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Investigational laquinimod did not change motor symptoms of Huntington's disease after 1 year but did significantly reduce caudate volume loss compared with placebo, the phase II LEGATO-HD trial found.

At week 52, mean change from baseline in Unified Huntington's Disease Rating Scale-Total Motor Score () was 1.98 in the laquinimod 1 mg group and 1.20 in the placebo group (difference 0.78, 95% CI -1.42 to 2.98, P=0.4853), according to Ralf Reilmann, PhD, of the George Huntington Institute in Germany, and colleagues.

Mean change in caudate volume was 3.10% with laquinimod 1 mg and 4.86% with placebo (difference -1.76%, 95% CI -2.67 to -0.85, P=0.0002), the researchers wrote in .

"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 [Quantitative Motor Battery] and other clinical outcomes in long-term observational studies," they noted.

"No treatments for Huntington's disease have improved motor symptoms other than chorea, and none has shown a joint effect on a clinical endpoint and brain volume," Reilmann and co-authors pointed out.

"To our knowledge, these results represent the first clinical observations supporting a possible role of neuroinflammation in the pathology of Huntington's disease that could be modulated by therapeutic intervention," they added.

is a neurodegenerative disorder characterized by progressive motor, psychiatric, and cognitive deterioration. It's caused by an autosomal dominant mutation in the HTT gene that leads to the production of mutated huntingtin protein. People with Huntington's have more than 35 cytosine-adenine-guanine (CAG) repeats within the HTT gene.

Laquinimod is an orally active central nervous system immunomodulator. "Clinical data from patients with relapsing-remitting multiple sclerosis show a benefit of laquinimod on brain atrophy and mixed effects on clinical endpoints after more than 1 year of treatment," Reilmann and colleagues observed.

included 352 adult Huntington's patients with a CAG repeat length between 36 and 49. All had symptomatic disease with a UHDRS-TMS higher than 5 and a Total Functional Capacity score of 8 or higher.

Participants were enrolled from 2014 to 2018 across 48 sites in 10 countries. About half (51%) were men and 97% were white. Mean age was about 44.

Patients were assigned to one of four groups: laquinimod 0.5 mg, 1 mg, 1.5 mg, or placebo, administered orally once a day for 52 weeks. The 1.5 mg group was discontinued before recruitment ended due to cardiovascular safety concerns that emerged in the multiple sclerosis studies.

The primary endpoint was 52-week change from baseline in UHDRS-TMS, and the secondary endpoint was percent change in caudate volume on MRI. Both endpoints were for the 1 mg group compared with placebo.

There were no new safety findings in LEGATO-HD compared with the multiple sclerosis studies. Serious adverse events were reported by 7%, 7%, 5%, and 3% of patients in the placebo, 0.5 mg, 1 mg, and 1.5 mg laquinimod groups, respectively. The most frequent side effects were headache (16%), diarrhea (10%), and irritability (4%).

At 52 weeks, the caudate volume loss of 4.86% in the placebo group was larger than expected, the researchers noted.

"A possible shorter time from diagnosis to baseline in the placebo group (32.3 months), compared with the laquinimod 0.5 mg group (45.8 months) and 1.0 mg group (41.5 months), with numerically similar baseline functional capacity, motor scores, and normalized caudate volume, raises the hypothesis that the placebo group could have had a more aggressive underlying pathology that was more reliably captured with neuroimaging, despite the randomization process," noted Tiago Mestre, MD, MsC, of the University of Ottawa in Ontario, writing in an .

"Since the completion of LEGATO-HD, in which laquinimod seemed to be associated with absent or inconclusive efficacy, the Huntington's disease field has experienced exciting times, with multiple drug development programs focused on disease modification," Mestre added. These include completed clinical trials for huntingtin-lowering therapies like tominersen and other ongoing studies.

LEGATO-HD's limitations included its relatively short treatment period and the limited sensitivity and reliability of clinical rating scales, the researchers acknowledged.

"Given the absence of treatment options that alter the disease process, we were disappointed that we did not observe a clinical benefit," Reilmann and colleagues noted. The study was planned primarily to obtain clinical and biomarker evidence and inform the design of a possible longer pivotal trial, they added.

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