ARTICLE IN BRIEF
The ALLEGRO Study demonstrated that not only did patients taking the 0.6 mg dose of laquinimod have fewer MS exacerbations, but also more patients on the drug either showed a slight improvement in disability measurements or had no perceived change in these standardized scores after two years of therapy when compared to patients assigned to placebo.
HONOLULU—The progression towards disability due to multiple sclerosis (MS) appears to be markedly slowed with treatment with the investigative oral drug laquinimod, researchers said here at the AAN annual meeting in April.
The so-called ALLEGRO Study demonstrated that not only did patients taking the 0.6 mg dose of laquinimod have fewer MS exacerbations, but also more patients on the drug either showed a slight improvement in disability measurements or had no perceived change in these standardized scores after two years of therapy when compared to patients assigned to placebo.
“Laquinimod stands to be a safe oral disease-modifying treatment that effectively addresses the irreversible pathological progression of multiple sclerosis,” said Giancarlo Comi, MD, director of the Institute of Experimental Neurology at the Scientific Institute and University Vita-Salute San Raffaele in Milan, Italy.
In a press briefing and during his late-breaker oral presentation, Dr. Comi reported that in the phase 3 clinical trial, the annualized relapse rate over the course of two years was 0.304 for those taking laquinimod, compared with a rate of 0.395 for patients randomly assigned to placebo. That translates to a relative risk reduction of 23 percent, said Dr. Comi, and achieved statistical significance (p=0.0024).
Patients on laquinimod achieved a 36 percent reduction in the risk of sustained disability progression when compared with placebo patients, based on the Expanded Disability Status Scale scores. About 10 percent of patients on laquinimod progressed, compared with about 15 percent of placebo patients. That difference also achieved statistical significance (p=0.0122).
Imaging studies revealed that patients on laquinimod had a 32.8 percent reduction in brain atrophy when compared with placebo patients. The placebo patients lost about 1.5 percent of brain volume over the two-year study period compared with about 0.8 percent loss of brain volume for those on laquinimod (p<0.0001).
The number of MRI gadolinium-enhanced lesions was reduced by 37 percent among those on laquinimod; the number of new T2 lesions was reduced by 30 percent; the cumulative number of new hypointense-T1 lesions was reduced by 27 percent. All the reduction in favor of laquinimod achieved statistical significance.
Dr. Comi and researchers in 24 countries enrolled 1,106 people diagnosed with relapsing-remitting MS. They had to have had at least one exacerbation of MS in the past year and at least two such attacks in the past two years to be eligible for the study.
The participants received either a once-daily oral dose of 0.6 milligrams of laquinimod or a matching placebo for two years. Dr. Comi noted that 427 placebo patients — about 76.8 percent — completed the 24-month trial compared with 437 or 79.5 percent of the patients who were assigned to laquinimod.
Exactly how laquinimod, a second-generation quinoline-3-carboxamide, produces its effects in MS is not completely understood. “The precise mechanisms of action are not defined,” said Scott Zamvil, MD, professor of neurology at the University of California-San Francisco, who was not involved in the study. “We understand the cellular effects but we don't understand the molecular mechanisms. The sense is that the drug does not cause immunodepletion as seen with other drugs. We think it is safer than other oral drugs.”
Dr. Zamvil noted that the trial was sponsored by Teva Pharmaceuticals, the same company that developed glatiramer acetate (Copaxone), which also has a mechanism of action that puzzles researchers.
Dr. Comi suggested that laquinimod has a novel mechanism of action that impacts the acute inflammatory activity and the accumulation of irreversible tissue damage. “This suggests a substantial future role for laquinimod in the treatment of multiple sclerosis,” he said.
Importantly, Dr. Comi said that the results seen with laquinimod in the ALLEGRO trial did not appear to compromise safety issues. Overall frequencies of adverse events were low and comparable to those observed in the placebo group, he reported. (See “Adverse Events: Laquinimod.”)
“The incidence of liver enzyme elevation was higher in laquinimod-treated patients,” said Dr. Comi. “However, these elevations were temporary, reversible, and did not lead to any signs of liver problems.”
WHERE DOES IT FIT IN?
Said Dr. Zamvil: “The question is: where does this fit in? Should it be used in early disease? The sense will be, yes. Laquinimod should be considered first line therapy.”
Dr. Zamvil explained that as treatments with disease modifying agents — the interferons and glatiramer acetate — have been used earlier and earlier among MS patients, the incidence of exacerbations and the need for hospitalization in multiple sclerosis has declined. As those data mature, more and more doctors are moving to use the agents earlier.
An oral agent such as laquinimod, Dr. Zamvil said, will be helpful among patients who have issues with injectable agents. “We have patients who are needle phobic who are not going to want to go on an injectible medication,” he said.
But another MS expert, John Corboy, MD, professor of neurology at the Rocky Mountain Multiple Sclerosis Center at the Anschutz Medical Campus of the University of Colorado-Aurora, said, where laquinimod will fit into treatment may require an extended treatment experience.
“This drug has shown a modest reduction in exacerbations and MRI lesions,” said Dr. Corboy, who is a member of the Neurology Today editorial advisory board.
“It does show an important impact on preventing disability, which is most important to patients. It is possible doctors may want to use more potent drug to prevent disease progression and then switch patients to laquinimod, assuming that subsequent studies are positive and the drug is approved by the FDA.”
Dr. Corboy noted that other MS medications have looked good at the start but then some adverse side effects have cropped up. “I don't think a lot of physicians want to be the first one on the block to use laquinimod. Even though the drug appears to have a very safe side effect profile, clinicians tend to be cautious when it comes to prescribing a new drug for patients.”
He said that on the basis of the work that has been presented with the drug he has not observed anything currently that would give him concerns regarding its safety.
Dr. Corboy and Dr. Comi both noted that a confirmatory trial required for regulatory approval is expected to be reported in the next few months, and if that trial shows similar results to ALLEGRO, submission to the FDA will follow.
ADVERSE EVENTS: LAQUINIMOD
No deaths among the 550 patients assigned to laquinimod; 3 patients taking placebo died. There were 122 serious adverse events among the laquinimod patients (22.2 percent) compared with 90 such events among the placebo patients (16.2 percent). Among them:
* Pericarditis: 1 case in a patient taking placebo.
* Appendicitis: 5 patients on laquinimod; 1 on placebo.
* Herpes Virus: 17 on laquinimod; 20 in placebo patients.
* Thrombosis or embolism: 3 cases in laquinimod patients; 2 cases in placebo patients.
* Neoplasms: 8 (1.5 percent) in laquinimod patients; 6 neoplasms (1.1 percent) in placebo patients.
DISCLOSURE: The study author Giancarlo Comi, MD, reports he has received personal compensation for activities with Novartis, Teva, Sanofi-Aventis, Merck Serono, and Bayer Schering.