Laquinimod (also known as nerventra or ABR-215062) is an investigational active immunomodulator, or a molecule that changes the behavior of immune cells of the central nervous system. An oral drug, laquinimod is currently being developed to treat primary progressive multiple sclerosis (PPMS) and Huntington’s disease. It was pulled from further testing in relapsing-remitting MS patients (RRMS) after a Phase 3 study failed to achieve its primary endpoint or goal.
How laquinimod works is not fully understood, but it is thought to stop immune cells from entering the brain and spinal cord, possibly preventing or lowering myelin damage. Early studies also suggest that laquinimod may have an anti-inflammatory effect and an ability to preserve the structure and function of nerve cells.
ALLEGRO was a two-year Phase 3 study in relapsing-remitting MS patients. Its results showed that 0.6 mg daily of laquinimod reduced relapse rates by 23% and disability progression by 36% compared to placebo.
Laquinimod’s developer, Teva Pharmaceutical Industries, also initiated a Phase 2 study, called ARPEGGIO (NCT02284568), in 2014 to test the efficacy, safety, and tolerability of two doses of the treatment (0.6 mg/day or 1.5mg/day) in people with PPMS.
The BRAVO study compared the effects of 0.6 mg of laquinimod to that of interferon beta-1a (Avonex) and a placebo in RRMS patients. No statistically significant reduction in relapse rates between groups was observed, but laquinimod significantly reduced the rates of brain shrinkage and disability progression.
Based on these relapsing MS trial results, the company began testing laquinimod at two doses (0.6 mg/day and 1.5mg/day) in a randomized, double-blind, parallel-group, placebo-controlled Phase 3 trial — CONCERTO (NCT01707992) — that opened in February 2013 in RRMS patients.
But in January 2016, the Data Monitoring Committee (DMC) of the U.S. Food and Drug Administration (FDA) called for the immediate discontinuation of the higher laquinimod dose in the ARPEGGIO and CONCERTO trials, after cardiovascular events (none fatal) were reported in eight participants (seven in the CONCERTO study and one in the ARPEGGIO study).
Teva and Active Biotech stopped higher doses immediately in both trials and encouraged participants to continue with follow-up examinations.
Then, in May 2017, the companies announced that laquinimod (0.6 mg/day) had failed to meet CONCERTO’s primary endpoint of slowing disease progression after three months of treatment. The drug also failed to meet a secondary endpoint of slowing disease progression at six and nine months. Laquinimod did show positive results in reducing patients’ brain volume loss by 40 percent (a measure of disability progression) at 15 months of treatment compared to a placebo. It was reduced by 30 percent the number of gadolinium-enhancing T1 lesions in the brain (a measure of inflammation) in treated patients over the same time period, and 28 percent saw their risk of relapse lowered. The CONCERTO trial also confirmed the safety of laquinimod (0.6 mg/day), with participants reporting minor side effects, such as headache, nasopharyngitis, back pain, and joint pain.
Because the trial’s primary endpoint was not achieved, Teva and Active Biotech decided to stop developing laquinimod as a potential RRMS treatment. “[W]e did see positive results on a number of secondary and exploratory endpoints which fuels our belief in the potential of laquinimod as a possible treatment for neurodegenerative diseases. While we have no current plans to further pursue laquinimod in RRMS, we are continuing to study it in two other trials,” Teva said in a May 5 release.
Those continuing trials are ARPEGGIO (PPMS) and LEGATO-HD (NCT02215616) , which is currently recruiting people with Huntington’s disease to evaluate the efficacy and safety of two doses of laquinimod (0.5, and 1.0 mg/day, a higher dose was discontinued). This trial expects to enroll 400 patients — in the U.S., Canada, Europe and elsewhere — and to finish collecting data in mid-2018.
Complete data from the CONCERTO trial will be published in a scientific journal and presented at a future medical meeting, the companies said.
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