A non-dopamine drug target for schizophrenia finally clears a trial

A four-week phase 2 trial randomly assigned 189 hospitalized adults with acute schizophrenia to one of two doses of the PDE10A inhibitor alofropodect or to placebo. 42.3% of those on the higher dose met the response threshold, compared with 3.8% on placebo.

Almost every antipsychotic in use works by blocking dopamine D2 receptors, and drugs aimed at other targets have a long record of failing in trials. PDE10A inhibitors are one of those graveyards: the enzyme is concentrated in the striatum and looked promising in animals, but earlier compounds did not help patients. This phase 2 trial tested alofropodect, a newer PDE10A inhibitor engineered to bind its target and release it quickly. Across 11 centers in three countries, 189 hospitalized adults who had carried a schizophrenia diagnosis for at least two years and scored 80 or higher on the PANSS symptom scale were randomly assigned to 20 mg of alofropodect, 40 mg, or placebo once daily for four weeks, with neither patients nor raters knowing the assignment. On the main measure, positive symptoms, both doses beat placebo (20 mg: 3.70 points lower; 40 mg: 6.35 points lower). Clinical response, defined as a drop of 30% or more in total PANSS score, occurred in 3.8% on placebo, 15.4% on 20 mg, and 42.3% on 40 mg. Tolerability looked good, with no rise in blood glucose, cholesterol, or triglycerides, though mild movement side effects and sleepiness appeared only in the drug groups. The limits are real: four weeks is short, 189 people is small, and every participant was White.