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Summary
Balancing efficacy versus burden of therapy is essential for the choice of disease-modifying
therapy in every MS patient. The first-line therapies, interferon–? and glatiramer
acetate, have well-established efficacy and present no major safety concerns. Certain
second-line therapies, such as natalizumab, offer potentially greater efficacy, but
are associated with an increased level of risk. Over the last year, the first two
oral treatments of relapsing–remitting multiple sclerosis, cladribine and fingolimod,
have been marketed in certain countries, although cladribine was subsequently withdrawn.
In the Phase III clinical development programme, both drugs appeared effective and
reasonably safe. However, there were cases of serious adverse events (malignancies
and fatal infections) whose relationship with treatment was unclear. Specific postmarketing
studies will be necessary to assess the risks of these new oral therapies. Indeed,
both natalizumab and mitoxantrone are known today to be associated with rare adverse
drug reactions (progressive multifocal leukoencephalopathy for natalizumab and treatment-related
leukaemia for mitoxantrone), which were not identified before the treatments were
approved. The use of therapies carrying potential serious risks is justified in patients
who cannot be treated effectively with safe first-line therapies, but probably not
in the average relapsing–remitting multiple sclerosis or clinical isolated syndrome
patient. Pivotal Phase III clinical trials, on which basis drug approval is generally
granted, are designed to demonstrate clinical efficacy and reveal frequently occurring
adverse effects of a new drug. However, post-approval trials with extensive patient
exposure are needed to generate knowledge of more patient-specific clinical effectiveness
and long-term safety, in particular with respect to rare adverse reactions. Other
post-approval measures, such as risk management programmes, pharmacovigilance studies,
or phased launch of the drug, may be useful to ensure that risks associated with new
treatments are identified and minimised. The final evaluation of the benefits to risks
balance of a drug should be made in every patient by weighing benefits in disease
activity and progression, quality of life and health economy against both commonly
occurring mild side-effects and rare potentially life-threatening adverse drug effects.
This decision should be shared between the physician and patient, who may not share
the same perceptions of acceptable risk.
Keywords
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References
- Interferon-beta: mechanism of action and dosing issues.Neurology. 2007; 68: S8-11
- Mechanisms of action of glatiramer acetate in multiple sclerosis.Neurology. 2001; 56: 702-708
- Glatiramer acetate: mechanisms of action in multiple sclerosis.Int Rev Neurobiol. 2007; 79: 537-570
- Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG).Ann Neurol. 1996; 39: 285-294
- Copolymer 1 reduces relapse rate and improves disability in relapsing–remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group.Neurology. 1995; 45: 1268-1276
- Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis.Lancet. 1998; 352: 1498-1504
- Interferon beta-1b is effective in relapsing–remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group.Neurology. 1993; 43: 655-661
- Efficacy of treatment of MS with IFNb-1b or glatiramer acetate by monthly brain MRI in the BECOME study.Neurology. 2009; 72: 1976-1983
- Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial.Lancet Neurol. 2008; 7: 903-914
- 250mug or 500mug interferon beta-1b versus 20mg glatiramer acetate in relapsing–remitting multiple sclerosis: a prospective, randomised, multicentre study.Lancet Neurol. 2009; 8: 889-897
- NORdic trial of oral Methylprednisolone as add-on therapy to Interferon beta-1a for treatment of relapsing–remitting Multiple Sclerosis (NORMIMS study): a randomised, placebo-controlled trial.Lancet Neurol. 2009; 8: 519-529
- A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis.N Engl J Med. 2006; 354: 899-910
- Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial.Lancet. 2002; 360: 2018-2025
- Natalizumab plus interferon beta-1a for relapsing multiple sclerosis.N Engl J Med. 2006; 354: 911-923
- Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis.N Engl J Med. 2005; 353: 369-374
- Progressive multifocal leukoencephalopathy in a patient treated with natalizumab.N Engl J Med. 2005; 353: 375-381
- New cases of progressive multifocal leukoencephalopathy after treatment with natalizumab.Lancet Neurol. 2009; 8: 28-31
- Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring.Lancet Neurol. 2011; 10: 745-758
- Safety profile of Tysabri: international risk management plan.Neurol Sci. 2009; 30: S159-S162
- Mitoxantrone treatment of multiple sclerosis: safety considerations.Neurology. 2005; 65: 1997
- Mitoxantrone: benefits and risks in multiple sclerosis patients.Neurol Sci. 2009; 30: S167-S170
- Evidence Report: The efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.Neurology. 2010; 74: 1463-1470
- A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis.N Engl J Med. 2010; 362: 387-401
- Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis.N Engl J Med. 2010; 362: 402-415
- A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis.N Engl J Med. 2010; 362: 416-426
- Predicting responders to therapies for multiple sclerosis.Nat Rev Neurol. 2009; 5: 553-560
- Breakthrough disease during interferon-b therapy in MS: No signs of impaired biologic response.Neurology. 2010; 74: 1455-1462
- Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination.Ann Neurol. 2000; 47: 707-717
- The immunopathology of multiple sclerosis: an overview.Brain Pathol. 2007; 17: 210-218
- Interferon beta-1b in secondary progressive MS: results from a 3-year controlled study.Neurology. 2004; 63: 1788-1795
- Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis.Lancet. 1998; 352: 1491-1497
- Benefit of interferon beta-1a on MSFC progression in secondary progressive MS.Neurology. 2002; 59: 679-687
- Multicentre, randomised, double blind, placebo controlled, phase III study of weekly, low dose, subcutaneous interferon beta-1a in secondary progressive multiple sclerosis.J Neurol Neurosurg Psychiatry. 2004; 75: 706-710
- Clinical importance of neutralising antibodies against interferon beta in patients with relapsing–remitting multiple sclerosis.Lancet. 2003; 362: 1184-1191
- Neutralizing antibodies during treatment of multiple sclerosis with interferon beta-1b: experience during the first three years.Neurology. 1996; 47: 889-894
- PRISMS-4: Long-term efficacy of interferon-beta-1a in relapsing MS.Neurology. 2001; 56: 1628-1636
- Neutralizing antibodies and efficacy of interferon beta-1a: a 4-year controlled study.Neurology. 2005; 65: 40-47
- Predictors of long-term clinical response to interferon beta therapy in relapsing multiple sclerosis.J Neurol. 2006; 253: 287-293
- Measures in the first year of therapy predict the response to interferon beta in MS.Mult Scler. 2009; 15: 848-853
- Rationale for early intervention with immunomodulatory treatments.J Neurol. 2008; 255: 37-43
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© 2011 Elsevier B.V. Published by Elsevier Inc. All rights reserved.
