Laquinimod is an investigational, oral, once-daily therapy for the treatment of relapsing-remitting multiple sclerosis (RRMS). The therapy (licensed to Teva Neuroscience) received Fast Track designation—meaning the therapy demonstrated the potential to fulfill an unmet need in the treatment of a serious disease, in this case MS—from the FDA in February 2009. FDA approval of laquinimod may occur in late 2012 or early 2013.
Laquinimod has gone through two pivotal Phase III trials, ALLEGRO and BRAVO, which each lasted between 24 and 30 months. In addition to MS clinical studies, laquinimod is currently in Phase II development for Crohn’s disease and Lupus, and is being studied in other autoimmune diseases.
Laquinimod appears to induce some neuroprotective mechanisms, and represents a new class of drugs that minimize disability in MS. While laquinimod does not suppress the immune system, it appears to work directly in the nervous system to minimize the damage done by the inflammatory attacks that characterize MS.
Dr. Tim Vollmer, MS Center Medical Director, said that laquinimod appears to act primarily within the central nervous system to inhibit inappropriate astrocyte activity and thereby reduce demyelination and neuronal loss, rather than by targeting peripheral immune cells as many other MS treatments do. As a result, a greater effect against neurodegeneration and disability, as opposed to acute attacks, is not surprising with the drug, he said.
“I think the future of MS therapy probably will be combination therapy, as in other fields,” Vollmer said. Because laquinimod “is not a primary immunosuppressant,” he added, it might produce “an additive and possibly a synergistic effect” with other drugs.
Phase III Studies
The first of two Phase III studies, ALLEGRO, examined the efficiency and safety of laquinimod versus placebo in patients with relapsing-remitting MS (RRMS). The study lasted two years, and was conducted at 139 sites in 24 countries and enrolled 1,106 MS patients. In the study, the primary outcome measure was the number of confirmed relapses, and secondary measures included confirmed disability progression and changes in MRI active lesions.
Laquinimod met ALLEGRO’s primary endpoint and demonstrated a significant positive impact on disease activity, disability progression and MRI measures of inflammation and neurodegeneration, while maintaining a favorable safety and tolerability profile. Results from the study demonstrated that RRMS patients treated with 0.6 mg daily oral laquinimod experienced a statistically significant 23% reduction in annualized relapse rate compared to placebo. There was also a 36% reduction in the risk of confirmed disability progression, as measured by EDSS. As mentioned above, the disproportionate reduction in the progression of disability may be explained by laquinimod’s unique mechanism of action that seems to include neuroprotective properties.
Laquinimod was found to be safe and well tolerated in the ALLEGRO study. The overall frequencies of adverse events and overall incidence of infections were comparable to those seen with placebo. No deaths were reported among those taking laquinimod. Patients who completed the ALLEGRO study are offered to join an open-label extension phase, in which they will be treated with laquinimod 0.6mg daily until the drug is commercially available.
The second of the two Phase III studies, BRAVO, which had a site at the Rocky Mountain MS Center at Anschutz Medical Campus, was also a placebo-controlled study. The study tested 0.6 mg of laquinimod compared to placebo, and tested the risk-to-benefit factor of laquinimod compared to the currently used injectable treatment, Avonex (Interferon Beta 1-A). Avonex is a common treatment of MS, and researchers were eager to see how laquinimod—as an oral treatment—stood up to Avonex. Enrollment of 1,332 patients at 154 sites in the U.S, Europe, Israel and South Africa was completed in June 2009.
Dr. Vollmer served as the co-principle investigator with Dr. Pers Sorenson of Copenhagen University Hospital in the BRAVO study. While data showed that BRAVO did not achieve its primary endpoint of a statistically significant reduction of the annualized relapse rate, there was a trend in favor of a reduced relapse rate similar to that seen in the ALLEGRO study. The BRAVO study did confirm the highly significant decrease in risk of sustained disability and a decrease in brain atrophy, as seen in the ALLEGRO study.
Although the phase III BRAVO trial’s primary efficacy endpoint did not demonstrate a statistically significant treatment effect of laquinimod over placebo, it did show a strong trend for treatment effect that matches that seen in the ALLEGRO study, said Dr. Vollmer. The drug was also clearly helpful in reducing the progression of disability and brain atrophy, which, Dr. Vollmer said, are arguably the issues that matter most to patients.
Phase II Studies
Laquinimod was tested in two Phase II studies and demonstrated an encouraging safety profile; it was well tolerated and no severe side effects were observed. One study included 209 people with RRMS. After six months of receiving 0.3 mg of laquinimod, study participants exhibited a 44% decrease in MRI activity. For participants with disease activity at the start of the study, a 52% decrease in MRI activity was seen.
The results of a second II trial were released in June 2008. The study included 306 participants with RRMS and tested both 0.3 mg and 0.6 mg doses—administered daily for nine months. MRI results demonstrated that the 0.6 mg dose significantly reduced the number of active lesions after month six compared to placebo. The lower dose did not demonstrate any effect.
After Phase II studies concluded, a 36-week extension study commenced and all study participants received either 0.3 mg or 0.6 mg of laquinimod. In study participants who switched from placebo to laquinimod, there was a 52% reduction in active lesions. In those who had been receiving laquinimod in the early studies, a 40% reduction in active lesions was sustained.