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Abstract

Summary 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.

Details

Title
Safety and efficacy of laquinimod for Huntington's disease (LEGATO-HD): a multicentre, randomised, double-blind, placebo-controlled, phase 2 study
Author
Reilmann, Ralf 1 ; Anderson, Karen E 2 ; Feigin, Andrew 3 ; Tabrizi, Sarah J 4 ; Leavitt, Blair R 5 ; Stout, Julie C 6 ; Piccini, Paola 7 ; Schubert, Robin 8 ; Loupe, Pippa 9 ; Wickenberg, Anna 10 ; Borowsky, Beth 11 ; Rynkowski, Gail 9 ; Volkinshtein, Rita 9 ; Li, Thomas 9 ; Juha-Matti Savola 12 ; Hayden, Michael 13 ; Mark Forrest Gordon 9 ; Guttman, Mark; Raymond, Lynn; Mendis, Tilak; Suchowersky, Oksana; Corey-Bloom, Jody; Geschwind, Michael D; Marshall, Frederick J; Marder, Karen S; Nance, Martha; Racette, Brad; Bang, Jee; Segro, Victoria; McDonell, Katherine; Kamholz, John; LeDoux, Mark S; Sanchez-Ramos, Juan; DeMichele, Giuseppe; Mariotti, Caterina; Squitieri, Ferdinando; Soliveri, Paola; Cortelli, Pietro; José Esteban Muñoz García; Bojarski, Jaime Kulisevsky; López-Sendón Moreno, José Luis; Corrales, Koldo Berganzo; Cubo, Esther; García Moreno, José Manuel; Orth, Michael; Priller, Josef; Saft, Carsten; Weindl, Adolf; Winkler, Juergen; Craufurd, David; Miedzybrodzka, Zofia; Rickards, Hugh; Davies, Rhys Richard; Lahiri, Nayana; Ruddy, Deborah; Komati, Suresh K; Oliver William John Quarrell; Guedes, Leonor Correira; Roos, Raymund A C; Zalyalova, Zuleykha; Illarioshkin, Sergey; Gustov, Aleksandr; Klempir, Jiri

 George Huntington Institute, Münster, Germany; Department of Clinical Radiology, University of Münster, Münster, Germany; Department of Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany 
 Department of Psychiatry and Department of Neurology, Georgetown University School of Medicine, Washington, DC, USA 
 New York University Langone Health, New York, NY, USA 
 University College London Queen Square Institute of Neurology, London, UK 
 Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada 
 School of Psychological Sciences and Turner Institute for Brain and Mental Health, Monash University, Clayton, VIC, Australia 
 Department of Brain Sciences, Imperial College London, London, UK 
 George Huntington Institute, Münster, Germany 
 Research and Development, Teva Pharmaceutical Industries, Petah Tikva, Israel 
10  Novo Nordisk, Bagsvaerd, Denmark 
11  Novartis Pharmaceuticals, East Hanover, NJ, USA 
12  Spark Therapeutics, Philadelphia, PA, USA 
13  Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada; Prilenia Therapeutics, Herzliya, Israel 
Pages
243-255
Section
Articles
Publication year
2024
Publication date
Mar 2024
Publisher
Elsevier Limited
ISSN
14744422
e-ISSN
14744465
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3039715539
Copyright
©2024. Elsevier Ltd