CONCERTO: A randomized, placebo-controlled trial of oral laquinimod in relapsing-remitting multiple sclerosis

Abstract

Background: Interventions targeting the adaptive immune response are needed in multiple sclerosis (MS). Objective: Evaluate laquinimod’s efficacy, safety, and tolerability in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: CONCERTO was a randomized, double-blind, placebo-controlled, phase-3 study. RRMS patients were randomized 1:1:1 to receive once-daily oral laquinimod 0.6 or 1.2 mg or placebo for ⩽24 months ( n = 727, n = 732, and n = 740, respectively). Primary endpoint was time to 3-month confirmed disability progression (CDP). The laquinimod 1.2-mg dose arm was discontinued (1 January 2016) due to cardiovascular events at high doses. Safety was monitored throughout the study. Results: CONCERTO did not meet the primary endpoint of significant effect with laquinimod 0.6-mg versus placebo on 3-month CDP (hazard ratio: 0.94; 95% confidence interval: 0.67–1.31; p = 0.706). Secondary endpoint p values were nominal and non-inferential. Laquinimod 0.6 mg demonstrated 40% reduction in percent brain volume change from baseline to Month 15 versus placebo ( p < 0.0001). The other secondary endpoint, time to first relapse, and annualized relapse rate (an exploratory endpoint) were numerically lower (both, p = 0.0001). No unexpected safety findings were reported with laquinimod 0.6 mg. Conclusion: Laquinimod 0.6 mg demonstrated only nominally significant effects on clinical relapses and magnetic resonance imaging (MRI) outcomes and was generally well tolerated. Clinical trial registration number: ClinicalTrials.gov (NCT01707992).

Astrocyte-Derived Pleiotrophin Mitigates Late-Stage Autoimmune CNS Inflammation

“…In this context, our findings of AHR regulation of Ptn expression might be of high relevance, as data from the BRAVO Phase III trial demonstrate the highest reduction in grey matter (GM) volume decrease following treatment with the AHR-agonist Laquinimod (Laq), compared to IFN-β- and Placebo-treated patients ( 42 ). This was further recapitulated in the recent CONCERTO trial, in which oral Laq treatment led to a significant reduction in brain volume loss compared to the placebo group, as well as a numerical reduction in time to first relapse and annualized relapse rate as exploratory endpoints, while it did not alter 3-month confirmed disability progression ( 43 ). Together with observations of protective astrocyte signaling following oral administration of Laq during EAE ( 28 ), one may speculate that this positive effect of Laq on GM loss may, at least to some extent, be carried by increased levels of PTN, which limits inflammatory signaling in glial cells and supports neuronal survival, as we have demonstrated in vitro and in vivo .…”

Thinking outside the box: non-canonical targets in multiple sclerosis

“…Among other effects, laquinimod activates AHR and demonstrated beneficial effects in initial clinical trials in MS 285 – 287 . In a phase III study (CONCERTO), laquinimod protected nervous tissue (as measured by brain volume), but this treatment was not able to reduce the risk of progressive disability 288 . Interestingly, the combination of AHR agonists and MOG 35-55 in nanoliposomes induced antigen-specific tolerance and strong bystander immunosuppression, which abrogated EAE 289 .…”

Astrocytes and Inflammatory T Helper Cells: A Dangerous Liaison in Multiple Sclerosis

“…Laquinimod (LQ) is a quinoline-3-carboxamide derivate under clinical trial evaluation for the treatment of RRMS ( 179 ). In EAE, LQ treatment ameliorated disease progression by reducing the polarization and recruitment of Th17 cells as well as the production of inflammatory cytokines ( 180 , 181 ).…”