Pirfenidone for chronic progressive multiple sclerosis

Abstract

Current treatment of secondary progressive multiple sclerosis is unsatisfactory in stabilizing or reversing the disabilities associated with the disease. Pirfenidone is a new non-peptide drug which has been shown in vitro and in vivo to decrease synthesis of Tumor Necrosis Factor-alpha (TNF-a) and block receptors for TNF-a. Since TNF-a seems to be a key cytokine in demyelination, a pilot study of oral pirfenidone was undertaken in an open-label baseline vs treatment protocol over a 2-year period in 20 patients. Fourteen (14/20) patients (70%) remained in the study for 2 years. Three (3/20) patients dropped out early because of gastrointestinal adverse reactions, and another three patients dropped out for personal reasons after 1 year (not because of adverse reactions). The remaining patients did not manifest any other drug-related adverse reactions and complications. Improvement or stabilization occurred in most patients at about 3 months, and it was sustained at 6, 12 and 24 months as evaluated by both primary and secondary outcome measures. Magnetic resonance imaging failed to reveal any new lesions. Thus, pirfenidone appears to offer protection against the usual slow progression of the disease. Most patients experienced a distinct decrease in their neurological disability. These findings indicate that an extensive multi-center double blind and placebo controlled trial is warranted.

Keywords

secondary progressive multiple sclerosis pirfenidone (oral)tumor necrosis factor-alpha disease stabilization disability reduction clinical trials

Get full access to this article

View all access options for this article.

References

Bashir K , Whitaker JN. (1999) Clinical and laboratory features of primary progressive and secondary progressive MS . Neurology 53: 765-771 .

Merrill JE , Benveniste EN. (1996) Cytokines in inflammatory brain lesions; helpful and harmful . Trends Neurosci 19: 331-338 .

Dosten BW et al. (1998) Increased production of tumor necrosis factor alpha, and not interferon-gamma, preceding disease activity in patients with multiple sclerosis . Arch Neurol 55: 793-798 .

Rieckmann P et al. (1994) Cytokine mRNA levels in mononuclear blood cells from patients with multiple sclerosis . Neurology 44: 1523-1526 .

Gayo A et al. (1999) Interferon beta-1b treatment modulates TNF-alpha and IFN-gamma spontaneous gene expression in MS . Neurology 52: 1764-1770 .

Sharief MK , Hentges R. (1991) Association between tumor necrosis factor alpha and disease progression in patients with multiple sclerosis . NE J Med 325: 467-472 .

Chofflon M et al. (1992) Tumor necrosis factor-a production as a possible predictor of relapse in patients with multiple sclerosis . Eur Cytokine Netw 3: 523-531 .

Bitsch A et al. (2000) Tumour necrosis factor alpha mRNA expression in early multiple sclerosis lesions GLIA 29: 366-375 .

Munoz-Fernandez MA et al. (1998) The role of tumour necrosis factor, interleukin 6, interferon-gamma and inducible nitric oxide synthase in the development and pathology of the nervous system . Progress in Neurobiology 56: 309-317 .

10.

Akassoglous K et al. (1999) Transgenic Models of TNF Induced Demyelination . Advances in Exper Med Biol 468: 245-259 .

11.

Prineas JN , Grinell F. (1979) Remyelination in multiple sclerosis . Ann Neurol 5: 22-27 .

12.

Cain WC et al. (1998) Inhibition of tumor necrosis factor and subsequent endotoxin shock by pirfenidone . Intern J Immunopharm 20: 685-695 .

13.

Lefkowitz SS et al. (1997) Pirfenidone inhibits tumor necrosis factor-alpha and subsequent endotoxin shock . The Immunologist (Sup1): 61-61 .

14.

Giri SN et al. (May1998) Pharmacokineticsofanovel antifibrotic drug, pirfenidone in mouse following intravenous administration. Submitted to Amer . Lung Association/Amer. Thoracic Society International Conference.

15.

Walker JE. (October 18, 1998) Oral pirfenidone in severe chronic Progressive multiple sclerosis , presented at ACTRIMS, Montreal).

16.

Poser CN et al. (1983) New diagnostic criteria for multiple sclerosis: guidelines for research protocols . Ann Neurol 13: 227-231 .

17.

Sipe JC et al. (1995) A neurologic rating scale (NRS) for use in multiple sclerosis . Neurology 345: 251-255 .

18.

Kurzke JF. (1983) Rating neurologic disability in multiple necrosis: an expanded disability status scale (EDSS) . Neurology 33: 1444-1452 .

19.

Hauser SL et al. (1983) Intensive immunosuppression in progressive multiple sclerosis: a randomized, three-arm study of high dose intravenous cyclophosphamide, plasma exchange, and ACTH . NE J Med 308: 173-182 .

20.

Goodkin DE et al. (1988) Upper extremity function in multiple sclerosis; improving assessment sensitivity; box and block and nine-hole peg tests . Arch Phys Med Rehabil 69: 850-854 .

21.

Goldstein A. (1964) An introductory text. Macmillan . Biostatistics, New York . 272-272 pp.

22.

Mainland D. (1954) Statistical methods . Canadian J Res 26: Sec. E, 104-165 .

23.

The Multiple Sclerosis Study Group . (1990) Efficacy and toxicity of cyclosporine in chronic progressive multiple sclerosis: a randomized, double-blind, placebo-controlled clinical trial . Ann Neurol 27: 5091-5605 .

24.

Myers LW et al. (1998) Pentoxyfylline is not a promising treatment for multiple sclerosis in progression phase . Neurology 51: 1483-1486 .

25.

Kapros L et al. (1998) Placebo-controlled multi-center randomized trial of interferon-beta-1b in treatment of secondary progressive multiple sclerosis . The Lancet 352: 1491-1497 .

26.

Weinschenker DM et al. (1997) Clinical outcome measures and rating scales in multiple sclerosis trials . Mayo Clin Proc 72: 170-1079 .

27.

Beutler B , Bazzoni F. (1998) TNF, apoptosis and autoimmunity: A common thread? Blood Cells Molecules and Diseases 24: 216-230 .

28.

Makhatadze NJ. (1998) Tumor necrosis factor locus: genetic organization and biological implications . Human Immunol 59: 571-579 .

29.

Erickson BJ , Noseworthy JH. (1997) Value of magnetic resonance imaging in assessing efficacy in clinical trials of multiple sclerosis therapies . Mayo Clin Proc 72: 1080-1089 .

30.

Kappos L et al. (1999) Predictive value of gadolinium-enhanced magnetic resonance imaging for relapse rate and changes in disability or impairment in multiple sclerosis; a meta-analysis . The Lancet 353: 964-969 .

31.

Arnason BGW et al. (1999) TNF neutralization in MS; results of a randomized, placebo-controlled multi-center study . Neurology 53: 457-465 .