A Proof-of-Concept Study Evaluating the Phosphodiesterase 10A Inhibitor PF-02545920 in the Adjunctive Treatment of Suboptimally Controlled Symptoms of Schizophrenia.

Abstract

BACKGROUND:

Effective treatments for managing suboptimal clinical responses to current therapy for schizophrenia remain a critical unmet need. Phosphodiesterase 10A (PDE10A) inhibition represents a mechanistically novel approach to the treatment of schizophrenia, with preclinical studies suggesting improvements in partially responsive symptoms could be achieved via adjunctive use of the PDE10A inhibitor PF-02545920. Therefore, the adjunctive safety, tolerability, pharmacokinetics, and efficacy of multiple repeat doses of PF-02545920 were investigated in a phase 1b study and subsequent phase 2 study.

METHODS:

The phase 1b study randomized 37 adult patients with stable symptomatology and stable antipsychotic regimens within 3 cohorts. Study participants received ascending doses of PF-02545920 or placebo for 10 to 18 days. The phase 2 study randomized 240 outpatients with stable symptomatology but suboptimal response to current antipsychotic regimens 1:1:1 to PF-02545920 5 mg, PF-02545920 15 mg, or placebo every 12 hours for 12 weeks. The primary efficacy end point of the phase 2 study was change in the Positive and Negative Syndrome Scale total score from baseline to week 12, with changes in other clinical assessments as secondary end points.

RESULTS:

Treatment was well tolerated, and observed PF-02545920 exposures were within the range predicted to be adequate for demonstrating efficacy. However, no significant differences in the prespecified efficacy end points between the 2 PF-02545920 treatment arms and placebo were observed.

CONCLUSIONS:

Current data and results of a prior monotherapy study in which PF-02545920 failed to differentiate from placebo refute the hypothesis that PDE10A inhibitors have use as antipsychotic agents for schizophrenia.

• Authors: Nicholas DeMartinis 3rd, Rene N Lopez, Eve H Pickering, Christopher J Schmidt, Lev Gertsik, David P Walling, Adam Ogden
• Journal: Journal of clinical psychopharmacology (J Clin Psychopharmacol) 2019 Jul/Aug Vol. 39 Issue 4 Pg. 318-328 ISSN: 1533-712X [Electronic] United States
• PMID: 31205187 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial)

Chemical References

• 2-((4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy)methyl)quinoline
• Antipsychotic Agents
• Phosphodiesterase Inhibitors
• Pyrazoles
• Quinolines

Topics

• Adult
• Antipsychotic Agents (therapeutic use)
• Double-Blind Method
• Drug Therapy, Combination
• Female
• Humans
• Male
• Middle Aged
• Phosphodiesterase Inhibitors (therapeutic use)
• Psychiatric Status Rating Scales
• Pyrazoles (therapeutic use)
• Quinolines (therapeutic use)
• Schizophrenia (drug therapy)