A new drug was approved for Huntington’s chorea in 2023, and novel insights about Huntington’s disease emerged in new research.
Valbenazine for Huntington’s Chorea
In August, the FDA expanded the label for valbenazine (Ingrezza) capsules to include chorea associated with Huntington’s disease.
Valbenazine is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor, with once-daily dosing and a relatively short titration period. An estimated 90% of patients with Huntington’s disease experience chorea.
“Clinical results that led to this important approval showed reduction in the severity of chorea as early as 2 weeks after starting Ingrezza at an initial dose of 40 mg, with consistently greater improvements versus placebo seen at all subsequent visits,” researcher Erin Furr Stimming, MD, of the McGovern Medical School at UTHealth in Houston, said in a statement.
“Data also demonstrated Ingrezza was generally well tolerated and showed clinically meaningful improvement in adults with chorea associated with Huntington’s disease,” Furr Stimming added.
The phase III KINECT-HD trial of 128 people with Huntington’s disease supported the FDA’s decision. In the 12-week study, Unified Huntington’s Disease Rating Scale Total Maximal Chorea (UHDRS-TMC) scores decreased by 4.6 points with valbenazine and by 1.4 points with placebo, a difference of 3.2 points on the 28-point scale (P<0.0001), Furr Stimming and co-authors wrote in Lancet Neurology.
The most common treatment-emergent adverse events with valbenazine were sleepiness, fatigue, and falls. Nine (14%) participants in the valbenazine group required a dose reduction because of treatment-emergent adverse events. Three participants, including one in the valbenazine group, experienced serious adverse events during the trial, but none were judged to be related to treatment.
Two other VMAT2 inhibitors, tetrabenazine (Xenazine) and deutetrabenazine (Austedo), are approved for treating Huntington’s-related chorea. They also are approved to treat tardive dyskinesia.
Tetrabenazine and deutetrabenazine are metabolized into four dihydrotetrabenazine stereoisomers with varying degrees of affinity for VMAT2. Valbenazine produces only the stereoisomer with the strongest affinity for VMAT2, Furr Stimming and co-authors noted.
“With the completion of KINECT-HD, there is now robust evidence that all three VMAT2 inhibitors can alleviate chorea in individuals with Huntington’s disease,” wrote Beatrice Heim, MD, PhD, and Klaus Seppi, MD, both of the Medical University of Innsbruck, Austria, in an accompanying editorial.
“Without head-to-head trials, no inferences can be drawn on the efficacy and safety of valbenazine relative to the other two VMAT2-inhibitors, but the phase III trials suggest a favorable side-effect profile of the tetrabenazine derivatives compared with the original drug, presumably related to their pharmacokinetic profiles,” they added.
Sigma-1 Selective Drug Tested in Huntington’s
At the 2023 American Academy of Neurology meeting, researchers showed that Huntington’s patients who received pridopidine, an investigational drug targeting the sigma-1 receptor, did not achieve better UHDRS Total Functional Capacity (TFC) scores after 65 weeks compared with placebo.
With scores in the PROOF-HD trial averaging about 9.9 at enrollment in the two arms, both groups saw declines of 1 point during the study, reported Andrew Feigin, MD, of New York University in New York City. Change from baseline in UHDRS-TFC score was the trial’s primary endpoint.
But Feigin was encouraged by results on another efficacy measure, the Q-Motor score, in which pridopidine was significantly better than placebo at week 26 and remained numerically superior to week 65. When participants on neuroleptics or anti-chorea drugs were removed, pridopidine significantly outperformed placebo throughout the entire study.
Pridopidine’s benefits appeared to peak in the first 6 months, however, then fade away. Q-Motor scores with neuroleptic or anti-chorea drug users excluded increased by about 20 points initially, while those in the placebo group declined, and the gap shrank with further treatment. Other secondary efficacy measures examining cognition showed the same pattern.
Further analyses are forthcoming, Feigin said. An open-label extension is also underway, which includes nearly all of the 437 patients who were still in the trial at week 65.
Huntington’s Disease in Black Patients
An analysis of data from the the multicenter Enroll-HD study showed that baseline clinical status was markedly different between Black and white patients with Huntington’s disease.
Across clinical measures, Black patients with Huntington’s had worse cognitive and motor symptoms at baseline, reported Daniel Claassen, MD, MS, of Vanderbilt University Medical Center in Nashville, Tennessee, and co-authors in Movement Disorders. Disease progression was similar among race groups.
In an interview with MedPage Today, Claassen noted that Huntington’s disease has long been considered a disease that affects a predominantly Caucasian population. “The findings suggest that our outreach efforts to minority patients need to improve,” Claassen observed. The data “indicate that we need to better understand how Huntington’s disease impacts Black patients clinically, as it may have a more severe clinical presentation,” he added.
Huntington’s disease is an autosomal dominant genetic disorder caused by extended cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin gene. Because a child has a 50% likelihood of inheriting the expanded repeat, family-based care may help identify people with Huntington’s, Claassen noted.
“We need to change our care model to look after not only the patient, but caregiver, children, and relatives,” he said. “This will allow us to improve our outreach and reduce care disparities.”
The findings suggest there may be a large cohort of Black patients not evaluated at Huntington’s disease centers, the researchers suggested.
“While Huntington’s is a rare disease, it is a microcosm of neurodegenerative disease in the United States,” Claassen said. “A comprehensive change to our care model will allow us to improve the identification, treatment, and monitoring of patients who suffer from neurodegenerative diseases.”
Widespread Selenium Deficiency in Huntington’s Brains
Postmortem data showed that Huntington’s disease brains had widespread differences in metal levels compared with controls.
Decreases in selenium levels were seen in 11 of 11 investigated brain regions in Huntington’s disease, reported Melissa Scholefield, PhD, of the University of Manchester in England, and co-authors in eBioMedicine. Increased sodium/potassium ratios were observed in every brain region studied except the substantia nigra. Several brain regions had increased calcium or zinc levels. Localized decreases in iron, copper, and manganese were seen in the globus pallidus, cerebellum, and substantia nigra, respectively.
“Despite all the research that has been performed on Huntington’s disease, we still currently have no treatments that can stop, slow, or reverse its symptoms,” Scholefield said in an interview with MedPage Today. “We hope this new discovery, with further research, could potentially lead to a new drug target in the future.”
Earlier evidence suggested blood selenium levels in Huntington’s disease were increased, which is one reason why patients should not self-medicate with supplements, she cautioned.
The researchers obtained brain tissues from nine decedents with Huntington’s disease and nine controls, focusing on 11 brain regions: the cerebellum, substantia nigra, motor cortex, middle frontal gyrus, middle temporal gyrus, sensory cortex, cingulate gyrus, hippocampus, entorhinal cortex, globus pallidus, and putamen. They measured the concentrations of eight essential metals — sodium, potassium, magnesium, calcium, iron, zinc, copper, and manganese — and the metalloid selenium in brain tissues, using inductively coupled plasma mass spectrometry.
The findings need validation in a larger study and further work to determine how selenium contributes to Huntington’s symptoms, Scholefield noted. It’s unclear whether selenium supplementation may have any effect on symptom development, she added.
“We are, at this point, in a very early stage,” Scholefield said. “We will not know the answers to any of these questions until further studies have been performed.”