LEGATO-HD: Laquinimod Misses Primary Aim in Huntington's

Damian McNamara

May 09, 2019

PHILADELPHIA — The disappointing news continues for researchers evaluating laquinimod (Teva/Active Biotech) in neurodegenerative disease. The LEGATO-HD study shows the agent did not meet its primary endpoint of improving total motor scores among people with Huntington disease (HD) at 1 year compared to baseline.

In 2017, laquinimod also failed to meet the primary outcome of the CONCERTO trial in relapsing-remitting multiple sclerosis, as previously reported by Medscape Medical News, a trial meant to break the tie between the positive ALLEGRO trial and the negative BRAVO trial.

"The primary endpoint of the study was negative, no doubt," Ralf Reilmann, MD, PhD, Founder of the George-Huntington-Institute and chair of the Huntington Unit in the Department of Neurology, University of Muenster, Germany, said of their study results here at the American Academy of Neurology (AAN) 2019 Annual Meeting.

However, a secondary outcome — changes in caudate volume on brain imaging — emerged as positive. The patients treated with laquinimod demonstrated significantly greater preservation of caudate volume compared with those assigned to placebo over the 52-week study.

LEGATO-HD investigators enrolled individuals ages 21 to 55 years with early stage, adult-onset HD. At baseline, participants had a Unified Huntington Disease Rating Scale-Total Motor Score (UHDRS-TMS) greater than 5 and a total functional capacity (TFC) score of 8 or higher.

The trial was conducted at 48 sites in 10 countries. Researchers randomly assigned participants to one of four groups: laquinimod 0.5 mg, laquinimod 1.0 mg, laquinimod 1.5 mg, or placebo. However, they discontinued the 1.5 mg dose group because of safety concerns in multiple sclerosis studies, as previously reported by Medscape Medical News.

The three remaining cohorts included 107 people in the 0.5 mg laquinimod group, 107 in the laquinimod 1.0 mg group, and another 108 taking a placebo once daily.

In terms of safety and tolerability, "We did not see anything of particular concern in terms of adverse events or serious adverse events," Reilmann said here at the meeting. Laquinimod "was very well tolerated, there were no issues with suicidal behavior or ideation, and no dose-effect was observed."

"So [it is] a safe drug as far as it seems in Huntington's disease," he added.

Change from baseline to 52 weeks in UHDRS-TMS scores was not statistically significant (P = .4853). "When we started this trial, we were aware of the fact that the UHDRS total motor score was probably not going to be a very good measure of efficacy of a potentially disease-modifying drug over one year," he noted.

Although there were no treatment effects seen in rater-dependent clinical outcome measures, certain Q-Motor rater-independent assessments, such as tap speed inter-onset-interval of the hands, provided evidence for a treatment effect, the researchers note.

The clinical relevance is unclear, Reilmann said, "but the Q-Motor findings are quantitative, clinical, and objective…and they seem to suggest a central mechanism of action of this immune modulating agent."

Imaging Findings

The study revealed "robust findings" on imaging with both doses of laquinimod, Reilmann said.

In the laquinimod 1.0 mg dose group, the percentage change in caudate volume from baseline to week 52 was significant (P = .0002). The researchers also reported a "highly significant rescue" of whole brain volume, (P = .004), white matter changes (P = .0004) and ventricular volume (P = .0033).

Whether the MRI findings correlate to a clinical benefit or not is a question for future research, Reilmann said. There is ongoing imaging with magnetic resonance spectroscopy (MRS) and positron emission tomography (PET).

Laquinimod is a small molecule with good bioavailability that reaches the brain and the whole body quickly, Reilmann said. "Let's see what future research shows us. It could be part of a cocktail of treatment for Huntington's disease in the future."

During the Q&A, session co-moderator Jee Bang, MD, assistant professor of neurology and clinical director of the Johns Hopkins Huntington Disease Center of Excellence in Baltimore, Maryland, asked if any of the UHDRS Total Motor Scale subscales showed a significant difference from baseline to 52 weeks.

"There were no significant findings on any of the subscores, to be honest. There was nothing relevant we could find in the subanalysis here," Reilmann replied.

One Piece of the Puzzle?

The relative short study duration in HD and/or the specific clinical measure used in the study could be reasons behind the failure to attain the primary outcome, session co-moderator Danny Bega, MD, assistant professor of neurology (movement disorders) at Northwestern University's Feinberg School of Medicine in Chicago, Illinois, told Medscape Medical News when asked to comment.

"My sense is the clinical outcome they were looking at, the Unified Huntington Disease Rating Scale-Total Motor Score changes…if treatment is effective, I would expect it to take years to really see that change," he said.

Another possibility is that laquinimod only targets one aspect of neurodegeneration, inflammation, "which is probably one piece of a larger puzzle," Bega said. "I think when he brought up the point about this being a potential part of a cocktail, I think that's exactly right."

The decrease in caudate volume was unexpected, Bega said. "You look at the imaging, and it's shocking. I really would not have predicted the imaging change to be significant."

"We know the [brain] area they're talking about correlates with disease progression, with changes that can be seen early in the disease," he added.

The findings raised more questions than answers for Bega, he said. "I'm not convinced it's not an effective drug."

Teva Pharmaceuticals sponsored the study but announced in September 2018 it would no longer to pursue development of laquinimod, and returned rights to the drug back to Active Biotech. Reilmann has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities from Teva Pharmaceuticals. He also has received research support from Teva. Bang and Bega have disclosed no relevant financial relationships.

American Academy of Neurology (AAN) 2019 Annual Meeting: Abstract S16.007. Presented May 7, 2019.

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