PDE10A Inhibition in Schizophrenia: A Randomised, Placebo-Controlled Phase 2 Study of Alofropodect (CPL’36) in Patients Experiencing Acute Schizophrenia

BACKGROUND: Drugs that inhibit phosphodiesterase 10A (PDE10A) activity have shown efficacy in animal models. However, clinical trials of PDE10A inhibitors in patients with schizophrenia have failed to provide clinically significant results up to this point. Our study investigated whether alofropodect (previously referred to as CPL'36 or CPL500036), a PDE10A inhibitor with an improved pharmacological profile compared with other PDE10A inhibitors, including a fast dissociation rate and high activity, could improve symptoms of acute schizophrenia. METHODS: In this phase 2, randomised, double-blind, placebo-controlled, parallel-group trial (11 centres, three countries), investigators randomly assigned hospitalised patients with acute schizophrenia to treatment or placebo groups. The main inclusion criteria were age 18-65 years, a documented diagnosis of schizophrenia for at least 2 years before screening and a positive and negative syndrome scale (PANSS) total score ≥ 80. Participants were randomly assigned (1:1:1) to receive oral alofropodect (20 mg or 40 mg) or placebo administered once daily in the morning for 4 weeks. The primary endpoint of the study was an improvement in the PANSS positive subscale at week 4. The secondary endpoints included improvements in PANSS total and negative subscale scores, along with other efficacy and safety assessments. Clinical responders were defined as those with a ≥ 30% reduction in PANSS total score from baseline at week 4. RESULTS: Between 24 May 2021 and 8 May 2024, investigators randomised 189 patients into three groups: 58 into the alofropodect 20 mg group, 66 into the alofropodect 40 mg group and 65 into the placebo group. The mean age was 41.7 years (standard deviation (SD) 10.1), and 119 (63%) participants were men, 70 (37%) were women. All participants were White. We measured the difference in PANSS positive subscale before and after treatment, and the change met the primary endpoints at week 4 with the group where alofropodect 20 mg was compared with placebo (- 3.70 [90% CI - 5.51 to - 1.89]; p < 0.001) and alofropodect 40 mg versus placebo (- 6.35 [90% CI - 8.12 to - 4.57]; p = 0.001). Both the 20-mg and 40-mg doses of alofropodect were effective in improving the total PANSS score compared with placebo and met most secondary efficacy endpoints. A clinical response was observed in 2 of 53 patients (3.8%) in the placebo group, 8 of 52 patients (15.4%) in the 20 mg group and 22 of 52 patients (42.3%) in the 40 mg group at week 4. The compound was well tolerated, with only a few serious adverse events. The discontinuation rates were similar in the placebo and treatment arms. Extrapyramidal symptoms (EPS) occurred only in the active treatment groups, but rates were low overall. Somnolence was also reported only in alofropodect groups. Vital signs and biochemical parameters remained unaffected by either dose at any time point. Specifically, blood glucose, total cholesterol and triglycerides did not increase at any dose compared with placebo within our study window. CONCLUSIONS: Alofropodect was effective in the treatment of acute schizophrenia symptoms and was well-tolerated, warranting further investigation in larger clinical studies. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT05278156; registration date: 2022-02-09.