Navacaprant (BTRX-335140): A Comprehensive Report on an Investigational Kappa-Opioid Receptor Antagonist for Major Depressive Disorder

1. Executive Summary

Navacaprant (BTRX-335140) is an orally active, selective small-molecule antagonist of the kappa-opioid receptor (KOR) that has been under investigation primarily for the treatment of Major Depressive Disorder (MDD). Originally developed by BlackThorn Therapeutics and later acquired and advanced by Neumora Therapeutics, navacaprant aimed to address MDD, particularly symptoms of anhedonia, by modulating the KOR system, a novel mechanism of action in depression therapeutics.

The compound demonstrated a promising preclinical profile, including high selectivity for KOR, favorable pharmacokinetics with central nervous system (CNS) penetration, and efficacy in animal models. Early clinical development included a Phase 2 trial (NCT04221230) which, while not meeting its primary endpoint in the overall population, showed statistically significant and clinically meaningful improvements in depressive symptoms and anhedonia in a prespecified subgroup of patients with moderate-to-severe MDD.[1] These encouraging signals, coupled with a generally favorable safety and tolerability profile characterized by a low incidence of adverse events and no serious adverse events attributed to the drug, supported its progression to a large Phase 3 program known as KOASTAL.[2]

However, the development trajectory of navacaprant encountered a significant setback in January 2025 with the announcement that the first of its pivotal Phase 3 trials, KOASTAL-1 (NCT06029426), failed to meet its primary endpoint of reducing depressive symptoms (as measured by the Montgomery-Åsberg Depression Rating Scale, MADRS) compared to placebo in adults with moderate-to-severe MDD.[3] Interestingly, a prespecified analysis suggested a potential efficacy signal in female participants, a finding Neumora intends to explore further.[5] Despite the efficacy failure, navacaprant maintained its favorable safety profile in KOASTAL-1.[5]

This outcome prompted Neumora Therapeutics to make strategic adjustments, including discontinuing a Phase 2 trial of navacaprant in bipolar depression to conserve resources and amending the protocols for the ongoing KOASTAL-2 and KOASTAL-3 MDD trials to optimize site selection and enhance medical monitoring.[7] These changes have delayed the expected data readouts for these trials to 2026.[7]

The journey of navacaprant underscores the inherent challenges in developing novel treatments for complex neuropsychiatric disorders like MDD, where promising early-phase data do not always translate to late-stage success. The failure of another KOR antagonist, aticaprant (Johnson & Johnson), in Phase 3 trials for MDD around the same period has further cast uncertainty on this therapeutic class for this indication.[10] The future of navacaprant now hinges on the results of the modified KOASTAL studies and a deeper understanding of its potential effects, particularly in specific patient populations.

2. Introduction to BTRX-335140 (Navacaprant)

2.1. Nomenclature and Identifiers

The investigational compound BTRX-335140 is most widely known by its International Nonproprietary Name (INN), Navacaprant.[3] Throughout its development, it has been referred to by several developmental codes and synonyms. These include BTRX-140, CYM-53093, NMRA-335140, and NMRA-140.[3] One of its early designations in scientific literature is "compound 58," often linked to its initial publication.[12]

For database and regulatory tracking, Navacaprant is assigned DrugBank ID DB16068 and CAS (Chemical Abstracts Service) Number 2244614-14-8.[3] Other identifiers include UNII (Unique Ingredient Identifier) XK5ILZ28KI and KEGG (Kyoto Encyclopedia of Genes and Genomes) ID D12869.[3] The multiplicity of these codes reflects the compound's progression through various research and development stages under different organizational umbrellas, a common occurrence in the pharmaceutical industry before a single INN is widely adopted.

2.2. Drug Type

Navacaprant is classified as a Small Molecule drug.[15] This classification typically implies that the compound is chemically synthesized, possesses a relatively low molecular weight, and often has the potential for oral administration and penetration of biological membranes, including the blood-brain barrier – characteristics that are indeed reported for Navacaprant.

2.3. Origin and Development History

Navacaprant was originated by BlackThorn Therapeutics.[3] BlackThorn Therapeutics was responsible for advancing the compound, then designated BTRX-140, into Phase 2 clinical development for neuropsychiatric disorders.[2]

Subsequently, Neumora Therapeutics acquired Navacaprant (BTRX-335140) as part of its buyout of BlackThorn Therapeutics.[2] Neumora Therapeutics has since been the primary entity responsible for its later-stage clinical development, including conducting and sponsoring the Phase 2 trial NCT04221230 (which it amended after acquisition) and the comprehensive Phase 3 KOASTAL program.[2] The acquisition by Neumora appears to have provided the necessary resources and strategic focus to advance Navacaprant into large-scale Phase 3 trials, a significant undertaking for any investigational compound.

3. Preclinical Profile

3.1. Chemical Properties and Structure

Navacaprant is a synthetic organic compound with defined chemical characteristics. Its molecular formula is C25​H32​FN5​O2​, and it has a molar mass (molecular weight) consistently reported around 453.56 g/mol (values such as 453.55 g/mol, 453.562 g/mol, and 453.25 g/mol appear across different sources).[3] The IUPAC (International Union of Pure and Applied Chemistry) name for Navacaprant is 1-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine (also referred to with "tetrahydro-2H-pyran-4-yl" instead of "oxan-4-yl", which is equivalent).[14]

Its chemical structure is represented by the canonical SMILES (Simplified Molecular Input Line Entry System) string: CCc1cc(F)c2c(c1)c(C)c(c(n2)N1CCC(CC1)NC1CCOCC1)c1onc(n1)C.[12] The InChIKey, another structural identifier, is CQOJHAJWCDJEAT-UHFFFAOYSA-N.[12] Physically, Navacaprant appears as a solid powder.[17] It is reported to be soluble in dimethyl sulfoxide (DMSO) [17], a common solvent for in vitro testing, and can be further diluted into aqueous media, with preheating recommended to prevent precipitation.[13]

Physico-chemical property calculations indicate Navacaprant has 5 hydrogen bond acceptors (or 6 by some predictions) and 1 hydrogen bond donor, with 5 rotatable bonds.[12] Its topological polar surface area (TPSA) is 76.31 A˚2.[12] The predicted lipophilicity (XLogP or logP) values range from approximately 4.09 to 5.56.[12] While some sources indicate it adheres to Lipinski's Rule of Five (a set of guidelines for "drug-likeness"), others note one violation due to a logP value potentially exceeding 5.[12] These properties are generally consistent with an orally bioavailable, CNS-penetrant small molecule.

Table 1: Key Identifiers and Chemical Properties of Navacaprant (BTRX-335140)

Property	Value	Reference(s)
Common Name	Navacaprant	3
Key Developmental Codes	BTRX-335140, CYM-53093, NMRA-140	3
DrugBank ID	DB16068	3
CAS Number	2244614-14-8	3
Molecular Formula	C25​H32​FN5​O2​	3
Molecular Weight	~453.56 g/mol	3
IUPAC Name	1-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine	14
KOR IC50	0.8 nM	13
MOR IC50	110 nM	13
DOR IC50	6500 nM	13
Solubility	Soluble in DMSO	17
Appearance	Solid powder	17

3.2. Mechanism of Action

Navacaprant is a potent and selective antagonist of the kappa-opioid receptor (KOR).[3] Its primary pharmacological action is achieved through binding to KORs and blocking the effects of endogenous ligands, such as dynorphin. The in vitro inhibitory constant (IC50​) for Navacaprant at the human KOR is approximately 0.8 nM.[13]

A key feature of Navacaprant's design is its selectivity for KOR over other opioid receptors. It exhibits an IC50​ of 110 nM for the µ-opioid receptor (MOR) and 6500 nM for the δ-opioid receptor (DOR).[13] This translates to a selectivity of over 100-fold for KOR versus MOR and DOR, with some reports indicating a 138-fold preference for KOR over MOR and over 8000-fold for KOR over DOR.[18] More recent analyses suggest a KOR binding specificity of approximately 310-fold relative to MOR.[21] Such high selectivity is crucial, as it aims to elicit therapeutic effects via KOR antagonism while minimizing potential MOR-related side effects, such as abuse liability or worsening of depressive symptoms, and other off-target effects associated with DOR interaction.[21]

KORs are G-protein coupled receptors widely expressed in the CNS and periphery. Activation of KORs by endogenous ligands like dynorphins is implicated in the pathophysiology of stress-related mood disorders, anxiety, anhedonia (the inability to experience pleasure), and drug abuse.[15] KOR activation generally leads to the inhibition of adenylate cyclase activity, modulation of ion channel function (reducing calcium currents and increasing potassium conductance), and subsequent inhibition of neurotransmitter release.[15] The therapeutic rationale for KOR antagonists like Navacaprant in MDD is based on the hypothesis that blocking KOR activity can normalize stress-induced dysregulation of brain circuits involved in mood, motivation, and reward processing, including dopamine pathways.[2]

3.3. Pharmacodynamics (In Vitro and In Vivo Activity)

The pharmacodynamic profile of Navacaprant has been characterized through various in vitro and in vivo studies.

In vitro, Navacaprant demonstrated selective antagonist activity at KOR in cellular assays, such as FRET (Förster Resonance Energy Transfer) and PathHunter assays using U2OS cells expressing opioid receptors.19 An important off-target assessment showed that Navacaprant inhibits the human ether-à-go-go-related gene (hERG) potassium channel with an IC50​ of 1 µM in patch clamp assays.19 While this indicates some hERG activity, the therapeutic window (the ratio of hERG IC50​ to KOR IC50​) is substantial (over 1000-fold). This suggests that at therapeutically relevant concentrations for KOR antagonism, the risk of hERG-related cardiac effects might be manageable, though it would necessitate careful cardiac monitoring in clinical trials.

In vivo studies in rodent models provided proof-of-concept for Navacaprant's KOR antagonist activity. Oral administration of Navacaprant (then CYM-53093) robustly antagonized KOR agonist (e.g., U-69,593)-induced prolactin secretion in rats, with efficacy observed at doses as low as 0.1 mg/kg.[17] It also blocked KOR agonist (U-50488)-induced antinociception in the tail-flick analgesia model in mice.[17] Notably, in this model, a 1 mg/kg intraperitoneal dose blocked the KOR agonist effect at 1 hour post-administration but not at 24 hours, indicating a "medication-like duration of action" rather than the prolonged antagonism seen with some earlier KOR antagonists.[19] Navacaprant also exhibited broad selectivity against a panel of other off-target proteins in preclinical assessments.[17]

Furthermore, studies in Rhesus macaques demonstrated that NMRA-140 (Navacaprant) could protect working memory performance from mild stress exposure induced by the benzodiazepine inverse agonist FG7142.[24] This finding is particularly relevant as cognitive impairments, including deficits in working memory, are common in MDD and often exacerbated by stress. This suggested a potential for Navacaprant to address not only core mood symptoms but also cognitive aspects of the disorder.

3.4. Pharmacokinetics (ADMET Profile, CNS Penetration)

Navacaprant has demonstrated favorable in vitro ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) and in vivo pharmacokinetic profiles in preclinical species.[17]

The compound is orally bioavailable. In rats, oral administration of 5 mg/kg resulted in a bioavailability (F%) of 30.2%, while in mice, a 10 mg/kg oral dose yielded an F% of 12%.[19] The plasma half-life (t1/2​) after oral dosing was 6.19 hours in rats and 2.57 hours in mice.[19]

Crucially for a drug targeting CNS disorders, Navacaprant distributes well into the CNS.[19] Studies in rats showed good CNS penetration with a brain-to-plasma concentration ratio of 2.2:1 and adequate cerebrospinal fluid (CSF) exposure (approximately 4 times its KOR IC50​) one hour after a 5 mg/kg oral dose.[23]

Regarding its metabolic profile, Navacaprant showed minimal inhibition of major cytochrome P450 (CYP450) enzymes in vitro (IC50​ values > 30 µM for CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4), and its potency was unchanged upon preincubation with these enzymes.[23] This suggests a low potential for clinically significant drug-drug interactions mediated by CYP450 inhibition. In terms of safety, Navacaprant was found to be non-mutagenic in Ames assays.[23]

While extensive preclinical ADME data exists, information on human absorption, metabolism, and route of elimination is listed as "Not Available" in some databases like DrugBank, which is typical for an investigational compound not yet approved.[15] The collective preclinical data, however, painted a picture of a well-characterized molecule with properties suitable for clinical development as an oral CNS therapeutic.

3.5. Key Preclinical Publications

The foundational preclinical research on Navacaprant (BTRX-335140, CYM-53093) is extensively detailed in a publication by Guerrero M, Urbano M, et al., titled "Design and Synthesis of a Novel and Selective Kappa Opioid Receptor (KOR) Antagonist (BTRX-335140)". This paper was published in the Journal of Medicinal Chemistry in February 2019 (Volume 62, Issue 4, pages 1761–1780) and is associated with PMID: 30707578.[3] This publication describes the discovery process, chemical synthesis, in vitro characterization (including potency, selectivity, and ADMET properties), and in vivo pharmacokinetic and pharmacodynamic studies in animal models that established Navacaprant as a viable clinical candidate. It serves as the primary scientific reference for the drug's initial development and rationale for its progression into human trials.

4. Clinical Development in Major Depressive Disorder (MDD)

The clinical development of Navacaprant for MDD has been a focal point, progressing from promising Phase 2 findings to a challenging Phase 3 program.

4.1. Phase 2 Study (NCT04221230)

The Phase 2 clinical trial, identified as NCT04221230 and titled "Study in Major Depressive Disorder With BTRX-335140 (NMRA-335140) vs Placebo," was a critical exploratory study.[12]

4.1.1. Study Design, Objectives, and Endpoints

This was a Phase 2a, randomized, double-blind, placebo-controlled, multicenter trial conducted over 8 weeks.[1] It was designed to assess the efficacy and safety of Navacaprant in adults with MDD.[1] The study initially enrolled participants with mild-to-moderate MDD, defined by 17-Item Hamilton Depression Rating Scale (HAMD-17) scores between 14 and 30.[1] Inclusion criteria also specified a primary DSM-5 diagnosis of MDD with prominent symptoms of anhedonia, and the current depressive episode lasting between 3 weeks and 12 months.[27] Participants were randomized 1:1 to receive either Navacaprant 80 mg once daily or placebo.[1]

The primary objective was to evaluate the change from baseline (CFB) in the HAMD-17 total score at week 8.[1] Key secondary endpoints included the CFB in the Snaith-Hamilton Pleasure Scale (SHAPS) total score, a measure of anhedonia.[1]

The trial was initiated by BlackThorn Therapeutics, Inc..[2] Following its acquisition of BlackThorn, Neumora Therapeutics took over the study and subsequently amended the protocol to focus enrollment on patients with moderate-to-severe MDD, defined by a baseline HAMD-17 score of ≥ 22.[2] This strategic shift aimed to align the study population with those typically investigated in MDD clinical trials and perceived as more likely to demonstrate a drug effect.

4.1.2. Efficacy Results

The efficacy results of NCT04221230 were mixed but provided important signals for future development.

In the total efficacy population (n=171, including participants with mild-to-severe MDD, baseline HAMD-17 scores as low as 14), Navacaprant did not achieve statistical significance on the primary endpoint: the CFB in HAMD-17 total score at Week 8 was -1.7 (SE 1.08) points greater with Navacaprant compared to placebo, which was not statistically significant (P = 0.121, using a mixed-models repeated-measures analysis).[1] However, at Week 4, a statistically significant improvement in HAMD-17 CFB was observed (LSMD -2.7, p = 0.003).[2] For anhedonia, measured by SHAPS CFB, Navacaprant showed statistically significant improvements compared to placebo at both Week 4 (LSMD -2.8, p = 0.004) and Week 8 (LSMD -3.4, p = 0.002) in this overall population.[1]

A prespecified sensitivity analysis using Last-Observation-Carried-Forward (LOCF) imputation in the efficacy population showed statistically significant improvements for Navacaprant on HAMD-17 CFB at Week 4 (-2.9 [0.88], P = 0.002) and Week 8 (-2.2 [0.98], P = 0.024), and on SHAPS CFB at Week 4 (-2.8 [0.96], P = 0.004) and Week 8 (-3.4 [1.10], P = 0.002).[1]

The most encouraging results emerged from the prespecified subgroup of participants with moderate-to-severe MDD (baseline HAMD-17 score ≥ 22; n = 100).[1] In this subgroup, Navacaprant demonstrated statistically significant improvements in HAMD-17 CFB versus placebo at both Week 4 (LSMD -3.0 [1.20], P = 0.015) and Week 8 (LSMD -2.8 [1.33], P = 0.037).[1] Furthermore, on the SHAPS, this subgroup showed a statistically significant and clinically meaningful improvement in anhedonia at Week 8 (LSMD -4.8 [1.35], P = 0.001).[1] The results in this moderate-to-severe subgroup, particularly the robust effect on anhedonia, were pivotal in Neumora's decision to advance Navacaprant into Phase 3 trials targeting this specific patient population.

4.1.3. Safety and Tolerability Profile

Navacaprant was generally well-tolerated in the Phase 2 study, exhibiting a favorable safety profile.[1] The incidence of treatment-emergent adverse events (TEAEs) was slightly lower in the Navacaprant group (35.3%) compared to the placebo group (44.1%).[2]

The most frequently reported adverse events were headache (occurring in 4.9% of participants in both the Navacaprant and placebo groups) and nausea (4.9% in the Navacaprant group versus 1.0% in the placebo group).[1] Importantly, no serious adverse events (SAEs) were reported in participants receiving Navacaprant.[1] In contrast, 4.9% of participants in the placebo group experienced severe TEAEs.[2]

Notably, Navacaprant was not associated with reports of sexual dysfunction or weight gain, common side effects that often lead to discontinuation of other antidepressant medications.[2] Furthermore, no evidence of suicidal ideation or behavior was identified as assessed by the Columbia Suicide Severity Rating Scale (C-SSRS).[2] This positive safety and tolerability profile was a significant factor supporting its continued development.

4.1.4. Published Findings

The results of the Phase 2 trial (NCT04221230) were published in the Journal of Clinical Psychopharmacology. The publication, titled "Navacaprant, a Novel and Highly Selective Kappa Opioid Receptor Antagonist, in Adults With Major Depressive Disorder: A Randomized, Double-Blind Phase 2 Clinical Trial" (PMID: 40199329, DOI: 10.1097/JCP.0000000000001967), corroborates the findings discussed above.[1] Neumora Therapeutics announced this publication in its first-quarter 2025 financial results update.[9] The peer-reviewed publication of these data allows for broader scientific dissemination and scrutiny of the trial's outcomes.

Table 2: Summary of Phase 2 Clinical Trial NCT04221230 Results for Navacaprant in MDD

Parameter	Details	Reference(s)
Trial ID	NCT04221230	3
Sponsor	BlackThorn Therapeutics (initiated) / Neumora Therapeutics (completed, amended)	2
Phase	Phase 2a / Phase 2	1
Population	Adults with MDD. Overall (HAMD-17 14-30, n=171); Moderate-to-Severe Subgroup (HAMD-17 ≥ 22, n=100)	1
Intervention	Navacaprant 80 mg QD vs. Placebo (8 weeks)	1
Primary Endpoint	HAMD-17 CFB at Week 8	1
Key Secondary Endpoint	SHAPS CFB at Week 8	1
Efficacy Results (Overall Population)	HAMD-17 Wk 8: LSMD -1.7 (P=0.121) <br> SHAPS Wk 8: LSMD -3.4 (P=0.002)	1
Efficacy Results (Moderate-to-Severe Subgroup)	HAMD-17 Wk 8: LSMD -2.8 (P=0.037) <br> SHAPS Wk 8: LSMD -4.8 (P=0.001)	1
Key Safety Findings	Generally well-tolerated. Common AEs: Headache (4.9% nav vs 4.9% pla), Nausea (4.9% nav vs 1.0% pla). No SAEs with navacaprant.	1

4.2. Phase 3 Program (KOASTAL Studies)

Following the encouraging signals from the Phase 2 study, particularly in the moderate-to-severe MDD subgroup, and a positive End-of-Phase 2 meeting with the U.S. Food and Drug Administration (FDA) in June 2023, Neumora Therapeutics initiated the KOASTAL Phase 3 program.[2] This pivotal program was designed to definitively evaluate the efficacy and safety of Navacaprant monotherapy in adult patients with moderate-to-severe MDD, defined by a Montgomery–Åsberg Depression Rating Scale (MADRS) total score of ≥ 25 at baseline.[2] The program initially comprised three replicate, randomized, placebo-controlled, double-blind studies (KOASTAL-1, KOASTAL-2, and KOASTAL-3) and an open-label, long-term extension study (KOASTAL-LT).[2] The primary endpoint for all three main studies was the change from baseline in MADRS total score at Week 6, with the key secondary endpoint being the change from baseline on the SHAPS at Week 6.[2] The planned dosage was Navacaprant 80 mg once daily.[4]

4.2.1. KOASTAL-1 (NCT06029426)

KOASTAL-1, titled "Study to Evaluate the Effects of Oral NMRA-335140 Versus Placebo in Participants With Major Depressive Disorder," was the first of the Phase 3 trials to yield results.[4] This study enrolled 383 adult patients with moderate-to-severe MDD in the United States, randomized to receive either Navacaprant 80 mg (n=191) or placebo (n=192) for 6 weeks.[4] The trial was completed, with an estimated primary completion date of January 2025.[4]

On January 2, 2025, Neumora Therapeutics announced topline results from KOASTAL-1, revealing a significant setback for the Navacaprant program.[3] The study failed to meet its primary endpoint: the change from baseline in MADRS total score at Week 6 did not demonstrate a statistically significant improvement for Navacaprant compared to placebo. Both treatment arms showed an identical mean improvement of 12.5 points on the MADRS (P = 0.993).[4] The study also failed to meet its key secondary endpoint of change from baseline in SHAPS total score at Week 6; while Navacaprant showed a numerically greater reduction (-5.8 points) compared to placebo (-5.5 points), the difference was not statistically significant (P = 0.648).[4]

Despite the overall negative outcome, a prespecified analysis by gender yielded intriguing observations. Female participants treated with Navacaprant demonstrated a numerically greater improvement on the MADRS total score (14.0-point reduction) compared to those on placebo (11.4-point reduction), a difference that approached statistical significance (P = 0.072).[4] For the SHAPS total score, female participants on Navacaprant showed a statistically significant improvement (-7.2 points) compared to placebo (-4.9 points) (P = 0.015).[4] Conversely, male participants on Navacaprant showed less improvement on both MADRS and SHAPS compared to males on placebo.[4] This unexpected gender-specific response pattern became a focal point for Neumora's subsequent analyses and strategic planning.

Consistent with earlier studies, Navacaprant was generally well-tolerated in KOASTAL-1, with a safety profile comparable to placebo.[4] No serious adverse events were reported in the Navacaprant arm, and there was no signal for increased suicidal ideation or behavior as measured by the C-SSRS.[5] Common adverse events included headache (6.8% Navacaprant vs. 7.3% placebo), diarrhea (5.2% Navacaprant vs. 2.1% placebo), and pruritus (3.7% Navacaprant vs. 2.1% placebo).[4] Treatment discontinuation rates due to TEAEs were low and similar between groups (2.1% for Navacaprant, 3.1% for placebo).[5]

The failure of KOASTAL-1 to meet its primary and key secondary endpoints represented a major challenge to the KOR antagonist hypothesis for the broad treatment of moderate-to-severe MDD and significantly impacted the perceived likelihood of success for Navacaprant.

4.2.2. KOASTAL-2 (NCT06058039) & KOASTAL-3 (NCT06058013)

KOASTAL-2 (NCT06058039) and KOASTAL-3 (NCT06058013) were initially planned as replicate studies to KOASTAL-1, intended to confirm its findings and provide the necessary data for regulatory submission.[4] KOASTAL-2 was planned for the U.S., Canada, and Latin America, while KOASTAL-3 was to include sites in the U.S., Asia Pacific, and Europe.[2]

Following the disappointing results from KOASTAL-1, Neumora Therapeutics announced in March 2025 that it was temporarily halting enrollment in KOASTAL-2 and KOASTAL-3 to implement protocol amendments based on learnings from the first trial.[7] These changes are primarily operational, aimed at improving trial execution and reducing variability. They include:

• Reducing the number of clinical trial sites to focus on those with the highest level of expertise in conducting MDD studies.
• Enhancing medical monitoring through collaboration with the Massachusetts General Hospital Clinical Trials Network and Institute's SAFER (Systematic Assessment for Follow-up Evaluation of Risk) approach, an independent psychiatric review.
• Implementing the Verified Clinical Trials screening database to prevent simultaneous enrollment of participants in multiple clinical trials.[7]

Neumora expected to resume these trials later in March 2025.[34] As a result of these modifications and the pause, the timelines for data readout have been revised. Topline data from KOASTAL-3 are now expected in the first quarter of 2026, and from KOASTAL-2 in the second quarter of 2026.[7] This pushes the potential for an NDA submission significantly beyond the original 2025 target.[2] Neumora's decision to amend and continue these trials, rather than terminate the program, suggests a belief that the KOASTAL-1 outcome may have been influenced by trial conduct issues or that the observed signal in female participants warrants further investigation within a more rigorously controlled setting. However, it remains a high-risk strategy given the initial Phase 3 failure.

4.2.3. KOASTAL-LT (Open-Label Extension)

The KOASTAL program includes an open-label, long-term extension study, KOASTAL-LT, designed to evaluate the long-term safety and tolerability of Navacaprant.[2] Participants who complete any of the main 6-week KOASTAL studies (KOASTAL-1, -2, or -3) are eligible to enroll in KOASTAL-LT if they meet criteria and provide consent.[2]

Despite the negative primary outcome of KOASTAL-1, a significant proportion of participants treated with Navacaprant (83.3%) who completed the 6-week study elected to enroll in the KOASTAL-LT study.[4] This high rollover rate might suggest that patients and investigators perceived some level of benefit or found the drug sufficiently tolerable for continued use. The data from KOASTAL-LT will be crucial for understanding the long-term safety profile of Navacaprant, an essential component for any potential future regulatory submission.

The identical MADRS improvement observed in both the Navacaprant and placebo arms of KOASTAL-1 (a 12.5-point reduction) [5] is particularly noteworthy. Such a high placebo response, or an inability of the drug to differentiate from it, poses a fundamental challenge in MDD trials. While Neumora is focusing on operational enhancements for KOASTAL-2 and -3 [7], the underlying reasons for this lack of separation will need careful consideration. The gender-specific finding, particularly the statistically significant SHAPS improvement in females [4], provides a narrow, specific hypothesis. However, relying on a post-hoc subgroup finding from a failed trial to guide future development is inherently risky and requires prospective validation.

The broader context of J&J's aticaprant, another KOR antagonist, also failing its Phase 3 MDD trial [10], amplifies concerns about the viability of this mechanism of action for MDD in general. These concurrent late-stage failures suggest that the translation from preclinical promise and early clinical signals to robust efficacy in large, heterogeneous MDD populations is proving exceptionally difficult for KOR antagonists, potentially indicating issues with the core hypothesis for broad MDD or with current trial designs to detect their specific effects.

Table 3: Overview of the KOASTAL Phase 3 Program for Navacaprant in MDD

Feature	KOASTAL-1 (NCT06029426)	KOASTAL-2 (NCT06058039)	KOASTAL-3 (NCT06058013)	KOASTAL-LT
Title	Study to Evaluate the Effects of Oral NMRA-335140 Versus Placebo in Participants With Major Depressive Disorder	A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Effects of Oral NMRA-335140 Versus Placebo in Participants With Major Depressive Disorder	A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Effects of Oral NMRA-335140 Versus Placebo in Participants With Major Depressive Disorder	Open-Label Extension Study
Population	Adults with moderate-to-severe MDD (MADRS ≥ 25)	Adults with moderate-to-severe MDD (MADRS ≥ 25)	Adults with moderate-to-severe MDD (MADRS ≥ 25)	Participants completing KOASTAL-1, -2, or -3
Intervention	Navacaprant 80 mg QD vs. Placebo (6 weeks)	Navacaprant 80 mg QD vs. Placebo (6 weeks)	Navacaprant 80 mg QD vs. Placebo (6 weeks)	Navacaprant 80 mg QD (long-term)
Primary Endpoint	MADRS CFB @ Wk 6	MADRS CFB @ Wk 6	MADRS CFB @ Wk 6	Long-term safety & tolerability
Key Secondary Endpoint	SHAPS CFB @ Wk 6	SHAPS CFB @ Wk 6	SHAPS CFB @ Wk 6	N/A
Original Status/Timeline	Completed Jan 2025	Initiated Q4 2023, data H1 2025	Initiated Q1 2024, data H1 2025	Ongoing
Current Status/Timeline (post-KOASTAL-1)	Completed; Failed primary/secondary endpoints	Paused March 2025 for protocol amendments; Expected restart March 2025; Data Q2 2026	Paused March 2025 for protocol amendments; Expected restart March 2025; Data Q1 2026	Ongoing; High rollover from KOASTAL-1
Key KOASTAL-1 Results	Failed primary (MADRS P=0.993) & secondary (SHAPS P=0.648) endpoints. Potential female signal: MADRS P=0.072, SHAPS P=0.015. Generally well-tolerated, no SAEs.	N/A	N/A	N/A
Reference(s)	4	2	2	2

5. Clinical Development in Other Indications

5.1. Bipolar Depression

Navacaprant was also being evaluated for the treatment of bipolar depression.[3] It had reached Phase 2 development for this indication, with a trial (NCT06429722, "A Phase 2a, Randomized, Double-blind, Placebo-controlled Pilot Study to Evaluate the Effects of Oral...source Bipolar II Disorder") listed as recruiting.[35] Neumora had previously guided that Phase 2 data for bipolar depression could be expected in the second half of 2025.[38]

However, in March 2025, following the negative results from the KOASTAL-1 MDD trial, Neumora Therapeutics announced the discontinuation of the Phase 2 trial of Navacaprant in bipolar depression.[7] The company stated that this decision was made to prioritize resources and focus efforts on the KOASTAL MDD program.[8] Despite halting the trial, Neumora indicated that it continues to believe Navacaprant may offer potential benefits for patients with bipolar depression and will evaluate opportunities to investigate it in this indication in the future.[8] This strategic pivot highlights the significant impact of the MDD program's setback on Neumora's broader development plans for Navacaprant, forcing a concentration of resources on the lead indication in an attempt to salvage the compound.

6. Regulatory Status and Intellectual Property

6.1. Current Regulatory Standing

Navacaprant (BTRX-335140) remains an investigational drug and has not received marketing approval from any regulatory agency.[3] It has progressed through Phase 1 and Phase 2 clinical trials and is currently in Phase 3 development for MDD.[2]

A key milestone was the successful completion of an End-of-Phase 2 meeting with the U.S. FDA in June 2023, which permitted Neumora to advance Navacaprant into the pivotal Phase 3 KOASTAL program.[2] Initially, Neumora anticipated that successful Phase 3 results could support a New Drug Application (NDA) submission to the FDA in 2025.[2] However, due to the failure of the KOASTAL-1 trial and the subsequent amendments and delays to the KOASTAL-2 and -3 trials (with data now expected in 2026), this timeline for a potential NDA submission is no longer achievable and has been significantly pushed back.[7]

There is no information in the provided materials to suggest that Navacaprant has received Orphan Drug Designation or Fast Track designation from the FDA or equivalent designations from other regulatory bodies like the European Medicines Agency (EMA).[3] Its current regulatory status is solely that of an investigational new drug undergoing clinical evaluation.

6.2. Patent Landscape

Detailed information regarding specific patent numbers or applications exclusively covering Navacaprant (BTRX-335140) is not fully available within the accessible portions of the provided research materials. The primary scientific publication detailing its discovery and preclinical characterization (J. Med. Chem. 2019, PMID: 30707578) does not explicitly list patent identifiers.[22]

Commercial patent databases, such as Synapse by Patsnap, indicate the existence of a significant number of patents potentially related to Navacaprant ("100 Patents (Medical) associated with Navacaprant"), but access to the specific details of these patents often requires a subscription or login.[36] General searches on Google Patents for assignees like "BlackThorn Therapeutics" or "Neumora Therapeutics" with relevant keywords (e.g., "kappa opioid receptor antagonist," "quinoline derivatives") reveal various patents related to quinoline derivatives and KOR antagonists.[42] For instance, patent application WO2018170492A1 ("Kappa opioid receptor antagonists and products and methods related thereto") and WO2019173653A1 ("Heterocyclic compounds as kappa opioid receptor antagonists") list BlackThorn Therapeutics as an applicant and describe compounds that may be structurally related, although a direct and unequivocal link to Navacaprant's specific structure (BTRX-335140/CYM-53093) requires detailed examination of the patent claims and examples, which is beyond the scope of the provided snippets. One Irish patent journal entry lists "Blackthorn Therapeutics, Inc. 3634968 HETEROCYCLIC COMPOUNDS..." which could be relevant.[45]

The development of Navacaprant involved contributions from The Scripps Research Institute and BlackThorn Therapeutics, with Neumora Therapeutics later acquiring the asset.[22] It is standard practice in pharmaceutical development for originating institutions and developing companies to secure intellectual property rights, typically including composition of matter patents for the novel chemical entity, as well as method of use and formulation patents. Such patents are crucial for protecting the innovation and ensuring market exclusivity if the drug eventually gains approval. The 2019 J. Med. Chem. publication would typically follow the filing of foundational patents to secure priority dates. The existence of a patent estate covering Navacaprant is highly probable, forming a critical component of its commercial potential.

The shift in the NDA timeline to post-2026, a consequence of the KOASTAL-1 failure and subsequent trial delays, significantly extends the development period. This impacts the remaining patent life upon potential market entry and influences investor confidence and the competitive landscape.

7. Discussion and Future Outlook

7.1. Summary of Efficacy and Safety Across Clinical Program

The clinical journey of Navacaprant has been characterized by early promise followed by significant late-stage challenges. In its Phase 2 trial (NCT04221230), Navacaprant, while not meeting its primary endpoint in the overall MDD population, demonstrated statistically significant and clinically meaningful improvements in depressive symptoms (HAMD-17) and, notably, anhedonia (SHAPS) in the prespecified subgroup of patients with moderate-to-severe MDD.[1] This signal in a more severely affected population, particularly the impact on anhedonia—a core MDD symptom often refractory to existing treatments—provided a strong rationale for advancing to Phase 3.

However, the first pivotal Phase 3 trial, KOASTAL-1, failed to replicate this efficacy in the broader moderate-to-severe MDD population, with Navacaprant not demonstrating superiority over placebo on either the primary MADRS endpoint or the key secondary SHAPS endpoint.[4] An intriguing, though exploratory, finding from KOASTAL-1 was a potential gender-specific response, with female participants showing numerically greater improvements with Navacaprant, particularly on the SHAPS, compared to placebo and to male participants.[4]

Across all reported clinical studies, Navacaprant has consistently demonstrated a favorable safety and tolerability profile.[1] It has been generally well-tolerated, with low rates of adverse events, no new safety signals emerging in Phase 3, and no reports of serious adverse events directly attributed to the drug. Importantly, it has not been associated with increased suicidal ideation or common problematic side effects of other antidepressants like sexual dysfunction or weight gain.[2] This consistent safety record is a significant positive attribute of the compound.

7.2. Analysis of Clinical Setbacks and Strategic Adjustments by Neumora Therapeutics

The failure of KOASTAL-1 was a major setback. The identical improvement on the MADRS scale for both Navacaprant and placebo (12.5 points) [5] suggests either an unusually high placebo response, an inability of the drug to provide additional benefit over this placebo effect in the overall study population, or potential issues with trial execution or patient heterogeneity that obscured a true drug effect. MDD trials are notoriously susceptible to high placebo response rates, making it difficult to demonstrate drug efficacy.

In response, Neumora Therapeutics undertook a strategic re-evaluation. The company discontinued its Phase 2 program for Navacaprant in bipolar depression to consolidate resources.[7] For the MDD program, Neumora paused the ongoing KOASTAL-2 and -3 trials to implement protocol amendments.[7] These changes focus on operational enhancements: reducing the number of trial sites to those with proven expertise in MDD research, augmenting medical monitoring through collaboration with the Massachusetts General Hospital Clinical Trials Network and Institute, and employing advanced screening tools to ensure appropriate patient enrollment and prevent participation in concurrent trials.[7]

These adjustments suggest that Neumora believes the KOASTAL-1 outcome might be, at least in part, attributable to trial conduct variability or "noise," rather than a complete lack of efficacy of Navacaprant, especially given the observed signal in female participants. The company is essentially making a calculated effort to salvage the program by optimizing the conditions under which the drug's effects are evaluated. The decision to proceed with these resource-intensive Phase 3 trials, albeit amended, underscores a belief in the potential of the KOR mechanism or specific findings from KOASTAL-1, such as the female responder signal, that warrant further investigation.

7.3. Potential Role of Navacaprant in Treating MDD and Challenges Ahead

If the amended KOASTAL-2 and -3 trials yield positive results, Navacaprant could potentially fill an unmet need in the MDD treatment landscape. Its novel KOR antagonist mechanism offers a different approach compared to existing monoaminergic antidepressants.[2] Given the Phase 2 data and the exploratory findings in KOASTAL-1, Navacaprant might be particularly beneficial for patients with prominent symptoms of anhedonia [1], or potentially for female patients with MDD, should the gender-specific signal be prospectively confirmed.[6] Its favorable safety profile, especially the lack of sexual dysfunction and weight gain, would also be a significant advantage.[2]

However, formidable challenges remain. The primary hurdle is to demonstrate robust and replicable efficacy in the ongoing Phase 3 trials. Overcoming the high placebo response inherent in MDD studies will be critical. Furthermore, the failure of Navacaprant in KOASTAL-1, compounded by the Phase 3 failure of Johnson & Johnson's KOR antagonist, aticaprant, for MDD [10], has cast considerable doubt on the general applicability of KOR antagonism as a therapeutic strategy for broad MDD populations. This raises the development risk for the entire class and may necessitate more refined patient selection strategies, potentially guided by biomarkers (if identified) or a focus on specific symptom clusters like anhedonia or cognitive dysfunction where the mechanism might still hold greater promise. The competitive landscape for MDD treatments is also evolving, with several novel mechanisms under investigation.[46]

7.4. Concluding Remarks

Navacaprant (BTRX-335140) currently stands at a critical juncture in its development. The promising preclinical data and encouraging signals from Phase 2, particularly for anhedonia and in moderate-to-severe MDD, have been overshadowed by the failure of the initial Phase 3 KOASTAL-1 trial. This outcome has necessitated significant strategic adjustments by Neumora Therapeutics, including a refocusing of resources and amendments to the ongoing pivotal trials.

The drug's consistently favorable safety and tolerability profile remains a key asset. The exploratory finding of a potential enhanced response in female participants in KOASTAL-1 offers a specific hypothesis that Neumora is likely to pursue, although such subgroup findings require cautious interpretation and prospective validation.

The future of Navacaprant is now highly dependent on the outcomes of the amended KOASTAL-2 and KOASTAL-3 trials, with data anticipated in 2026.[9] Success in these trials would require overcoming the challenges that led to the KOASTAL-1 failure, including the high placebo response and demonstrating a clear, clinically meaningful benefit. Neumora's financial runway, reportedly extending into 2027 [9], provides the opportunity to see this revised strategy through. However, the broader skepticism surrounding the KOR antagonist class for MDD following multiple late-stage setbacks means that the bar for success will be high, and the results will be closely scrutinized by the scientific, medical, and investment communities. The path forward for Navacaprant is undoubtedly challenging, but the pursuit of novel mechanisms for complex conditions like MDD inherently involves navigating such uncertainties.

Works cited

1. Navacaprant, a Novel and Highly Selective Kappa Opioid Receptor Antagonist, in Adults With Major Depressive Disorder: A Randomized, Double-Blind Phase 2 Clinical Trial - PubMed, accessed May 23, 2025, https://pubmed.ncbi.nlm.nih.gov/40199329/
2. Neumora Therapeutics Announces Initiation of Phase 3 Clinical ..., accessed May 23, 2025, https://neumoratx.com/news/neumora-therapeutics-announces-initiation-of-phase-3-clinical-program-for-navacaprant-nmra-140-in-major-depressive-disorder/
3. Navacaprant - Wikipedia, accessed May 23, 2025, https://en.wikipedia.org/wiki/Navacaprant
4. Navacaprant Did Not Show Statistically Significant Improvements When Treating Patients With Major Depressive Disorder - Pharmacy Times, accessed May 23, 2025, https://www.pharmacytimes.com/view/navacaprant-did-not-show-statistically-significant-improvements-when-treating-patients-with-major-depressive-disorder
5. Neumora Therapeutics Reports Data from KOASTAL-1 Study of Navacaprant in Major Depressive Disorder, accessed May 23, 2025, https://ir.neumoratx.com/news-releases/news-release-details/neumora-therapeutics-reports-data-koastal-1-study-navacaprant/
6. Phase 3 KOASTAL-1 Trial Fails to Show Navacaprant Significantly Improves MDD, accessed May 23, 2025, https://www.hcplive.com/view/phase-3-koastal-1-trial-fails-show-navacaprant-significantly-improves-mdd
7. Neumora Shakes Up Phase III MDD Trials After January Miss - BioSpace, accessed May 23, 2025, https://www.biospace.com/drug-development/neumora-shakes-up-phase-iii-mdd-trials-after-january-miss
8. Neumora makes protocol changes to salvage depression drug after recent trial failure, accessed May 23, 2025, https://firstwordpharma.com/story/5939222
9. Neumora Therapeutics Reports First Quarter 2025 Financial Results and Provides Business Update - BioSpace, accessed May 23, 2025, https://www.biospace.com/press-releases/neumora-therapeutics-reports-first-quarter-2025-financial-results-and-provides-business-update
10. J&J drops Phase III MDD programme due to lack of efficacy - Clinical Trials Arena, accessed May 23, 2025, https://www.clinicaltrialsarena.com/news/johnson-johnson-mdd-trial-failure-termination/
11. Johnson & Johnson Discontinues Pivotal Depression Drug Trial Due to Lack of Efficacy, accessed May 23, 2025, https://medcitynews.com/2025/03/jnj-johnson-depression-major-depressive-disorder-aticapant-kappa-opioid-receptor-antidepressant/
12. navacaprant | Ligand page - IUPHAR/BPS Guide to PHARMACOLOGY, accessed May 23, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=clinical&ligandId=10452
13. BTRX-335140 | CYM-53093 | KOR Antagonist | TargetMol, accessed May 23, 2025, https://www.targetmol.com/compound/btrx-335140
14. navacaprant | Ligand page - IUPHAR/BPS Guide to PHARMACOLOGY, accessed May 23, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=10452
15. BTRX-335140: Uses, Interactions, Mechanism of Action | DrugBank ..., accessed May 23, 2025, https://go.drugbank.com/drugs/DB16068
16. NAVACAPRANT HYDROCHLORIDE, accessed May 23, 2025, https://searchusan.ama-assn.org/usan/documentDownload?uri=/unstructured/binary/usan/navacaprant-HCl.pdf
17. BTRX-335140 | CYM-53093 | CAS#2244614-14-8 | KOR antagonist | MedKoo, accessed May 23, 2025, https://www.medkoo.com/products/32198
18. BTRX-335140 | KOR antagonist | Probechem Biochemicals, accessed May 23, 2025, http://www.probechem.com/products_BTRX-335140.aspx
19. Navacaprant (BTRX-335140) | KOR Antagonist | MedChemExpress, accessed May 23, 2025, https://www.medchemexpress.com/navacaprant.html
20. Design and Synthesis of a Novel and Selective Kappa Opioid Receptor (KOR) Antagonist (BTRX-335140) | Request PDF - ResearchGate, accessed May 23, 2025, https://www.researchgate.net/publication/330812785_Design_and_Synthesis_of_a_Novel_and_Selective_Kappa_Opioid_Receptor_KOR_Antagonist_BTRX-335140
21. New Drug for Major Depressive Disorder Gets Good Surprise - The Streetwise Reports, accessed May 23, 2025, https://www.streetwisereports.com/article/2025/03/10/new-drug-for-major-depressive-disorder-gets-good-surprise.html
22. Design and Synthesis of a Novel and Selective Kappa Opioid Receptor (KOR) Antagonist (BTRX-335140) - PMC - PubMed Central, accessed May 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6395531/
23. Design and Synthesis of a Novel and Selective Kappa Opioid ..., accessed May 23, 2025, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395531/
24. Kappa opioid receptor antagonism protects working memory performance from mild stress exposure in Rhesus macaques - PubMed Central, accessed May 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9755019/
25. btrx-335140 | MedChemExpress (MCE) Life Science Reagents, accessed May 23, 2025, https://www.medchemexpress.com/btrx-335140.html
26. Design and Synthesis of a Novel and Selective Kappa Opioid ..., accessed May 23, 2025, https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01679
27. Study in Major Depressive Disorder With BTRX-335140 (NMRA-335140) vs Placebo - ClinicalTrials.Veeva, accessed May 23, 2025, https://ctv.veeva.com/study/study-in-major-depressive-disorder-with-btrx-335140-nmra-335140-vs-placebo
28. Phase 3 Study Initiated: Osavampator as Adjunctive Therapy for Major Depressive Disorder, accessed May 23, 2025, https://www.psychiatrictimes.com/view/phase-3-study-initiated-osavampator-as-adjunctive-therapy-for-major-depressive-disorder
29. Neumora Therapeutics Reports First Quarter 2025 Financial Results and Provides Business Update, accessed May 23, 2025, https://ir.neumoratx.com/news-releases/news-release-details/neumora-therapeutics-reports-first-quarter-2025-financial/
30. NMRA 335140 for Depression · 2025 Clinical Trial · Phase 3 | Power, accessed May 23, 2025, https://www.withpower.com/trial/phase-3-depressive-disorder-8-2023-a2b22?condition=depression&phaseList=Phase+3&overallStatus=Recruiting&hasNoPlacebo=false
31. Study to Evaluate the Effects of Oral NMRA-335140 Versus Placebo in Participants With Major Depressive Disorder | Clinical Research Trial Listing - CenterWatch, accessed May 23, 2025, https://www.centerwatch.com/clinical-trials/listings/NCT06029426/study-to-evaluate-the-effects-of-oral-nmra-335140-versus-placebo-in-participants-with-major-depressive-disorder
32. Neumora Therapeutics Reports Disappointing Results from Phase 3 Study of Navacaprant in MDD - Patient Care Online, accessed May 23, 2025, https://www.patientcareonline.com/view/neumora-therapeutics-reports-disappointing-results-from-phase-3-study-of-navacaprant-in-mdd
33. NMRA-266 - Drug Targets, Indications, Patents - Patsnap Synapse, accessed May 23, 2025, https://synapse.patsnap.com/drug/ca9c3ea606254754852da37f38f6a896
34. Neumora halts trial of depression drug, rethinks 2 others to apply lessons from phase 3 failure - Fierce Biotech, accessed May 23, 2025, https://www.fiercebiotech.com/biotech/neumora-halts-trial-depression-drug-rethinks-2-others-apply-learnings-phase-3-failure
35. Navacaprant - Neumora Therapeutics - AdisInsight - Springer, accessed May 23, 2025, https://adisinsight.springer.com/drugs/800054451
36. Navacaprant - Drug Targets, Indications, Patents - Patsnap Synapse, accessed May 23, 2025, https://synapse.patsnap.com/drug/d460210ca63b41c38c09bc578c9f4ebb
37. Neumora Therapeutics, Inc. - Drug pipelines, Patents, Clinical trials - PatSnap Synapse, accessed May 23, 2025, https://synapse.patsnap.com/organization/c7b2593cda8d79be95445b6de2803080
38. SEC Filing - Neumora Therapeutics, Inc., accessed May 23, 2025, https://ir.neumoratx.com/node/7536/html
39. NMRA-335140: A Promising New Treatment for Major Depressive Disorder - Clinical trials, accessed May 23, 2025, https://clinicaltrials.eu/inn/nmra-335140/
40. Oncology Drugs Fast-Tracked by the FDA in December 2024, accessed May 23, 2025, https://www.oncologynewscentral.com/drug/oncology-drugs-fast-tracked-by-the-fda-in-december-2024
41. Fast Track | FDA, accessed May 23, 2025, https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/fast-track
42. WO2018170492A1 - Kappa opioid receptor antagonists and products and methods related thereto - Google Patents, accessed May 23, 2025, https://patents.google.com/patent/WO2018170492A1/ko
43. WO2019173653A1 - Composés d'acides aminés et leurs procédés d'utilisation - Google Patents, accessed May 23, 2025, https://patents.google.com/patent/WO2019173653A1/fr
44. US20090186873A1 - Kappa selective opioid receptor antagonist - Google Patents, accessed May 23, 2025, https://patents.google.com/patent/US20090186873A1/deFl
45. Iris um Oifig Maoine Intleachtúla na hÉireann Journal of the Intellectual Property Office of Ireland, accessed May 23, 2025, https://www.ipoi.gov.ie/en/ip-search-tools/search-the-journal/download-journals/journal-2512.pdf
46. Major Depressive Disorder (MDD) | DrugBank Online, accessed May 23, 2025, https://go.drugbank.com/indications/DBCOND0030181
47. Pharmacological Monotherapy for Depressive Disorders: Current and Future—A Narrative Review - PMC, accessed May 23, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC12028769/