Treatment of Multiple Sclerosis

Poynard, T., V. Leroy, M. Cohard, et al., Meta-analysis of interferon randomized trials in the treatment of viral hepatitis C effects of dose and duration. Hepatology, 1996. 24 778. 

McHutchison, J.G., S. Gordon, E.R. Schiff, et al.. Interferon alfa-2b montherapy versus interferon alfa-2b plus ribavirin as initial treatment for chronic hepatitis C results of a US. multicenter randomized controlled study. New Engl J Med, 1998. 339 1485-92. 

Poynard, T., P. MarceUin, S. Lee, et al., Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha-2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet, 1998.352 1426-32. 

Schalm, S.W., O. Welland, B.E. Hansen, et al.. Interferon-ribavirin for chronic hepatitis C with and without cirrhosis analysis of individual patient data of six controlled studies. Gastroenterology, 1999.117 408-13. 

Zeuzem, S., S.V.Eernman, J. Rasenack, et al., Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med, 2000. 343 1666-72. 

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This experimental drug is a derivative of myriocin. After phosphorylation FTY720 modulates chemotactic responses and lymphocyte trafficking, leading to reversible lymphocyte sequestration in secondary lymphoid tissues. It is in clinical trials for the treatment of multiple sclerosis. 

PRS-211,096 (8.8) is a CB2-selective agonist, thus avoiding the psychotropic side effects related to CBl. It is currently in clinical trial for the treatment of multiple sclerosis. 

Cohen BA, Mikol DD. Mitroxantrone treatment of multiple sclerosis safety considerations. Neurology 2004 63 S28-S32. 

Hartung HP, Munschauer F, Schellekens H. Significance of neutralizing antibodies to interferon beta during treatment of multiple sclerosis expert opinions based on the Proceedings of an International Consensus Conference. Eur J Neurol 2005 12 588-601. 

Martyn CN, Illis LS and Thom J (1995). Nabilone in the treatment of multiple sclerosis. 

Avonex (Biogen) Interferon-P (IFN-P treatment of multiple sclerosis) 1.2... 

Leger, O. J. et al., Humanization of a mouse antibody against human a-4 integrin A potential therapeutic for the treatment of multiple sclerosis, Hum. Antibodies, 8, 3, 1997. 

Smith PF. (2007) Symptomatic treatment of multiple sclerosis using cannabinoids Recent advances. Expert Rev Neurother 7 1157-1163. 

Poser CM, Brinar VV. The symptomatic treatment of multiple sclerosis. Clin Neurol Neurosurg 2002 104(3) 231-5. 

Interferon 3-la (Avonex) and interferon 3-lb (Betaseron) are used in the treatment of multiple sclerosis. Interferon y-lb (Actimmune) is used to prevent and diminish the severity of infections associated with chronic granulomatous disease and for delaying the progression of severe, malignant osteopetrosis. 

This protein tends to be somewhat unstable for routine clinical use. Accordingly, a 165-amino acid, stable, recombinant analog of IFN-P-lb (in which a serine replaces cysteine at position 17) is used. The IFN-P proteins have a molecular weight of 18,500 Da. Various IFN-P proteins have been studied for the treatment of multiple sclerosis. 

Recent development highlighted a shift in FDA position and interpretation of the market exclusivity clause. Under the orphan designation, three interferon products, Betaseron (IFN-pib), Avonex (IFN-pia) and Rebif (IFN-pia) are currently approved for treatment of multiple sclerosis (MS). The interplay in drug safety and efficacy consideration, business strategies, and regulatory rationale permitting approval of the three drugs for MS treatment is discussed in Box 3.5. 

A recombinant IFN-P, IFN-pia (Rebif Serono and Avonex Biogen) is produced for commercial use in Chinese hamster ovary (CHO) cells. A synthetic mutant produced in bacteria has a substitution of serine for cysteine at amino acid 17, yielding IFN-pib Betaseron Berlex). Both IFN-pia and IFN-pib are approved by the FDA for treatment of multiple sclerosis (MS) and have shown comparable biological activity (see Section 7.3). In vivo IFN-a2 and IFN-alb show comparable biological activity as well as similar side effects [54,55]. However, IFN-P is eliminated faster, resulting in no detectable serum peak levels [56]. The clinical consequence of this is not known. Objective responses, whether partial or complete tumor regression, have been documented in patients with carcinoma of the breast, hairy-cell leukemia, and non-small-cell lung cancer [57,58]. 

Interferon beta-Ib in the treatment of multiple sclerosis final outcome of the randomized controlled trial. The IFNB Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. Neurology, 1995.45(7) 1277-85. 

F. Place in therapy Avonex has shown significant advantages over interferon beta-lb (Betaseron) in the treatment of multiple sclerosis. It is administered once a week rather than every other day, and it is not associated with the high incidence of injection site skin necrosis reported with interferon beta-lb in some studies. It appears (based on indirect comparison) at... 

Goodin DS. Treatment of multiple sclerosis with human beta interferon. Int MS J. 2005 12 96-108. 

Many recombinant proteins that are not antibodies are also on the market for distinct applications (see Chapter 16). Examples are factor VIII for hemophilia A treatment (Bayer, 1993, produced from BHK cells), erythropoietin as an anti-anemic agent (Amgen, 1989, produced from CHO cells) and /1-interferon for the treatment of multiple sclerosis (Biogen and Serono, 1996, produced from CHO cells). 

IFN 3 is produced in vivo normally by fibroblasts. In humans, only one IFN 3 is found, which has 166 amino acids and a molar mass larger than 20 kDa. The molecule has a disulfide bond as well as an N-linked carbohydrate chain bound to asparagine 80. Structurally, it is characterized by the presence of five a-helices. Recombinant IFN 3 is marketed under the names of Betaferon , Betaseron , Avonex , and Rebif , being indicated for the treatment of multiple sclerosis, since it blocks the secretion of other cytokines involved in the pathogenesis of this disease. 

The glycoprotein interferon-p-la (IFN-p-la), an essential biotherapeutic for the treatment of multiple sclerosis, was synthesized by Kajihara and coworkers (Scheme 11.17) [88], IFN-p-la consists of 166 amino acids and has one N-glycosylation site. IFN-p-la... 

Natalizumab (Tysabri), an anti-a4 integrin monoclonal antibody approved for the treatment of multiple sclerosis, was recently withdrawn from the market temporarily due to cases of progressive multifocal leukoencephalopathy, a demyelinating disease of the central nervous system associated with immunosuppression [32], These cases highlight our incomplete understanding of the immune system and the translation of preclinical results to humans. 

Malucchi S, Sala A, Gilli F, Bottero R, Di Sapio A, Capobianco M, Bertolotto A. Neutralizing antibodies reduce the efficacy of beta IFN during treatment of multiple sclerosis. Neurology 2004 62 2031-7. 

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