BTRX-246040 / Neumora Therap - LARVOL DELTA

Pharmaco-Neuroimaging Studies of Approach/Avoidance Behaviors and Post-Mortem Studies: Pharmacological Manipulation (clinicaltrials.gov) - P2 | N=112 | Recruiting | Sponsor: Mclean Hospital | Not yet recruiting ➔ Recruiting

Enrollment open • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Investigating the Protective Impact of LY-2940094 on Stress-induced Depression- and Anxiety-related Phenotypes in Humans (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: Mclean Hospital | N=50 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Nociceptin Orphanin F/Q Pathways are Dysregulated by Stress and Modulate Reward Learning and Motivation Across Species. (PubMed, bioRxiv) - "Finally, in depressed humans, relative to placebo, 8-week treatment with BTRX-246040 increased incentive motivation (Study 4). Collectively, our findings indicate that chronic stressors alter Pnoc and mRNA levels of Pnoc -expressing cells in a sex-selective and region-specific manner impacting reward structures, and that NOPR antagonism shows anti-anhedonic properties."

Journal

BTRX-246040 Study in Participants With Parkinson's Disease With Motor Fluctuations (clinicaltrials.gov) - P2 | N=24 | Completed | Sponsor: BlackThorn Therapeutics, Inc. | Phase classification: P2a ➔ P2

Phase classification • CNS Disorders • Movement Disorders • Parkinson's Disease

Mining the Nociceptin Receptor to Mitigate Opioid-Taking and -Seeking in Preclinical Models (CPDD 2025) - " Male, Sprague-Dawley rats (n=6-18) were trained to stability on fentanyl self-administration (3.2 µg/kg/inf, i.v.) prior to LY2940094 (0 or 30 mg/kg, i.p.) and reassessment of fentanyl intake. These findings support the NOPr system as a neurobiological substrate of 1 opioid-taking and cue-evoked drug-seeking behaviors in rodents. As NOPr agonists and antagonists can evoke overlapping outcomes to positively alter mood and behavior in populations with reward dysfunction, a deeper understanding of the NOPr system in these OUD-like behaviors is an active area of research."

Preclinical • Addiction (Opioid and Alcohol) • CNS Disorders • Psychiatry • Substance Abuse

Investigating the Protective Impact of LY-2940094 on Stress-induced Depression- and Anxiety-related Phenotypes in Humans (clinicaltrials.gov) - P2 | N=50 | Not yet recruiting | Sponsor: Mclean Hospital | Initiation date: Feb 2025 ➔ Jun 2025

Trial initiation date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Investigating the Protective Impact of LY-2940094 on Stress-induced Depression- and Anxiety-related Phenotypes in Humans (clinicaltrials.gov) - P2 | N=50 | Not yet recruiting | Sponsor: Mclean Hospital

New P2 trial • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Pharmaco-Neuroimaging Studies of Approach/Avoidance Behaviors and Post-Mortem Studies: Pharmacological Manipulation (clinicaltrials.gov) - P2 | N=112 | Not yet recruiting | Sponsor: Mclean Hospital | Trial completion date: Mar 2025 ➔ Dec 2025 | Trial primary completion date: Mar 2025 ➔ Dec 2025

Trial completion date • Trial primary completion date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

LY2940094, an NOPR antagonist, promotes oligodendrocyte generation and myelin recovery in an NOPR independent manner. (PubMed, Neurotherapeutics) - "LY2940094 was found to modulate the expression of the oligodendrocytes differentiation-associated transcription factors ID4 and Myrf, although the exact mechanism remains unclear. Since LY2940094 has been tested clinically to treat depression and alcohol dependency and has displayed an acceptable safety profile, it may provide an alternative approach to treat demyelinating diseases."

Journal • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Psychiatry • Solid Tumor

The Nociceptin Receptor System as a Target for Novel Opioid Use Disorder Therapeutics (ACNP 2023) - "In the present studies, we assessed the efficacy of LY2940094 to alter opioid intake and relapse vulnerability as well as physiological measures, naloxone-induced fentanyl withdrawal symptoms and fentanyl-induced analgesia in preclinical models. Our findings implicate the N/OFQ-NOPr axis as a biological mediator of opioid-related reward and cue-evoked drug-seeking behavior in rodents. A greater understanding of the role of the N/OFQ-NOPr system in these behaviors is an active area of research as NOPr agonists and antagonists have been reported to paradoxically evoke overlapping outcomes, and may be explained by N/OFQ activation of N/OFQ-sensitive neural circuits that compete for behavioral control or perhaps NOPr desensitization factors. Nonetheless, our preclinical data position the NOPr antagonist LY2940094 as a potential therapeutic strategy to mitigate opioid intake and relapse vulnerability without inherent abuse liability and with a limited side effect profile."

Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Psychiatry • Substance Abuse

BTRX-246040 acts through the ventrolateral periaqueductal gray to exert antidepressant-relevant actions in mice. (PubMed, Int J Neuropsychopharmacol) - "The results suggested that BTRX-246040 may act through the vlPAG to exert antidepressant-relevant actions. The present study provides new insight into a vlPAG-dependent mechanism underlying the antidepressant-like actions of BTRX-246040."

Journal • Preclinical

The Nociceptin Receptor Antagonist LY2940094 Suppresses Opioid Self-Administration in Male Rats (CPDD 2023) - " Male, Sprague-Dawley rats (n=6-18/group) were trained to acquire stable fentanyl (3.2 µg/kg/inf, i.v.) self-administration prior to pretreatment with acute or repeated doses of ‘094 (0-30 mg/kg, i.p.; 15 min). Our preclinical data position the NOPr antagonist ‘094 as a potential therapeutic strategy to mitigate opioid intake and relapse vulnerability without inherent abuse liability and with a limited side effect profile. 1"

Preclinical • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Psychiatry • Substance Abuse

Pharmaco-Neuroimaging Studies of Approach/Avoidance Behaviors and Post-Mortem Studies: Study 1.1. (Pharmacological Manipulation) (clinicaltrials.gov) - P2 | N=112 | Not yet recruiting | Sponsor: Mclean Hospital | Initiation date: Sep 2022 ➔ Dec 2022

Trial initiation date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

The NOP antagonist BTRX-246040 increases stress resilience in mice without affecting adult neurogenesis in the hippocampus. (PubMed, Neuropharmacology) - "Under these experimental conditions, BTRX-246040 did not modulate adult hippocampal neurogenesis, neither in naive nor in stressed mice. This study, performed with a clinically viable ligand, further corroborates growing evidence indicating that the blockade of the NOP signaling may provide an innovative strategy for the treatment of stress related psychopathologies."

Journal • Preclinical • CNS Disorders • Depression • Psychiatry

Pharmaco-Neuroimaging Studies of Approach/Avoidance Behaviors and Post-Mortem Studies: Study 1.1. (Pharmacological Manipulation) (clinicaltrials.gov) - P2 | N=112 | Not yet recruiting | Sponsor: Mclean Hospital

New P2 trial • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Accuracy in recognising happy facial expressions is associated with antidepressant response to a NOP receptor antagonist but not placebo treatment. (PubMed, J Psychopharmacol) - "In a secondary analysis, we examined the association of early effects on emotional processing with later clinical outcome following treatment with the novel NOP antagonist LY2940094 versus placebo...These data suggest that emotional processing biomarkers may be sensitive to early effects of antidepressant treatment indicative of later clinical response. Further studies in this area may be useful in developing new treatments and clinical trial designs for predicting antidepressant response."

Clinical • Journal • CNS Disorders • Depression • Major Depressive Disorder • Psychiatry

Detailed in vitro pharmacological characterization of the clinically viable NOP receptor antagonist BTRX-246040. (PubMed, J Pharmacol Exp Ther) - "In this research BTRX-246040 has been deeply characterized in vitro in a panel of assays. BTRX-246040 resulted a pure, potent and selective NOP antagonist."

Journal • CNS Disorders • Depression • Movement Disorders • Parkinson's Disease

Targeting opioid dysregulation in depression for the development of novel therapeutics. (PubMed, Pharmacol Ther) - "Finally, putative opioid based antidepressants that are being tested in clinical trials, ALKS5461, JNJ-67953964 (formerly LY2456302 and CERC-501) and BTRX-246040 (formerly LY-2940094) will be discussed. This review will illustrate the potential therapeutic value of targeting opioid dysregulation in developing novel therapies for major depression disorder."

Journal • CNS Disorders • Depression • Mood Disorders

A Study of LY2940094 in Participants With Alcohol Dependency (clinicaltrials.gov) - P2; N=130; Completed; Sponsor: Eli Lilly and Company; Active, not recruiting -> Completed

Trial completion • Biosimilar

Study of the Efficacy and Safety of LY2940094 in Participants With Major Depressive Disorder (MDD) (clinicaltrials.gov) - P2; N=120; Completed; Sponsor: Eli Lilly and Company; Active, not recruiting -> Completed

Trial completion • Biosimilar

Blackthorn Therapeutics presents preclinical and clinical data from its first-in-class NOPR antagonist at American College of Neuropsychopharmacology Annual Meeting (Businesswire) - P2b, N=100; NCT03193398; “BlackThorn Therapeutics…announced preclinical and clinical data from its lead program, BTRX-246040… in patients with major depressive disorder (MDD)…. Preclinical studies demonstrated for the first time that NOPR modulation has a significant influence on brain regions related to emotional processing, and clinical data demonstrate our ability to identify certain patient subtypes, both of which may improve our potential for clinical success.”

P2b data • Preclinical • CNS Disorders • Depression

Preclinical findings predicting efficacy and side-effect profile of LY2940094, an antagonist of nociceptin receptors. (PubMed) - Pharmacol Res Perspect - "These data suggest that LY2940094 has unique antidepressant- and anxiolytic-related pharmacological effects in rodents. Clinical proof of concept data on this molecule in depressed patients have been reported elsewhere."

Journal • Biosimilar • Depression

Novel Treatment Targets For Affective Disorders Through Cross-Species Investigation of Approach/Avoidance Decision Making (clinicaltrials.gov) - P; N=208; Not yet recruiting; Sponsor: Mclean Hospital

New trial

"In silico" study of the binding of two novel antagonists to the nociceptin receptor. (PubMed, J Comput Aided Mol Des) - "While the high selectivity for NOP of BTRX-246040 can be explained by interactions with NOP specific residues, the lack of selectivity of AT-076 could be associated to its ability to penetrate into the deep hydrophobic pocket of NOP, while retaining a conformation very similar to the one assumed by the antagonist JDTic into the K-opioid receptor. The proposed binding geometries fit better the binding pocket environment providing clues for experimental studies aimed to design selective or multifunctional opioid drugs."

Journal

Explainable AI Approach Reveals Treatment Responders in a Randomized Controlled Trial of BTRX-246040, a Potent and Selective NOP receptor Antagonist (ACNP 2019) - P2; "The NEP-MDD-201 study did not apply a specific enrichment strategy. However, the inclusion of multidimensional assessments proved valuable because they provided insights across multiple symptom dimensions and because they enabled more robust treatment prediction models. In addition to practical lessons about deployment of these tools in multisite trials, we learned that no single analytical approach is sufficient to predict placebo vs."

Clinical