Friday, June 20, 2008
By Charles Bankhead, Staff Writer, MedPage Today
Published: June 19, 2008
MILAN, Italy, June 19 -- A new type of immumodulatory agent for relapsing-remitting multiple sclerosis led to a 40% reduction in lesions, according to results of a multicenter, placebo-controlled phase IIb trial.
Patients treated with laquinimod at a dose of 0.6 mg a day averaged 2.6 gadolinium-enhancing lesions on MRI compared with 4.2 for the placebo group (P=0.0048), Giancarlo Comi, M.D., of the University Vita-Salute here, and colleagues reported in the June 21 issue of The Lancet.
The between-group difference emerged early in the trial, and follow-up beyond the primary study period demonstrated even larger reductions in MRI-detected lesions with laquinimod versus placebo.
Additionally, the number of new lesions was reduced by 50% in the laquinimod group.
"The decrease of MRI activity during the last part of the study was evidence for both [gadolinium-enhancing] and new T2 lesions, indicating that laquinimod reduces not only the extent of blood-brain barrier opening, but also the accrual of fixed lesions," the authors said.
Available therapies for multiple sclerosis all target inflammatory aspects of the disease. In addition, all of the approved therapies require injection, creating a potential advantage for any oral agent.
Laquinimod is structurally related to linomide, a drug that reduced disease activity in MS but had unacceptable toxicity, the authors said. Preclinical and phase I clinical studies suggested laquinimod had greater activity and a more favorable safety profile compared with linomide.
In a previous 24-week, randomized phase II study, laquinimod 0.3 mg/d suppressed formation of new MS lesions and was well tolerated. Those results led to the current evaluation of two different doses of the drug.
The study involved 306 patients relapsing-remitting multiple sclerosis with who had had one or more relapses in the previous year and at least one gadolinium-enhancing lesion on screening MRI. Investigators at 51 centers in nine countries randomized the patients to placebo or to laquinimod 0.3 mg/d or 0.6 mg/d.
The trial lasted 36 weeks, and the primary outcome was the cumulative total of gadolinium-enhancing lesions from the final four MRI scans at weeks 24, 28, 32, and 36.
Compared with placebo, laquinimod 0.6 mg reduced the average number of lesions per scan on the final four MRI scans by 40.4%.
The 0.3 mg dose did not significantly reduce the number of lesions compared with placebo (3.9 versus 2.6).
Comparison of the median cumulative number of lesions from the last four MRI scans resulted in a 55% reduction in the number of lesions with laquinimod 0.6 mg versus placebo (4.0 versus 9.0).
The number of new T2 lesions on the last four scans was 44% lower with laquinimod 0.6 mg (P=0.0013), and the number of new T1-hypointense lesions was 51% lower in the laquinimod 0.6 mg group (P=0.0064).
Examination of MRI scans from weeks 12 through 36 demonstrated a 51% reduction in the mean number of gadolinium-enhancing lesions with laquinimod 0.6 mg (2.7 versus 4.4) and a 60% decrease in the median number of lesions (6.0 versus 15.0).
Patients in the laquinimod 0.6 mg group had an annualized relapse rate of 0.52 compared with 0.77 for those on placebo which was not statistically significant (P=0.0978). Additionally, 70.8% of laquinimod 0.6 mg patients were relapse-free compared with 62.7% of the placebo group.
Both doses of laquinimod were well tolerated, the authors said. The primary treatment-related effect was a transient, dose-related increase in liver enzymes.
In an accompanying commentary, B. Mark Keegan, M.D., and Brian G. Weinshenker, M.D., of the Mayo Clinic in Rochester, Minn., said the results raised several questions:
* Why was the 0.3 dose effective in the earlier phase II study but not in the current study?
* Was the limited duration the reason for the lack of difference in relapse rate?
* How does laquinimod's efficacy compare with that of other immunomodulatory agents?
They also noted that MRI gadolinium-enhanced lesions are not a perfect surrogate outcome: "The correlation between MRI ﬁndings and clinical disease course is, however, imperfect. Gadolinium-enhancing lesions are mildly predictive of relapse rate but not of clinical disability."
The Mayo clinicians also remained circumspect about the generally favorable safety profile of laquinimod.
"Continued vigilance is needed because serious adverse effects are commonly not in evidence until phase III studies are started . . . or until after approval," they said.
Teva Pharmaceutical Industries supported the study.
Dr. Comi reported consulting and speaking relationships with Teva, Novartis, sanofi-aventis, Merck-Serono, Biogen-Dompe, and Bayer Schering. Several coauthors also reported relationships with the pharmaceutical industry.
Dr. Weinshenker disclosed that he is a paid member of the data-safety monitoring committee for another oral agent being evaluated for multiple sclerosis.
Dr. Keegan declared that he has no conflicts.
Primary source: The Lancet
Comi G, et al "Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicenter, randomized, double-blind, placebo-controlled phase IIb study" Lancet 2008; 371: 2085-2092.
Additional source: The Lancet
Keegan BM, Weinshenker BG "Laquinimod, a new oral drug for multiple sclerosis" Lancet 2008; 371: 2059-2060.