Overview

Name: MK-8189
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Merck

Background

MK-8189 is a selective inhibitor of phosphodiesterase 10A (PDE10A). This enzyme catalyzes the breakdown of second messengers cGMP and cAMP. PDE10A is abundantly expressed in the striatum in the human brain, and not in other tissues. Abnormal output from the striatum is implicated in positive schizophrenia symptoms of psychosis, hallucinations and delusions. These symptoms also occur in people with Alzheimer’s disease, and are frequently treated with antipsychotic medications.

Preclinical work suggests that PDE10A inhibitors have the potential to alleviate both dopaminergic and glutamatergic dysfunction, which suggests compounds like MK-8189 could have broad-spectrum activity against cognitive impairment in addition to psychosis symptoms (Grauer et al., 2009).

Discovered at Merck, MK-8189 was shown to cross the blood-brain barrier in rats, and to achieve complete brain receptor occupancy by PET displacement studies. It was active in a rat model of psychosis, and in the novel object recognition test of memory (Layton et al., 2023).

Findings

This drug has completed five Phase 1 trials in healthy people and schizophrenia patients, and some data is posted on clinicaltrials.gov (see NCT02181803, NCT03565068). According to a meeting abstract, in a Phase 2a study with 224 participants, 12 mg daily for four weeks did not significantly affect the primary outcome of total symptoms, but did improve positive symptoms (Mukai et al., 2022). Side effects were mild, and few participants discontinued the drug. It caused significant weight loss, compared to the antipsychotic risperidone, which caused weight gain. A larger Phase 2 study began in December 2020, testing higher doses of 16 and 24 mg, for 12 weeks.

From July 2022 to January 2023, Merck ran a Phase 1 trial testing multiple ascending doses of MK-8189 in 29 people with Alzheimer’s disease, with or without symptoms of agitation-aggression and/or psychosis. The placebo-controlled trial compared three titration schedules, from 4 or 8 mg per day to 16 or 24 mg final dose over 28 days. Primary outcomes are adverse events and discontinuations. No results have been made public.

For details on registered trials, see clinicaltrials.gov.

Last Updated: 21 Sep 2023

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References

Paper Citations

Mukai Y, Lupinacci R, Marder S, Mackle M, Snow-Adami L, Voss T, Smith SM, Egan MF, Kent J. Initial clinical profile of the PDE10A inhibitor MK-8189 in people with an acute episode of schizophrenia. Neuroscience Applied 2022 Neuroscience Applied
Grauer SM, Pulito VL, Navarra RL, Kelly MP, Kelley C, Graf R, Langen B, Logue S, Brennan J, Jiang L, Charych E, Egerland U, Liu F, Marquis KL, Malamas M, Hage T, Comery TA, Brandon NJ. Phosphodiesterase 10A inhibitor activity in preclinical models of the positive, cognitive, and negative symptoms of schizophrenia. J Pharmacol Exp Ther. 2009 Nov;331(2):574-90. Epub 2009 Aug 6 PubMed.
Layton ME, Kern JC, Hartingh TJ, Shipe WD, Raheem I, Kandebo M, Hayes RP, Huszar S, Eddins D, Ma B, Fuerst J, Wollenberg GK, Li J, Fritzen J, McGaughey GB, Uslaner JM, Smith SM, Coleman PJ, Cox CD. Discovery of MK-8189, a Highly Potent and Selective PDE10A Inhibitor for the Treatment of Schizophrenia. J Med Chem. 2023 Jan 26;66(2):1157-1171. Epub 2023 Jan 9 PubMed.

Therapeutics

MK-8189

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