RRMS – Current Treatment Options and Perspectives for the Future Natalizumab
Natalizumab is the first monoclonal antibody approved for use in MS. Currently, natalizumab is FDA-approved for RRMS, but primarily for patients with continued disease activity despite disease-modifying therapy. Natalizumab is a humanised monoclonal antibody directed at α4 integrins.54
leukocyte entry into the CNS.55
Binding of natalizumab to α4β1 integrin suppresses Natalizumab is administered by
monthly intravenous infusion at a dose of 300mg.
The clinical effects of matalizumab have been studied in two large phase III controlled trials. The Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) multicentre, placebo- controlled, double-blinded trial studied 942 patients with RRMS. Natalizumab was found to decrease the relapse rate by 68% and additionally decreased sustained progression compared with placebo over the three-year study duration.56
This study also found 92% fewer gadolinium-enhancing lesions compared with placebo.
The Safety and Efficacy of Natalizumab in Combination with Interferon-β1-a (SENTINEL) trial studied 1,171 patients on IFN-β1-a who had suffered at least one relapse over the 12 months preceding trial enrollment. Patients were randomised to natalizumab or placebo in addition to IFN. The study found a relapse rate reduction and a decrease in enhancing lesions as well as a decrease in the sustained progression rate, all in favour of the natalizumab group.57
Natalizumab has been generally well tolerated; however, three cases of progressive multifocal leukoencephalopathy (PML) led to voluntary withdrawal of natalizumab for one year.58–60
Since being re-introduced
in 2006, the total number of PML cases reported with the use of natalizumab has exceeded 28, of which eight have been fatal.61
The
rate of PML is less than one per 1,000 in the first year, and rises to 1.5 per 1,000 between years two and three. Treatment for natalizumab-induced PML includes plasma exchange therapy62
and
high-dose intravenous steroids for the occurrence of the immune reconstitution inflammatory syndrome (IRIS).63
Non-US Food and Drug Administration-approved Medications in Multiple Sclerosis
Methotrexate has also been used orally for MS. Data from a Cochrane review showed a trend for improvement in RRMS; however, this was non-significant.66
Non-FDA-approved medications have been used and studied in MS historically. The majority of these are immunosuppressive or chemotherapeutic agents (see Table 2). Azathioprine is an oral immunosuppressant, and a recent Cochrane database analysis found that the medication significantly reduced the number of patients who had relapses during one year of treatment.64 Cyclophosphamide is an intravenous immunosuppressant that has been studied in aggressive MS that has not responded to IFN or copaxone.65
There are limited data for the use
of mycophenolate mophetil in MS and further clinical trials are needed to establish the efficacy of this medication.67
US Food and Drug Administration-approved Non-disease-modifying Agents
Extended-release fampridine (Dalfampridine) is a twice-daily oral medication that is FDA-approved for improving speed of walking in MS patients. A placebo-controlled phase II trial found that fampridine improved walking times in treatment responders with all types of MS.
EUROPEAN NEUROLOGICAL REVIEW
The medication was well tolerated, but it carried a significant risk of lowering the seizure threshold in a dose-dependent manner.68
Treatments Currently Under Investigation Fingolimod is a sphingosine 1-phosphate receptor modulator that sequesters T and B cells in secondary lymphoid organs.69
It was
studied in a recent double-blind parallel phase III study in which 1,153 RRMS patients were treated with fingolimod or IFN-β1-a IM.70 Fingolimod was found to reduce annualised relapse rate compared with IFN-β1-a IM. Two deaths were reported in the study group from herpes simplex virus (HSV) encephalitis and disseminated varicella zoster infection. FDA approval is currently pending (see Table 3).
Cladribine, through its active metabolite 2-chlorodeoxyadenosine triphosphate, induces apoptosis of lymphocytes.71
It has been
studied in a placebo-controlled clinical phase III trial in RRMS that studied 1,326 patients.72
The study found a decreased relapse
rate and there was a higher relapse-free rate in the cladrabine group. Significant adverse effects included lymphocytopenia and localised herpes zoster.
BG-12 (oral dimethyl-fumarate) is a fumaric acid derivative that has a complex mechanism of action involving altered gene expression crucial in oxidative stress and immune homeostasis.73
BG-12 was
studied in a randomised, placebo-controlled phase IIb trial in 257 patients with RRMS where the number of new gadolinium-enhancing lesions was the primary end-point. Subjects treated with BG-12 had a reduction in gadolinium-enhancing lesions of 69% compared with placebo. Adverse effects included abdominal pain and flushing. Phase III trials are under way.
Rituximab is a chimeric monoclonal antibody directed at CD20. It acts in MS by inducing B-cell depletion. It has been studied in a phase II clinical trial compared with placebo and showed reduced numbers of gadolinium-enhancing and new gadolinium-enhancing lesions.74
A
humanised CD20 monoclonal antibody (ocrelizumab) has been developed and is undergoing clinical trials. Teriflunomide is another oral medication that acts by inhibiting pyrimidine synthesis and has met primary end-points in RR phase II trials.75
Alemtuzumab and
daclizumab are monoclonal antibodies directed at CD52 and CD25, respectively; both have been studied in phase II trials.76,77
Conclusion
There are currently seven FDA-approved disease-modifying therapies for relapsing forms of MS. Good level I evidence exists for all these compounds. Natalizumab and novantrone are effective medications, but their use may be limited by their adverse effect profile, which includes potentially lethal conditions. Fampridine is an oral medication that improves walking speed in various types of MS and is FDA-approved for that use. Medications that appear to be close to FDA approval after large phase III trials include cladribine and fingolimod. The potential adverse effects of these medications will be weighed against their benefit and ease of use (both are oral medications).
There are currently multiple medications under phase II–III testing that may bring further options for treatment in the future. Treatment of MS in the near future will include multiple agents with diverse mechanisms of action, and clinicians will need to know how to treat and identify the adverse events that result from these agents. n
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