Multiple Sclerosis
Table 2: Medications Used for Relapsing–Remitting Multiple Sclerosis Not Currently Approved
Generic Name Azathioprine Methotrexate
Cyclophosphamide
Mycophenolate mofetil IV = intravenously; PO = orally.
Route PO PO IV
PO
(SPECTRIMS) trial studied 618 patients with SPMS in a placebo- controlled fashion. Treatment was allocated at 44 and 22mcg doses. No effect on progression was observed in the treatment groups. A reduction in relapse rate was observed in both treatment groups.43
Glatiramer Acetate
GA is approved for use in relapsing forms of MS. GA is a synthetic co-polymer that resembles the amino-acid sequence of myelin basic protein (MBP).44
It is used as a daily subcutaneous 20mg dose.
Table 3: Future Prospective Medications for Relapsing–Remitting Multiple Sclerosis
Generic Name Route Mechanism of Action Adverse Effects Fingolimod PO Sphingosine 1-phosphate Herpes encephalitis,
modulator, sequesters disseminated VZV lymphocytes in
infection
secondary lymphoid organs
Cladribine PO Toxic metabolite induces Localised herpes T-cell apoptosis
infection, lymphocytopenia BG-12
PO Alters gene expression Flushing, abdominal involved in oxidative
pain
stress and immune homeostasis
Teriflunomide PO Pyrimidine synthesis inhibitor in T cells
Rituximab IV
Targets CD20, B-cell depletion
Alemtuzumab IV Targets CD52, Elevated liver enzymes,
hepatic dysfunction, infections
Infusion reactions, PML (lymphoma patients) Immune
lymphocyte suppression thrombocytopenic purpura, thyroid dysfunction
Daclizumab IV
Targets CD25, blocks IL-2 binding, T-cell regulation
Cardiac toxicity, infections
IL = interleukin; IV = intravenously; PML = progressive multifocal leukoencephalopathy; PO = orally; VZV = varicella zoster virus.
IFN-β1-a Subcutaneous The SC formulation of IFN-β1-a has been studied in RRMS, CIS and SPMS. The Prevention of Relapses and Disability by IFN-β1-a Subcutaneously in Multiple Sclerosis (PRISMS) trial studied 560 patients in a phase III double-blinded, placebo-controlled fashion. It found that patients on SC IFN-β1-a three times a week at high doses (44mcg) and low doses (22mcg) had a significantly lower relapse rate than placebo.40
Multiple mechanisms of action have been described for GA. GA competes with MBP at the MHCII molecule. It then forms a MHC/ GA complex that competes with the MBP/MHC complex at the T-cell receptor. Additionally, GA induces activation of regulatory TH-2 cells. GA is also felt to act as a ligand and induce tolerance of MBP- specific T cells.
The clinical effects of GA in RRMS have been studied in a placebo- controlled, randomised phase III trial. The trial involved 251 patients and showed that GA reduced the two-year relapse rate compared with placebo.45
The treatment was well tolerated except for the occurrence of local skin reactions and a systemic self-limited reaction present at least once in 15% of patients over the course of the study. A second placebo-controlled phase III clinical trial (239 patients) showed that patients taking GA had a significantly reduced number of gadolinium-enhancing lesions during a nine- month study period.46
The effectiveness of GA in CIS was studied in the Early Glatiramer Acetate Treatment in Delaying Conversion to Clinically Definite Multiple Sclerosis in Subjects Presenting with a Clinically Isolated Syndrome (PreCISe) trial that studied 481 patients with a single neurologic event and two or more brain MRI lesions.47
Results showed
that patients on GA had a 45% reduced risk of developing CDMS over the 36-month study period. Adverse effects were similar to those described in the RR trials above.
Mitoxantrone
Mitoxantrone is currently FDA-approved for use in worsening RRMS and SPMS. Mitoxantrone is a 517.4Da anthracenedione derivate that has been used for treatment of lymphoma, leukaemias and breast and prostate cancers.48
Mitoxantrone is
Time to first relapse was also increased in both IFN arms. MRI data from that same cohort of patients showed the medication arms to have a decreased active lesion burden compared with placebo.41
The effect of IFN-β1-a SC on CIS was studied in the Early Treatment of Multiple Sclerosis study group (ETOMS) trial.42
In total, 309 patients
were randomised to placebo or 22mcg of IFN-β1-a SC three times weekly. Results showed that time to conversion of CDMS was delayed in the treatment group, and fewer patients in the treatment group converted to CDMS over the two-year follow-up.
IFN-β1-a SC has also been studied in SPMS. The Secondary Progressive Efficacy Clinical Trial of Recombinant IFN-β1-a in MS
80
delivered by infusion at a dose of 12mg/m2 of body surface every three months. Due to dose-dependent toxicity a therapeutic ceiling is reached at 140mg/m2. Mitoxantrone is a topoisomerase II inhibitor and exerts its beneficial effects in MS by a number of different mechanisms, including inhibiting proliferation of T and B cells, enhancing suppressor T-cell functions and limiting the secretion of pro-inflammatory chemokines.49
Mitoxantrone has been studied in the more advanced stages of MS. A randomised placebo-controlled phase III trial studying 194 patients with worsening RRMS or SPMS showed a benefit of mitoxantrone in a composite clinical outcome.50
In active RRMS mitoxantrone has
been shown to reduce the number of new enhancing lesions compared with methylprednisolone.51
Adverse events are a major
and an echocardiogram or multigated acquisition (MUGA) scan is conducted before each dose in the US. This medication has also been related to cases of acute myeloid leukaemia (0.15–0.80% incidence).53
consideration when using this medication. Cardiac toxicity has been well documented52
EUROPEAN NEUROLOGICAL REVIEW
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