

Volumn 22, Issue 3, 2009, Pages 226-232

  Giacomini, Paul S ^a   Darlington, Peter J ^b   Bar Or, Amit ^a,b,c  

^a Multiple Sclerosis Clinic   (Canada)

^b Neuroimmunology Unit   (Canada)

^c MCGILL UNIVERSITY   (Canada)

Author keywords

Cladribine; Fingolimod; Fumarate; Monoclonal antibodies; Multiple sclerosis; Teriflunomide

Indexed keywords

ALEMTUZUMAB; BETA INTERFERON; BETA1A INTERFERON; BG 00012; BHT 3009; CLADRIBINE; DACLIZUMAB; DIRUCOTIDE; DNA VACCINE; FINGOLIMOD; FUMADERM; HYBRID PROTEIN; LAQUINIMOD; MYELIN BASIC PROTEIN[82-98]; PROTEIN CTLA4IG; RITUXIMAB; TERIFLUNOMIDE; UNCLASSIFIED DRUG;

ACUTE GRAFT REJECTION; ALOPECIA; ARTHRALGIA; BACKACHE; BRADYCARDIA; BUDD CHIARI SYNDROME; CLINICAL FEATURE; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; DIARRHEA; DOSE RESPONSE; DRUG DOSE COMPARISON; DRUG DOSE REDUCTION; DRUG EFFICACY; DRUG MECHANISM; DRUG TOLERABILITY; DYSPNEA; HEADACHE; HEART DISEASE; HUMAN; IMMUNE RESPONSE; IMMUNOPATHOLOGY; IMMUNOSTIMULATION; INFECTION; LEUKOENCEPHALOPATHY; LIMB PAIN; LUNG FUNCTION TEST; MULTIPLE SCLEROSIS; NAUSEA; NONHUMAN; PARESTHESIA; PSORIASIS; RANDOMIZED CONTROLLED TRIAL; RECURRENT DISEASE; RESPIRATORY TRACT INFECTION; REVIEW; RHINOPHARYNGITIS; SIDE EFFECT; SKIN DISEASE; THROMBOCYTOPENIC PURPURA; THYROID DISEASE; URINARY TRACT INFECTION;

ANIMALS; CLINICAL TRIALS, PHASE II AS TOPIC; CLINICAL TRIALS, PHASE III AS TOPIC; HUMANS; IMMUNE TOLERANCE; IMMUNOLOGIC FACTORS; IMMUNOSUPPRESSIVE AGENTS; INFLAMMATION; MULTIPLE SCLEROSIS; NERVE TISSUE PROTEINS; RECOMBINANT FUSION PROTEINS;

EID: 67049108843     PISSN: 13507540     EISSN: None     Source Type: Journal    
DOI: 10.1097/WCO.0b013e32832b4ca1     Document Type: Review

References (46)

1. Bar-Or A. The immunology of multiple sclerosis. Semin Neurol 2008; 28:29-45. A comprehensive review of the immunology of MS detailing evolving concepts of pathogenesis.
2. Filippi M, Rocca MA. MRI evidence for multiple sclerosis as a diffuse disease of the central nervous system. J Neurol 2005; 252 (Suppl 5):v16-v24.
3. Williams A, Piaton G, Lubetzki C. Astrocytes: friends or foes in multiple sclerosis? Glia 2007; 55:1300-1312.
4. Dutta R, Trapp BD. Pathogenesis of axonal and neuronal damage in multiple sclerosis. Neurology 2007; 68:S22-S31; discussion S43-S54.
5. Bo L, Vedeler CA, Nyland HI, et al. Subpial demyelination in the cerebral cortex of multiple sclerosis patients. J Neuropathol Exp Neurol 2003; 62:723-732.
6. Magliozzi R, Howell O, Vora A, et al. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 2007; 130:1089-1104.
7. Panitch H, Miller A, Paty D, Weinshenker B. Interferon beta-1 b in secondary progressive MS: results from a 3-year controlled study. Neurology 2004; 63:1788-1795.
8. Lassmann H. Multiple sclerosis: is there neurodegeneration independent from inflammation? J Neurol Sci 2007; 259:3-6.
9. Lopez-Diego RS, Weiner HL. Novel therapeutic strategies for multiple sclero-sis: a multifaceted adversary. Nat Rev Drug Discov 2008; 7:909-925. A fine review detailing the immunopathogenesis of MS and the different points of action of novel therapies.
10. Garren H, Robinson WH, Krasulova E, et al. Phase 2 trial of a DNA vaccine encoding myelin basic protein for multiple sclerosis. Ann Neurol 2008; 63:611-620. The most recent study on the MBP DNA vaccine describing clinical trial results and immunological impact.
11. Bar-Or A, Vollmer T, Antel J, et al. Induction of antigen-specific tolerance in multiple sclerosis after immunization with DNA encoding myelin basic protein in a randomized, placebo-controlled phase 1/2 trial. Arch Neurol 2007; 64:1407-1415.
12. Warren KG, Catz I, Ferenczi LZ, Krantz Ml Intravenous synthetic peptide MBP8298 delayed disease progression in an HLA class ll-defined cohort of patients with progressive multiple sclerosis: results of a 24-month double-blind placebo-controlled clinical trial and 5 years of follow-up treatment. Eur J Neurol 2006; 13:887-895.
13. Viglietta V, Bourcìer K, Buckle GJ, et al. CTLA4lg treatment in patients with multiple sclerosis: an open-label, phase 1 clinical trial. Neurology 2008; 71:917-924. Preliminary results on CTLA4lg, a potential new therapy that interferes with costimulatory signalling between T cells and APCs.
14. Rose JW, Burns JB, Bjorklund J, et al. Daclizumab phase II trial in relapsing and remitting multiple sclerosis: MRI and clinical results. Neurology 2007; 69:785-789.
15. Rose JW, Lorberboum-Galski H, Fitzgerald D, et al. Chimeric cytotoxin IL2-PE40 inhibits relapsing experimental allergic encephalomyelitis. J Neuroim-munol 1991; 32:209-217.
16. Montalban XD, Wynn M, Kaufmann M, Wang FA. Preliminary CHOICE results: a phase 2, randomized, double-blind, placebo controlled multicentre study of subcutaneous daclizumab in patients with active, relapsing forms of multiple sclerosis on interferon beta. Mult Scler 2007; 13:S18.
17. Bielekova B, Catalfamo M, Reichert-Scrivner S, ef al. Regulatory CD56(bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis. Proc Natl Acad Sci U S A 2006; 103:5941-5946.
18. Kappos L, Antel J, Comi G, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med 2006; 355:1124-1140.
19. O'Connor P, Comi G, Montalban X, et al. Oral fingolimod (FTY720) in multiple sclerosis: two-year results of a phase II extension study. Neurology 2009; 72:73-79. The most recent study detailing efficacy and safety results from the phase II fingolimod trial.
20. Mehling M, Brinkmann V, Antel J, et al. FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis. Neurology 2008; 71:1261-1267. An interesting study exploring the impact of fingolimod on different T cell subsets in MS and how they may be implicated in disease.
21. Miron VE, Schubart A, Antel JP. Central nervous system-directed effects of FTY720 (fingolimod). J Neurol Sci 2008; 274:13-17. Article detailing the multiple actions of fingolimod in the CNS.
22. Miron VE, Jung CG, Kim HJ, ef al. FTY720 modulates human oligodendrocyte progenitor process extension and survival. Ann Neurol 2008; 63:61-71. A very elegant study describing how fingolimod can modulate responses in human oligodendrocyte precursors that are potentially relevant to remyelination.
23. Altmeyer PJ, Matthes U, Pawlak F, et al. Antipsoriatic effect of fumaric acid derivatives. Results of a multicenter double-blind study in 100 patients. J Am Acad Dermatol 1994; 30:977-981.
24. Schimrigk S, Brune N, Hellwig K, et al. Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline-controlled pilot study. Eur J Neurol 2006; 13:604-610.
25. Kappos L, Gold R, Miller DH, et al. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase llb study. Lancet 2008; 372:1463-1472. A study describing the most recent clinical trial results for fumarate and also providing insight about how it may modulate disease.
26. Schilling S, Goelz S, Linker R, et al. Fumaric acid esters are effective in chronic experimental autoimmune encephalomyelitis and suppress macrophage infiltration. Clin Exp Immunol 2006; 145:101-107.
27. Zhao C, Zawadzka M, Roulois AJ, et al. Promoting remyelination in multiple sclerosis by endogenous adult neural stem/precursor cells: defining cellular targets. J Neurol Sci 2008; 265:12-16. An article detailing different mechanisms that can foster remyelination.
28. Hubbs AF, Benkovic SA, Miller DB, et al. Vacuolar leukoencephalopathy with widespread astrogliosis in mice lacking transcription factor Nrf2. Am J Pathol 2007; 170:2068-2076.
29. O'Connor PW, Li D, Freedman MS, et al. A phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology 2006; 66:894-900.
30. Bruneau JM, Yea CM, Spinella-Jaegle S, et al. Purification of human dihydro-orotate dehydrogenase and its inhibition by A77 1726, the active metabolite of leflunomide. Biochem J 1998; 336:299-303.
31. Zeyda M, Poglitsch M, Geyeregger R, et al. Disruption of the interaction of T cells with antigen-presenting cells by the active leflunomide metabolite teriflunomide: involvement of impaired integrin activation and immunologic synapse formation. Arthritis Rheum 2005; 52:2730-2739.
32. Comi G, Pulizzi A, Rovaris M, et al. Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multi-centre, randomised, double-blind, placebo-controlled phase lib study. Lancet 2008; 371:2085-2092. The most recent clinical trial data exploring the efficacy and safety of laquinimod.
33. Zou LP, Abbas N, Volkmann I, et al. Suppression of experimental autoimmune neuritis by ABR-215062 is associated with altered Th1/Th2 balance and inhibited migration of inflammatory cells into the peripheral nerve tissue. Neuropharmacology 2002; 42:731-739.
34. Beutler E. Cladribine (2-chlorodeoxyadenosine). Lancet 1992; 340:952-956.
35. Romine JS, Sipe JC, Koziol JA, et al. A double-blind, placebo-controlled, randomized trial of cladribine in relapsing-remitting multiple sclerosis. Proc Assoc Am Physicians 1999; 111:35-44.
36. Rice GP, Filippi M, Comi G. Cladribine and progressive MS: clinical and MRI outcomes of a multicenter controlled trial. Cladribine MRI Study Group. Neurology 2000; 54:1145-1155.
37. Coles AJ, Cox A, Le Page E, et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neural 2006; 253:98-108.
38. Cox AL, Thompson SA, Jones JL, et al. Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur J Immunol 2005; 35:3332-3342.
39. Coles AJ, Compston DA, Selmaj KW, et al. Alemtuzumab vs. interferon beta-1 a in early multiple sclerosis. N Engl J Med 2008; 359:1786-1801. The recent phase II clinical trial results describing the robust efficacy and safety of alemtuzumab.
40. Bar-Or A, Calabresi PA, Arnold D, et al. Rituximab in relapsing-remitting multiple sclerosis: a 72-week, open-label, phase I trial. Ann Neurol 2008; 63:395-400. The phase I clinical trial results for rituximab that established it as a relatively well tolerated potential therapy in MS.
41. Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 2008; 358:676-688. The phase II clinical trial results that established B cells as a potential therapeutic target in MS by showing that rituximab reduced inflammatory lesions and relapses.
42. Hawker KS, O'Connor P, Freedman MS, et al. Efficacy and safety of rituximab in patients with primary progressive multiple sclerosis: results of a randomized, double-blind, placebo-controlled, multicenter trial [abstract #78]. 1st World Congress on Treatment and Research in Multiple Sclerosis; 17-20 September 2008; Montreal, Canada; 2008.
43. Dalakas MC. B cells as therapeutic targets in autoimmune neurological disorders. Nat Clin Pract Neurol 2008; 4:557-567. A superb review detailing our evolving understanding of the role of B cells in autoimmune diseases.
44. Cross AH, Stark JL, Lauber J, et al. Rituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients. J Neuroimmunol 2006; 180:63-70.
45. Salomonsson S, Jonsson MV, Skarstein K, et al. Cellular basis of ectopic germinal center formation and autoantibody production in the target organ of patients with Sjogren's syndrome. Arthritis Rheum 2003; 48:3187-3201.
46. Edwards JC, Cambridge G. B-cell targeting in rheumatoid arthritis and other autoimmune diseases. Nat Rev Immunol 2006; 6:394-403.