MK-8189 / Merck (MSD) - LARVOL DELTA

Uncovering mechanistic differences among PDE10A inhibitors: a multilevel molecular, functional and behavioral comparison underlying the clinical efficacy of CPL'36 (ECNP 2025) - "At 2 mg/kg, CPL'36 produced a robust cataleptogenic effect comparable to that of haloperidol (1 mg/kg, i.p.). Here, we report that CPL'36 offers significant pharmacodynamic advantages over other PDE10A inhibitors, such as MP-10, TAK-063, and MK-8189. To date, PDE10AIs have been shown to produce minimal and non–dose-dependent catalepsy. Our data confirm these findings for the reference compounds, with the exception of CPL'036, which demonstrated a dose-dependent and pronounced cataleptic effect at high dose."

Clinical • CNS Disorders • Movement Disorders • Parkinson's Disease • Psychiatry • Schizophrenia

Unlocking the potential of lumateperone and novel anti-psychotics for schizophrenia. (PubMed, Bioimpacts) - "This review also focuses on a few more emerging antipsychotics like brexpiprazole, brilaroxazine, roluperidone, F17464, pimavanserin (ACP-103), xanomeline, BI 409306, BI 425809 and MK-8189 which are under different phase of clinical trials and might get approved soon. All the antipsychotic drugs covered did not show any other severe adverse effects except gastrointestinal issues and cardiometabolic risk factors. However, still rigorous clinical trials and modifications are needed to manage adverse effects, and we can expect a few antipsychotics to be on the market soon."

Journal • Review • Anesthesia • CNS Disorders • Constipation • Fatigue • Gastroenterology • Gastrointestinal Disorder • Psychiatry • Schizophrenia

Preclinical evaluation of MK-8189: A novel phosphodiesterase 10A inhibitor for the treatment of schizophrenia. (PubMed, J Pharmacol Exp Ther) - "MK-8189 significantly reversed an MK-801-induced deficit in prepulse inhibition at PDE10A EO of ∼47% and higher...MK-8189 significantly attenuated a ketamine-induced deficit in object retrieval performance at exposure that yielded ∼29% PDE10A EO...The PDE10A occupancy achieved by MK-8189 in behavioral studies was used to support dose selection in clinical trials. This work provides evidence to support exploration of higher levels of PDE10A occupancy in clinical trials to determine if this translates to improved efficacy in patients."

Journal • Preclinical • CNS Disorders • Psychiatry • Schizophrenia • PENK

Preclinical Evaluation of MK-8189: A Novel Phosphodiesterase 10A Inhibitor for the Treatment of Schizophrenia. (PubMed, J Pharmacol Exp Ther) - "MK-8189 significantly reversed an MK-801-induced deficit in pre-pulse inhibition at PDE10A EO of ~47% and higher...MK-8189 significantly attenuated a ketamine-induced deficit in object retrieval performance at exposure that yielded ~29% PDE10A EO...The PDE10A occupancy achieved by MK-8189 in behavioral studies was used to support dose selection in clinical trials. This work provides evidence to support exploration of higher levels of PDE10A occupancy in clinical trials to determine if this translates to improved efficacy in patients."

Journal • Preclinical • CNS Disorders • Psychiatry • Schizophrenia

A Study of MK-8189 Human Absorption, Metabolism, and Excretion in Healthy Male Participants (MK-8189-010) (clinicaltrials.gov) - P1 | N=6 | Completed | Sponsor: Merck Sharp & Dohme LLC

New P1 trial

A Study of MK-8189 in Participants With Bipolar I Disorder (MK-8189-020) (clinicaltrials.gov) - P1 | N=34 | Completed | Sponsor: Merck Sharp & Dohme LLC | Active, not recruiting ➔ Completed

Trial completion • Bipolar Disorder • CNS Disorders • Psychiatry

An Active-Controlled Early Phase Study of MK-8189 in Adults With Schizophrenia (MK-8189-005) (clinicaltrials.gov) - P2 | N=224 | Completed | Sponsor: Merck Sharp & Dohme LLC | Phase classification: P2a ➔ P2

Phase classification • CNS Disorders • Psychiatry • Schizophrenia

A Study of MK-8189 in Participants With Bipolar I Disorder (MK-8189-020) (clinicaltrials.gov) - P1 | N=32 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Recruiting ➔ Active, not recruiting

Enrollment closed • Bipolar Disorder • CNS Disorders • Psychiatry

Efficacy and Safety of MK-8189 in Participants With an Acute Episode of Schizophrenia (MK-8189-008) (clinicaltrials.gov) - P2 | N=500 | Completed | Sponsor: Merck Sharp & Dohme LLC | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Psychiatry • Schizophrenia

Effects of PDE10A inhibitor MK-8189 in people with an acute episode of schizophrenia: A randomized proof-of-concept clinical trial. (PubMed, Schizophr Res) - P2a | "These findings suggest that PDE10A inhibition may produce antipsychotic effects and associated weight loss and that further trials with PDE10A inhibitors are warranted."

Clinical • Journal • CNS Disorders • Psychiatry • Schizophrenia • DRD2

A Study of MK-8189 in Participants With Bipolar I Disorder (MK-8189-020) (clinicaltrials.gov) - P1 | N=32 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Not yet recruiting ➔ Recruiting

Enrollment open • Bipolar Disorder • CNS Disorders • Psychiatry

A Study of MK-5720 in Participants With Schizophrenia (MK-5720-001) (clinicaltrials.gov) - P1 | N=17 | Completed | Sponsor: Merck Sharp & Dohme LLC | Recruiting ➔ Completed | N=64 ➔ 17 | Trial completion date: Sep 2024 ➔ Feb 2024 | Trial primary completion date: Sep 2024 ➔ Feb 2024

Enrollment change • Trial completion • Trial completion date • Trial primary completion date • CNS Disorders • Psychiatry • Schizophrenia

Efficacy and Safety of MK-8189 in Participants With an Acute Episode of Schizophrenia (MK-8189-008) (clinicaltrials.gov) - P2 | N=500 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Psychiatry • Schizophrenia

TQT: A Study To Evaluate The Effect Of A Supratherapeutic Dose Of MK-8189 On The QTc Interval In Participants With Schizophrenia (MK-8189-019) (clinicaltrials.gov) - P1 | N=107 | Completed | Sponsor: Merck Sharp & Dohme LLC | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Psychiatry • Schizophrenia

A Study of MK-8189 in Participants With Bipolar I Disorder (MK-8189-020) (clinicaltrials.gov) - P1 | N=32 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC

New P1 trial • Bipolar Disorder • CNS Disorders • Psychiatry

TQT: A Study To Evaluate The Effect Of A Supratherapeutic Dose Of MK-8189 On The QTc Interval In Participants With Schizophrenia (MK-8189-019) (clinicaltrials.gov) - P1 | N=84 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Psychiatry • Schizophrenia

Fragment-to-Lead Medicinal Chemistry Publications in 2022. (PubMed, J Med Chem) - "In addition, trends and new developments in the field are summarized. In 2022, 18 publications described successful fragment-to-lead studies, including the development of three clinical compounds (MTRX1719, MK-8189, and BI-823911)."

Journal • Review

Impact of MK-8189 in Preclinical Models of Cognition and Electroencephalography (EEG) Spectral Power (ACNP 2023) - "Effects were similar in magnitude to the acetylcholinesterase inhibitor donepezil...MK-8189 reversed a ketamine-induced deficit in this task... These preclinical findings suggest that PDE10A inhibition via MK-8189 could potentially impact cognitive impairment in humans. MK-8189 has a significant impact on executive function and episodic memory at similar PDE10A enzyme occupancies (~25 – 50% PDE10A enzyme occupancy). Accordingly, MK-8189 produced significant effects on qEEG spectral power further demonstrating the ability of MK-8189 to modulate signaling in cortical areas associated with cognition."

Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Pharmacokinetics and Tolerability of a Once-Daily Controlled-Release Formulation of MK-8189, an Investigational PDE10A Inhibitor for Treating Schizophrenia (ACNP 2023) - P2 | "All events responded immediately to benztropine. MK-8189 CR was generally well-tolerated in schizophrenia participants. Dystonia was observed at lower doses but not at doses ≥20mg. Based on the enzyme occupancy-concentration relationship, 24mg MK-8189 CR is expected to produce sustained enzyme occupancy ≥80%, while being well-tolerated."

PK/PD data • CNS Disorders • Dystonia • Psychiatry • Schizophrenia

Efficacy and Safety of MK-8189 in Participants With an Acute Episode of Schizophrenia (MK-8189-008) (clinicaltrials.gov) - P2 | N=500 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Phase classification: P2b ➔ P2

Phase classification • CNS Disorders • Psychiatry • Schizophrenia

Pharmacological profile of MK-8189, a novel phosphodiesterase 10A inhibitor, and relationship between phosphodiesterase 10A enzyme occupancy and preclinical efficacy (ECNP 2023) - "MK-8189 (0.25–0.75mg/kg, p.o.) produced a dose-dependent decrease in the rodent MK-801 (non-competitive NMDA receptor antagonist) locomotor response at plasma exposures that corresponded to ~25–50% PDE10A EO. MK-8189 is a potent and selective PDE10A inhibitor with excellent pharmaceutical properties. MK-8189 inhibited PDE10A in vivo and produced robust activation of the striatum as measured by cAMP and pGluR1 signaling. Data from preclinical models of antipsychotic behaviors suggested that a minimum level of ~30% PDE10A EO was required to produce an efficacy signal in some assays, however, full antipsychotic-like activity across assays required >50% PDE10A EO."

Preclinical • CNS Disorders • Psychiatry • Schizophrenia • ACYP1 • LINC00473 • PDE10A

A once-daily controlled-release formulation of MK-8189, a phosphodiesterase 10A inhibitor, achieves an optimal enzyme occupancy, pharmacokinetic profile and is well-tolerated (ECNP 2023) - P2b | "All events responded immediately to benztropine. MK-8189 CR was generally well-tolerated in schizophrenia participants. Dystonia was observed at lower doses but not at doses ≥20mg. Based on the EO-concentration relationship, 24mg MK-8189 CR is expected to produce sustained EO ≥80%, while being well-tolerated."

PK/PD data • CNS Disorders • Dystonia • Psychiatry • Schizophrenia

Weight loss following phosphodiesterase 10A inhibitor schizophrenia treatment explained by adipose tissue physiology changes in obese mice (ECNP 2023) - "Interestingly, MK-8189 was also observed to reduce body weight, particularly in those who were overweight and obese, while a significant weight gain was observed for the standard-of-care risperidone. Mice receiving THPP-6 showed greater weight loss than vehicle-treated animals (-7.1±0.2g vs -0.8±0.4g THPP-6 vs Veh, p<10 -9 ). Imaging showed lower fat fraction in brown adipose tissue in THPP-6 treated vs Veh animals (FF=0.607±0.014 vs 0.700±0.0.008 THPP-6 vs Veh, p=0.0001), consistent with brown fat activation, as well as decreased fat fraction (FF=0.860±0.003 vs 0.8715±0.0.0014 THPP-6 vs Veh, p=0.003) and increased vascular infiltration in inguinal WAT (VF=0.022±0.005 vs 0.0086±0.0.0010 THPP-6 vs Veh, p=0.003), consistent with conversion of white fat to brown fat deposits. Gene expression analysis showed significant upregulation (p=0.02) of Ucp1 and PGC1alpha in the inguinal WAT of THPP-6 vs Veh animals (p=0.03 and p=0.01..."

Preclinical • CNS Disorders • Psychiatry • Schizophrenia

MK-8189, a PDE10A inhibitor, for the treatment of schizophrenia (ECNP 2023) - P2b | "Efficacy results from previous proof-of-concept clinical trials with PF-02545920 and TAK-063 in individuals with acute psychosis have been unimpressive but their enzyme inhibition over 24 hours was likely modest ( 80% trough EO. Consequently, doses up to 24mg, predicted to produce > 80% sustained EO, are being evaluated in an ongoing Phase 2b trial [NCT04624243]."

CNS Disorders • Dystonia • Psychiatry • Schizophrenia • ACYP1 • LINC00473

A Study of MK-5720 in Participants With Schizophrenia (MK-5720-001) (clinicaltrials.gov) - P1 | N=64 | Recruiting | Sponsor: Merck Sharp & Dohme LLC | Not yet recruiting ➔ Recruiting

Enrollment open • CNS Disorders • Psychiatry • Schizophrenia