Safety and efficacy of laquinimod for Huntington's disease (LEGATO-HD): a multicentre, randomised, double-blind, placebo-controlled, phase 2 study.

Background: Laquinimod modulates CNS inflammatory pathways thought to be involved in the pathology of Huntington's disease. Studies with laquinimod in transgenic rodent models of Huntington's disease suggested improvements in motor function, reduction of brain volume loss, and prolonged survival. We aimed to evaluate the safety and efficacy of laquinimod in improving motor function and reducing caudate volume loss in patients with Huntington's disease.

Methods: LEGATO-HD was a multicentre, double-blind, placebo-controlled, phase 2 study done at 48 sites across ten countries (Canada, Czech Republic, Germany, Italy, Netherlands, Portugal, Russia, Spain, UK, and USA). Patients aged 21-55 years with a cytosine-adenosine-guanine (CAG) repeat length of between 36 and 49 who had symptomatic Huntington's disease with a Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS) of higher than 5 and a Total Functional Capacity score of 8 or higher were randomly assigned (1:1:1:1) by centralised interactive response technology to laquinimod 0·5 mg, 1·0 mg, or 1·5 mg, or to matching placebo, administered orally once daily over 52 weeks; people involved in the randomisation had no other role in the study. Participants, investigators, and study personnel were masked to treatment assignment. The 1·5 mg group was discontinued before recruitment was finished because of cardiovascular safety concerns in multiple sclerosis studies. The primary endpoint was change from baseline in the UHDRS-TMS and the secondary endpoint was percent change in caudate volume, both comparing the 1·0 mg group with the placebo group at week 52. Primary and secondary endpoints were assessed in the full analysis set (ie, all randomised patients who received at least one dose of study drug and had at least one post-baseline UHDRS-TMS assessment). Safety measures included adverse event frequency and severity, and clinical and laboratory examinations, and were assessed in the safety analysis set (ie, all randomised patients who received at least one dose of study drug). This trial is registered with ClinicalTrials.gov, NCT02215616, and EudraCT, 2014-000418-75, and is now complete.

Findings: Between Oct 28, 2014, and June 19, 2018, 352 adults with Huntington's disease (179 [51%] men and 173 [49%] women; mean age 43·9 [SD 7·6] years and 340 [97%] White) were randomly assigned: 107 to laquinimod 0·5 mg, 107 to laquinimod 1·0 mg, 30 to laquinimod 1·5 mg, and 108 to matching placebo. Least squares mean change from baseline in UHDRS-TMS at week 52 was 1·98 (SE 0·83) in the laquinimod 1·0 mg group and 1·2 (0·82) in the placebo group (least squares mean difference 0·78 [95% CI -1·42 to 2·98], p=0·4853). Least squares mean change in caudate volume was 3·10% (SE 0·38) in the 1·0 mg group and 4·86% (0·38) in the placebo group (least squares mean difference -1·76% [95% CI -2·67 to -0·85]; p=0·0002). Laquinimod was well tolerated and there were no new safety findings. Serious adverse events were reported by eight (7%) patients on placebo, seven (7%) on laquinimod 0·5 mg, five (5%) on laquinimod 1·0 mg, and one (3%) on laquinimod 1·5 mg. There was one death, which occurred in the placebo group and was unrelated to treatment. The most frequent adverse events in all laquinimod dosed groups (0·5 mg, 1·0 mg, and 1·5 mg) were headache (38 [16%]), diarrhoea (24 [10%]), fall (18 [7%]), nasopharyngitis (20 [8%]), influenza (15 [6%]), vomiting (13 [5%]), arthralgia (11 [5%]), irritability (ten [4%]), fatigue (eight [3%]), and insomnia (eight [3%]).

Interpretation: Laquinimod did not show a significant effect on motor symptoms assessed by the UHDRS-TMS, but significantly reduced caudate volume loss compared with placebo at week 52. Huntington's disease has a chronic and slowly progressive course, and this study does not address whether a longer duration of laquinimod treatment could have produced detectable and meaningful changes in the clinical assessments.

Funding: Teva Pharmaceutical Industries.

Competing Interests: Declaration of interests RR is founding director and owner of the George Huntington Institute, a private research institute focused on clinical and preclinical research in Huntington's disease, and QuantiMedis, a clinical research organisation providing Q-Motor services in clinical trials and research. He served as an elected member of the executive committees of the European Huntington's Disease Network and the Huntington's Study Group, and as co-chair of the Task Force on Huntington's Disease of the International Parkinson and Movement Disorder Society. He has provided consulting services to Teva Pharmaceuticals, all payments to institution. He reports receiving payments for clinical trial services (global coordinating principal investigator role, patient recruitment, and quantitative motor assessment) and consulting services from Actelion, Alnylam, Amarin, AOP Orphan Pharmaceuticals, AskBio, Cure Huntington Disease Initiative Foundation, Desitin, Hoffmann-La Roche, IONIS, Ipsen, Lundbeck, MEDA Pharma, Medivation, Mitoconix, Neurocrine, Neurosearch, Novartis, Omeros, Pfizer, Prana Biotechnology, Prilenia, PTC Therapeutics, Raptor, Sage, Siena Biotech, Solaxa, Temmler Pharma, Teva, uniQure, Vaccinex, Voyager, Wave Life Sciences, and Zevra, all payments to institution. KEA reports that salary support was paid by Teva to her institution, Georgetown University, for work as co-principal investigator for North American sites, and that she has received honoraria from Teva for giving lectures and participation in advisory boards. She is also a paid consultant to Novartis Pharmaceuticals, Azevan Pharmaceuticals, Cure Huntington Disease Initiative Foundation, the Lundbeck Foundation, and Neurocrine Pharmaceuticals. She receives salary support, paid to her institution, from the Griffin Foundation and the Huntington Study Group. She receives salary support, paid to her institution, as a site investigator for clinical trials for SAGE Pharmaceuticals and Prilenia Pharmaceuticals. She has received salary support, paid to her institution, as a site investigator for observational studies from Cure Huntington Disease Initiative Foundation. AF served as chair of the Huntington Study Group from 2018 to 2022. He is on the data and safety monitoring board for Alzheimer's Disease Cooperative Study/Alzheimer's Therapeutic Research Institute and chairs a data and safety monitoring board for PTC Therapeutics. He has received institutional grant support to New York University, as a co-principal investigator of the LEGATO-HD study. He has also received grants to his institution, New York University, from Prilenia Therapeutics and the Huntington Study Group, and consulting fees from AskBio and Annexon. SJT reports receiving a research contract from Teva Pharmaceuticals to run LEGATO-HD at the University College London Hospital site. SJT reports receiving grant support from the following groups: the Cure Huntington Disease Initiative Foundation, Vertex Pharmaceuticals, UK Medical Research Council, Wellcome Trust, and UK Dementia Research Institute. SJT reports that consultancy fees for advisory services were paid to University College London Consultants, a wholly-owned subsidiary of University College London from the following companies: F Hoffman LaRoche, Annexon Biosciences, PTC Therapeutics, Takeda Pharmaceuticals, Vertex Pharmaceuticals, Alnylam Pharmaceuticals, Genentech, LoQus23 Therapeutics, Triplet Therapeutics, Novartis, Atalanta, Spark Therapeutics, Horama, University College Irvine, Rgenta Therapeutics, Locanobio, Adrestia Therapeutics, Alchemab, Biogen, Design Therapeutics, HCD Economics, Ipsen Bioscience, Iris Medicine, Latus Therapeutics/8V, Life Edit Therapeutics, Pfizer, Prilenia Therapeutics, Regeneron Pharmaceutics, Remix Therapeutics, Sanofi, and Unique. SJT reports consulting fees and advisory services with payment directly to SJT from Alphasight, Guidepoint, and Iqvia, and reports a patent issued on application number 2105484·6, 25 licensed to Adrestia Therapeutics. BRL reports grant support from Teva Pharmaceuticals to his university, University of British Columbia, as a site for LEGATO-HD. BRL reports receiving grant support to his university, University of British Columbia, from the following groups: Huntington Society of Canada, Canadian Institutes of Health Research, and NanoMedicines Innovation Network. BRL reports receiving consulting fees as a scientific consultant from the following companies: uniQure, Teva Pharmaceuticals, Takeda, Triplet, Novartis, PTC, Remix, LifeEdit, Spark, Design, Scientetica, Roche/Genentech, and Camp4, and reports many patents with University of British Columbia and Incisive Genetics. BRL is chief executive officer, board member, and co-founder of Incisive Genetics, a biotech startup, and holds stock in this company. BRL has participated on the scientific advisory board for sRNAlytics and has received stock options. He is co-editor-in-chief of the Journal of Huntington's Disease, an unpaid position which receives some expense reimbursement. JCS was director of Stout Neuropath (now Zindametrix), a commercial research service that provided assistance in implementing the HD-CAB for the LEGATO-HD study. Stout Neuropath neuropsychology staff were masked to participant group assignment during the LEGATO-HD study. PP reports receiving grant support from Cure Huntington Disease Initiative Foundation, Parkinson's UK, the UK Medical Research Council, and the Michael J Fox Foundation. RS is an employee of the George Huntington Institute, a private research institute focused on clinical and preclinical research in Huntington's disease, and QuantiMedis, a clinical research organisation providing Q-Motor services in clinical trials and research. PL, GR, RV, TL, and MFG are employees of Teva Pharmaceuticals and own stock. AW is a former employee of Teva Pharmaceuticals and current employee of Novo Nordisk. BB is a former employee of Teva Pharmaceuticals and current employee of Novartis Pharmaceuticals. J-MS is a former employee of Teva Pharmaceuticals and current employee of Spark Therapeutics. MH is the former head of Teva Global Research and Development and is currently the founder and chief executive officer of Prilenia Therapeutics.

(Copyright © 2024 Elsevier Ltd. All rights reserved.)