F40 Proof-of-concept study testing SOM3355, a VMAT2 inhibitor for the treatment of chorea in huntington’s disease

Background SOM3355 (bevantolol hydrochloride), a β1-adrenoceptor blocker used in hypertension, was identified as a vesicular monoamine transporter type 2 (VMAT2) inhibitor by artificial intelligence screening, and then selected by in vitro functional studies as the best candidate to be repositioned for treatment of dyskinetic movement disorders, such as chorea in Huntington’s disease (HD). Aim A proof-of-concept phase IIa study was performed to assess SOM3355 efficacy and safety in patients with HD presenting chorea. Methods In this double-blind, randomized, crossover, placebo-controlled study, 32 patients were randomly assigned to one of the two arms of 4 sequential 6-week periods to receive placebo and SOM3355 at 100 and 200 mg BID in a crossover design. The primary endpoint was the improvement of at least 2 points in the total maximal chorea (TMC) score of the Unified Huntington’s Disease Rating Scale (UHDRS) in any SOM3355 period compared with the placebo period. Results Almost 60% of the patients had improvements in the TMC score of at least 2 points in any period with SOM3355 compared with placebo, thus reaching the primary endpoint. Even greater TMC score improvements of 3, 4, 5, and 6 points compared with placebo were seen with SOM3355 in 28.6%, 25.0%, 17.9%, and 10.7% of the patients, respectively. The mixed-model analysis comparing the different periods revealed significant improvement in the TMC score with SOM3355 at 200 mg BID compared with placebo (P = 0.0224), as confirmed in Clinical and Patient Global Impression of Change ratings. Mild elevations in plasma prolactin levels were recorded with SOM3355 (P Conclusion This study confirms that SOM3355 reduces chorea in patients with HD and has a good safety profile.