A randomized, placebo-controlled, phase 2 trial of laquinimod in primary progressive multiple sclerosis

Abstract

<jats:sec><jats:title>Objective:</jats:title><jats:p>To evaluate efficacy, safety, and tolerability of laquinimod in patients with primary progressive multiple sclerosis (PPMS).</jats:p></jats:sec><jats:sec><jats:title>Methods:</jats:title><jats:p>In the randomized, double-blind, placebo-controlled, phase 2 study ARPEGGIO (A Randomized Placebo-controlled trial Evaluating laquinimod in PPMS, Gauging Gradations In MRI and clinical Outcomes), eligible PPMS patients were randomized 1:1:1 to receive once-daily oral laquinimod 0.6 mg or 1.5 mg or matching placebo. Percentage brain volume change (PBVC; primary endpoint) from baseline to week 48 was assessed by MRI. Secondary and exploratory endpoints included clinical and MRI measures. Efficacy endpoints were evaluated using a predefined, hierarchical statistical testing procedure. Safety was monitored throughout the study. The laquinimod 1.5 mg dose arm was discontinued on January 1, 2016 due to findings of cardiovascular events.</jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p>374 patients were randomized to laquinimod 0.6 mg (n = 139) or 1.5 mg (n = 95) or placebo (n = 140). ARPEGGIO did not meet the primary endpoint of significant treatment effect with laquinimod 0.6 mg versus placebo on PBVC from baseline to week 48 (adjusted mean difference = 0.016%, <jats:italic>p</jats:italic> = 0.903). Laquinimod 0.6 mg reduced the number of new T2 brain lesions at week 48 (risk ratio = 0.4; 95% confidence interval, 0.26–0.69; <jats:italic>p</jats:italic> = 0.001). Incidence of adverse events was higher among patients treated with laquinimod 0.6 mg (83%) versus laquinimod 1.5 mg (66%) and placebo (78%).</jats:p></jats:sec><jats:sec><jats:title>Conclusions:</jats:title><jats:p>Laquinimod 0.6 mg did not demonstrate a statistically significant effect on brain volume loss in PPMS at week 48.</jats:p></jats:sec>

Spinal cord atrophy in a primary progressive multiple sclerosis trial: Improved sample size using GBSI

“…Patients were randomised in a 1:1:1 ratio to receive oral Laquinimod 0.6 mg or 1.5 mg, or placebo once daily, from January 2015 to April 2016, at 85 sites in 10 countries. Duration of the core study was 48 weeks ( Giovannoni et al, 2020 ).…”

“…The latter approach can be compromised by differences in spinal cord coverage, miss-segmentations and/or changes in spinal cord curvature ( Prados and Barkhof, 2018 , Moccia et al, 2019 ). Reductions in measurement noise using GBSI could be particularly relevant to clinical trials, that, so far, have failed to show any significant treatment effect on spinal cord atrophy, especially in progressive MS patients ( Giovannoni et al, 2020 , Ciccarelli et al, 2019 ), where this outcome measure provides the strongest clinical correlates ( Moccia et al, 2019 , Ciccarelli et al, 2019 ).…”

Laquinimod dampens IL-1β signaling and Th17-polarizing capacity of monocytes in patients with MS

“…Second, our study lacks data from patients with PPMS, in which laquinimod has been tested as well. 17 Further investigations need to elucidate how monocyte subsets relevant to MS 39,52 are differentially affected by laquinimod.…”

“…16 In the phase 2 trial ARPEGGIO, laquinimod did not demonstrate a significant effect on brain volume loss in primary progressive MS (PPMS). 17 Furthermore, laquinimod treatment of patients with Huntington disease did not improve total motor scores in the LEGATO-HD trial. 18 Subsequently, its development for treatment of MS and Huntington disease was discontinued.…”

The Effect of CYP3A Induction and Inhibition on the Pharmacokinetics of Laquinimod, a Novel Neuroimmunomodulator

“…Clinical studies previously evaluated the effect of laquinimod as a treatment for multiple sclerosis (MS) and Huntington's disease. The clinical development program in MS included three completed phase 3 studies (ALLEGRO, BRAVO, and CONCERTO) in relapsing remitting MS, [6][7][8] and a completed phase 2 study (ARPEGGIO) in primary progressive MS. 9 Development of laquinimod in MS has been discontinued. A phase 2 study evaluating the safety and efficacy of laquinimod as a treatment in Huntington's disease (LEGATO-HD) failed to meet its primary endpoint; however, the secondary endpoint, reduction of brain atrophy, was met.…”