osavampator (TAK-653) / Takeda, Neurocrine Biosciences, Ligand - LARVOL DELTA

Next-Generation Pharmacotherapies for Unipolar Mood Disorders: A Leading Article on Phase II/III Drug Development Across Diverse Mechanisms. (PubMed, CNS Drugs) - "Following the US Food and Drug Administration (FDA) approval of esketamine and brexanolone in 2019, industry investment in therapeutics with novel mechanisms for mood and anxiety disorders has expanded, catalyzing a new wave of innovative interventions...The drug names discussed are ALTO-100, ALTO-203, ALTO-207, ALTO-300, BHV-7000, BI-1569912, BPL-003, COMP360, DT120, ELE-101, GATE-251, GH001, GM-1020, GM-2505, HLP003, MK-1942, NBI-1065845, NBI-1070770, NV-5138, PIPE-307, SEP-363856, SPT-300, VLS-01, and XEN1101. The US Clinical Trials registry (clinicaltrials.gov), MEDLINE, conference proceedings, and company communications such as press releases were consulted to obtain up-to-date trial information and reported outcomes. Overall, the therapeutic landscape shows an expanding range of clinical compounds under active development; nonetheless, persistent challenges remain, including approaches to therapeutics where functional unblinding may occur, the ways in which to..."

Journal • P2/3 data • Review • CNS Disorders • Mood Disorders • Psychiatry

Ligand Completes Acquisition of XOMA Royalty, Creating a Portfolio of More than 200 Biopharmaceutical Royalty Assets (The Manila Times) - Acquisition adds seven commercial products including VABYSMO (faricimab-svoa), OJEMDA (tovorafenib), and MIPLYFFA (arimoclomol), andmore than 100 development and commercial-stage assets, creating long-term opportunities to drive growth...Additionally, it includes 14 late-stage development programs, featuring Takeda’s mezagitamab and certain assets from Takeda’s externalized asset portfolio, such as osavampator, volixibat, and OHB-607, along with more than 100 assets in various stages of development....Ligand will provide an updated 5-year outlook during the Company’s Investor Day on December 8, 2026."

M&A • Bronchopulmonary Dysplasia • Diabetic Macular Edema • Diabetic Retinopathy • IgA Nephropathy • Immune Thrombocytopenic Purpura • Immunology • Low Grade Glioma • Lysosomal Storage Diseases • Metabolic Dysfunction-Associated Steatohepatitis • Primary Biliary Cholangitis • Wet Age-related Macular Degeneration

Long-Term Study to Assess the Safety and Tolerability of NBI-1065845 as an Adjunctive Treatment in Participants With Major Depressive Disorder (MDD) (clinicaltrials.gov) - P3 | N=850 | Recruiting | Sponsor: Neurocrine Biosciences | N=271 ➔ 850

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

NBI-1065845-MDD3027: Study to assess the maintenance of effect of NBI-1065845 as an adjunctive treatment in participants with Major Depressive Disorder (MDD) (clinicaltrialsregister.eu) - P2/3 | N=158 | Recruiting | Sponsor: Neurocrine Biosciences Inc.

New P2/3 trial • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

A Study to Evaluate the Maintenance Effect of NBI-1065845 as an Adjunctive Treatment in Participants With Major Depressive Disorder (MDD) (clinicaltrials.gov) - P3 | N=550 | Recruiting | Sponsor: Neurocrine Biosciences

New P3 trial • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

All Roads Lead to Glutamate: NMDA and AMPA Receptors as Targets for Rapid-Acting Antidepressants. (PubMed, Pharmacol Res) - "Beyond established rapid-acting antidepressants (RAADs), such as (es)ketamine and dextromethorphan/bupropion (AXS-05), we highlight novel therapeutic directions involving esmethadone (REL-1017), nitrous oxide, and positive allosteric modulators (PAMs) of NMDA receptors (e.g. rapastinel, zelquistinel, and apimostinel). Moreover, we discuss forward-looking strategies using AMPA receptor PAMs (e.g. osavampator and tulrampator) and targeting of AMPA receptor-interacting proteins...Together, targeting glutamatergic signalling represents a transformative path for TRD treatment with high efficacy by more directly modulating pathologically affected signalling modules. These developments place glutamatergic agents at the forefront of next-generation AD strategies."

Journal • Review • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Long-Term Study to Assess the Safety and Tolerability of NBI-1065845 as an Adjunctive Treatment in Participants With Major Depressive Disorder (MDD) (clinicaltrials.gov) - P3 | N=600 | Recruiting | Sponsor: Neurocrine Biosciences | Not yet recruiting ➔ Recruiting

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

NBI-1065845-MDD3026: Study to Assess the Efficacy and Safety of NBI-1065845 as an Adjunctive Treatment in Participants With Major Depressive Disorder (MDD) (clinicaltrials.gov) - P3 | N=200 | Recruiting | Sponsor: Neurocrine Biosciences | Not yet recruiting ➔ Recruiting

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

TAK-653 Reverses Core Depressive Symptoms in Chronic Stress-Induced Monkey Model. (PubMed, Biomedicines) - "Additionally, the plasma analysis revealed a marked decrease in cortisol and IL-6 levels, along with an increased expression of BDNF. These findings indicate that TAK-653 effectively alleviates depression-like behaviors in nonhuman primate models, thereby paving the way for a promising new strategy in the treatment of depression."

Journal • Preclinical • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry • BDNF • CXCL8 • IL6

Long-Term Study to Assess the Safety and Tolerability of NBI-1065845 as an Adjunctive Treatment in Participants With Major Depressive Disorder (MDD) (clinicaltrials.gov) - P3 | N=600 | Not yet recruiting | Sponsor: Neurocrine Biosciences

New P3 trial • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

NBI-1065845-MDD3026: Study to Assess the Efficacy and Safety of NBI-1065845 as an Adjunctive Treatment in Participants With Major Depressive Disorder (MDD) (clinicaltrials.gov) - P3 | N=200 | Not yet recruiting | Sponsor: Neurocrine Biosciences

New P3 trial • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

NBI-1065845-MDD3025: Study to Assess the Efficacy and Safety of NBI-1065845 as an Adjunctive Treatment in Participants With Major Depressive Disorder (MDD) (clinicaltrials.gov) - P3 | N=200 | Recruiting | Sponsor: Neurocrine Biosciences | Not yet recruiting ➔ Recruiting

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

NBI-1065845-MDD3025: Study to Assess the Efficacy and Safety of NBI-1065845 as an Adjunctive Treatment in Participants With Major Depressive Disorder (MDD) (clinicaltrials.gov) - P3 | N=200 | Not yet recruiting | Sponsor: Neurocrine Biosciences

New P3 trial • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Study to Assess the Efficacy and Safety of NBI-1065845 as an Adjunctive Treatment in Participants With Major Depressive Disorder (MDD) (clinicaltrials.gov) - P3 | N=200 | Recruiting | Sponsor: Neurocrine Biosciences | Not yet recruiting ➔ Recruiting

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

Study to Assess the Efficacy and Safety of NBI-1065845 as an Adjunctive Treatment in Participants With Major Depressive Disorder (MDD) (clinicaltrials.gov) - P3 | N=200 | Not yet recruiting | Sponsor: Neurocrine Biosciences | Trial completion date: Nov 2026 ➔ Jul 2027 | Trial primary completion date: Nov 2026 ➔ Jul 2027

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

Study to Assess the Efficacy and Safety of NBI-1065845 as an Adjunctive Treatment in Participants With Major Depressive Disorder (MDD) (clinicaltrials.gov) - P3 | N=200 | Not yet recruiting | Sponsor: Neurocrine Biosciences

New P3 trial • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Neurocrine Biosciences Announces Amendment to Strategic Collaboration with Takeda to Develop and Commercialize Osavampator (formerly NBI-1065845/TAK-653) (PRNewswire) - "Under the amended agreement, Neurocrine will obtain exclusive rights for all indications to develop and commercialize osavampator, a potential first-in-class AMPA positive allosteric modulator in development for patients with inadequate response to treatment of major depressive disorder (MDD) in all territories worldwide except Japan, where Takeda will reacquire exclusive rights. Under the terms of the updated agreement, each company is responsible for development costs in their respective region, and both companies are eligible to receive royalty payments....'With the recent successful completion of our End-of-Phase 2 meeting with FDA for osavampator, we look forward to beginning the Phase 3 program in the first half of this year'."

Licensing / partnership • New P3 trial • Major Depressive Disorder

Neurocrine Biosciences Provides Update on ERUDITE Phase 2 Data for Luvadaxistat in Adults with Cognitive Impairment Associated with Schizophrenia (PRNewswire) - P2 | N=216 | ERUDITE (NCT05182476) | Sponsor: Neurocrine Biosciences | "Neurocrine Biosciences, Inc...today announced that its ERUDITE Phase 2 clinical study of investigational compound luvadaxistat (NBI-1065844) failed to meet its primary endpoint as a potential treatment to improve cognitive impairment in patients with schizophrenia....The ERUDITE study was the second Phase 2 trial for luvadaxistat. It failed to replicate the cognitive endpoints data seen in the earlier INTERACT study, due in part to the large variability seen in the cognitive measures across the population studied and a potential imbalance in the baseline characteristics of subjects enrolled across the treatment arms....We therefore plan to halt further development of luvadaxistat at this time and instead will focus our efforts and resources on the advancement into Phase 3 clinical development of NBI-1117568 for schizophrenia and NBI-1065845 for major depressive disorder."

New P3 trial • P2 data • Major Depressive Disorder • Schizophrenia

Emerging trends in antipsychotic and antidepressant drug development: Targeting nonmonoamine receptors and innovative mechanisms. (PubMed, PCN Rep) - "One noteworthy candidate is Ulotaront (SEP-363856), an agent acting as a TAAR1 agonist with 5-HT1A agonist activity, demonstrating promising outcomes in the treatment of schizophrenia, devoid of extrapyramidal symptoms or metabolic side-effects. Similarly, MIN-101 (Roluperidone) and KarXT are currently in development, with its focus on addressing the symptoms in schizophrenia. In the domain of antidepressants, novel therapeutic approaches have surfaced, such as Auvelity, a Food and Drug Administration (FDA)-approved NMDA receptor antagonist synergistically combined with Bupropion to enhance its effects. Another notable candidate is Zuranolone, operating as a GABA A receptor-positive allosteric modulator, showcasing efficacy in treating major depressive disorder (MDD) and postpartum depression. Additionally, TAK-653 (NBI-1065845) and MJI821 (Onfasprodil) have emerged as potential antidepressants targeting AMPA receptors and NMDA receptor 2B (NR2B) negative allosteric..."

Journal • Review • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Postpartum Depression • Psychiatry • Schizophrenia

Effects of the selective AMPA modulator NBI-1065845 on the pharmacokinetics of midazolam or ethinyl estradiol-levonorgestrel in healthy adults. (PubMed, Clin Transl Sci) - "These findings indicate that NBI-1065845 is not a CYP3A inducer and support its administration with CYP3A substrates. NBI-1065845 was generally well tolerated, with no new safety signals observed after coadministration of midazolam, ethinyl estradiol, or levonorgestrel."

Clinical • Journal • P1 data • PK/PD data • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

SAVITRI: Study to Assess the Efficacy and Safety of NBI-1065845 in Adults With Major Depressive Disorder (MDD) (clinicaltrials.gov) - P2 | N=183 | Completed | Sponsor: Neurocrine Biosciences | Active, not recruiting ➔ Completed

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

SAVITRI: Study to Assess the Efficacy and Safety of NBI-1065845 in Adults With Major Depressive Disorder (MDD) (clinicaltrials.gov) - P2 | N=183 | Active, not recruiting | Sponsor: Neurocrine Biosciences | Recruiting ➔ Active, not recruiting

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

Effects of the Selective Ampa Modulator NBI-1065845 on the Pharmacokinetics of Ethinyl Estradiol Levonorgestrel or Midazolam in Healthy Adults (ASCP 2023) - P2 | "Study funded by Neurocrine Biosciences, Inc. Learning Objectives To understand potential drug-drug interaction of NBI-1065845 with oral contraceptives To understand potential drug-drug interaction of NBI-1065845 with midazolam"

Clinical • PK/PD data • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

SAVITRI: Study to Assess the Efficacy and Safety of NBI-1065845 in Adults With Major Depressive Disorder (MDD) (clinicaltrials.gov) - P2 | N=155 | Recruiting | Sponsor: Neurocrine Biosciences | Trial completion date: Oct 2023 ➔ Jan 2024

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

Role of the AMPA receptor in antidepressant effects of ketamine and potential of AMPA receptor potentiators as a novel antidepressant. (PubMed, Neuropharmacology) - "Accumulating evidence from preclinical studies has shown that the antidepressant effects of ketamine are dependent on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R) activation, which triggers activation of the mechanistic target of rapamycin pathway and brain-derived neurotrophic factor release. We further review the in vitro and in vivo profiles of TAK-653, including its procognitive and antidepressant-like effects, as well as its safety profile, in comparison with known AMPA-R potentiators with agonistic activity and AMPA, an AMPA-R agonist. The low agnostic activity of TAK-653 may overcome limitations of known AMPA-R potentiators."

Journal • Review • CNS Disorders • Depression • Epilepsy • Psychiatry • BDNF