Laquinimod, a new oral autoimmune modulator for the treatment of relapsing-remitting multiple sclerosis

Current Opinion in Investigational Drugs

Volumn 11, Issue 5, 2010, Pages 577-585

  Tselis, Alex ^a  

^a WAYNE STATE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BETA1A INTERFERON; CLADRIBINE; CORTICOSTEROID; DEXAMETHASONE; FINGOLIMOD; GLATIRAMER; INTERFERON BETA SERINE; LAQUINIMOD; MITOXANTRONE; MYCOPHENOLIC ACID 2 MORPHOLINOETHYL ESTER; NATALIZUMAB; PLACEBO; ROQUINIMEX;

ALLERGIC ENCEPHALOMYELITIS; ARTHRALGIA; BACKACHE; BREAST CANCER; BUDD CHIARI SYNDROME; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; CROHN DISEASE; DEPRESSION; DOSE RESPONSE; DRUG ACTIVITY; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG FORMULATION; DRUG MECHANISM; DRUG MEGADOSE; DRUG METABOLISM; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG WITHDRAWAL; HEADACHE; HEART INFARCTION; HEART MUSCLE ISCHEMIA; HUMAN; IMMUNOMODULATION; INFLUENZA; LOW DRUG DOSE; LUPUS ERYTHEMATOSUS NEPHRITIS; MULTIPLE SCLEROSIS; MUSCLE TIGHTNESS; MYALGIA; NEURITIS; NEUROPROTECTION; NONHUMAN; PANCREATITIS; PATHOGENESIS; PERICARDITIS; RANDOMIZED CONTROLLED TRIAL; RECURRENT DISEASE; REVIEW; RHINOPHARYNGITIS; SYSTEMIC LUPUS ERYTHEMATOSUS; TH1 CELL; TH2 CELL; TH3 CELL; TONSILLITIS;

ANIMALS; CLINICAL TRIALS AS TOPIC; DRUG DESIGN; DRUG EVALUATION, PRECLINICAL; HUMANS; IMMUNOSUPPRESSIVE AGENTS; MOLECULAR STRUCTURE; MULTIPLE SCLEROSIS, RELAPSING-REMITTING; QUINOLONES; TREATMENT OUTCOME;

EID: 77952137971     PISSN: 14724472     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (63)

1. Design, synthesis and structure-activity relationships of 2-substituted-2-amino-1, 3-propanediols: Discovery of a novel immunosuppressant, FTY720. Adachi K, Kohara T, Nakao N, Arita M, Chiba K, Mishina T, Sasaki S, Fujita T BIOORG MED CHEM LETT 1995 25 8 853-856
2. Drug OK'd as cure for rare leukaemia. SAN DIEGO UNION TRIBUNE 1993 March 03 A1
3. US FDA cladribine approved for hairy cell leukaemia. CANCER WKLY 1993 March 15
4. Linomide reduces the rate of active lesions in relapsingremitting multiple sclerosis. Andersen O, Lycke J, Tollesson PO, Svenningsson A, Runmarker B, Linde AS, Astrom M, Gjorstrup P, Ekholm S NEUROLOGY 1996 47 4 895-900 • This paper discusses important data on clinical, immunological and MRI measures of disease activity which formed the basis for measures in further studies.
5. Suppression of experimental autoimmune neuritis by ABR-215062 is associated with altered Th1/Th2 balance and inhibited migration of inflammatory cells in to the peripheral nerve tissue. Zou LP, Abbas N, Volkmann I, Nennesmo I, Zhu J NEUROPHARMACOLOGY 2002 42 5 731-739
6. Teva and Active Biotech announce agreement for laquinimod. Active Biotech AB PRESS RELEASE 2004 June 14
7. Teva and Active Biotech announce agreement for laquinimod potential oral therapy for multiple sclerosis. Teva Pharmaceutical Industries Ltd PRESS RELEASE 2004 June 15
8. Synthesis and biological evaluation of new 1, 2-dihydro-4-hydroxy-2-oxo- 3-quinoline carboxamides for treatment of autoimmune disorders: Structure-activity relationships. Jonsson S, Andersson G, Fex T, Fristedt T, Hedlund G, Jansson K, Abramo L, Fritzson I, Pekarski O, Runstrom A, Sandin H et al J MED CHEM 2004 47 8 2075-2088
9. Laquinimod (ABR-215062) suppresses the development of experimental autoimmune encephalomyelitis, modulates the Th1/Th2 balance and induces the Th3 cytokine TGF-β in Lewis rats. Yang JS, Xu LY, Xiao BG, Hedlund G, Link H J NEUROIMMUNOL 2004 156 1-2 3-9 • This is an important paper discussing some of the potential mechanisms of action of laquinimod, demonstrating its induction of immune deviation from a Th1 to a Th2 response, suppressing the pathological T-cell response and promoting anti-inflammatory activity.
10. The new orally active immunoregulator laquinimod (ABR-215062) effectively inhibits development and relapses of experimental autoimmune encephalomyelitis. Brunmark C, Runstrom A, Ohlsson L, Sparre B, Brodin T, Astrom M, Hedlund G J IMMUNOL 2002 130 1-2 163-172 • This paper provides detailed information on the effect of laquinimod on the histopathology of murine EAE, including data on the effects of laquinimod, roquinimex and dexamethasone, demonstrating that laquinimod does not exert its effects by immunosuppression.
11. Treatment with laquinimod reduces development of active MRI lesions in relapsing MS. Polman C, Barkhof F, Sandberg-Wollheim M, Linde A, Nordle O, Nederman T NEUROLOGY 2005 64 6 987-991 •• This is an important report from one of the phase II clinical trials of laquinimod, with details of both the MRI activity and adverse events following treatment. There is a short discussion of the monitoring for inflammatory markers based on results from phase II clinical trials and preclinical data.
12. Serono: Form 20-F for the Securities and Exchange Commission. Serono SA FORM 20-F 2004 December 31
13. Oral fngolimod (FTY720) for relapsing multiple sclerosis. Kappos L, Antel J, Comi G, Montalban X, O'Connor P, Polman CH, Haas T, Korn AA, Karlsson G, Radue EW, FTY720 DSG NEW ENGL J MED 2006 355 11 1124-1140
14. Laquinimod modulates inflammation and prevents demyelination in MOG-induced EAE: A novel wet SEM technology showing potential neuroprotective effect. Bruck W, Kaye J, Fine T, Mayk A NEUROLOGY 2007 68 12 a318
15. The effect of two doses of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: A multi-center randomized, double-blind, placebocontrolled study. Comi G, Abramsky O, Arbizu T, Boiko A, Gold R, Havrdova E, Komoly S, Selmaj KW, Sharrack B, Filippi M NEUROLOGY 2007 68 12 Suppl 1 Abs 38
16. Determination of the immunomodulator laquinimod in human plasma by liquid chromatography/tandem mass spectrometry; development, validation and application of two methods in clinical pharmacokinetic profiling. Sennbro CJ, Olin M, Edman K, Hansson G, Gunnarsson PO, Svensson LD RAPID COMM MASS SPECTROMETRY 2006 20 22 3313-3318
17. Synthesis and reactivity of laquinimod, a quinoline-3-carboxamide: Intramolecular transfer of the enol proton to a nitrogen atom as a plausible mechanism of ketene formation. Jansson K, Fristedt T, Olsson A, Svensson B, Jonsson S J ORG CHEM 2006 71 4 1658-1667
18. Inhibition of the development of chronic experimental autoimmune encephalomyelitis by laquinimod (ABR-215062) in IFN-β K. O. and wild type mice. Runstrom A, Leanderson T, Ohlsson L, Axelsson B J NEUROIMMUNOL 2006 173 1-2 69-78
19. Cytochrome P450 3A4 is the major enzyme responsible for the metabolism of laquinimod, a novel immunomodulator. Tuvesson H, Hallin I, Persson R, Sparre B, Gunnarsson PO, Seidegard J DRUG METAB DISPO 2005 33 6 866-872
20. -/- and in wild type mice. Leanderson T, Runstrom A, Ohlsson L, Nederman T, Axelsson B NEUROLOGY 2004 62 7 Suppl 5 A113
21. Oral treatment with laquinimod reduces development of active MRI lesions in relapsing MS. Barkhof F, Polman CH, Sandberg-Wollheim M, Linde A, Nederman T NEUROLOGY 2004 62 7 Suppl 5 Abs 99
22. Active Biotech interim report January-June 2007. Active Biotech AB PRESS RELEASE 2007 August 09
23. Development of a practical and reliable synthesis of laquinimod. Wennerberg J, Bjork A, Fristedt T, Granquist B, Jansson K, Thuvesson I ORG PROCESS RES DEV 2007 11 4 674-680
24. 48-Week open safety study with a high-dose oral laquinimod in MS patients. Sandberg-Wollheim M, Nederman T, Linde A MULT SCLER 2005 11 Suppl 1 Abs S154
25. Pharmacokinetic evaluation in a double blind, randomised, phase II study of oral laquinimod versus placebo in patients with relapsing multiple sclerosis. Nordle O, Sparre B, Linde A, Nederman T, Gunnarsson PO MULT SCLER 2004 10 7032 Suppl 2 Abs S259
26. Active Biotech year-end report January-December 2007. Active Biotech AB PRESS RELEASE 2008 February 15
27. Effect of laquinimod on MRI-monitored disease activity in patient with relapsing-remitting multiple sclerosis: A multicentre, randomized, double-blind, placebo-controlled phase IIb study. Comi G, Pulizzi A, Rovaris M, Abramsky O, Arbizu T, Boiko A, Gold R, Havrdova E, Komoly S, Selmaj KW, Sharrack B et al LANCET 2008 371 9630 2085-2092 •• This report discusses the results of a phase II clinical trial comparing the effects of three doses of laquinimod with placebo in a closely monitored group of RRMS patients, with considerable detail both on MRI activity and potential toxicities.
28. Teva company website. Teva Pharmaceutical Industries Ltd COMPANY WORLD WIDE WEB SITE 2008 August 19
29. Oral laquinimod in patients with relapsing-remitting multiple sclerosis: 9-month double-blind active extension of the multicenter, randomized, double-blind, parallel-group placebo-controlled study. Comi G, Abramsky O, Arbizu T, Boyko A, Gold R, Havrdova E, Komoly S, Selmaj K, Sharrack B, Filippi M MULT SCLER 2008 14 Suppl 1 Abs S37
30. The effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: A double-blind active extension of the multicentre, randomised, double-blind, parallel-group placebo-controlled study. Comi G, Abramsky O, Arbizu T, Boiko A, Gold R, Havrdova E, Komoly S, Selmaj KW, Sharrack B, Filippi M J NEUROL 2008 255 Suppl 2 46
31. Laquinimod induced downregulation of MHC class II gene expression in cultured peripheral blood cells of untreated patients with multiple sclerosis. Achiron A, Or-Bach R, Barsilay S, Gurevich M NEUROLOGY 2008 70 11 A376
32. Down regulation of antigen presentation and inflammatory pathways by laquinimod in cultured peripheral blood mononuclear cells of untreated multiple sclerosis patients and healthy subjects. Or-Bach R, Sonis P, Gurevich M, Achiron A NEUROLOGY 2009 72 11 A38
33. EMD Serono submits application for cladribine tablets as a potential oral short-course multiple sclerosis therapy in the United States. EMD Serono Inc PRESS RELEASE 2009 September 30
34. Merck submits application for cladribine tablets as a potential oral short-course multiple sclerosis therapy in the United States. Merck KGaA PRESS RELEASE 2009 September 30
35. A new immunomodulator, ABR-215062, suppresses TNF-α secretion and nitric oxide production in mixed glial cell cultures. Pelidou SH, Andell-Jonsson S, Iverfeldt K MULT SCLER 2005 11 S49
36. Laquinimod reduces level of IL-17 in cultured splenocytes from treated MOG-induced experimental autoimmune encephagomyelitis and in cultured PBMCs from health human donors. Achiron A, Timan B, Kaye J, Hayardeny L NEUROLOGY 2008 70 11 A374
37. Laquinimod given before and after disease onset reduces inflammatory cell infiltration and demyelination in experimental autoimmune encephalomyelitis. Wegner C, Stadelmann C, Kaye J, Fine T, Mayk A, Raymond E, Bruck W MULT SCLER 2008 14 S276
38. Therapeutic treatment with laquinimod reduces inflammation, demyelination and axonal damage in experimental autoimmune encephalomyelitis. Wegner C, Stadelmann C, Bruck W ACTA NEUROPATHOL 2009 15 9 S246
39. The effect of laquinimod on cell VLA-4 properties under shear fow conditions. Hayardeny L, Feigelson S, Grabovsky V, Kaye J, Keshet R, Cinamon G, Alon R MULT SCLER 2009 15 9 S188
40. Reduced inflammation, demyelination, and axonal damage after therapeutic laquinimod treatment in experimental autoimmune encephalomyelitis. Wegner C, Stadelmann C, Bruck W MULT SCLER 2009 15 9 S127
41. Long-term open extension of oral laquinimod in patients with relapsing remitting multiple sclerosis shows favorable safety and sustained low relapse rate and MRI activity. Comi G, Abramsky O, Arbizu T, Boyko AN, Gold R, Havrdova E, Komoly S, Mesaros S, Selmaj K, Sharrack B, Filippi M et al MULT SCLER 2009 15 9 S127-S128
42. Laquinimod induces upregulation of neurotrophins in serum of patients with relapsing-remitting multiple sclerosis. Linker R, Thone J, Comi G, Gold R MULT SCLER 2009 15 9 S237
43. Laquinimod modulates inflammation and prevents demyelination in MOG-induced EAE: A novel wet SEM technology showing potential neuroprotective effect. Tarcic N, Raymond E, Kaye J NEUROLOGY 2009 72 11 A378-A379
44. Beneft-to-risk ratio comparison of oral laquinimod and interferon β-1a im in relapsing-remitting multiple sclerosis: Study design of the 2-year phase III BRAVO trial. Sorensen PS, Vollmer T, Arnold D, Havrdova E, Selmaj K, Zipp F, Cohen J MULT SCLER 2009 15 9 S119-S120
45. Baseline demographics of a placebo-controlled, double-blind, randomised of oral laquinimod 0.6 mg in treating relapsing-remitting multiple sclerosis: The ALLEGRO study. Comi G, Jeffery D, Kappos L, Montalban X, Boyko AN, Filippi M MULT SCLER 2009 15 S127
46. Anti-inflammatory pathways activated by laquinimod in CD4+, CD8+, CD14+, CD19+ and NK peripheral blood cells subtypes of relapsing-remitting multiple sclerosis patients. Gurevich M, Timan B, Hayardeny L, Achiron A MULT SCLER 2009 15 9 S69-S70
47. Teva Pharmaceutical Industries Ltd: Third quarter 2009 factsheet. Teva Pharmaceutical Industries Ltd COMPANY WORLD WIDE WEB SITE 2009 November 03
48. Active Biotech pipeline. Active Biotech AB COMPANY WORLD WIDE WEB SITE 2010 January 21
49. Novartis oral MS therapy FTY720 shows reduced risk of confrmed disability progression as published in New England Journal of Medicine. Novartis AG PRESS RELEASE 2010 January 21
50. Teva acquires marketing rights for oral laquinimod in the nordic and baltic regions. Teva Pharmaceutical Industries Ltd PRESS RELEASE 2010 February 08
51. Inhibition of acute, experimental autoimmune encephalomyelitis by the synthetic immunomodulator linomide. Karussis DM, Lehmann D, Slavin S, Vourkakarussis U, Mizrachikoll R, Ovadia H, Bennum A, Kalland T, Abramsky O ANN NEUROL 1993 34 5 654-660 (Pubitemid 23333236)
52. Treatment of chronic-relapsing experimental autoimmune encephalomyelitis with the synthetic immunomodulator linomide (quinoline-3-carboxamide). Karussis DM, Lehmann D, Slavin S, Vourkakarussis U, Mizrachikoll R, Ovadia H, Kalland T, Abramsky O PROC NAT ACAD SCI USA 1993 90 14 6400-6404 (Pubitemid 23207220)
53. Treatment of secondary progressive multiple sclerosis with the immunomodulator linomide: A double-blind, placebocontrolled pilot study with monthly magnetic resonance imaging evaluation. Karussis DM, Meiner Z, Lehmann D, Gomori JM, Schwarz A, Linde A, Abramsky O NEUROLOGY 1996 47 2 341-346
54. Linomide in relapsing and secondary progressive MS. Part I: Trial design and clinical results. Noseworthy JH, Wolinsky JS, Lublin FD, Whitaker JN, Linde A, Gjorstrup P, Sullivan HC, NO ALI NEUROLOGY 2000 54 9 1726-1733 • This important paper gives considerable detail on the adverse effects of roquinimex, which appear to be peculiar to this class of drug and which mandate close follow-up of patients receiving them. (Pubitemid 30428397)
55. Linomide in relapsing and secondary progressive MS. Part II: MRI results. Wolinsky JS, Narayana PA, Noseworthy JH, Lublin FD, Whitaker JN, Linde A, Gjorstrup P, Sullivan HC, Univ TH, No ALI NEUROLOGY 2000 54 9 1734-1741 • This paper discusses in detail the MRI results from the phase III roquinimex clinical trial
56. Defning the clinical course of multiple sclerosis: Results of an international survey. National Multiple Sclerosis Society (USA) advisory committee on clinical trials of new agents in multiple sclerosis. Lublin FD, Reingold SC NEUROLOGY 1996 46 4 907-911
57. Multiple sclerosis. Compston A, Coles A LANCET 2008 372 9648 1502-1517
58. Epidemiologic contributions to multiple sclerosis: An overview. Kurtzke JF NEUROLOGY 1980 30 7 Pt 2 61-79.
59. A specific viral cause of multiple sclerosis: One virus, one disease. Lipton HL, Liang Z, Hertzler S, Son KN ANN NEUROL 2007 61 6 514-523.
60. Injectable medication for the treatment of multiple sclerosis: The infuence of self-efficacy expectations and injection anxiety on adherence and ability to self-inject. Mohr DC, Boudewyn AC, Likosky W, Levine E, Goodkin DE ANN BEHAV MED 2001 23 2 125-132
61. Self-injection anxiety training: A treatment for patients unable to self-inject injectable medications. Mohr DC, Cox D, Merluzzi N MULT SCLER 2005 11 2 182-185
62. Multiple sclerosis. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG NEW ENGL J MED 2000 343 13 938-952.
63. Mortality in multiple sclerosis: A review. Ragonese P, Aridon P, Salemi G, D'Amelio M, Savettieri G EUR J NEUROL 2008 15 2 123-127