SOM3355’s Multimodal Mechanism May Differentiate It From Existing VMAT2 Inhibitors in Huntington Disease

A newly published translational pharmacology study has characterized the mechanism of action of SOM3355 (bevantolol hydrochloride), an investigational therapy for Huntington disease (HD), identifying a combination of vesicular monoamine transporter 1 (VMAT1) inhibition, VMAT2-mediated dopamine modulation, and β1-adrenergic antagonism that may distinguish it from currently approved therapies for chorea.¹

The findings, published by investigators from SOM Innovation Biotech and collaborating academic centers, provided preclinical evidence supporting a pharmacologic profile that extends beyond traditional VMAT2 inhibition. All told, the authors suggested that this multimodal activity could potentially address both motor and neuropsychiatric manifestations of HD, although the clinical relevance of these mechanistic findings remains to be established in larger late-stage trials.

HD is a progressive neurodegenerative disorder characterized by motor dysfunction, psychiatric symptoms, and cognitive decline. Chorea remains one of the most visible and disabling manifestations of the disease. Current FDA-approved pharmacologic options for HD-associated chorea primarily target VMAT2, including tetrabenazine, deutetrabenazine, and valbenazine. Although effective in reducing choreiform movements, these agents can be associated with adverse effects including depression, somnolence, parkinsonism, akathisia, and other neuropsychiatric complications that may complicate long-term management.^2,3

Preclinical Evaluation Reveals Distinct VMAT Profile

In a series of in vitro and translational studies, investigators compared SOM3355 with tetrabenazine and related VMAT2 inhibitors. Mechanistically, SOM3355 inhibited VMAT2-mediated dopamine uptake with potency similar to tetrabenazine, demonstrating an IC50 of approximately 98 nM in rat striatal vesicles compared with 75 nM for tetrabenazine.¹

However, binding studies suggested a substantially different interaction with the VMAT2 transporter. SOM3355 displayed markedly lower affinity for the α-dihydrotetrabenazine (α-DHTBZ) binding site than tetrabenazine, with an IC50 of 1.35 μM compared with 19.23 nM for tetrabenazine. Differential scanning fluorimetry experiments also demonstrated less thermal stabilization of VMAT2, findings the authors interpreted as potentially consistent with a more reversible interaction with the transporter.

Perhaps the most notable differentiating feature was potent inhibition of VMAT1. SOM3355 inhibited VMAT1-mediated serotonin uptake with an IC50 of 44 nM, whereas tetrabenazine and its active metabolites demonstrated little to no VMAT1 activity.

VMAT1 is expressed in several brain regions implicated in cognition, emotion, and behavioral regulation, including the frontal cortex, hippocampus, amygdala, and thalamus. The investigators hypothesize that modulation of VMAT1 may contribute to effects beyond chorea control, although direct clinical evidence linking VMAT1 inhibition to neuropsychiatric benefit in HD is currently lacking.¹

Clinical Signals Extend Beyond Chorea

The mechanistic study builded on previously reported clinical findings from the SOM3355 development program. According to data from a phase 2b randomized, placebo-controlled study reported by the sponsor in 2025, SOM3355 demonstrated statistically significant improvements in chorea while showing no signal for worsening depression, suicidality, cognition, somnolence, or akathisia. The company also reported improvements in several behavioral domains, including anxiety, irritability, compulsive behaviors, and apathy. However, these findings have not yet been fully published in a peer-reviewed clinical trial manuscript.⁴

In October 2025, SOM Biotech announced that the FDA had agreed with a proposed phase 3 development strategy following an End-of-Phase 2 meeting, potentially establishing a regulatory pathway toward a future new drug application in HD.⁵

Potential Implications for the Treatment Landscape

The therapeutic rationale for SOM3355 reflects ongoing efforts to address limitations associated with existing dopamine-depleting therapies.

Tetrabenazine became the first FDA-approved treatment for HD-associated chorea in 2008, followed by deutetrabenazine in 2017. Deutetrabenazine was developed in part to improve pharmacokinetic stability and tolerability relative to tetrabenazine.^2,3 Nevertheless, clinicians continue to balance chorea reduction against potential psychiatric and motor adverse effects when selecting and titrating VMAT2 inhibitors.

The current study suggests that SOM3355 may achieve modulation of dopaminergic signaling through a mechanism distinct from classical VMAT2 blockade while simultaneously affecting adrenergic and VMAT1 pathways. Whether this pharmacology translates into clinically meaningful advantages remains uncertain.

Limitations and Next Steps

Several limitations should be considered when interpreting the findings. Much of the evidence presented derives from in vitro assays, receptor binding studies, and animal models. The article also includes several mechanistic hypotheses regarding psychiatric, cognitive, and potentially disease-modifying effects that have not been demonstrated in prospective clinical trials. In addition, several clinical observations cited by the authors originate from company-sponsored studies that have yet to undergo full peer-reviewed publication.¹

As a result, the study should primarily be viewed as a translational framework for understanding the compound’s mechanism rather than definitive evidence of clinical superiority over established VMAT2 inhibitors.

Future phase 3 studies will be necessary to determine whether the mechanistic differences observed with SOM3355 translate into improved efficacy, tolerability, or broader symptom control for patients with HD.

REFERENCES
1. Turilli-Ghisolfi ES, Støve SI, Huertas O, et al. SOM3355: a unique pharmacological profile combining VMAT1 inhibition, VMAT2-mediated dopamine modulation, and β1-adrenergic antagonism for the treatment of movement and neuropsychiatric disorders. Front Pharmacol. 2026. DOI pending/full article available through Frontiers. Link: https://www.frontiersin.org/
2. Frank S, Testa CM, Stamler D, et al. Effect of deutetrabenazine on chorea among patients with Huntington disease: a randomized clinical trial. JAMA. 2016;316(1):40-50. https://doi.org/10.1001/jama.2016.8655
3. FDA approval history for deutetrabenazine (Austedo) in Huntington disease chorea and tardive dyskinesia. Link: https://www.fda.gov/ and product information available through Teva Pharmaceuticals.
4. SOM Biotech announces phase 2b study results for SOM3355 in Huntington disease. February 2025. International Huntington Association. https://huntington-disease.org/2025/02/06/som-biotech-announces-phase-2b-study-results/
5. SOM Biotech secures registrational pathway for SOM3355 following FDA End-of-Phase 2 meeting. October 2025. https://sombiotech.com/news/som-biotech-secures-clear-registrational-path-for-som3355-in-huntingtons-disease-after-fda-end-of-phase-2-meeting/