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Motor symptoms of Huntington's disease (HD) are so central to the genetic neurodegenerative disease that it was long called Huntington's chorea. However, they're often untreated, despite a growing number of treatments.

"While we don't have a disease-modifying therapy approved yet, we do have effective symptomatic therapies available to address the motor and many of the nonmotor symptoms in HD," said Erin Furr Stimming, MD, of McGovern Medical School at UTHealth Houston.

First-line treatment of these involuntary, jerky movements has largely focused on dysregulation of dopamine, noted Daniel Claassen, MD, of Vanderbilt University Medical Center in Nashville.

Targeting dopamine receptors with antipsychotics has been effective, albeit with side effects that include weight gain, metabolic changes, and internal restlessness relieved by movement.

Blocking presynaptic release of dopamine with the vesicular monoamine transporter 2 (VMAT2) inhibitor tetrabenazine (Xenazine) reduced chorea by 8.1 units among those with baseline scores of 19 or greater on the Unified Huntington's Disease Rating Scale in the randomized .

Then deutetrabenazine (Austedo) came along and showed benefits with twice rather than three-times-a-day dosing. In the , mean total maximal chorea scores improved from 12.1 to 7.7 points, which was 2.5 points better than the improvement in the placebo group, a advantage.

Now a third VMAT2 inhibitor, valbenazine (Ingrezza; FDA-approved for tardive dyskinesia), is in development for Huntington's disease chorea. At the 2022 American Academy of Neurology (AAN) meeting, Furr Stimming and Claassen presented data from the , showing that the once-a-day drug improved chorea severity from baseline by 3.2 units more than did placebo. Drug maker Neurocrine is planning to file for an indication in Huntington's-associated chorea later in 2022.

Off-label medications used for chorea include N-methyl-D-aspartate (NMDA) receptor antagonists, like amantadine (Symmetrel); benzodiazepines; and antiepileptic medications, like carbamazepine.

For dystonia, these sustained pulling, turning, or twisting movements that are not uncommon in HD can also be tackled with botulinum toxin in the case of focal dystonia or by physical therapy to optimize gait and fall protections.

However, even with these options, chorea is undertreated, Furr Stimming said.

Her group's of more than 20,000 Huntington's disease patients worldwide documented chorea in nearly 97% of participants, but only 36% were prescribed medications for chorea.

"What's interesting about these [VMAT2 inhibitor] trials is that the last two trials in particular have used patient global impression of change endpoints," Claassen noted. While anosognosia may remove much of the distress patients feel about hyperkinetic movements, the trials still showed that patients felt better overall when treated with VMAT2 inhibitors, he pointed out.

"It's really forced us to reconsider when should we practice our treatment interventions for patients, because previously a lot of physicians would say, 'Ah, it's not really important to the patients. We're not going to treat it.' Now a lot of us are saying, 'Gosh, maybe the patient doesn't have insight into it, but if we treat it patients will feel better,' which has caused a lot of us to try and recognize earlier the presence of chorea earlier and treat earlier."

Furr Stimming added that just asking patients whether their chorea is troublesome or bothersome usually is not sufficient.

"We can start the conversation by asking that question, but we need to get a bit more granular and ask questions about the impact of chorea on activities of daily living, balance, and quality of life, for example, in an attempt to determine if the chorea is troublesome or bothersome," she said. "Not all chorea has to be treated. If the chorea is mild and we feel confident it is not impacting quality of life or functional independence, we may wait and watch, since all medications have potential side effects."

A potential side effect across the VMAT2 inhibitors approved for HD is the risk of worsening depression and suicidality, which is already common in this population. Both carry a black box warning for depression and suicidality.

Depression, however, is not an absolute contraindication to using this class of medications, as long as the depression is well controlled prior to initiating a VMAT2 inhibitor, Furr Stimming said.

"In a patient with problematic neuropsychiatric symptoms in addition to bothersome chorea, we may opt for an antipsychotic (off label) to treat the motor and nonmotor symptoms," she said. "We want to ensure our patients are well informed of the risks and benefits associated with any medication. Upon initiating a new medication, close follow-up and an open line of communication are imperative."

No head-to-head trials have compared the VMAT2 inhibitors' side effect profile, but there was no suicidal behavior or worsening of suicidal ideation with valbenazine in KINECT-HD, unlike the pivotal trials for the other VMAT2 inhibitors.

Adherence data from real-world insurance claims showed that lower-daily pill burden and reduced side effect profile appeared to make a difference. In a by Claassen's group presented at AAN, the proportion of days covered by medication was 78.5% with deutetrabenazine compared with 69.3% on tetrabenazine, with similar advantage to the twice-daily drug over the thrice-daily drug in discontinuation over 6 months.

Overall, "when people are treated appropriately, they stay on the medication and there are low discontinuation rates," Claassen concluded.

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