PDE10A inhibition in schizophrenia: unique pharmacodynamic profile of CPL’36 improves positive and negative symptoms

CPL’36 (alofropodect) , a second-generation phosphodiesterase 10A (PDE10A) inhibitor, demonstrated robust efficacy in a multinational, randomized, placebo-controlled Phase II study in patients with acute exacerbation of schizophrenia. A total of 189 patients with moderately to severely symptomatic schizophrenia received once-daily CPL’36 20 mg, 40 mg, or placebo for 4 weeks.

At Week 4, CPL’36 significantly reduced PANSS total scores versus placebo, with least-squares (LS) mean differences of 9.7 points for 20 mg (p<0.001; Cohen’s d=0.77) and 16.4 points for 40 mg (p<0.001; Cohen’s d=1.47). The primary endpoint, change in the PANSS positive subscale, was also significantly improved, with LS mean differences of 3.7 points for 20 mg (p<0.001; Cohen’s d=0.73) and 6.3 points for 40 mg (p<0.001; Cohen’s d=1.38). Significant improvements were also observed in negative symptoms (LS mean difference of 1.0 and 2.6 , p-value 0.08 and <0.001, and Cohen’s d 0.4 and 1.0. for 20 and 40 mg, respectively), supporting efficacy beyond the positive symptom domain.

CPL’36 was generally well tolerated. Treatment-emergent serious adverse events occurred in 1.5%, 1.8%, and 3.1% of patients receiving placebo, 20 mg, and 40 mg, respectively. Treatment-related adverse events leading to discontinuation occurred in 3.1%, 1.8%, and 7.7%, respectively.

These findings provide clinical evidence of robust antipsychotic efficacy mediated by alofropodect (CPL’36). The unique pharmacodynamic profile of the fast-dissociating PDE10A inhibitor CPL’36, with preferential modulation of D2- over D1-mediated striatal pathways, may contribute to its therapeutic profile and successful clinical translation