Laquinimod Polman, C. et al. Neurology 2005;64:987- 991 Multicenter, double-blind, randomized trial, patients with RR MS received 0.1 mg or 0.3 mg laquinimod or placebo as three daily tablets for 24 weeks Gadolinium-enhanced brain MRI scans were performed at screening, every eighth week during treatment, and 8 weeks after end of treatment The primary efficacy variable was the cumulative number of active lesions over 24 weeks
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Laquinimod
Polman, C. et al. Neurology 2005;64:987-991
Multicenter, double-blind, randomized trial, patients with RR MS received 0.1 mg or 0.3 mg laquinimod
or placebo as three daily tablets for 24 weeks
Gadolinium-enhanced brain MRI scans were performed at screening, every eighth week during treatment, and 8 weeks after end of treatment
The primary efficacy variable was the cumulative number of active lesions over 24 weeks
Polman, C. et al. Neurology 2005;64:987-991
Figure 2. Cumulative number of active lesions (mean {+/-} SE) by visit (primary endpoint)
No statistically significant differences in the primary endpoint of active scans but there
was a strong trend (37% active in placebo, 31% in 0.1 and 21% in 0.3 group).
Polman, C. et al. Neurology 2005;64:987-991
Table 3 Statistical evaluation of the reduction in the cumulative number of active lesions at week 24
Phase III ALLEGRO Trial
2 year randomized, double blind, placebo
controlled with 1106 RRMS participants – 0.6
mg qday
Primary outcome - # confirmed relapses –
showed a 26% reduction (p=0.0024)
36% decrease in risk of progression by EDSS
(p=0.0122)
33% reduction in brain atrophy (p=0.0001)
Phase III BRAVO Trial
Comparing 0.6 mg qday with placebo
Did not reach primary endpoint of reducing
ARR (p=0.075) !
However, the laquinimod and placebo groups
had dissimilar baseline MRI measures – after
reanalysis adjusted for baseline MRI there was
21.3% reduction in ARR, 33.5% reduction in
risk of progression in EDSS and 27.5%
reduction of brain volume loss (all p<0.05)
Safety
The most common side effects have been
occasional liver enzyme elevations which are
reversible
Summary
Laquinimod has modest benefit in RRMS
Nevertheless, it is well tolerated
Teriflunomide
Oral immunomodulator with anti-inflammatory activity
Inhibits pyrimidine synthesis in T cells and other
rapidly dividing cells
Results in reduced T cell proliferation, IFN-gamma, IL-
2, IgG1, and cytostatic action on B cells
Ongoing trials – TOPIC (CIS trial) and TERACLES
(teriflunomide added to interferon or placebo)
Teriflunomide
O’Connor et al. NEUROLOGY 2006;66:894-900
Phase II, randomized, double blind, placebo controlled trial in RR (157) and SP with relapses (22)
Primary end point # combined unique active MRI lesions - Treatment with either terflunomide 7 or 14 mg/day resulted in the significant suppression of 61.1% or 61.3%, respectively (p < 0.03 or p < 0.01)
Also fewer enhancing and new T2 lesions, trend in fewer relapses and less disability
Efficacy of teriflunomide on the primary outcome measure in the phase II study.
TEMSO
Trial involving 1088 patients with multiple sclerosis, 18
to 55 years of age, with a score of 0 to 5.5 on the
Expanded Disability Status Scale
Randomly assigned (in a 1:1:1 ratio) to placebo, 7 mg of
teriflunomide, or 14 mg of teriflunomide once daily for
108 weeks
The primary end point was the annualized relapse rate,
and the key secondary end point was confirmed
progression of disability for at least 12 weeks N Engl J Med. 2011 Oct 6;365(14):1293-303.
Randomized trial of oral teriflunomide for relapsing multiple sclerosis.