Laquinimod in Relapsing–Remitting Multiple Sclerosis
In the group treated with laquinimod 0.6mg there was a 55% decrease in the median cumulative number of Gd-enhancing lesions between weeks 24 and 36 and a 40.4% reduction in the mean cumulative number of Gd-enhancing lesions during the same period (p=0.0048). The
cumulative number of new T2 lesions decreased by 44% (p=0.0013) and the cumulative number of new T1 hypointense lesions decreased by 51% (p=0.0064). There was also a trend toward a slowing of the rate of
cerebral volume loss (p=0.07). Relapse rates were reduced by 33%, but this did not reach statistical significance because of the small sample size employed. The study was not powered to detect an effect on relapse rates. In the group treated with laquinimod 0.3mg there was no significant effect on any outcome measure.24
An extension of this trial was carried out in which the placebo group was randomized to either the 0.3 or the 0.6mg dose and followed prospectively for an additional 36 weeks.25
There were 119 patients in
the 0.3mg group and 138 in the 0.6mg group. Patient retention in the study was quite good, with more than 90% completing the study. The effects of laquinimod in the main trial were duplicated in the extension. In placebo patients switched to laquinimod, the mean number of Gd-enhancing lesions decreased by 52% (p<0.0007); this was significant for both the 0.6mg and 0.3mg doses. In the group initially randomized to 0.6mg at the start of the phase II trial, Gd-enhancing lesions continued to be suppressed, indicating that there was no loss of effect over time.25
At the end of the extension,
all patients were placed on the 0.6mg dose and continue to be followed. Two hundred and fifty-seven patients entered the extension phase, of whom 209 completed. At the last follow-up, 50% of 0.6mg laquinimod-treated, 44% of 0.3mg laquinimod-treated and 47% of placebo-treated patients were free of Gd-enhancing lesions.25
These two phase II trials suggest that laquinimod has potent anti-inflammatory effects in MS. There was a significant reduction in the
frequency of enhancing lesions, new T2 lesions, and new T1 hypointense lesions and a trend toward an effect on cerebral volume loss. In the extension, these effects were confirmed. Relapse rates were reduced by 33% and, while not significant, this magnitude of effect is similar to that achieved with IFNs and glatiramer acetate. Of note is that these effects were brought to bear in a group of patients with quite active disease. The placebo relapse rate in the second phase II trial was 0.78. This is much higher than observed in the most recent clinical trial, in which placebo relapse rates were in the range of 0.3–0.4.26
Safety and Tolerability
Laquinimod was well tolerated in both phase II trials, having few side effects and a paucity of AEs. There was no difference in the number of AEs and serious AEs (SAEs) between the placebo and the treated groups. In the initial phase II trial there was one SAE in the placebo group, one in the 0.1mg group, and four in the 0.3mg group. One patient developed iritis in the 0.3mg group. Erythrocyte sedimentation rate (ESR) was increased on at least one assessment in 6% of the placebo group, 13.2% of the 0.1mg group, and 17.6% of the 0.3mg group. C-reactive protein (CRP) was elevated on at least one assessment in 34% of the placebo group, 25% of the 0.1mg group, and 34% of the 0.3mg group. Liver function tests were elevated on at least one occasion in 34% of the placebo group, 34% of the 0.1mg group, and 47% of the 0.6mg group.
US NEUROLOGY Phase III Trials
There are two phase III trials of laquinimod in RRMS currently under way. The first is the ALLEGRO Trial. This is a randomized, double-blind, placebo-controlled trial of laquinimod in RRMS. Inclusion criteria for this trial required patients to have had at least one relapse in the year prior to study entry, two relapses in the two years preceding study entry, or one relapse between months 12 and 24 preceding study entry and one enhancing lesion in the year prior to study entry. The primary outcome measure is relapse rate reduction and the main secondary outcome measure is disability progression as measured by the expanded disability status scale (EDSS). It is a two-year study involving 1,100 MS patients. Results are expected in late 2010.28
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There were no associated elevations of bilirubin, and elevations of liver function enzymes were generally mild and transient and not considered to be clinically significant.23
Laquinimod was also well tolerated in the second phase II trial. There was a higher early termination rate due to AEs in the placebo group. There were four SAEs in the placebo group, five in the 0.3mg group, and two in the 0.6mg group. One of each was assessed as being possibly study-drug-related. In the 0.3mg group there were two early terminations due to liver function test abnormalities. In the 0.6mg group there was an early termination because of an elevated CRP in the setting of a throat infection that was felt not to be drug-related. A second patient developed fever and eosinophilia accompanied by an elevation of liver enzymes, and was diagnosed with Budd-Chiari syndrome (hepatic vein thrombosis); this patient was treated with anticoagulants and recovered fully. This patient had a factor V Leiden deficiency that may have caused a predisposition to thrombotic events. Some elevations of liver function tests were noted. Elevations of alanine transaminase (ALT) were noted, but most normalized while on therapy. There were no associated increases in bilirubin, suggesting an absence of hepatocellular injury. CRP was elevated to a greater extent in the placebo than in the laquinimod 0.6mg group (17.6 versus 13.2%). Transient elevations of fibrinogen occurred in 29.4% of the placebo group, 32.6% of the 0.3mg group, and 44.4% of the 0.6mg group. All elevations of fibrinogen were reversible. Some patients developed mild arthralgias, arthritis, and edema, but all resolved spontaneously without intervention. There were no instances of leukopenia or life-threatening infections.24
Another study evaluated the safety and tolerability of laquinimod at a dose of 0.9mg in an open-label design.27
This study enrolled 22
patients with RRMS or SPMS who were treated for 48 weeks. Three patients withdrew and two patients required a reduction in dose to 0.6mg; the 17 remaining patients completed the study. Two patients were treated at the reduced dose level of 0.6mg/day and three discontinued treatment during the course of the study. Transient elevations of liver function tests were observed but were mild and found to be reversible.
In summary, laquinimod had a good safety profile in phase II trials. The initial concerns regarding the safety of this agent centered on elevation of liver function tests and pro-inflammatory effects. There was no indication of either toxicity in the phase II trials.
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