medwireNews: Treatment with the immunomodulator laquinimod for a year does not result in motor benefits for patients with Huntington’s disease (HD), but it does significantly slow caudate volume loss, suggests the LEGATO-HD study.
“[C]audate volume loss […] 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,” the study researchers observe.
Ralf Reilmann (George Huntington Institute, Mϋnster, Germany) and colleagues carried out a double-blind, placebo-controlled trial across 48 sites in Europe, the UK, the USA, Canada, and Russia, between 2014 and 2018.
They randomly assigned 352 adults (mean age 44 years, 51% men, 97% White) to receive oral laquinimod once daily at doses of 0.5 mg (n=107), 1.0 mg (n=107), 1.5 mg (n=30), or placebo (n=108) for 52 weeks. The smaller number of participants in the 1.5 mg group was due to this dose of laquinimod being discontinued following cardiovascular risks that were flagged in multiple sclerosis studies.
All the participants had blood results showing a cytosine-adenine-guanine repeat length of 36-49 and scored greater than 5 on the Unified Huntingdon’s Disease Rating Scale-Total Motor Score (UHDRS-TMS), and 8 or above on the UHDRS-Total Functional Capacity (UHDRS-TFC) scale, indicating an early disease stage of 1 or 2.
The primary outcome for the study – the change from baseline in UHDRS-TMS score with laquinimod 1.0 mg versus placebo – showed no significant difference between the two groups at 52 weeks.
Those receiving laquinimod 1.0 mg had a least squares mean change in UHDRS-TMS score of 1.98, compared with 1.20 for those taking placebo.
However, there was a significant difference between the two groups in the secondary outcome of percent change in caudate volume, with a 3.10% least squares mean reduction in caudate volume at 52 weeks relative to baseline among patients in the laquinimod 1.0 mg group versus 4.86% in the placebo group.
This finding was supported by additional exploratory MRI measures showing reduced caudate volume loss also in the laquinimod 0.5 mg group, as well as smaller reductions in ventricular volume, and whole brain and white matter volume with both the 0.5 mg and 1.0 mg doses of the drug than with placebo.
Reilmann and team explain that these results concord with findings of reduced brain volume loss with laquinimod in patients with multiple sclerosis.
They acknowledge that inconsistent study results have led to the discontinuation of laquinimod development for this population as other evidence-based treatments are available. But they point out that “given the absence of treatments that influence the course of Huntington’s disease, the beneficial effects on brain volume loss in the multiple sclerosis studies are valuable when assessing the potential of laquinimod and immune modulation in Huntingdon’s disease.”
Laquinimod was generally well tolerated by participants and no new safety signals emerged. Treatment-emergent adverse events (TEAEs) were reported by 83%, 71%, 76%, and 77% of those in the 0.5 mg, 1.0 mg, 1.5 mg, and placebo groups, respectively. The most common events were headache (18%, 13%, 17%, and 6%, respectively), diarrhoea (11%, 8%, 10%, and 8%, respectively), and falls (10%, 5%, 7%, and 8%, respectively). Discontinuations due to AEs occurred in a corresponding 6%, 8%, 10%, and 6% of patients.
Reilmann et al note the limitations of the trial duration, which, at 12 months, was half the length of multiple sclerosis studies with laquinimod, and potentially too short to detect a clinical effect on HD neurodegeneration, and the effects of immune modulation may take time to emerge.
Tiago Mestre (University of Ottawa, Ontario, Canada) writes in a related comment that “[a]lthough laquinimod has not been further explored in Huntington’s disease, neuroinflammation continues to be a valid therapeutic target.”
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