Small Molecule · RO6889450

Ralmitaront

DiscontinuedF. Hoffmann-La Roche Ltd (ROG)

Oral, selective partial agonist of the trace amine-associated receptor 1 (TAAR1) developed by Roche (RO6889450 / RG7906) for schizophrenia and schizoaffective disorder, and the first TAAR1-selective antipsychotic candidate to fail in Phase 2. Unlike ulotaront (a full TAAR1 agonist with additional 5-HT1A agonism), ralmitaront is a lower-efficacy TAAR1 partial agonist with ~30-fold slower receptor activation kinetics and no detectable 5-HT1A or D2 receptor activity — a contrast the field now reads as the likely reason the two molecules diverged clinically. Both Roche Phase 2 studies failed: the acute-exacerbation monotherapy trial (NCT04512066) showed no separation from placebo on Week-4 PANSS total while the risperidone active control separated clearly, and the negative-symptoms trial (NCT03669640) was terminated after a negative interim analysis. Roche removed ralmitaront from its Phase II pipeline at the Q3 2023 results (19 October 2023). Meta-analytically, ralmitaront was significantly less efficacious than risperidone (SMD -0.53, 95% CI -0.86 to -0.20). In February 2025 Newleos Therapeutics licensed the molecule from Roche as NTX-2001 to develop in alcohol use disorder. Structurally a pyrazole-3-carboxamide bearing a (2S)-morpholin-2-yl-phenyl group (WO2017157873A1 Example 1).

Also known as: RO6889450, RG7906, RG-7906, RO-6889450, NTX-2001, ralmitaront, 2133417-13-5, 5-ethyl-4-methyl-N-[4-[(2S)-morpholin-2-yl]phenyl]-1H-pyrazole-3-carboxamide

Data current as of

Key facts

Modality
Small molecule
Chemical class
pyrazole, carboxamide, morpholine
Chemistry
Single enantiomer
Mechanism
TAAR1 Partial agonist
Highest phase
Discontinued
Lead indication
Schizophrenia
Developer
F. Hoffmann-La Roche Ltd (ROG)
Trials
3 tracked · 89 sites

Mechanism of action#

Selective partial agonist of the trace amine-associated receptor 1 (TAAR1), a Gs-coupled intracellular/plasma-membrane GPCR that modulates dopaminergic tone. Head-to-head in vitro characterization against ulotaront (Agren et al., Int J Neuropsychopharmacol 2023) found ralmitaront to be a lower-efficacy TAAR1 agonist in every assay — G-protein recruitment efficacy 1.26 vs 1.32 (ulotaront) and 1.30 (p-tyramine); steady-state cAMP accumulation 6.9 vs ~10.8-10.9; GIRK-current relative efficacy 0.63 vs p-tyramine (ulotaront 0.91) — with cAMP pEC50 7.75, an activation rate ~30-fold slower than ulotaront and minimal reversibility on washout. Critically, ralmitaront showed no detectable 5-HT1A receptor activity at concentrations up to 300 uM and no appreciable D2 receptor activity, whereas ulotaront is also a 5-HT1A agonist. The post-hoc mechanistic reading in the literature (Englisch & Zink, CNS Drugs 2026) is that TAAR1 partial agonism alone, without 5-HT1A co-agonism, proved clinically insufficient: both ralmitaront Phase 2 trials failed while the risperidone control separated from placebo.

TargetActionAffinity
TAAR1primaryTAAR1Partial agonistpEC50 7.75ⓘ

Formulations#

FormulationRouteRegimenPharmacokinetics
Ralmitaront oral, once daily (45-300 mg)
45 mg or 150 mg once daily as monotherapy in the acute-exacerbation Phase 2 (NCT04512066, vs placebo and risperidone 4 mg); 150 mg once daily as monotherapy (Part A) and 45, 150 or 300 mg once daily as add-on to ongoing antipsychotics (Part B) in the negative-symptoms Phase 2 (NCT03669640); 150 mg for 2 weeks in the 18F-DOPA PET study (NCT06880328).
OralOnce daily—

Development timeline#

2019202020212022202320242025Phase 210 Oct 2023 — readout (missed) — Acute-exacerbation Phase 2 failed: neither ralmitaront 45 mg (+0.60 vs placebo, p=0.849) nor 150 mg (-2.83, p=0.362) separated on Week-4 PANSS total, while the risperidone 4 mg active control did (-10.45, p=0.001).23 May 2023 — readout (missed) — Negative-symptoms Phase 2 terminated after an interim analysis indicated ralmitaront was unlikely to meet its BNSS primary endpoint at Week 12.23 May 2023 — Trial terminated — Roche terminates the ralmitaront negative-symptoms Phase 2 (NCT03669640) after a negative interim analysis21 Jun 2022 — phase change — The acute-exacerbation study NCT04512066 reached actual completion. Roche issued no press release; results posted to the registry on 2023-10-10 show both ralmitaront doses failed to separate from placebo on Week-4 PANSS total while risperidone separated. After this date only the negative-symptoms study remained active.8 Sept 2020 — phase change — Second Phase 2 study started: NCT04512066 (BP41743), monotherapy in acute exacerbation of schizophrenia or schizoaffective disorder — 45 mg and 150 mg QD vs placebo with a risperidone 4 mg active control; primary endpoint change from baseline in PANSS total at Week 4; 287 enrolled.4 Dec 2018 — phase change — Phase 2 negative-symptoms study NCT03669640 (BP40283) started per ClinicalTrials.gov: randomized, quadruple-blind, placebo-controlled; Part A monotherapy (150 mg QD) and Part B add-on (45/150/300 mg QD), primary endpoint BNSS avolition/apathy subscore and total score at Week 12. The Roche-sponsored 18F-DOPA PET study (BP39833, NCT06880328) had begun a month earlier (2018-11-07) but was registered only retrospectively in 2025.Discontinued13 Feb 2025 — Licensing deal — Newleos Therapeutics licenses ralmitaront from Roche as NTX-200119 Oct 2023 — phase change — Roche removed ralmitaront from its development pipeline at the Q3 2023 investor update (Basel, 19 October 2023): the presentation appendix lists 'Removed from phase II — RG7906 ralmitaront – schizophrenia'. This followed the May 2023 termination of the negative-symptoms study (negative interim analysis) and the earlier negative acute-exacerbation readout. No event code exists for a program discontinuation, so this row is the canonical record of it.
Phase change Readout Event UpcomingHover a marker for details.
DiscontinuedOct 2023 – Feb 2025
  1. Licensing dealNewleos Therapeutics licenses ralmitaront from Roche as NTX-2001↗
  2. Roche removed ralmitaront from its development pipeline at the Q3 2023 investor update (Basel, 19 October 2023): the presentation appendix lists 'Removed from phase II — RG7906 ralmitaront – schizophrenia'. This followed the May 2023 termination of the negative-symptoms study (negative interim analysis) and the earlier negative acute-exacerbation readout. No event code exists for a program discontinuation, so this row is the canonical record of it.↗
Phase 2Dec 2018 – Oct 2023
  1. missedAcute-exacerbation Phase 2 failed: neither ralmitaront 45 mg (+0.60 vs placebo, p=0.849) nor 150 mg (-2.83, p=0.362) separated on Week-4 PANSS total, while the risperidone 4 mg active control did (-10.45, p=0.001).
  2. missedNegative-symptoms Phase 2 terminated after an interim analysis indicated ralmitaront was unlikely to meet its BNSS primary endpoint at Week 12.
  3. Trial terminatedRoche terminates the ralmitaront negative-symptoms Phase 2 (NCT03669640) after a negative interim analysis↗
  4. The acute-exacerbation study NCT04512066 reached actual completion. Roche issued no press release; results posted to the registry on 2023-10-10 show both ralmitaront doses failed to separate from placebo on Week-4 PANSS total while risperidone separated. After this date only the negative-symptoms study remained active.
  5. Second Phase 2 study started: NCT04512066 (BP41743), monotherapy in acute exacerbation of schizophrenia or schizoaffective disorder — 45 mg and 150 mg QD vs placebo with a risperidone 4 mg active control; primary endpoint change from baseline in PANSS total at Week 4; 287 enrolled.
  6. Phase 2 negative-symptoms study NCT03669640 (BP40283) started per ClinicalTrials.gov: randomized, quadruple-blind, placebo-controlled; Part A monotherapy (150 mg QD) and Part B add-on (45/150/300 mg QD), primary endpoint BNSS avolition/apathy subscore and total score at Week 12. The Roche-sponsored 18F-DOPA PET study (BP39833, NCT06880328) had begun a month earlier (2018-11-07) but was registered only retrospectively in 2025.

Ralmitaront for Schizophrenia#

DiscontinuedDiscontinuedSchizophrenia indication →

Roche's Phase 2 program of ralmitaront (RO6889450/RG7906), a selective TAAR1 partial agonist, in schizophrenia and schizoaffective disorder — discontinued October 2023 after both Phase 2 trials failed. The negative-symptoms study (NCT03669640, BP40283, started December 2018) tested 150 mg monotherapy and 45/150/300 mg add-on against the BNSS avolition/apathy primary at Week 12; it was terminated after an interim analysis indicated the primary endpoint was unlikely to be met (registry completion 2023-03-12; termination surfaced publicly May 2023). The acute-exacerbation monotherapy study (NCT04512066, BP41743, started September 2020, n=287) completed in June 2022 and posted clearly negative results: neither 45 mg (+0.60 vs placebo, p=0.849) nor 150 mg (-2.83, p=0.362) separated on Week-4 PANSS total, while risperidone 4 mg did (-10.45, p=0.001) — an efficacy failure with intact assay sensitivity. Roche removed ralmitaront from its Phase II pipeline at the Q3 2023 investor update (Basel, 19 October 2023). Meta-analytically, ralmitaront was significantly less efficacious than risperidone (SMD -0.53, 95% CI -0.86 to -0.20), and TAAR1 agonists pooled showed only a modest effect in acute schizophrenia (SMD 0.15, 95% CI -0.05 to 0.34). The molecule was licensed to Newleos Therapeutics in February 2025 as NTX-2001 for development in alcohol use disorder (a separate program, not this record).

Readouts

  • 2023-10-10ReportedFull resultsmissedNCT04512066

    Acute-exacerbation Phase 2 failed: neither ralmitaront 45 mg (+0.60 vs placebo, p=0.849) nor 150 mg (-2.83, p=0.362) separated on Week-4 PANSS total, while the risperidone 4 mg active control did (-10.45, p=0.001).

  • 2023-05-23ReportedInterim analysismissedNCT03669640

    Negative-symptoms Phase 2 terminated after an interim analysis indicated ralmitaront was unlikely to meet its BNSS primary endpoint at Week 12.

Clinical trials#

NCT04512066BP41743Phase 2Completedn=287

A Phase II, Multi-Center, Randomized, Double-Blind, Parallel Group, Placebo-Controlled Trial of the Efficacy and the Safety of RO6889450 (Ralmitaront) vs Placebo in Patients With an Acute Exacerbation of Schizophrenia or Schizoaffective Disorder

Started Sept 2020· Primary completion Jun 2022· 40 sites across 4 countries

United StatesRussiaUkraineJapan

missedprimaryPANSS total score change from baseline at Week 4 (45 mg and 150 mg vs placebo; risperidone 4 mg active control) — 45 mg: +0.60 vs placebo (95% CI -4.58 to 5.78); 150 mg: -2.83 (95% CI -7.96 to 2.29); risperidone: -10.45 (95% CI -15.46 to -5.43) (0.849 (45 mg); 0.362 (150 mg); 0.001 (risperidone))

Neither ralmitaront dose separated from placebo on Week-4 PANSS total, while the risperidone 4 mg active control separated clearly — a true efficacy failure with intact assay sensitivity, not a failed-trial artifact. Results posted to ClinicalTrials.gov 2023-10-10; Roche issued no press release.

NCT03669640BP40283Phase 2Discontinuedn=131

Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Effects of RO6889450 (Ralmitaront) in Patients With Schizophrenia or Schizoaffective Disorder and Negative Symptoms

Started Dec 2018· Primary completion Mar 2023· 45 sites across 4 countries

United StatesUkraineSpainJapan

terminatedprimaryBNSS avolition/apathy subscore and total score at Week 12 (Part A monotherapy 150 mg; Part B add-on 45/150/300 mg)

Terminated: registry whyStopped states the study 'was discontinued due to an interim analysis which indicated that ralmitaront was unlikely to meet its primary endpoint'. Descriptive results (131 enrolled across Part A monotherapy and Part B add-on arms) were posted 2024-08-12; no inferential analyses of the truncated primary were reported.

NCT06880328BP39833Phase 1Completedn=35

18F-Dihydroxyphenylalanine (DOPA) Positron Emission Tomography (PET), Randomized, Double-blind, Crossover Study to Explore Dopamine Synthesis Capacity in the Whole Striatum After 2 Weeks of Treatment With 150mg of RO6889450 or Placebo in Patients With Schizophrenia

Started Nov 2018· Primary completion Sept 2019· 4 sites across 1 country

United States

Sources#

  1. Agren R, Betari N, Saarinen M, Zeberg H, Svenningsson P, Sahlholm K. In vitro comparison of ulotaront (SEP-363856) and ralmitaront (RO6889450): two TAAR1 agonist candidate antipsychotics. Int J Neuropsychopharmacol. 2023;26(9):599-606 — International Journal of Neuropsychopharmacology (Oxford University Press)
  2. NCT03669640 (BP40283) — Phase 2, ralmitaront in schizophrenia/schizoaffective disorder with negative symptoms; TERMINATED after negative interim analysis, results posted 2024-08-12 — ClinicalTrials.gov (U.S. National Library of Medicine)
  3. NCT04512066 (BP41743) — Phase 2, ralmitaront 45/150 mg vs placebo (risperidone control) in acute exacerbation of schizophrenia or schizoaffective disorder; completed 2022-06-21, results posted 2023-10-10 — ClinicalTrials.gov (U.S. National Library of Medicine)
  4. NCT06880328 (BP39833) — 18F-DOPA PET crossover study of ralmitaront 150 mg in schizophrenia (Roche-sponsored, 2018-2019; registered retrospectively 2025-03-17) — ClinicalTrials.gov (U.S. National Library of Medicine)
  5. Roche Q3 2023 investor presentation with appendix (Basel, 19 October 2023) — pipeline changes appendix lists 'Removed from phase II: RG7906 ralmitaront – schizophrenia' — F. Hoffmann-La Roche Ltd
  6. Roche Terminates Second Phase II Schizophrenia Trial (2023-05-23) — reports the NCT03669640 termination on a negative preliminary/interim analysis and notes the acute-exacerbation study's earlier demise — BioSpace
  7. VC Longwood Fund unveils neuro biotech with $93M, assets licensed from Roche (2025-02-13) — Newleos Therapeutics licenses ralmitaront as NTX-2001 for alcohol use disorder — Fierce Biotech