Small Molecule · NBI-1117568

Direclidine (NBI-1117568)

Phase 3Neurocrine Biosciences, Inc. (NBIX)

Oral, once-daily, brain-penetrant small molecule that is a selective orthosteric agonist of the muscarinic acetylcholine M4 receptor (CHRM4), with very low affinity for the M1, M2, M3 and M5 subtypes. Described by the developer as the first and only investigational oral muscarinic M4-selective orthosteric agonist in clinical development for schizophrenia: unlike allosteric (PAM) approaches it does not depend on the presence of acetylcholine for efficacy, and unlike non-selective muscarinic agonists it aims to avoid peripheral M1/M2/M3-mediated gastrointestinal and cardiovascular side effects without requiring a co-administered peripheral antagonist. Discovered (as HTL-0016878) by Sosei Heptares (now Nxera Pharma) using structure-based drug design and licensed to Neurocrine Biosciences in 2021. Phase 2 in schizophrenia was positive (2024); a Phase 3 registrational program was initiated in April 2025.

Also known as: NBI-1117568, NBI-'568, HTL-0016878, HTL0016878, direclidine, 1803346-98-6, ethyl (2R,4S)-2-[4-(1-methyl-1H-pyrazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate

Data current as of

Modality
Small molecule
Chemical class
azaspiro compound, carbamate, piperidine, pyrazole
Chemistry
Achiral
Mechanism
M4 agonist
Highest phase
Phase 3
Lead indication
Schizophrenia
Developer
Neurocrine Biosciences, Inc. (NBIX)
Trials
6 tracked · 5 recruiting · 134 sites
Next catalyst
Q4 2027 — Topline data (Schizophrenia)

Mechanism of action

Selective orthosteric agonist at the muscarinic acetylcholine M4 receptor (CHRM4 / Gi/o-coupled GPCR), with very low affinity at the M1, M2, M3 and M5 muscarinic subtypes. M4 agonism in striatal and cortical circuits is hypothesized to reduce dopaminergic hyperactivity and produce antipsychotic effects via a non-D2 mechanism. As an orthosteric agonist (binding the acetylcholine site, competitive, non-covalent) it does not require the presence of endogenous acetylcholine for activity, distinguishing it from allosteric M4 PAMs. The molecule's M4 selectivity is intended to deliver antipsychotic efficacy while limiting the peripheral cholinergic (GI/cardiovascular) burden seen with non-selective muscarinic agonists, so no co-administered peripheral muscarinic antagonist is needed.

TargetActionAffinity
M4primaryCHRM4Agonist—ⓘ

Formulations

FormulationRouteRegimenPharmacokinetics
Direclidine oral tablet
20 mg once daily (dose that met the Phase 2 primary endpoint and advanced into the Phase 3 registrational program); additional Phase 2 arms evaluated 40 mg once daily, 60 mg once daily, and 30 mg twice daily
OralOnce daily—

Development timeline

Phase 2Oct 2022 – Feb 2028
  1. UpcomingAnticipated topline from the Phase 2 bipolar I mania study (NBI-1117568-BPD2036): change from baseline in YMRS total score at Day 21.Bipolar disorder
  2. Phase 2 bipolar I mania study (NCT07288320 / NBI-1117568-BPD2036, n~150) started (actual start date 2025-12-24 per ClinicalTrials.gov); status RECRUITING. Primary endpoint: change from baseline in YMRS total score at Day 21; estimated primary completion Feb 2028.Bipolar disorder
  3. Neurocrine guided (via partner Nxera Pharma portfolio update) that it expected to initiate a Phase 2 study of NBI-1117568 ('NBI-'568') in bipolar mania in 2H 2025.Bipolar disorder↗
  4. metPhase 2 met its primary endpoint: 20 mg QD gave placebo-adjusted PANSS -7.5 at Week 6 (p=0.011, ES 0.61).Schizophrenia↗
  5. Phase 2 inpatient schizophrenia study (NCT05545111) started (first dosing Oct 2022); Neurocrine/Sosei Heptares announced initiation 27 Oct 2022.Schizophrenia↗
Phase 3Apr 2025 – Nov 2027
  1. UpcomingAnticipated topline from Phase 3 acute study SCZ3030 (PANSS at Week 6).Schizophrenia
  2. UpcomingAnticipated topline from Phase 3 acute study SCZ3029 (PANSS at Week 6).Schizophrenia
  3. Phase 3 registrational program initiated (acute studies SCZ3029/SCZ3030, long-term SCZ3032, relapse-prevention) following positive Phase 2 data.Schizophrenia↗

Direclidine (NBI-1117568) for Schizophrenia

Phase 3ActiveSchizophrenia indication →

Schizophrenia is the lead indication for NBI-1117568 (direclidine). A Phase 2, randomized, double-blind, placebo-controlled inpatient study (NCT05545111, n=210) met its primary endpoint: the once-daily 20 mg dose produced a placebo-adjusted PANSS total reduction of 7.5 points at Week 6 (p=0.011, effect size 0.61) with an 18.2-point reduction from baseline, plus significant improvement on CGI-S and Marder positive- and negative-symptom factors; the drug was generally safe and well tolerated with minimal GI/cardiovascular adverse events (reported 28 Aug 2024). On 30 Apr 2025 Neurocrine initiated a global Phase 3 registrational program comprising replicate acute-exacerbation inpatient studies (SCZ3029 / NCT06963034 and SCZ3030 / NCT07105098, ~284 each; primary endpoint PANSS change, key secondary CGI-S), a long-term safety study (SCZ3032 / NCT07114874, ~600), and a relapse-prevention study (NCT07227818, ~560). As of mid-2026 the program is active and recruiting in Phase 3.

Readouts

  • Q4 2027AnticipatedTopline dataNCT07105098

    Anticipated topline from Phase 3 acute study SCZ3030 (PANSS at Week 6).

  • Q4 2027AnticipatedTopline dataNCT06963034

    Anticipated topline from Phase 3 acute study SCZ3029 (PANSS at Week 6).

  • 2024-08-28ReportedTopline datametNCT05545111

    Phase 2 met its primary endpoint: 20 mg QD gave placebo-adjusted PANSS -7.5 at Week 6 (p=0.011, ES 0.61). ↗

Direclidine (NBI-1117568) for Bipolar disorder

Phase 2RecruitingBipolar disorder indication →

Bipolar I disorder with current mania is a secondary indication for NBI-1117568 (direclidine), Neurocrine's oral, once-daily, M4-selective orthosteric muscarinic agonist (lead indication: schizophrenia). Building on the muscarinic-agonist antipsychotic rationale, Neurocrine is running a single Phase 2, multicenter, randomized, double-blind, placebo-controlled study (NCT07288320 / NBI-1117568-BPD2036, ~150 adults aged 18-65) evaluating NBI-1117568 vs. placebo for the acute treatment of a manic episode (with or without mixed features) in adults with bipolar I disorder. The primary endpoint is the change from baseline in the Young Mania Rating Scale (YMRS) total score at Day 21. Neurocrine had previously guided (via partner Nxera Pharma, Jan 2025) to initiate this study in 2H 2025; the trial began dosing on 24 Dec 2025 and is recruiting, with an estimated primary completion in February 2028. No topline data have been reported yet.

Readouts

  • 1H 2028AnticipatedTopline dataNCT07288320

    Anticipated topline from the Phase 2 bipolar I mania study (NBI-1117568-BPD2036): change from baseline in YMRS total score at Day 21.

Clinical trials

NCT07288320NBI-1117568-BPD2036Phase 2Recruitingn=150

A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy, Safety, and Pharmacokinetics of NBI-1117568 in Adults With Bipolar I Disorder With Current Mania

Started Dec 2025· Primary completion Feb 2028· 📍 6 sites across 1 country (United States)

NCT07227818Phase 3Recruitingn=560

Efficacy of NBI-1117568 in Preventing Relapse in Adults With Schizophrenia

Started Dec 2025· Primary completion Jul 2029· 📍 20 sites across 1 country (United States)

NCT07105098NBI-1117568-SCZ3030Phase 3Recruitingn=284

NBI-1117568-SCZ3030: Evaluation of NBI-1117568 in Inpatient Adults With Schizophrenia

Started Aug 2025· Primary completion Nov 2027· 📍 15 sites across 5 countries (United States, Romania, Bulgaria, Serbia)

NCT07114874NBI-1117568-SCZ3032Phase 3Recruitingn=600

NBI-1117568-SCZ3032: Long-Term Evaluation of NBI-1117568 in Adults With Schizophrenia

Started Jul 2025· Primary completion Dec 2031· 📍 57 sites across 4 countries (United States, Serbia, Romania, Bulgaria)

NCT06963034NBI-1117568-SCZ3029Phase 3Recruitingn=284

NBI-1117568-SCZ3029: Evaluation of NBI-1117568 in Inpatient Adults With Schizophrenia

Started May 2025· Primary completion Oct 2027· 📍 21 sites across 1 country (United States)

NCT05545111NBI-1117568-SCZ2027Phase 2Completedn=210

A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of NBI-1117568 in Adults With Schizophrenia Who Warrant Inpatient Hospitalization

Started Oct 2022· Primary completion Jul 2024· 📍 15 sites across 1 country (United States)

metsecondaryCGI-S and Marder Positive / Negative symptom factor scores (Week 6)

Statistically significant improvement across several secondary endpoints, including CGI-S and the Marder Factor Score for positive- and negative-symptom change. Generally safe and well tolerated at all doses with minimal GI and cardiovascular adverse events.

metprimaryPANSS total change from baseline at Week 6 (20 mg once-daily dose) — Placebo-adjusted mean reduction 7.5 points; effect size 0.61; 18.2-point reduction from baseline (0.011)

Primary endpoint met for the 20 mg QD arm: clinically meaningful and statistically significant placebo-adjusted reduction in PANSS total at Week 6. Reported 28 Aug 2024.

Related compounds

Other M4 compounds

More from Neurocrine Biosciences, Inc.

Identifiers

Sources

  1. An Assessment of Efficacy, Safety, and Pharmacokinetics of NBI-1117568 in Adults With Bipolar I Disorder With Current Mania (NCT07288320) — ClinicalTrials.gov
  2. M4 receptor (CHRM4), GtoPdb object 16 — IUPHAR/BPS Guide to Pharmacology
  3. NBI-1117568-SCZ3029 Phase 3 inpatient schizophrenia study (NCT06963034) — ClinicalTrials.gov
  4. NBI-1117568-SCZ3030 Phase 3 inpatient schizophrenia study (NCT07105098) — ClinicalTrials.gov
  5. NBI-1117568-SCZ3032 long-term Phase 3 schizophrenia study (NCT07114874) — ClinicalTrials.gov
  6. Neurocrine Biosciences Initiates Phase 3 Registrational Program for NBI-1117568 as Potential Treatment for Adults with Schizophrenia — Neurocrine Biosciences / IR
  7. Neurocrine Biosciences Initiates Phase 3 Registrational Program for NBI-1117568 as Potential Treatment for Adults with Schizophrenia — Neurocrine Biosciences (via PR Newswire)
  8. Neurocrine Biosciences Reports Positive Phase 2 Data for NBI-1117568 in Adults with Schizophrenia — Neurocrine Biosciences / IR
  9. Nxera Pharma provides update on Neurocrine's progress with its partnered muscarinic agonist portfolio — Nxera Pharma (via BioIndustry Association)
  10. Phase 2 study of NBI-1117568 in adults with schizophrenia (NCT05545111) — ClinicalTrials.gov
  11. Phase 3 relapse-prevention study of NBI-1117568 in schizophrenia (NCT07227818) — ClinicalTrials.gov
  12. Sosei Heptares' Partner Neurocrine Biosciences Initiates Phase 2 Clinical Study Evaluating NBI-1117568 in Adults with Schizophrenia — Sosei Heptares (Nxera Pharma) / GlobeNewswire