Small Molecule · MK-8189
Elpipodect (MK-8189)
Oral, once-daily, highly potent and selective phosphodiesterase 10A (PDE10A) inhibitor (functional Ki 0.029 nM at human PDE10A; >500,000-fold selectivity over PDE1-PDE11) developed by Merck (MSD) for schizophrenia. PDE10A is enriched in striatal medium spiny neurons; its inhibition raises cAMP/cGMP tone and was hypothesized to normalize dysregulated striatal signaling in psychosis. The schizophrenia efficacy program (Phase 2a and Phase 2b) failed to demonstrate antipsychotic efficacy versus placebo on PANSS total score at the doses tested; a notable signal was weight reduction (vs risperidone-associated weight gain). Development subsequently moved toward bipolar I disorder and Alzheimer's disease agitation.
Also known as: MK-8189, MK8189, elpipodect, 1424371-93-6
- Modality
- Small molecule
- Chemical class
- pyrimidine, 1,3,4-thiadiazole, cyclopropane, pyridine
- Chemistry
- Single enantiomer
- Mechanism
- PDE10A inhibitor
- Highest phase
- Discontinued
- Lead indication
- Schizophrenia
- Developer
- Merck & Co., Inc. (MRK)
- Trials
- 2 tracked · 149 sites
Mechanism of action
Highly potent, selective, reversible inhibitor of phosphodiesterase 10A (PDE10A; gene PDE10A), a dual cAMP/cGMP phosphodiesterase highly enriched in striatal medium spiny neurons. Functional Ki at the human PDE10A enzyme is 0.029 nM, with a cellular IC50 of ~1.6 nM and greater than 500,000-fold selectivity over the other PDE families (PDE1-PDE11). PDE10A inhibition increases intracellular cyclic-nucleotide signaling in both the direct and indirect striatal output pathways, a mechanism hypothesized to normalize the aberrant striatal signaling implicated in schizophrenia.
| Target | Action | Affinity |
|---|---|---|
| PDE10AprimaryPDE10A | Inhibitor | Ki 0.029 nMⓘ |
Formulations
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| MK-8189 oral controlled-release tabletcontrolled_release Controlled-release (CR) oral tablets built from 4 mg CR units; clinical doses of 8 mg, 16 mg, and 24 mg once daily evaluated in schizophrenia. | Oral | Once daily | t½ 8.4 h · Tmax 10 h |
Development timeline
- missedPhase 2b (NCT04624243) missed: neither MK-8189 16 mg nor 24 mg separated from placebo on PANSS total at Week 6.↗
- Phase 2b (NCT04624243) completed; MK-8189 16 mg and 24 mg failed to separate from placebo on PANSS total at Week 6.
- Phase 2b study (NCT04624243, MK-8189-008) initiated to test higher doses (8/16/24 mg) over 12 weeks vs placebo and risperidone.
- Phase 2a proof-of-concept (NCT03055338, MK-8189-005, n=224) completed; primary PANSS total endpoint at Week 4 not met (difference -4.7 vs placebo, p=0.074), with a nominally significant effect on the PANSS positive subscale (p=0.011). Results published in Schizophr Res 2024;270:37-43.↗
Elpipodect (MK-8189) for Schizophrenia
DiscontinuedDiscontinuedSchizophrenia indication →
Phase 2 schizophrenia efficacy program (Merck/MSD; co-funded via a 2022 Royalty Pharma R&D collaboration). The Phase 2a proof-of-concept study (NCT03055338, MK-8189-005, 12 mg, n=224) missed its primary PANSS total endpoint at Week 4 (difference -4.7 vs placebo, p=0.074; nominal effect on the PANSS positive subscale, p=0.011) but supported higher-dose testing. The Phase 2b study (NCT04624243, MK-8189-008, 8/16/24 mg, n=499) then failed: neither the 16 mg (difference -2.8, p=0.241) nor 24 mg (difference -0.7, p=0.784) dose separated from placebo on PANSS total at Week 6, while the risperidone active control did (difference -6.2, p=0.040). The investigators concluded that PDE10A inhibition does not produce an antipsychotic effect at the doses tested (J Clin Psychopharmacol 2026). A consistent finding was weight reduction on MK-8189 vs weight gain on risperidone. No further schizophrenia trial has been initiated; subsequent MK-8189 development pivoted to bipolar I disorder and Alzheimer's-disease agitation, so the schizophrenia program is treated here as discontinued. NOTE: there is no explicit Merck/Royalty Pharma discontinuation press release for the schizophrenia indication -- see _comment reviewer flags.
Readouts
- 2026-02-23ReportedFull resultsmissedNCT04624243
Phase 2b (NCT04624243) missed: neither MK-8189 16 mg nor 24 mg separated from placebo on PANSS total at Week 6. ↗
- 2024-08-01ReportedFull resultsmissedNCT03055338
Phase 2a (NCT03055338) missed primary PANSS total endpoint at Week 4 (trend only, p=0.074). ↗
Clinical trials
NCT04624243MK-8189-008Phase 2Completedn=499
A Phase 2B Randomized, Double-Blind, Placebo- and Active-Controlled Trial of the Efficacy and Safety of MK-8189 in Participants Experiencing an Acute Episode of Schizophrenia
mixedsecondaryBody weight change over 12 weeks (acute + extension)
Replicating the Phase 2a signal, MK-8189 was associated with weight reduction (~4-5 kg at 12 weeks) whereas risperidone was associated with weight gain (~3 kg). A metabolic differentiator but not an efficacy benefit.
missedprimaryPANSS total score change from baseline at Week 6 (MK-8189 16 mg vs placebo) — difference -2.8 (95% CI -8.3, 2.6) vs placebo (0.241)
MK-8189 16 mg did not separate from placebo on the primary PANSS total endpoint at Week 6 (n=132). Risperidone 6 mg did separate (difference -6.2, p=0.040).
missedprimaryPANSS total score change from baseline at Week 6 (MK-8189 24 mg vs placebo) — difference -0.7 (95% CI -6.3, 4.9) vs placebo (0.784)
MK-8189 24 mg did not separate from placebo on the primary PANSS total endpoint at Week 6 (n=132). Discontinuations due to adverse events were highest in this arm (25.0%).
NCT03055338MK-8189-005Phase 2Completedn=224
A Phase IIa, Randomized, Double-Blind, Placebo-Controlled Clinical Trial of the Efficacy and Safety of MK-8189 Using Risperidone as an Active Control in Subjects Experiencing an Acute Episode of Schizophrenia
metsecondaryPANSS positive subscale change from baseline at Week 4 (0.011)
Nominally significant improvement on the PANSS positive symptom subscale vs placebo, supporting higher-dose evaluation in Phase 2b.
missedprimaryPANSS total score change from baseline at Week 4 — difference -4.7 (95% CI -9.8, 0.5) vs placebo (0.074)
Primary endpoint not met: MK-8189 12 mg showed only a non-significant trend vs placebo on PANSS total at Week 4. Risperidone separated from placebo (difference -7.3, p=0.033). MK-8189 reduced body weight while risperidone increased it.
Identifiers
- ChEMBL CHEMBL5314924
- PubChem CID 71271414
- FDA UNII 7M430JI73B
Sources
- Discovery of MK-8189, a Highly Potent and Selective PDE10A Inhibitor for the Treatment of Schizophrenia (Layton et al., J Med Chem 2023) — J Med Chem (PMC)
- Effects of PDE10A inhibitor MK-8189 in people with an acute episode of schizophrenia: A randomized proof-of-concept clinical trial — Schizophrenia Research (ScienceDirect)
- Effects of PDE10A inhibitor MK-8189 in people with an acute episode of schizophrenia: A randomized proof-of-concept clinical trial (Schizophr Res 2024;270:37-43) — Schizophrenia Research (PubMed)
- Efficacy and Safety of Elpipodect (MK-8189) in Participants With an Acute Episode of Schizophrenia (MK-8189-008) — ClinicalTrials.gov
- MK-8189-005: Phase 2a active-controlled study of elpipodect (MK-8189) in adults with schizophrenia (NCT03055338) — ClinicalTrials.gov
- Phase 2b Trial of the PDE10A Inhibitor MK-8189 in People With an Acute Episode of Schizophrenia (J Clin Psychopharmacol 2026;46(3):311-319) — Journal of Clinical Psychopharmacology (PubMed)