Laquinimod (also known as Nerventra®)
Experimental Medications: Administered Orally
Company: Teva Neuroscience, Inc. and Active Biotech
- Oral medication taken once daily; dosing TBD
- Being studied in RRMS and PPMS
Although its exact mechanisms of action are unknown, laquinimod is an immunomodulator, apparently through its effects on cytokines (small proteins that may stimulate or inhibit the function of other cells) and interleukins (immune-system signaling chemicals). It enhances T-regulatory cell activity, which reduces Th1-inflammatory T-cell activity. It also appears to reduce white-blood-cell penetration of the CNS. In addition to its immunomodulatory actions, laquinimod increases levels of the brain-derived neurotrophic factor (BDNF), possibly contributing to neuroprotection (protecting the nerves and myelin from damage) in MS patients. BDNF is a protein found in the brain that helps to support nerves and their development.
The Phase III ALLEGRO study of 1,106 individuals with RRMS showed that, compared to placebo, laquinimod reduced the annualized relapse rate by 23 percent and the progression of disability by 36 percent. It also was effective on several MRI outcomes, including a reduction in brain atrophy by 33 percent.
The BRAVO Phase III trial was another global, 24-month, double-blind study with 1,300 participants. It was designed to evaluate laquinimod’s efficacy, safety, and tolerability versus placebo. In August 2011, the sponsors announced that the study had failed to achieve its primary goal of reducing the annualized relapse rate, although a trend was seen in that direction if the data are adjusted for differences in MRI characteristics at the start of the study.
Because the effect of laquinimod on relapses was more modest than has been seen with other disease-modifying therapies for RRMS, the drug was not considered for approval in the United States in 2012. In 2013, the results of two separate analyses of pooled data from the Phase III ALLEGRO and BRAVO trials studying laquinimod were presented.11
The first analysis compared the expected risk of disability progression (given a particular relapse rate) with that seen in the pooled data. In this analysis, the effect of laquinimod on reducing the risk of disability progression was larger than predicted. The second analysis examined the relationship between relapses and disability by looking at disability progression in both relapsing and relapse-free patients in the two trials. About one-third of the patients who progressed were relapse-free, suggesting that these two outcome measures are mediated through different pathways.
Since laquinimod may have more of an effect on disability than on relapses, a new trial looking primarily at laquinimod’s disability-preventing impact was designed. This 24-month trial, The Efficacy and Safety and Tolerability of Laquinimod in Subjects With Relapsing Remitting Multiple Sclerosis (CONCERTO12), was designed to compare two doses of laquinimod (including a 1.2 mg dose, which was higher than that tested in prior Phase III studies) with placebo, looking at confirmed disease progression (CDP) as the primary outcome. This is the first modern RRMS trial to prioritize prevention of disability over prevention of relapses. The trial began enrollment of 1,800 patients in 2013, and is expected to run into 2018.
Furthermore, based on its effect on disability in prior trials, laquinimod is also being studied in a PPMS trial (ARPEGGIO) that began in 2015.13 This trial will primarily evaluate the effect of laquinimod on brain atrophy, and secondarily on clinical outcomes. It was designed to enroll approximately 375 people and is anticipated to run through the end of 2017.
Although both the CONCERTO and ARPEGGIO trials were designed to study both the 0.6 mg dose of laquinimod evaluated in prior trials along with higher doses, in January 2016, Teva announced the decision to discontinue the higher doses of laquinimod in both ongoing studies. Eight patients in the high-dose arms of the CONCERTO and ARPEGGIO trials had cardiovascular events versus none in the lower-dose and the placebo arms, so the decision was made to continue to study with only the lower, 0.6 mg dose in which no such events had occurred. In May 2017, an announcement stated that CONCERTO’s primary endpoint (time to CDP) was not met, but encouraging results were seen in secondary endpoints.