An In-Depth Review of MK-5720: A Long-Acting Injectable PDE10A Inhibitor for Schizophrenia

I. Executive Summary

MK-5720, a small molecule drug candidate, has been under development by Merck Sharp & Dohme LLC (Merck) as a long-acting injectable (LAI) formulation targeting phosphodiesterase 10A (PDE10A) for the treatment of schizophrenia. Its development is intrinsically linked to MK-8189, an oral PDE10A inhibitor also from Merck. The primary clinical investigation for MK-5720, a Phase 1 trial (NCT05953740), which included an oral lead-in with MK-8189, was completed in early 2024, focusing on safety, tolerability, and pharmacokinetics. Concurrently, MK-8189 completed a Phase 2a trial (NCT03055338), the results of which, published in June 2024, indicated a trend towards efficacy on the primary PANSS total score endpoint and nominal significance on positive symptoms, alongside a favorable safety profile, notably inducing weight loss compared to placebo and active comparator risperidone.

Despite these developments, a critical observation is the absence of both MK-5720 and MK-8189 from Merck's publicly disclosed pipeline as of February 2025. This omission, following the completion of their respective trial phases, strongly suggests a potential discontinuation or strategic deprioritization of Merck's PDE10A inhibitor program for schizophrenia. This decision occurs within a challenging landscape for PDE10A inhibitors, a class that has seen multiple clinical trial failures from various pharmaceutical companies despite a strong preclinical rationale for treating the complex symptoms of schizophrenia. The precise reasons for Merck's apparent shift remain undisclosed, but likely reflect a comprehensive assessment of the clinical data, the historical difficulties in translating PDE10A inhibition into robust clinical efficacy, and broader portfolio management considerations.

II. Introduction to MK-5720

A. Overview of MK-5720