Immunotherapy candidate laquinimod failed to meet its primary objective of improving motor function in Huntington’s disease patients after 12 months of treatment in a Phase 2 clinical trial. However, it did meet its secondary goal of reducing brain atrophy, according to a press release from Active Biotech.
Laquinimod, developed by Active Biotech and Teva Pharmaceutical Industries, is an oral small molecule designed to cross the blood-brain barrier to ease inflammation in the brain. Preclinical studies in animals showed that laquinimod increases the levels of a growth factor called BDNF, which is critical for the survival of nerve cells and is reduced in Huntington’s patients.
The LEGATO-HD Phase 2 trial (NCT02215616) is evaluating the effectiveness and safety of laquinimod in patients with Huntington’s disease. The multicenter, randomized, double-blind study originally evaluated three daily doses of the potential therapy — 0.5 mg, 1 mg, and 1.5 mg — compared with placebo. However, the team discontinued the 1.5 mg dose in January 2016 after cardiovascular safety concerns were found in studies of multiple sclerosis (MS).
A total of 352 patients were enrolled, with a mean age of 43.9 and similar numbers of men and women. Of these patients, 287 completed the study.
The trial’s primary objective, changes in motor skills and function from the beginning of study, for the 1 mg dose compared with placebo, was assessed using the Unified Huntington’s Disease Rating Scale-Total Motor Scale (UHDRS-TMS).
The study’s secondary goal, reduction of brain atrophy for the 1 mg dose compared with placebo, was assessed by determining the volume of structures called caudate nuclei, located centrally in the brain.
Exploratory outcomes included changes in motor function and brain atrophy for the 0.5 mg dose. Changes in cognitive function and functional capacity were also explored for both doses.
Safety measures included reports of adverse events, clinical laboratory tests, vital signs, electrocardiograms — to measure the heart’s electrical activity — physical examinations, and suicidal thoughts or attempts. Safety results were in accordance with expectations in this patient population, according to the release.
Laquinimod was found to ease motor impairment, improve weight, and extend survival in previous preclinical studies using a mouse model of the disease. These benefits were associated with higher BDNF levels in a brain region called the motor cortex, an area involved in the planning, control, and execution of voluntary movements that is affected in Huntington’s patients. However, a 2017 study, also in mice, found no improvements in survival and weight.
Also in 2017, laquinimod failed to slow the rate of brain atrophy and disease progression in a Phase 2 trial (NCT02284568) in patients with primary progressive MS. Earlier the same year, Active Biotech stopped developing laquinimod for relapsing-remitting MS due to a similar failure in slowing disease progression in a Phase 3 study (NCT01707992).
However, recent data in a mouse model of the disease showed that laquinimod eased damage to vision when given before symptom onset.
The scientists will now conduct a full analysis of the results. Teva plans to present the data at future medical meetings and publish the study in peer-reviewed journals.