RRMS – Current Treatment Options and Perspectives for the Future
Table 1: US Food and Drug Administration-approved Therapies in Multiple Sclerosis Dosage
Route
Interferon-beta-1b Interferon-beta-1a Interferon-beta-1a
Glatiramer acetate Natalizumab Mitoxantrone
250mcg every other day 30mcg weekly
22 or 44mcg 3 times per week 20mg daily
300mg every 4 weeks 12mg/m2 every 3 months
SC IM SC
SC
IV infusion IV infusion
RRMS Yes Yes Yes
Yes Yes
Yes (worsening)
Approved Uses
CIS Yes Yes Yes
Yes No No
SPMS with Relapses Yes No No
No No
Yes
CIS = clinically isolated syndrome; IM = intramuscular; IV = intravenous; RRMS = relapsing–remitting multiple sclerosis; SC = subcutaneous; SPMS = secondary progressive multiple sclerosis.
induce animal models of demyelination and hence IFN-β was studied due to its antagonistic effects on IFN-γ. It was in 1993 that the first results of a large randomised trial of IFN-β1-b were published, leading to FDA approval of medications for treatment of MS. This was followed by phase II and phase III trials studying IFN-β1-a and glatiramer acetate (GA), which subsequently led to FDA approval of these medications. A second brand of IFN-β1-b was recently approved for the US market without additional testing. A single chemotherapeutic agent, mitoxantrone, has been approved for use in worsening relapsing–remitting multiple sclerosis (RRMS) and secondary progressive MS (SPMS). Natalizumab was the first monoclonal antibody used to treat RRMS and was approved in 2004. No known therapy has proved effective for primary progressive MS (PPMS) despite multiple negative trials.
IFN-β1-b IFN-β1-b is FDA-approved to treat RRMS, CIS and relapsing SPMS. IFN-β1-b is composed of 165 amino acids arranged in five paired alpha helices and is produced in Escherichia coli with a molecular weight of 18.5kDa.24,25
The medication is administered subcutaneously
at a dose of 250mcg 8 million units [MUI]) every other day. The medication is available in two different commercial forms. IFN-β1-b binds to receptors on the cell surface and induces transcription and signal activation within the cell.26
The exact mechanism of action of
IFN-β1-b is not fully understood; however, it is felt to exert its effects by inhibiting T-cell activation,27
inducing T-cell apoptosis28 decreasing the permeability of the blood–brain barrier.29
IFN-β1-b has been studied in phase III clinical trials in RRMS, SPMS and CIS. The efficacy of the medication in RRMS was demonstrated in the pivotal 1993 trial.30
This trial was double-blinded and placebo-
IFN-β1-b was well tolerated in most patients. Adverse effects leading to study drop-out included liver enzyme abnormalities, injection-site pain, fatigue, cardiac arrhythmia, allergic reaction, nausea, headache and flu-like syndrome. Five-year follow-up data showed that the effects on relapse and MRI data were sustained.32 Depression and suicide were identified as adverse effects during years three and four of the trial.
controlled and studied a total of 372 subjects. Placebo was compared with two different IFN-β1-b doses. Primary end-points for the trial included exacerbation rates and proportion of exacerbation-free patients. The results demonstrated that patients on both doses of study medication had a significantly lower exacerbation rate compared with controls. The higher-dose group (8MIU) was more effective at reducing the exacerbation rate than the low-dose group (1.6MIU). MRI data from these patients also demonstrated a decrease in active scans and number of new lesions that was statistically significant.31
EUROPEAN NEUROLOGICAL REVIEW and
The BEtaferon© in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT) trial studied the efficacy of IFN-β1-b in CIS.33
The
trial was a double-blind, placebo-controlled phase III study that examined a total of 468 patients who had a single clinical event and at least two silent brain MRI lesions. The results showed that IFN-β1-b delayed the conversion from CIS to RRMS compared with placebo. Follow-up data at three years showed that patients with early treatment had less confirmed Expanded Disability Status Scale (EDSS) progression during the study time.34
The effect of IFN-β1-b in SPMS has been studied in two large phase III trials in Europe and North America. The North American trial studied 939 subjects and did not meet its primary end-point (time to EDSS progression). However, there were fewer relapses and MRI burden was lower in the treatment groups. The European trial met its primary end-point of time to confirmed progression of disability.35 This study additionally found that IFN-β1-b delayed progression from a time of nine to 12 months over the two- to three-year study period. Adverse effects were similar to those described above for both these trials. These populations differed in that patients were younger and had more relapses in the European group.
IFN-β1-a IFN-β1-a is approved for use in RRMS and CIS. IFN-β1-a is identical to human IFN and is produced in mammalian (hamster) cells. It has a molecular weight of 25.5kDa. IFN-β1-a is available in two forms. The subcutaneous (SC) form is used at a dose of 22 or 44mcg three times weekly and is approved for use in relapsing SPMS. The intramuscular (IM) form is administered at a dose of 30mcg once weekly. The mechanism of action of IFN-β1-a is similar to that of IFN-β1-b, as described above.36
IFN-β1-a Intramuscular The IM formulation of IFN-β1-a was studied in RRMS in a placebo- controlled phase III trial involving a total of 301 patients. The treatment group had decreased time to sustained EDSS progression, fewer relapses and a lower number and volume of gadolinium- enhancing lesions.37
The annual relapse rate was reduced by
approximately one-third. No major adverse effects were reported in the study. IM IFN-β1-a was the first agent studied in CIS. The controlled high-risk subjects Avonex© multiple sclerosis prevention study (CHAMPS) trial was a placebo-controlled phase III trial that included 383 patients with a single clinical and exam-documented event and at least two MRI lesions.38
The results showed that patients
on IM IFN-β1-a had a lower cumulative probability of developing clinically definite MS (CDMS) compared with placebo. IFN-β1-a has not shown efficacy in slowing progression of SPMS.39
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