Treatment of secondary progressive multiple sclerosis with the immunomodulator linomide
A double-blind, placebo-controlled pilot study with monthly magnetic resonance imaging evaluation
Abstract
Linomide (quinoline-3-carboxamide) is a synthetic immunomodulator that increases the natural killer cell activity. We previously demonstrated that linomide effectively inhibited the clinical and histopathologic signs of acute and chronic relapsing experimental autoimmune encephalomyelitis. We report a double-blind, placebo-controlled study to evaluate tolerability and to obtain preliminary indications of the clinical efficacy of linomide on secondary progressive MS. Thirty patients suffering from clinically definite and laboratory-supported secondary progressive MS, with an expanded disability status scale (EDSS) of 3.0 to 7.0, were included in this study. Patients were treated daily with linomide (2.5 mg) or placebo orally and were followed up for side effects and changes in their neurologic status; monthly MRI scans were taken throughout the treatment period. Twenty-four patients completed at least 6 months of treatment. Mild to moderate side effects, including muscle pains, arthralgia, and edema, were present in 11 of the 15 patients receiving placebo and in 13 of the 15 patients treated with linomide. At 24 weeks, the mean shift in EDSS was +0.272 +/- 0.156 in the placebo group versus -0.166 +/- 0.167 in the linomide group (p = 0.0451). The percentage of patients with evidence of ``activity'' on their MRI (new, enlarging, or new gadolinium diethylenetriaminepentaacetic acid [Gd-DTPA]-enhancing lesions) throughout the treatment period was 75% in the placebo group and 33% in the linomide group (p = 0.0205). The mean total number of new Gd-DTPA-enhancing lesions per MRI scan for the same period was 0.42 +/- 0.143 in the placebo group and 0.19 +/- 0.114 in the linomide group (p = 0.0387). In this study, linomide proved to be safe and well tolerated in patients with secondary progressive MS. In addition, our results indicate that linomide tends to inhibit the progression of the disease, especially preventing the appearance of new active lesions in the MRI scans. Based on these results, two multicenter phase III trials are currently under way in the United States and in Europe and Australia.
NEUROLOGY 1996;47: 341-346
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REFERENCES
1.
Ransohoff RM. Pathogenesis of multiple sclerosis: relationship to therapeutic strategies. In: Rudick RA, Goodkin DE, eds. Treatment of multiple sclerosis: trial design, results, and future perspectives. London: Springer-Verlag, 1992:123-133.
2.
Hafler DA, Weiner HL. MS: a CNS and systemic autoimmune disease. Immunol Today 1989;10:104-107.
3.
The Multiple Sclerosis Study Group. Efficacy and toxicity of cyclosporine in chronic progressive multiple sclerosis: a randomized, double-blinded, placebo-controlled clinical trial. Ann Neurol 1990;27:591-605.
4.
Weiner HL, Hafler DA. Immunotherapy of multiple sclerosis. Ann Neurol 1988;23:211-222.
5.
Merrill J, Jondal M, Seeley J, Ullberg M, Siden A. Decreased NK killing in patients with MS: an analysis on the level of the single effector cell in peripheral blood and cerebrospinal fluid in relation to the activity of the disease. Clin Exp Immunol 1982;47:419-430.
6.
Neighbour PA, Miller AE, Bloom BR. Interferon responses of leucocytes in multiple sclerosis. Neurology 1981;31:561-566.
7.
Noronha A, Toscas A, Jensen MA. Interferon beta augments suppressor cell function in multiple sclerosis. Ann Neurol 1990;27:207-210.
8.
Sharief MK, Hentges R. Association between tumor necrosis factor-alpha and disease progression in patients with multiple sclerosis. N Engl J Med 1991;325:467-472.
9.
Achiron A, Pras E, Gilad R, et al. Open controlled therapeutic trial of intravenous immune globulin in relapsing-remitting multiple sclerosis. Arch Neurol 1992;49:1233-1236.
10.
Bornstein MB, Miller A, Slage S, et al. A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis. N Engl J Med 1987;317:408-414.
11.
The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993;43:655-661.
12.
Weiner HL. Double-blind pilot trial of oral tolerization with myelin antigens in multiple sclerosis. Science 1993;26:1321-1324.
13.
Bengtsson M, Simonsson B, Carlsson K, et al. Stimulation of NK cell, T cell, and monocyte functions by the novel immunomodulator linomide after autologous bone marrow transplantation. A pilot study in patients with acute myeloid leukemia. Transplantation 1992;53:882-888.
14.
Kalland T. Regulation of natural killer progenitors. Studies with a novel immunomodulator with distinct effects at the precursor level. J Immunol 1990;144:4472-4476.
15.
Kalland T, Alm G, Stalhandske T. Augmentation of mouse natural killer activity by LS-2616, a new immunomodulator. J Immunol 1985;134:3956-3961.
16.
Stalhandske T, Kalland T. Effects of the novel immunomodulator LS 2616 on the delayed-type hypersensitivity reaction to Bordetella pertussis in the rat. Immunopharmacology 1986;11:87-92.
17.
Harning R, Szalay J. A treatment for metastasis of murine ocular melanoma. Invest Ophthalmol Vis Sci 1988;29:1505-1510.
18.
Kalland T. Effects of immunomodulator LS 2616 on growth and metastasis of the murine B16-F10 melanoma. Cancer Res 1986;46:3018-3022.
19.
Larsson EL, Joki A, Stalhandske T. Mechanism of action of the new immunomodulator LS-2616 on T-cell responses. Int J Immunopharmacol 1987;9:425-431.
20.
Gross DJ, Sidi H, Kalland T, Rosenmann E, Weiss L, Slavin S. Prevention of diabetes in non-obese diabetic mice by linomide, a novel immunomodulating drug. Diabetologia 1994;37:1195-1201.
21.
Spetz-Hagberg AL, Larsson-Sciard EL. Decreased levels of pathogenic IgG anti-DNA antibodies in autoimmune mice after linomide treatment. Res Immunol 1989;140:517-525.
22.
Spetz-Hagberg AL, Goldschmidt TJ, Stalhandske T, Larsson-Sciard EL. Amelioration of intrathymic T cell development and peripheral T cell reactivities in autoimmune mice under-going therapy with a novel immunomodulator. Int Immunol 1990;2:645-650.
23.
Tarkowski A, Gunnarsson K, Nilsson LA, Lindholm L, Stalhandske T. Successful treatment of autoimmunity in MRL/J mice with LS-2616, a new immunomodulator. Arthritis Rheum 1986;29:1405-1409.
24.
Tarkowski A, Gunnarsson K, Stalhandske T. Effects of LS-2616 administration upon the autoimmune disease of (NZBXNZW)F1 hybrid mice. Immunology 1986;59:589-594.
25.
Ilback NG, Fohlan J, Slorach S, Friman G. Effects of the immunomodulator LS 2616 on lymphocyte subpopulations in murine Coxsackie virus B3 myocarditis. J Immunol 1989;142:3225-3228.
26.
Karussis DM, Lehmann D, Slavin S, et al. Treatment of chronic-relapsing experimental autoimmune encephalomyelitis by the synthetic immunomodulator linomide (quinoline-3-carboxamide). Proc Natl Acad Sci USA 1993;90:6400-6404.
27.
Karussis DM, Lehmann D, Vourka-Karussis U, et al. Inhibition of acute-EAE with linomide (LS-2616), an activator of natural killer cells. Ann Neurol 1993;34:654-660.
28.
Nauta JJP, Thompson AJ, Barkhof F, Miller DH. Magnetic resonance imaging in monitoring the treatment of multiple sclerosis: statistical analysis power of parallel-groups and crossover designs. J Neurol Sci 1994;122:6-14.
29.
Smith ME, Stone LA, Albert PA, et al. Clinical worsening in multiple sclerosis is associated with increased frequency and area of gadopentate dimeglumine-enhancing magnetic resonance imaging lesions. Ann Neurol 1993;33:480-489.
30.
Frank JA, Stone LA, Smith ME, Albert PS, Maloni H, McFarland HF. Serial contrast-enhanced magnetic resonance imaging in patients with early relapsing-remitting multiple sclerosis: implications for treatment trials. Ann Neurol 1994;36:S86-S90.
31.
Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227-231.
32.
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33:1444-1452.
33.
Morimoto C, Letvin NL, Aldrich WR, Schlossman SF. The isolation and characterization of the human suppressor inducer T cell subset. J Immunol 1985;134:1508-1515.
34.
Morimoto C, Hafler DA, Weiner HL, et al. Selective loss of the suppressor-inducer T-cell subset in progressive multiple sclerosis. N Engl J Med 1987;316:67-72.
35.
Khoury SJ, Guttmann C, Ahn S, et al. Correlation between MRI and immunologic studies in MS patients. Neurology 1993;43(suppl): A182.
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Neurology®
Volume 47 • Number 2 • August 1996
Pages: 341-346
Copyright
Copyright 1996 by Advanstar Communications Inc.
Publication History
Published online: August 1, 1996
Published in print: August 1996
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