MK-8189 · program
Elpipodect (MK-8189) for Schizophrenia
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.
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.↗
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 in Schizophrenia
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.
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 |
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ⓘ |
← Full MK-8189 compound page (identity, identifiers, all indications)
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)