Old Blood Pressure Drug Shows Promise Against Huntington’s Disease Chorea

A drug that has quietly treated hypertension for more than three decades may be about to find a second life in one of neurology’s most challenging diseases. In a phase 2b clinical trial published in eClinicalMedicine, researchers report that SOM3355, the hydrochloride salt of the beta-blocker bevantolol, reduced the involuntary writhing movements known as chorea in patients with Huntington’s disease while avoiding the psychiatric hazards that shadow the currently approved treatments. The study, conducted across 23 sites in seven European countries, enrolled 139 patients and tested two doses of the drug against placebo over a twelve-week period. Its results, while nuanced, offer something the Huntington’s community has rarely seen: a chorea therapy that did not worsen depression, trigger akathisia, or induce the sedation that plagues existing options.

Huntington’s disease is a relentlessly progressive neurodegenerative disorder caused by an expanded CAG repeat in the Huntingtin gene, which produces a mutant protein that accumulates in neurons and exerts a toxic gain of function. The hallmark motor symptom, chorea, consists of involuntary, irregular movements that grow more severe over time and often interfere with daily activities. But the disease extends far beyond movement. Patients face progressive cognitive decline and a heavy burden of psychiatric symptoms, including anxiety and depression, with roughly twenty percent experiencing suicidal ideation. No preventive or disease-modifying therapy exists, so treatment remains purely symptomatic, and the pharmacological toolkit is thin.

The current standard of care for chorea rests on inhibitors of the vesicular monoamine transporter type 2, or VMAT2, a protein that packages monoamine neurotransmitters into synaptic vesicles. By blocking this transporter, drugs such as tetrabenazine, deutetrabenazine, and valbenazine deplete presynaptic dopamine, dampening the excess dopaminergic tone that drives chorea. This mechanism makes physiological sense: in Huntington’s disease, elevated presynaptic dopamine coincides with reduced postsynaptic D1 and D2 receptor expression on striatal neurons, so reducing dopamine release addresses the core imbalance more directly than postsynaptic dopamine receptor blockers like antipsychotics. Yet the same dopamine depletion carries a steep price. These drugs can precipitate or worsen depression, suicidality, akathisia, parkinsonism, and somnolence, and tetrabenazine carries a black box warning in the United States and is contraindicated in patients with depression or suicidal ideation in Europe.

SOM3355 emerged from an unusual route. SOM Biotech, the Spanish company behind the drug, identified bevantolol hydrochloride, a mild beta-1 blocker with thirty years of clinical use and cumulative exposure in more than 2.5 million people, through its proprietary artificial intelligence platform SOMAI PRO as a VMAT2 inhibitor. Subsequent pharmacological characterisation revealed a profile that distinguishes it from tetrabenazine in three ways. Its interaction with the VMAT2 binding site differs, producing monoamine signalling changes with a similar effect on dopamine but a significantly weaker effect on serotonin, roughly ten-fold lower serotonin affinity than tetrabenazine. It also inhibits VMAT1, a transporter tetrabenazine does not touch, and it retains beta-1 adrenergic blockade, a property that lipophilic beta-blockers have used to treat anxiety, irritability, agitation, memory disorders, and akathisia in other neuropsychiatric conditions.

The SOMCT03 trial was designed to test whether this polypharmacology translates into clinical benefit. It was a double-blind, randomised, placebo-controlled, dose-ranging study in which adults with genetically confirmed Huntington’s disease and a baseline Total Maximal Chorea score of at least ten were allocated in a one-to-one-to-one ratio to SOM3355 400 mg per day, SOM3355 600 mg per day, or placebo. The primary endpoint was the change in Total Maximal Chorea score, measured on the Unified Huntington’s Disease Rating Scale, between baseline and the end of the maintenance dose period, analysed with a mixed-effect model for repeated measures. The trial also broke new ground by incorporating Huntington’s-specific safety endpoints, including the Problem Behaviour Assessment-short form for behavioural symptoms, alongside scales for depression, sleepiness, and akathisia, aiming to define the drug’s profile beyond chorea alone.

The headline result was complicated by a phenomenon familiar to anyone who follows clinical trials: a strikingly strong placebo response. In the full modified intention-to-treat population, neither dose separated significantly from placebo on the primary endpoint, with the 600 mg per day dose showing a least-squares mean difference of minus 1.0 points and the 400 mg dose minus 0.2 points. Placebo patients improved by up to 2.3 points, roughly twice what the investigators had anticipated, possibly reflecting expectation effects and the unusually extensive contact with healthcare professionals in a disease with few effective treatments available in Europe.

However, the picture changed in the predefined sensitivity analysis restricted to the 122 patients, eighty-eight percent of the cohort, who were not taking concomitant antipsychotics, which act as dopamine receptor blockers and confound the assessment of any dopaminergic agent. In this subgroup, the 600 mg per day dose achieved a statistically significant reduction in chorea compared with placebo, with a least-squares mean difference of minus 1.3 points. A post-hoc analysis of the 57 patients who were both antipsychotic-free and had baseline chorea scores above twelve, corresponding to the upper mild range and more comparable to populations in other VMAT2 inhibitor trials, showed an even stronger effect, with chorea scores falling by 4.5 points at the final on-treatment visit and a placebo-adjusted difference of minus 1.8 points. These figures sit comfortably alongside the phase 3 results for valbenazine and deutetrabenazine, which produced placebo-adjusted differences of minus 3.2 and minus 2.5 points respectively.

Crucially, the numeric improvements were echoed by global clinical impressions. On the Clinical Global Impression of Change, seventy percent of patients on 400 mg per day and fifty-six percent on 600 mg per day were rated as improved at the final visit, compared with thirty-seven percent on placebo, and in the antipsychotic-free subgroup with higher baseline chorea, seventy-four percent of patients on the higher dose were rated improved versus twenty-one percent on placebo. Patient-rated impressions told the same story. The investigators argue that this convergence between score reductions and validated global measures of real-world change demonstrates that the observed effects are clinically meaningful to both patients and physicians, a point they intend to address directly in the design of the upcoming phase 3 study.

The safety findings may prove to be the trial’s most consequential contribution. Eighty-four percent of participants completed the study, most adverse events were mild and judged unrelated to treatment, and there were no deaths. The most notable drug-related event was bradycardia, an expected consequence of beta-1 blockade, reported in twelve percent of patients on the higher dose and leading to discontinuation in a handful of cases; heart rate reduction plateaued at around fifteen beats per minute at the 400 mg dose with no further decline at 600 mg. Blood pressure changes remained within normal limits and no QT interval prolongation was observed. More striking was what did not happen: no suicidality or suicide attempts occurred on the Columbia-Suicide Severity Rating Scale among drug-treated patients, the Beck Depression Inventory score actually fell by three points in the 600 mg arm, the Epworth Sleepiness and Montreal Cognitive Assessment scales showed no negative effects, and the Barnes Akathisia Rating Scale detected no emergence of akathisia in any group. The behavioural assessment even hinted at mild improvements in anxiety, apathy, and certain abnormal behaviours.

The trial has limitations the authors acknowledge candidly. Concomitant antipsychotic use confounded the primary analysis, the final visit assessments in the high-dose arm were performed during dose down-titration at lower plasma concentrations, the largely white European cohort limits generalisability, and the protocol did not follow sex and gender equity reporting guidelines. Still, the overall picture is of a drug that matches existing VMAT2 inhibitors on chorea control in the patients most relevant to such treatment, while eliminating the psychiatric and motor liabilities that constrain current therapy. A double-blind, placebo-controlled phase 3 study of SOM3355 at 600 mg per day is planned to confirm efficacy and long-term safety across the disease course. If it succeeds, a fifty-year-old antihypertensive, resurrected by an algorithm, could become the first chorea treatment that Huntington’s patients can take without trading away their mood, their sleep, or their peace of mind.

Subject of Research: A phase 2b trial of the repurposed beta-blocker SOM3355 for treating chorea in Huntington's disease

Article Title: Safety and efficacy of SOM3355 in patients with Huntington’s disease (SOMCT03): a phase 2b, randomised, placebo-controlled, multicentre, dose-ranging study

Article References: Kulisevsky, J., Craufurd, D., Lewerenz, J., Scaglione, C., Squitieri, F., Youssov, K., Burgunder, J.-M., Ferré, A., Panigone, S., & Medori, R. (2026). Safety and efficacy of SOM3355 in patients with Huntington’s disease (SOMCT03): a phase 2b, randomised, placebo-controlled, multicentre, dose-ranging study. eClinicalMedicine, 100, Article 104234. https://doi.org/10.1016/j.eclinm.2026.104234

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104234

Keywords: Huntington's disease, chorea, SOM3355, bevantolol, VMAT2 inhibitor, drug repurposing, clinical trial, neurodegeneration, psychiatric safety, phase 2b, tetrabenazine, artificial intelligence drug discovery