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).

Keywords

Multiple sclerosis relapsing-remitting laquinimod disability progression

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References

Pardo

Jones

DE.

The sequence of disease-modifying therapies in relapsing multiple sclerosis: Safety and immunologic considerations. J Neurol 2017; 264(12): 2351–2374.

Kaye

Piryatinsky

Birnberg

, et al. Laquinimod arrests experimental autoimmune encephalomyelitis by activating the aryl hydrocarbon receptor. Proc Natl Acad Sci USA 2016; 113(41): E6145–E6152.

Quintana

Basso

Iglesias

, et al. Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature 2008; 453(7191): 65–71.

Quintana

Murugaiyan

Farez

, et al. An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 2010; 107(48): 20768–20773.

Quintana

Sherr

DH.

Aryl hydrocarbon receptor control of adaptive immunity. Pharmacol Rev 2013; 65(4): 1148–1161.

Brück

Pförtner

Pham

, et al. Reduced astrocytic NF-kappaB activation by laquinimod protects from cuprizone-induced demyelination. Acta Neuropathol 2012; 124(3): 411–424.

Thöne

Ellrichmann

Seubert

, et al. Modulation of autoimmune demyelination by laquinimod via induction of brain-derived neurotrophic factor. Am J Pathol 2012; 180(1): 267–274.

Aharoni

Saada

Eilam

, et al. Oral treatment with laquinimod augments regulatory T-cells and brain-derived neurotrophic factor expression and reduces injury in the CNS of mice with experimental autoimmune encephalomyelitis. J Neuroimmunol 2012; 251(1–2): 14–24.

Comi

Jeffery

Kappos

, et al. Placebo-controlled trial of oral laquinimod for multiple sclerosis. N Engl J Med 2012; 366(11): 1000–1009.

10.

Vollmer

Sorensen

Selmaj

, et al. A randomized placebo-controlled phase III trial of oral laquinimod for multiple sclerosis. J Neurol 2014; 261(4): 773–783.

11.

Sørensen

Comi

Vollmer

, et al. Laquinimod safety profile: Pooled analyses from the ALLEGRO and BRAVO Trials. Int J MS Care 2017; 19(1): 16–24.

12.

Kappos

Radue

E-W

O’Connor

, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010; 362(5): 387–401.

13.

Polman

O’Connor

Havrdova

, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354(8): 899–910.

14.

Radue

E-W

Barkhof

Kappos

, et al. Correlation between brain volume loss and clinical and MRI outcomes in multiple sclerosis. Neurology 2015; 84(8): 784–793.

15.

Bovis

Carmisciano

Signori

, et al. Defining responders to therapies by a statistical modeling approach applied to randomized clinical trial data. BMC Med 2019; 17(1): 113.

16.

Ziemssen

Tumani

Sehr

, et al. Safety and in vivo immune assessment of escalating doses of oral laquinimod in patients with RRMS. J Neuroinflamm 2017; 14(1): 172.

17.

Tan

Lycklama

Nijeholt

Polman

, et al. Linomide in the treatment of multiple sclerosis: MRI results from prematurely terminated phase-III trials. Mult Scler 2000; 6(2): 99–104.

18.

Varrin-Doyer

Zamvil

Schulze-Topphoff

Laquinimod, an up-and-coming immunomodulatory agent for treatment of multiple sclerosis. Exp Neurol 2014; 262(Pt. A): 66–71.

19.

Hainke

Thomas

Ziemssen

Laquinimod in the treatment of relapsing remitting multiple sclerosis. Expert Opin Drug Met Toxicol 2016; 12: 701–709.

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