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

Background: SOM3355 is a β1-blocker and a vesicular monoamine transporter type 1 and 2 inhibitor developed for the treatment of Huntington's disease (HD). Its novel polypharmacology makes it suited for the effective and safe treatment of chorea and other HD symptoms. Methods: SOMCT03 was a double-blind, randomised, placebo-controlled, parallel-group phase 2b study conducted at 23 sites across seven European countries. Eligible adults with genetically confirmed HD and baseline Total Maximal Chorea (TMC) score ≥10 were randomly assigned (1:1:1) to either orally administered SOM3355 400 mg/day, SOM3355 600 mg/day, or placebo for 12 weeks. The primary efficacy endpoint was the TMC score change from baseline to end of maintenance analysed in the modified intention-to-treat population (mITT) using a mixed-effect model for repeated measures. Values are reported as least-squares mean estimates between active treatments and placebo, with their confidence intervals. Safety assessments included clinical scales for suicidality, depression, sleepiness, akathisia, cognition, and behavioural symptoms in HD. SOMCT03 is registered with EudraCT (2021-003453-28) and ClinicalTrials.gov (NCT05475483). Findings: Between August 2, 2022, and June 25, 2024, 139 patients (66 females and 73 males) were enrolled and received the assigned treatment and were included in the mITT and safety populations. The TMC least-squares mean (LSM) difference between SOM3355 600 mg/day and placebo was -1.0 (CI -2.3 to 0.3, p = 0.0961) in the mITT population. In the predefined sensitivity analysis of 122 patients not taking concomitant antipsychotics (88% of mITT) SOM3355 600 mg/day showed a statistically significant difference from placebo with a LSM difference of -1.3 (CI -2.5 to -0.0; p = 0.0449). In the post-hoc analysis with 57 patients not taking antipsychotics and baseline TMC >12 (41% of mITT), SOM3355 600 mg/day reduced TMC score in -4.5, with a LSM difference vs. placebo of -1.8 (CI -3.4 to -0.2, p = 0.0320). The most reported adverse event per group was bradycardia, six (12%) with SOM3355 600 mg/day and two (5%) with SOM3355 400 mg/day. No suicidality or suicide attempts were reported in patients treated with SOM3355. SOM3355 600 mg/day showed a trend in decreasing depression, anxiety, apathy, and some abnormal behaviours. Interpretation: Although the primary efficacy outcome of this phase 2b study was not met, these findings show SOM3355 600 mg/day is safe and well-tolerated. Prespecified sensitivity analyses showed preliminary evidence that SOM3355 600 mg/day is efficacious in patients with HD not taking concomitant antipsychotics. Further research is needed to confirm these safety data and to investigate the effectiveness of SOM3355. A phase 3 study is planned. Funding: SOM Innovation Biotech SA (SOM Biotech).