Laquinimod Significantly Reduces Caudate Volume in Phase 2 LEGATO-HD Study

Ralf Reilmann

George Huntington Institute

Recently published data from the double-blind, placebo-controlled LEGATO-HD study (NCT02215616) showed that treatment with laquinimod did not impact motor symptoms in patients with Huntington disease (HD); however, it did significantly reduce caudate volume loss compared with placebo over a 52-week period. These findings represent the first clinical observations supporting a possible role of neuroinflammation in the pathology of HD that could be modulated by therapeutic intervention.¹

Published in The Lancet Neurology, the phase 2 trial randomly assigned patients with HD to either laquinimod 0.5 mg (n = 107), 1.0 mg (n = 107), and 1.5 mg (n = 30) or placebo (n = 108), for 52 weeks. Key inclusion criteria included having a CAG repeat length of 36-49, and motor symptoms of HD, as assessed by a Unified Huntington’s Disease Rating Scale (UHDRS)-Total Motor Score (TMS) of more than 5, and a UHDRS-Total Functional Capacity (TFC) score of 8 or higher. Of note, the 1.5 mg group was ultimately discontinued before recruitment was finished because of cardiovascular safety concerns addressed in previous studies of multiple sclerosis.

Led by Ralf Reilmann, founding director of the George Huntington Institut, Münster, Germany, 81% (n = 286) of the cohort completed the study, 64 discontinued treatment, and 2 did not receive treatment. After 52 weeks of treatment, change in the UHDRS-TMS, the primary end point, did not differ significantly between the laquinimod 1.0 mg group (least squares mean [LSM] 1.98 [SE, 0.83]) and placebo group (LSM, 1.20 [SE, 0.82]; P = .4853). A subgroup analyses based on sex, CAG repeat length, site location median, and baseline values of UHDRS-TMS, UDHRS-TFC, and caudate volume, did not show a response to laquinimod.

Despite not meeting the primary end point, those on laquinimod 1.0 mg demonstrated a change in caudate volume (LSM, 3.10 [SE, 0.38]) that differed significantly from placebo (LSM, 4.86 [SE, 0.38]); P = .0002). The exploratory MRI volumetric measures of caudate volume loss for the laquinimod 0.5 mg group, and whole brain volume loss, white matter volume loss, and ventricular volume for the laquinimod 0.5 mg and 1.0 mg groups all consistently showed improvements compared with placebo.

"Progressive volume losses in the striatum, which are best assessable in the caudate, but also seen in various other brain regions (white matter, grey matter, and whole brain) are well established hallmarks of Huntington's disease pathology," Reilmann et al wrote. "Caudate volume loss, in particular, is a sensitive marker very early in premanifest and manifest Huntington's disease, and correlates with disease progression and motor, specifically Q-Motor, and other clinical outcomes in long-term observational studies."

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In terms of safety, there were no unexpected signals, as headache, diarrhea, and fall, were among the most commonly reported adverse events (AEs). Treatment-related AEs occurred in 22% (n = 24) of patients on placebo, 43% (n = 46) of those in the laquinimod 0.5 group, 34% (n = 36) of those on laquinimod 1.0 mg, and 41% (n = 12) of those in the laquinimod 1.5 mg group. Cardiovascular events recorded included 1 first-degree atrioventricular block and 1 defect intraventricular conduction in the laquinimod 1.5 mg group, and 1 left ventricular hypertrophy and 4 tachycardias in the laquinimod 1.0 mg group.

There was 1 death in the study: a patient in the placebo group who died because of multiple injuries in a road traffic accident. Serious AEs were reported by 8 (7%) patients in the placebo group, 7 (7%) in the laquinimod 0.5 mg group, 5 (5%) in the laquinimod 1.0 mg group, and 1 (3%) in the laquinimod 1.5 mg group.

On other exploratory analyses, investigators observed no significant between-group differences in scales assessing functional capacity, clinical global impression, psychiatric conditions, and quality of life. Both laquinimod doses demonstrated some improvements on dysdiadochomotography (pronation or supination hand tapping) and pedomotography (speeded foot tapping); however, there was no effect on manumotography (grip force) and choreomotography (chorea) analyses.

"Considering a further exploration of the risks and benefits of immunomodulatory therapies in Huntington's disease, it should be appreciated that their safe application in other diseases for several years offers perspectives for early and long lasting treatment regimens, which are required in a slowly developing neurodegenerative disease," Reilmann et al concluded. "Careful consideration of the evidence available for other treatment approaches is therefore timely. Immune modulation is available orally and could be distributed easily and applied for long periods within current medical care systems. If proven to have a clinical effect in future studies, such therapy could be used alone or in combination with other possible therapeutic approaches to modulate the course of Huntington's disease."

REFERENCE
1. Reilmann R, Anderson KE, Feigin A, et al. Safety and efficacy of laquinimod for Huntington’s disease (LEGATO-HD): a multicenter, randomized, double-blind, placebo-controlled, phase 2 study. Lancet Neurol. Published online January 24, 2024. doi:10.1016/S1474-4422(23)00454-4