Aticaprant (LY-2456302): A Comprehensive Pharmacological and Clinical Development Review of a Kappa-Opioid Receptor Antagonist

Executive Summary

Aticaprant (LY-2456302) is a potent, selective, orally bioavailable, and short-acting small molecule antagonist of the kappa-opioid receptor (KOR).[1] The compound emerged from a sophisticated drug discovery program aimed at creating a clinically viable therapeutic to target the endogenous dynorphin/KOR system, a key neuromodulatory pathway implicated in the pathophysiology of stress, anhedonia, and addictive behaviors.[3] The therapeutic rationale was compelling: by blocking the "anti-reward" signaling of the KOR system, Aticaprant was hypothesized to alleviate the core symptoms of major depressive disorder (MDD), particularly anhedonia, and mitigate the negative affective states associated with substance withdrawal. Its development history reflects a common paradigm in the pharmaceutical industry, originating at Eli Lilly, being advanced through mid-stage clinical trials by the smaller biotech Cerecor, and ultimately being acquired by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson, for a large-scale, pivotal Phase 3 program.[1]

Pharmacologically, Aticaprant represented a significant advancement over earlier KOR antagonist tool compounds, such as nor-binaltorphimine (nor-BNI) and JDTic. While those agents were limited by extremely long-lasting, quasi-irreversible pharmacodynamic effects, Aticaprant was designed with favorable, "canonical" pharmacokinetic and pharmacodynamic properties, including a long plasma half-life suitable for once-daily dosing and a reversible, non-inactivating mechanism of action at the receptor level.[2] Preclinical studies provided a robust and compelling evidence package, demonstrating central nervous system penetration, selective target engagement

in vivo, and efficacy in animal models predictive of antidepressant and anti-addictive activity.[2] Early human trials further bolstered confidence in the program. Positron Emission Tomography (PET) imaging studies confirmed that a clinically relevant oral dose (10 mg) achieved near-complete saturation of KORs in the human brain, effectively de-risking the critical issue of target engagement.[1] Furthermore, Phase 2 studies provided encouraging signals, including proof-of-mechanism evidence showing modulation of reward-related neural circuitry and a statistically significant reduction in depressive symptoms, particularly in patients with high levels of anhedonia.[8]

Despite this strong scientific foundation and promising early clinical data, the extensive Phase 3 VENTURA program, which enrolled thousands of patients across multiple studies, was abruptly discontinued in March 2025.[1] The stated reason for termination was "insufficient efficacy," not safety concerns, as the drug was consistently found to be safe and well-tolerated.[12] This outcome, contextualized by the concurrent Phase 3 failure of a mechanistically similar drug, navacaprant, from Neumora Therapeutics, represents a profound setback for the KOR antagonist class as a potential new treatment for MDD.[11] The story of Aticaprant serves as a critical and cautionary case study in modern neuropsychiatric drug development, highlighting the immense translational challenges between a well-validated mechanism and clinical efficacy, the confounding influence of the placebo effect in psychiatric trials, and the strategic portfolio management decisions that govern the lifecycle of investigational medicines in a high-risk, high-reward industry.

Section 1: Compound Identification and Physicochemical Profile

This section provides a definitive summary of the nomenclature, unique identifiers, and core chemical and physical properties of Aticaprant, establishing a foundational reference for the compound.

1.1 Nomenclature and Identifiers

Throughout its multi-stage development lifecycle, the compound has been known by several names and codes, reflecting its passage through different corporate entities. This varied nomenclature is crucial for accurately tracking the molecule across scientific literature, clinical trial registries, and patent filings.

• International Nonproprietary Name (INN): Aticaprant [1]
• Developmental Codes:
• LY-2456302: Original designation by the discovering company, Eli Lilly.[1]
• CERC-501: Designation used by Cerecor Inc. following its acquisition of the compound's development rights.[1]
• JNJ-67953964: Designation used by Janssen Pharmaceuticals after its acquisition from Cerecor.[1]
• Database and Registry Identifiers:
• DrugBank ID: DB12341 [16]
• CAS Number: 1174130-61-0 [1]
• PubChem Compound ID (CID): 44129648, 56851586 [1]
• IUPHAR/BPS ID: 9194 [1]

The progression of these developmental codes—from LY- to CERC- to JNJ-—chronicles the strategic pathway of the asset. This journey is representative of a common industry model where a large pharmaceutical originator (Eli Lilly) conducts initial discovery and de-risking, a smaller, more specialized biotechnology company (Cerecor) funds and executes the riskier mid-stage clinical development, and another major pharmaceutical player (Janssen) acquires the promising asset to fund and manage the large-scale, capital-intensive pivotal trials required for regulatory submission. Each transition marks a key value inflection point based on the accumulation of positive preclinical and clinical data.

1.2 Chemical Structure and Properties

Aticaprant is a synthetic organic small molecule with a well-defined chemical structure and set of physicochemical properties that underpin its pharmacological activity and suitability for oral administration.

• IUPAC Name: 4-(4-{methyl}}phenoxy)-3-fluorobenzamide.[1]
• Chemical Formula: C26​H27​FN2​O2​.[15]
• Molecular Weight:
• Average Mass: 418.512 g/mol.[15]
• Monoisotopic Mass: 418.205656 g/mol.[16]
• Chemical Classifications: The molecule belongs to the class of organic compounds known as diphenylethers, characterized by two benzene rings linked via an ether group. It is further classified as a benzamide and a pyrrolidine derivative, reflecting key functional groups in its structure.[2]
• Physicochemical Data:
• Appearance: A solid, described as white to off-white in color.[20]
• Solubility: The compound exhibits solubility in common organic solvents. Reported values include: dimethylformamide (DMF) at 1 mg/mL, dimethyl sulfoxide (DMSO) at 5 mg/mL, and Ethanol at 3 mg/mL.[15] Another source indicates higher solubility in DMSO, at ≥ 90 mg/mL.[22]
• Stability: The compound is chemically stable, with data indicating stability for at least 4 years when stored at room temperature.[15]

A consolidated summary of these key identifiers and properties is provided in Table 1.

Table 1: Compound Identifiers and Chemical Properties of Aticaprant

Property	Value
International Nonproprietary Name (INN)	Aticaprant
Developmental Codes	LY-2456302, CERC-501, JNJ-67953964
DrugBank ID	DB12341
CAS Number	1174130-61-0
PubChem CID	44129648
IUPAC Name	4-(4-{methyl}}phenoxy)-3-fluorobenzamide
Chemical Formula	C26​H27​FN2​O2​
Average Molecular Weight	418.512 g/mol
Monoisotopic Mass	418.205656 g/mol
Chemical Class	Small Molecule; Diphenylether; Benzamide; Pyrrolidine
Solubility	DMSO: 5 mg/mL; DMF: 1 mg/mL; Ethanol: 3 mg/mL
Stability	≥ 4 years at room temperature

Section 2: Pharmacological Profile: Mechanism of Action and Therapeutic Rationale

The development of Aticaprant was predicated on a sophisticated understanding of the brain's endogenous opioid system and its role in regulating mood and stress. This section details the neurobiological target, the specific molecular mechanism of Aticaprant, and the resulting scientific hypothesis that justified its investigation for mood and addictive disorders.

2.1 The Endogenous Dynorphin/Kappa-Opioid Receptor (KOR) System

The therapeutic target of Aticaprant is the kappa-opioid receptor (KOR), a member of the G-protein coupled receptor (GPCR) superfamily.[3] KORs are widely expressed throughout the central and peripheral nervous systems, with particularly dense localization in brain regions integral to the modulation of emotion, motivation, stress, and reward, including the prefrontal cortex, amygdala, nucleus accumbens, and ventral tegmental area.[2]

The primary endogenous ligand for the KOR is the neuropeptide dynorphin.[1] The dynorphin/KOR system functions as a critical homeostatic regulator. When activated by dynorphin, KORs trigger intracellular signaling cascades that typically lead to the inhibition of neuronal activity and neurotransmitter release.[16]

A crucial aspect of KOR signaling is its role in mediating negative affective states. Unlike the mu-opioid receptor (MOR), whose activation by endorphins or exogenous opioids is associated with euphoria and analgesia, the activation of the KOR system by dynorphin is strongly linked to dysphoria, aversion, anhedonia (the inability to experience pleasure), and pro-depressive effects.[3] This has led to the conceptualization of the dynorphin/KOR system as an endogenous "anti-reward" or stress-response system.[26] Exposure to stress is a potent trigger for the release of dynorphin in the brain. This increased dynorphin activity subsequently activates KORs on dopamine neurons, leading to an inhibition of dopamine release in key reward circuits like the nucleus accumbens. This neurochemical cascade is believed to be a primary driver of the anhedonia and negative mood states that characterize both stress-induced psychiatric conditions and drug withdrawal syndromes.[3]

2.2 Molecular Mechanism of Aticaprant

Aticaprant was designed to directly counteract the effects of the dynorphin/KOR system. Its molecular mechanism is that of a potent, selective, and reversible competitive antagonist of the KOR.[1]

The pharmacological precision of Aticaprant is defined by its binding affinity and selectivity profile for the three main opioid receptor subtypes, as summarized in Table 2. It binds with high, sub-nanomolar affinity to the KOR, while exhibiting significantly lower affinity for the MOR and DOR. This selectivity is a key feature, intended to isolate the therapeutic effects of KOR blockade while avoiding the complex pharmacology associated with MOR or DOR modulation. Furthermore, extensive screening has shown that Aticaprant has no appreciable affinity for a wide panel of other non-opioid CNS receptors, ion channels, or transporters, indicating a low potential for off-target effects.[28]

Table 2: Opioid Receptor Binding and Selectivity Profile of Aticaprant

Receptor	Binding Affinity (Ki​, nM)	Selectivity Ratio (vs. KOR)
Kappa-Opioid Receptor (KOR)	0.81	1x
Mu-Opioid Receptor (MOR)	24.0	~30x
Delta-Opioid Receptor (DOR)	155	~190x

Data compiled from.[1]

A critical aspect of Aticaprant's design is its characterization as a "short-acting" or non-"inactivating" antagonist.[1] This feature represents a deliberate and significant improvement over earlier KOR antagonist research tools like nor-BNI and JDTic. These first-generation compounds, while valuable for preclinical research, exhibited extremely long-lasting pharmacodynamic effects, effectively inactivating the receptor for days or even weeks after a single dose.[2] Such a prolonged and quasi-irreversible profile is clinically untenable, as it complicates dosing, precludes effective management of potential adverse events, and increases the risk of undesirable drug-drug interactions. The development of Aticaprant with conventional pharmacokinetics and a reversible binding profile was a strategic effort to create a "drug-like" molecule suitable for human therapeutic use, marking it as a second-generation clinical candidate for this target class.

2.3 Rationale for Development in Mood and Addictive Disorders

The therapeutic hypothesis for Aticaprant is a direct extension of its mechanism of action. By competitively blocking KORs in the brain, the drug is intended to prevent endogenous dynorphin from binding and activating the receptor. This blockade is expected to disinhibit, or "release the brake" from, the neuronal pathways that are tonically suppressed by the KOR system, particularly the mesolimbic dopamine reward pathway.[2]

• Rationale in Major Depressive Disorder: The core rationale in MDD was to provide a novel, non-monoaminergic treatment approach. By blocking the dysphoric and anhedonic signaling of the dynorphin/KOR system, Aticaprant was expected to restore function in the brain's reward circuits, thereby directly treating anhedonia—a core symptom of depression that is often poorly addressed by standard-of-care selective serotonin reuptake inhibitors (SSRIs).[3] The mechanism suggested a direct path to improving mood and motivation by counteracting a key neurobiological substrate of stress-induced pathology. This focus on anhedonia was not arbitrary but was a strategic decision rooted in the drug's fundamental pharmacology, providing a strong basis for the specific patient populations selected for the pivotal clinical trials.
• Rationale in Addictive Disorders: The dynorphin/KOR system is also heavily implicated in the negative affective states that characterize withdrawal from substances of abuse, such as alcohol and nicotine.[4] This aversive withdrawal state is a powerful driver of craving and relapse. The hypothesis was that by blocking KORs, Aticaprant could alleviate the dysphoria and anxiety of withdrawal, reduce the motivation for drug-seeking behavior, and ultimately help maintain abstinence.[2]

Section 3: Non-Clinical Pharmacology and Preclinical Efficacy

Prior to human testing, Aticaprant underwent extensive non-clinical evaluation to characterize its activity and to build a body of evidence supporting its therapeutic potential. The preclinical data package was exceptionally robust, demonstrating target engagement, functional activity, and efficacy in established animal models of mood and addictive disorders.

3.1 In Vitro Characterization

Initial laboratory studies using cell-based assays confirmed the fundamental pharmacological properties of Aticaprant. Radioligand binding assays performed with cloned human opioid receptors validated its high, sub-nanomolar binding affinity for the KOR (Ki​ = 0.807 nM).[28] These same assays quantified its selectivity, confirming a 30-fold lower affinity for the MOR and a 190-fold lower affinity for the DOR.[28] To ensure specificity, the compound was screened against a broad panel of non-opioid G-protein-coupled receptors, monoaminergic transporters, and ion channels. Aticaprant showed no appreciable affinity for any of these other potential targets, confirming a highly specific interaction with the KOR and reducing the likelihood of off-target pharmacological effects.[28]

3.2 In Vivo Animal Models

The in vivo studies in animals were critical for demonstrating that the promising in vitro profile translated into meaningful biological activity in a living system. The results from these studies were consistently positive and strongly supported the decision to advance Aticaprant into clinical development.

• Central Target Engagement and Selectivity: A key first step was to confirm that orally administered Aticaprant could cross the blood-brain barrier and engage its intended target. Studies in rodents showed that oral Aticaprant selectively and potently occupied central KORs, with an ED₅₀ (the dose required to occupy 50% of receptors) of 0.33 mg/kg. Importantly, even at doses up to 30 mg/kg, there was no evidence of significant MOR or DOR occupancy, confirming its selectivity in vivo.[2]
• Functional KOR Antagonism: Beyond simple receptor occupancy, studies confirmed that Aticaprant functionally blocked the effects of KOR activation. In animal models, it potently reversed the analgesic effects and the disruption of prepulse inhibition caused by KOR-selective agonists. In contrast, it did not affect MOR agonist-mediated analgesia at doses more than 30-fold higher, further validating its functional selectivity in a whole-animal system.[2] This demonstrated that the drug was not merely binding to the receptor but was actively preventing it from signaling.
• Antidepressant-like Effects: In standard behavioral paradigms used to screen for antidepressant activity, Aticaprant showed significant efficacy.
• In the mouse forced swim test, an oral dose of 10 mg/kg reduced immobility time to a degree comparable to that of the established tricyclic antidepressant imipramine.[2]
• In the intracranial self-stimulation paradigm, which measures reward-seeking behavior, Aticaprant dose-dependently blocked the anhedonia-producing (depressive) effects of the KOR agonist U50,488.[25]
• In a mouse model of chronic stress (unpredictable chronic mild stress), treatment with Aticaprant reversed key depression-relevant behavioral deficits, including reduced preference for sucrose (a measure of anhedonia) and impaired nest-building (a measure of self-care and motivation).[30]
• Synergy with Existing Antidepressants: A particularly important finding from the preclinical studies was the observation that Aticaprant enhanced the antidepressant-like effects of existing medications. When co-administered with the SSRI citalopram or the tricyclic imipramine, Aticaprant produced a greater effect in the forced swim test than either drug alone.[2] This synergistic potential provided a strong scientific rationale for the eventual clinical strategy of testing Aticaprant as an adjunctive therapy for patients who had an inadequate response to standard antidepressants.
• Anti-Addictive Effects: The preclinical data also supported the hypothesis that KOR antagonism could be beneficial for substance use disorders.
• In alcohol-preferring rats, Aticaprant significantly reduced ethanol self-administration.[2] Notably, unlike the non-selective opioid antagonist naltrexone, Aticaprant did not show evidence of tolerance developing after four days of repeated dosing, suggesting a potentially more durable effect.[2]
• In mice undergoing nicotine withdrawal, Aticaprant alleviated both the physical and affective signs of the withdrawal syndrome, including anxiety-related behaviors and conditioned place aversion.[4]

Taken together, the preclinical evidence package for Aticaprant represented a near-ideal profile for an investigational CNS drug. It demonstrated oral bioavailability, brain penetration, selective and functional target engagement, and robust efficacy in multiple, validated animal models relevant to the target indications. This comprehensive and consistently positive dataset provided a compelling justification for its advancement into human clinical trials and makes its ultimate failure in Phase 3 a particularly stark example of the translational gap in psychiatric drug development.

Section 4: Clinical Pharmacokinetics and Pharmacodynamics

Following the successful preclinical program, Aticaprant was advanced into Phase 1 clinical trials to characterize its behavior in humans. These studies focused on defining its pharmacokinetics (PK)—what the body does to the drug—and its pharmacodynamics (PD)—what the drug does to the body, particularly its interaction with the KOR target in the human brain.

4.1 Absorption, Distribution, Metabolism, and Ecretion (ADME)

Studies in healthy human volunteers established a clear and predictable pharmacokinetic profile for Aticaprant, which was favorable for clinical development.[1] Key parameters are summarized in Table 3.

• Absorption: Following oral administration, Aticaprant was rapidly absorbed, with the time to reach maximum plasma concentration (Tmax​) occurring between 1 and 2 hours post-dose.[1]
• Bioavailability: The absolute oral bioavailability was determined to be approximately 25%.[1]
• Dose Proportionality: The drug exhibited linear and dose-proportional pharmacokinetics. Plasma exposure, as measured by both maximum concentration (Cmax​) and the area under the concentration-time curve (AUC), increased proportionally with increasing single oral doses (ranging from 2 mg to 60 mg) and multiple daily doses (2 mg, 10 mg, and 35 mg).[1]
• Elimination and Steady State: Aticaprant has a relatively long terminal elimination half-life (t1/2​) of approximately 30 to 40 hours in healthy subjects.[1] This long half-life supports a convenient once-daily dosing regimen. With once-daily administration, steady-state plasma concentrations were achieved after 6 to 8 days.[1]

This combination of properties—a long pharmacokinetic half-life for convenient dosing, but a reversible, "short-acting" pharmacodynamic profile (as established preclinically)—is highly desirable. It distinguishes Aticaprant from earlier KOR antagonists that had irreversible, long-lasting effects, providing a profile that is both practical for patients and manageable for clinicians.

Table 3: Summary of Human Pharmacokinetic Parameters for Aticaprant

Parameter	Value	Source(s)
Oral Bioavailability (F)	~25%	1
Time to Maximum Concentration (Tmax​)	1–2 hours	1
Elimination Half-Life (t1/2​)	30–40 hours	1
Time to Steady State (Once-Daily Dosing)	6–8 days	1
Dose Proportionality	Linear and proportional over 2-60 mg range	31

4.2 Central Nervous System Penetration and Receptor Occupancy

A major hurdle in CNS drug development is ensuring that an orally administered drug reaches its target in the brain at a sufficient concentration to exert a pharmacological effect. For Aticaprant, this was definitively confirmed using advanced neuroimaging techniques.

• Blood-Brain Barrier Penetration: The drug was shown to reproducibly penetrate the blood-brain barrier in humans.[1]
• Positron Emission Tomography (PET) Imaging: The most direct and compelling evidence of target engagement came from PET studies.[7] Using a novel KOR-specific radiotracer, ¹¹C-LY2795050, researchers were able to visualize and quantify the percentage of KORs in the human brain that were occupied by Aticaprant at various doses and time points.[1]
• The results demonstrated high, dose-dependent receptor occupancy. A single 10 mg oral dose led to near-complete saturation (94% occupancy) of brain KORs at 2.5 hours post-dose.[1] A lower 0.5 mg dose resulted in 35% occupancy.[1]
• The occupancy was also durable, consistent with the drug's long half-life. At 24 hours after a 25 mg dose, KOR occupancy remained very high at 82%.[1]

This PET data was a pivotal component of the development program. It provided unambiguous, quantitative proof that the selected 10 mg dose engaged the target receptor in the human brain to a very high degree. This evidence effectively eliminated "lack of target engagement" as a potential reason for failure, giving the developers high confidence that any clinical outcome observed with this dose would be a true reflection of the therapeutic hypothesis. This de-risking step was instrumental in justifying the major investment required for the large-scale Phase 3 program.

4.3 Drug-Drug Interaction Profile

Understanding a drug's potential interactions with other substances is critical for its safe clinical use.

• Interaction with Ethanol: Given the potential use of Aticaprant in substance use disorders, its interaction with alcohol was specifically studied. A clinical trial co-administering Aticaprant with ethanol found no clinically significant interactions. The pharmacokinetics of Aticaprant were not affected by ethanol, and vice versa. Furthermore, there were no additive or synergistic effects on cognitive or motor performance, and no new safety concerns emerged.[1]
• Pharmacodynamic Interaction with Opioid Agonists: To confirm Aticaprant's in vivo selectivity in humans, translational pupillometry was used. This technique measures changes in pupil size (miosis) induced by a MOR agonist like fentanyl, which serves as a sensitive biomarker for MOR activity.[34]
• The study found that higher doses of Aticaprant (25 mg and 60 mg) did significantly block fentanyl-induced miosis, indicating meaningful MOR antagonism at these dose levels.[1]
• However, at doses of 10 mg and below, there was minimal to no blockade of the fentanyl effect.[1] This finding was critical, as it provided a clinical rationale for selecting the 10 mg dose for the pivotal efficacy trials. This dose was shown by PET to achieve maximal KOR occupancy while having a minimal effect on the MOR, thus preserving the desired selectivity of action.
• Based on its mechanism as an opioid receptor antagonist, Aticaprant is predicted to decrease the analgesic and therapeutic efficacy of a wide range of prescription opioid agonists, including codeine, hydrocodone, oxycodone, morphine, methadone, and tramadol.[16]

Section 5: Clinical Development and Efficacy for Major Depressive Disorder

The clinical development of Aticaprant was a multi-year, multi-company endeavor that progressed from early-phase safety and proof-of-concept studies to a large-scale, global Phase 3 program. This section chronicles that journey, culminating in the program's discontinuation for Major Depressive Disorder (MDD).

5.1 Development History and Corporate Sponsorship

The stewardship of the Aticaprant program changed hands twice, reflecting key strategic decisions and the evolving value proposition of the asset as data accumulated.

• Origination (Eli Lilly): Aticaprant was discovered and initially developed by Eli Lilly under the code LY-2456302. The compound was first patented in 2009, and the first scientific publications appeared in 2010-2011.[1]
• Mid-Stage Development (Cerecor): In February 2015, Eli Lilly out-licensed the rights to Cerecor Inc., a smaller biotechnology company. Cerecor renamed the drug CERC-501 and took on the responsibility of advancing it through mid-stage clinical trials. Under Cerecor's stewardship, Aticaprant was investigated in Phase 2 trials for treatment-resistant depression and as a potential aid for smoking cessation.[1] The smoking cessation trial (NCT02800928) ultimately failed to meet its primary endpoint for nicotine withdrawal.[1]
• Pivotal Development (Janssen): In August 2017, following the generation of promising Phase 2 data in mood disorders, Cerecor sold the rights to Aticaprant to Janssen Pharmaceuticals, Inc., a Johnson & Johnson company.[1] Janssen applied its own developmental code, JNJ-67953964, and leveraged its extensive resources to launch the comprehensive, global Phase 3 VENTURA program aimed at securing regulatory approval for MDD.

5.2 Phase 1 and 2 Clinical Program

The early-phase clinical program was designed to establish the safety, tolerability, PK/PD profile, and initial signs of efficacy for Aticaprant.

• Phase 1 Studies: A series of Phase 1 trials were conducted in healthy volunteers. These studies successfully established the drug's safety profile, confirmed its rapid absorption and long half-life, and demonstrated dose-proportional pharmacokinetics.[31] Specific studies were conducted to assess the drug in Japanese subjects (NCT04791332), to evaluate its metabolism using a radiolabeled version (NCT05197062), and to confirm its lack of interaction with ethanol.[1] A dedicated study (NCT05387759) also confirmed that the drug did not have a clinically significant effect on the QT interval, a key cardiac safety measure.[35]
• Phase 2 Studies: The Phase 2 program provided the first indications of therapeutic potential in patient populations.
• FAST-MAS (NCT02218736): This was a landmark Phase 2a "proof-of-mechanism" study conducted at Duke University and other academic centers.[8] It was not designed as a traditional efficacy trial but rather to test whether Aticaprant engaged the specific neural circuits hypothesized to be involved in anhedonia. In patients with mood and anxiety spectrum disorders, 8 weeks of treatment with Aticaprant 10 mg daily resulted in a significant increase in ventral striatum activation during a reward anticipation task (measured by fMRI) compared to placebo. This neuroimaging finding was accompanied by clinical improvements in reward learning and a reduction in anhedonia symptoms as measured by the Snaith-Hamilton Pleasure Scale (SHAPS).[9] This study provided crucial, objective evidence linking the drug's mechanism to a relevant clinical and neurobiological outcome.
• Phase 2 Efficacy Study (NCT03559192): This randomized, double-blind, placebo-controlled study provided the first formal test of Aticaprant's antidepressant efficacy.[11] The results, published in Neuropsychopharmacology in 2024, showed that adjunctive Aticaprant 10 mg significantly reduced depressive symptoms compared to placebo over 6 weeks, as measured by the primary endpoint of change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. The effect size was modest but statistically significant (p=0.044 in the primary analysis population).[9] Critically, a pre-specified subgroup analysis revealed that the therapeutic effect was larger and more robust in patients who had higher levels of anhedonia at baseline.[9]

The positive outcomes from these Phase 2 studies, particularly the convergence of neuroimaging proof-of-mechanism and a statistically significant efficacy signal in a relevant patient population, provided a strong rationale for Janssen to proceed with the large and costly Phase 3 program.

5.3 The Phase 3 VENTURA Program

The VENTURA program was a comprehensive set of global, multicenter, randomized, double-blind, placebo-controlled studies designed to definitively establish the efficacy and safety of Aticaprant as an adjunctive therapy for MDD, with a specific focus on patients with anhedonia. The program included multiple interlocking trials to assess acute efficacy, long-term safety, and relapse prevention.[39] An overview of the key trials is presented in Table 4.

Table 4: Overview of Key Aticaprant Clinical Trials

NCT Identifier	Phase	Condition(s) Studied	Sponsor	Status	Key Purpose / Design	Outcome Summary
NCT01232439	1	Healthy Subjects	Eli Lilly	Completed	PET study to measure KOR occupancy after single doses	Confirmed high, dose-dependent KOR occupancy 32
NCT02218736	2a	Mood/Anxiety Disorders, Anhedonia	Duke University	Completed	Proof-of-mechanism fMRI study	Increased ventral striatum activation during reward task 8
NCT03559192	2	MDD, Treatment-Resistant	Janssen R&D	Completed	6-week adjunctive efficacy study	Met primary endpoint (significant reduction in MADRS) 9
NCT02800928	2	Smoking Cessation	Yale University	Completed	Efficacy for nicotine withdrawal	Failed to meet primary endpoint 11
VENTURA Program
NCT05455684 (VENTURA-1)	3	MDD with Anhedonia	Janssen R&D	Completed	6-week adjunctive efficacy study (N=513)	Part of program discontinued for insufficient efficacy 11
NCT05550532 (VENTURA-2)	3	MDD with Anhedonia	Janssen R&D	Completed	6-week adjunctive efficacy study	Part of program discontinued for insufficient efficacy 11
NCT05518149 (VENTURA-LT)	3	MDD	Janssen R&D	Active, not recruiting	Long-term open-label extension study	Part of program discontinued for insufficient efficacy 11
NCT06635135 (VENTURA-5)	3	MDD with Anhedonia	Janssen R&D	Terminated	Relapse prevention study	Part of program discontinued for insufficient efficacy 11

The core of the program consisted of two large, nearly identical acute efficacy studies, VENTURA-1 (NCT05455684) and VENTURA-2 (NCT05550532). Both were designed to evaluate Aticaprant 10 mg once daily versus placebo as an add-on to an existing SSRI or SNRI antidepressant in adult patients with MDD who had an inadequate response to their current therapy and also presented with moderate-to-severe anhedonia.[41] The primary endpoint for both studies was the change from baseline in the MADRS total score at the end of the 6-week treatment period (Day 43).[46]

5.4 Analysis of Phase 3 Outcomes and Program Discontinuation

On March 6, 2025, Johnson & Johnson issued a press release announcing the decision to discontinue the entire Phase 3 VENTURA development program for Aticaprant in MDD.[12]

• Reason for Discontinuation: The decision was based on a finding of "insufficient efficacy in the target patient population".[11] Although specific data from the trials have not yet been publicly presented, this statement implies that the primary endpoint—a statistically significant separation from placebo on the MADRS total score—was not met in the pivotal studies.
• Safety Confirmation: The company was explicit in stating that the discontinuation was not due to any safety or tolerability issues. The data from the program confirmed that Aticaprant was safe and well-tolerated, and no new safety signals were identified.[12]
• Future of the Compound: Despite halting the MDD program, Johnson & Johnson indicated that it would continue to "explore future development opportunities for aticaprant in other areas of high unmet need," citing the potential of the mechanism of action.[1]

The failure of the VENTURA program, despite a promising Phase 2 result, exemplifies a common and challenging phenomenon in pharmaceutical R&D. The discrepancy suggests that the modest effect size observed in the smaller Phase 2 study was not replicable in the larger, more heterogeneous global Phase 3 population, possibly due to a higher-than-expected placebo response or other confounding factors. The strategy to enrich the trial population with anhedonic patients, while mechanistically sound, was ultimately not sufficient to drive a significant effect on the broader measure of overall depression severity required for regulatory approval.

Section 6: Safety and Tolerability Profile

A thorough assessment of a drug's safety and tolerability is paramount throughout its development. For Aticaprant, the clinical data consistently demonstrated a favorable safety profile, which was a notable achievement for a novel CNS-active agent and a key distinction from some earlier compounds in its class.

6.1 Preclinical Toxicology

While detailed preclinical toxicology reports are not publicly available, the successful progression of Aticaprant through Investigational New Drug (IND) submission and into a large, multi-year Phase 3 program implies that it had a clean preclinical safety profile. No major toxicological findings that would have constituted a clinical hold or prevented human testing were evident.

6.2 Clinical Safety Database

The safety of Aticaprant was evaluated extensively in Phase 1 studies in healthy volunteers and subsequently in patient populations across the Phase 2 and 3 programs.

• Overall Assessment: Across all clinical trials, Aticaprant was consistently reported to be safe and well-tolerated.[13] The official press release from Johnson & Johnson announcing the discontinuation of the Phase 3 VENTURA program explicitly stated that the decision was based on efficacy, not safety, and that "no new safety signals were identified".[12] Early Phase 1 studies concluded that single and multiple ascending doses were well-tolerated with no clinically significant findings.[1]
• Common Adverse Events: The most detailed public data on adverse events comes from the published Phase 2 efficacy study (NCT03559192). In this study, the most common treatment-emergent adverse events (TEAEs) reported more frequently with Aticaprant 10 mg compared to placebo were [9]:
• Headache (11.8% in the Aticaprant group vs. 7.1% in the placebo group)
• Diarrhea (8.2% vs. 2.4%)
• Nasopharyngitis (5.9% vs. 2.4%)
• Pruritus (itching) (5.9% vs. 0%)
• Severity and Discontinuation Rates: The vast majority of reported adverse events were mild to moderate in severity and were transient.[1] Critically, the rate of discontinuation due to adverse events was very low and was identical between the treatment and placebo groups in the Phase 2 study, at 1.2% (one participant in each arm).[9] This indicates that the drug was highly tolerable for most patients.
• Absence of Opioid-Related Concerns: Given its action on the opioid system, specific attention was paid to signals related to abuse potential or withdrawal. Clinical studies found no evidence of abuse potential during treatment and no signs or symptoms of opiate withdrawal upon discontinuation of the drug.[50]

6.3 Comparative Safety within the KOR Antagonist Class

Aticaprant's safety profile appears particularly favorable when compared to some of its predecessors. For instance, the clinical development of another KOR antagonist, JDTic, was halted after Phase 1 trials due to the emergence of a serious cardiac safety signal—specifically, episodes of non-sustained ventricular tachycardia—in healthy volunteers.[49] This adverse effect was hypothesized to be related to off-target activation of the JNK signaling pathway. Aticaprant, which does not strongly activate this pathway, showed no such cardiac concerns in its clinical program.[49]

The benign safety and tolerability profile of Aticaprant was a significant success of its drug design program. However, its ultimate fate starkly illustrates a fundamental principle of modern drug development: safety, while a necessary condition for approval, is not sufficient. Without a clear and statistically robust demonstration of efficacy, even a very safe and well-tolerated drug cannot succeed in the current regulatory and clinical landscape.

Section 7: Synthesis, Critical Analysis, and Future Outlook

The development and ultimate failure of Aticaprant for Major Depressive Disorder provides a rich and informative case study on the complexities of modern CNS drug development. Its journey from a promising, mechanistically elegant molecule to a discontinued Phase 3 program offers critical lessons about translational science, clinical trial design, and the strategic landscape of the pharmaceutical industry.

7.1 The Efficacy-Safety Paradox: Reconciling Preclinical Promise with Clinical Failure

Aticaprant presents a classic efficacy-safety paradox. The compound was a model of successful drug design from a safety and pharmacological perspective, yet it failed at the final hurdle of clinical efficacy. The profound disconnect between its exceptionally strong preclinical and early clinical data and its "insufficient efficacy" in Phase 3 demands a critical analysis of the potential reasons for this translational failure.

• The Confounding Role of the Placebo Effect: Psychiatric drug trials, and particularly those for MDD, are notoriously plagued by high placebo response rates.[51] A significant portion of patients in the placebo arm of a trial will experience a meaningful improvement in their symptoms, driven by factors such as expectation, increased clinical attention, and the natural waxing and waning of the illness. The placebo response rate in depression trials can be as high as 35-45%.[52] This high baseline of improvement makes it statistically challenging for an active drug to demonstrate a significant additional benefit, especially if its true effect size is modest. It is highly probable that the modest but significant effect of Aticaprant seen in the smaller Phase 2 trial was overwhelmed by a larger and more variable placebo effect in the global, multi-site Phase 3 program.
• The Limits of Preclinical Model Validity: The failure of Aticaprant calls into question the predictive validity of the animal models used to support its development. While models like the forced swim test and chronic stress paradigms showed robust, positive effects [2], these models may be more indicative of engagement with specific neurobiological circuits (e.g., stress-response pathways) than predictive of overall efficacy in the complex, heterogeneous human condition of MDD. The drug may have successfully modulated the target system as predicted by the animal models, but this modulation was simply not sufficient to produce a clinically meaningful antidepressant effect in humans.
• The Heterogeneity of Major Depressive Disorder: MDD is increasingly understood not as a single, monolithic entity but as a syndrome with diverse underlying biological causes. The core hypothesis for Aticaprant was most strongly linked to the symptom of anhedonia. While the clinical program strategically enriched its population for this symptom, it is possible that KOR antagonism is only effective for a more specific, biologically-defined subtype of depression that was not adequately isolated by clinical rating scales alone. The improvement in anhedonia may not have been sufficient to drive a significant change in the multi-domain MADRS score, which also assesses sleep, appetite, and negative cognitions that may be driven by different neurobiological pathways.

7.2 Implications for the KOR Antagonist Drug Class

The failure of Aticaprant does not exist in a vacuum. It occurred within months of the Phase 3 failure of another selective KOR antagonist, Neumora Therapeutics' navacaprant (BTRX-335140), for the same indication.[11] The navacaprant KOASTAL-1 trial also failed to separate from placebo on the primary MADRS endpoint.[53]

This sequence of events has profound implications. While the failure of a single drug can often be attributed to compound-specific issues (e.g., poor pharmacokinetics, off-target effects), the near-simultaneous failure of two well-designed, pharmacologically distinct molecules with the same mechanism of action from two different major pharmaceutical sponsors strongly suggests a mechanism-level or hypothesis-level failure for this indication. This "double-kill" significantly diminishes confidence in selective KOR antagonism as a viable monotherapeutic or adjunctive strategy for the broad treatment of MDD.[13] It creates a substantial barrier to future investment and development in this space, as any new entrant would face deep skepticism from investors, partners, and regulators. The field may now pivot to exploring more complex opioid modulators, such as ALKS 5461 (buprenorphine/samidorphan), which combines KOR antagonism with MOR partial agonism/antagonism and has shown some inconsistent but positive signals in MDD trials.[25]

7.3 Future Directions for Aticaprant

In its discontinuation announcement, Johnson & Johnson noted its intent to "explore future development opportunities for aticaprant in other areas of high unmet need".[12] This decision is likely based on the drug's confirmed safety profile and the strong preclinical data in other domains. Based on the original scientific rationale and preclinical evidence, logical alternative indications could include:

• Anxiety Disorders: The role of the dynorphin/KOR system in stress suggests a potential application in anxiety disorders, such as generalized anxiety disorder or post-traumatic stress disorder.
• Substance Use Disorders: The robust preclinical data showing a reduction in alcohol self-administration and an alleviation of nicotine withdrawal symptoms suggest that Aticaprant could be re-evaluated in specific addiction populations.[2] These indications may provide a more direct and more easily measurable target engagement signal than the broad and heterogeneous syndrome of MDD.

The development path of Aticaprant also serves as a real-time example of strategic portfolio management by a large pharmaceutical company. As the high-risk, novel-mechanism VENTURA program was underway, Johnson & Johnson made a significant strategic move to acquire Intra-Cellular Therapies for its late-stage MDD asset, Caplyta.[13] This acquisition can be viewed as both a strengthening of their neuroscience pipeline and a strategic hedge against the potential failure of Aticaprant. When the VENTURA data proved insufficient, the company was able to make a swift, financially disciplined decision to terminate the program while still maintaining a strong position in the MDD market with a different asset.

7.4 Concluding Remarks

Aticaprant represents a pinnacle of rational drug design in modern neuroscience. It was a pharmacologically elegant, selective, and safe molecule developed from a compelling and well-researched neurobiological hypothesis. Its development program was rigorous, employing advanced tools like PET imaging to confirm target engagement and progressing through a logical sequence of clinical trials. However, its story is ultimately a cautionary tale. Aticaprant's failure in Phase 3 underscores the immense difficulty of translating promising preclinical science into clinically meaningful therapeutic effects for complex psychiatric disorders. It highlights the persistent challenges of the placebo effect, the limitations of our current disease models, and the unforgiving nature of the "valley of death" between mechanism and medicine. While the failure of Aticaprant and its class for MDD is a significant disappointment, the scientific rigor and strategic execution of its development program provide invaluable lessons that will undoubtedly inform the next generation of CNS drug discovery.

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