Design of the LEGATO-HD study: A multinational, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of laquinimod (0.5, 1.0 and 1.5 mg/day) as treatment in patients with Huntington's disease

Objective: The primary objective of this study is to assess the efficacy and safety of laquinimod 0.5, 1.0, and 1.5mg versus placebo in a 12‐month study in patients with HD. Background: Introduction: Huntington's disease (HD) is a neurodegenerative disorder with an autosomal dominant mode of inheritance, associated with a triad of motor, behavioral, and cognitive symptoms. Laquinimod, is an orally active, CNS penetrant, immunomodulator believed to downregulate the inflammatory monocytic, microglial and astrocytic activation, that may contribute to neuronal loss in patients with HD. Laquinimod up‐regulates BDNF secretion which is reduced in HD and thought to contribute to degeneration of the striatum. Laquinimod treatment reduces brain atrophy and disability progression in patients with multiple sclerosis, an immunemediated neurodegenerative disease. Laquinimod is in clinical development as a possible candidate for modulation of disease course and reduction of neurodegeneration in patients with HD. Methods: A total enrollment of 400 patients (100 patients per dose arm, 1:1:1:1) is planned. Primary endpoint is change from baseline in the Unified Huntington's Disease Rating Scale Total Motor Score (UHDRS‐TMS) at month 12. Secondary endpoints include assessing safety of laquinimod, its' effect on brain atrophy (in particular caudate volume) and cognitive capacity using Huntington's disease cognitive assessment battery (HD‐CAB), clinical global impression using the Clinician's Interview‐Based Impression of Change plus Caregiver Input (CIBIC‐Plus), and change from baseline in functional capacity using the UHDRS TFC (Total Functional Capacity). Ancillary studies will investigate laquinimod's effect on microglial activation using PET imaging, peripheral inflammatory markers, and neuronal integrity using MRS analysis. Conclusions: There is a significant unmet medical need to ameliorate the progressive neurodegeneration that occurs in HD. This study will provide essential data towards possible effective and safe use of laquinimod to reduce neuronal loss and subsequent disease progression. Enrollment for this study is underway.