An Expert Report on JNJ-42165279: A Comprehensive Review of Chemistry, Pharmacology, and Clinical Development

Executive Summary

JNJ-42165279 is an investigational small molecule drug developed by Janssen Pharmaceutica as a potent, selective, and orally bioavailable inhibitor of the enzyme fatty acid amide hydrolase (FAAH). The compound, identified by DrugBank ID DB15173 and CAS Number 1346528-50-4, was designed to enhance the signaling of endogenous cannabinoids, particularly anandamide (AEA), by preventing their metabolic degradation. This mechanism of action was hypothesized to offer therapeutic benefits for a range of central nervous system (CNS) disorders, including anxiety, depression, and pain.

Pharmacologically, JNJ-42165279 is distinguished by its mechanism as a covalently binding but slowly reversible inhibitor of FAAH. This provides a durable pharmacodynamic effect suitable for once-daily dosing while potentially mitigating the risks associated with irreversible enzyme inactivation. Preclinical studies established a strong profile, demonstrating high potency and selectivity, oral activity, CNS penetration, and efficacy in a neuropathic pain model. Subsequent Phase I studies in humans provided unequivocal evidence of both peripheral and central target engagement. Positron Emission Tomography (PET) imaging confirmed near-complete saturation of brain FAAH at clinically relevant doses (≥10 mg), which translated into a profound, 40- to 77-fold increase in anandamide concentrations in the cerebrospinal fluid.

Despite this powerful and unambiguous target engagement, the clinical development of JNJ-42165279 has yielded mixed results. In a Phase IIa proof-of-concept study for Social Anxiety Disorder (SAD), the drug failed to meet its primary endpoint of a statistically significant mean reduction in the Liebowitz Social Anxiety Scale (LSAS) score compared to placebo. However, it did achieve statistical significance on key secondary endpoints, including responder rates and clinician-assessed global improvement, suggesting a meaningful anxiolytic effect in a subpopulation of patients. Subsequent Phase II trials in Autism Spectrum Disorder (ASD) and Post-Traumatic Stress Disorder (PTSD) also failed to meet their primary efficacy objectives, although signals of potential benefit in specific symptom domains were observed. The results of a Phase II trial in Major Depressive Disorder with Anxious Distress have not been publicly disclosed.

Throughout its clinical evaluation, JNJ-42165279 has demonstrated an acceptable safety and tolerability profile, a critical attribute that allowed its development to continue after a tragic incident with a different FAAH inhibitor, BIA 10-2474, temporarily halted the field. The central challenge for JNJ-42165279 is the significant disconnect between its robust pharmacodynamic effects and its inconsistent clinical efficacy. This report provides a comprehensive analysis of the compound's chemical properties, mechanism of action, and the full scope of its preclinical and clinical data, culminating in an integrated assessment of its therapeutic potential and the key questions that remain for its future development.

I. Compound Profile and Physicochemical Properties

This section establishes the fundamental identity of JNJ-42165279, providing a complete chemical and physical characterization that serves as the foundation for understanding its behavior as a drug substance.

1.1. Identification and Nomenclature

To ensure unambiguous identification across scientific literature and regulatory databases, the compound is cataloged under several key identifiers.

• Primary Name: JNJ-42165279.[1]
• DrugBank ID: DB15173.[1]
• CAS Number: 1346528-50-4.[1]
• Synonyms: JNJ 42165279, JNJ-5279, JNJ42165279.[2]
• UNII (Unique Ingredient Identifier): AH2E5UQ11Y.[1]
• Developer: Janssen Pharmaceutica / Janssen Research & Development, LLC.[3]

1.2. Structural and Chemical Data

JNJ-42165279 is a synthetic organic small molecule belonging to the aryl piperazinyl urea class of compounds.[1] Its detailed structural information defines the molecule's architecture and is crucial for understanding its interaction with the FAAH enzyme.

• Type: Small Molecule.[1]
• IUPAC Name: N-(4-chloropyridin-3-yl)-4-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]piperazine-1-carboxamide.[1]
• Molecular Formula: $C_{18}H_{17}ClF_{2}N_{4}O_{3}$.[3]
• SMILES (Simplified Molecular-Input Line-Entry System): C1CN(CCN1CC2=CC3=C(C=C2)OC(O3)(F)F)C(=O)NC4=C(C=CN=C4)Cl.[1]
• InChIKey (International Chemical Identifier Key): YWGYNGCRVZLMCS-UHFFFAOYSA-N.[1]
• Other Forms: A dihydrochloride salt form of the compound, with CAS Number 1346528-51-5, has been synthesized and is available for research purposes. The creation of salt forms is a common strategy in pharmaceutical development to improve physicochemical properties such as solubility and stability, which can enhance formulation and bioavailability.[12]

1.3. Physicochemical and Computed Properties

The physicochemical properties of JNJ-42165279 are critical determinants of its absorption, distribution, metabolism, and excretion (ADME) profile, and thus its suitability as an orally administered therapeutic agent. These properties suggest a molecule deliberately designed for oral bioavailability, though not without potential development challenges.

• Molecular Weight: The average molecular weight is 410.8 g/mol, with a monoisotopic mass of 410.0957244 Da.[1] This value is well within the typical range for orally available small molecule drugs.
• Solubility: Experimental data indicate good solubility in common organic solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and ethanol, at concentrations of 30 mg/mL.[4] However, its predicted aqueous solubility is low at 0.141 mg/mL.[6] This characteristic is common for CNS-penetrant drugs but can present biopharmaceutical challenges, such as dissolution rate-limited absorption, often requiring specialized formulations for preclinical and clinical studies.[12]
• Lipophilicity: The predicted partition coefficient (logP), a measure of lipophilicity, is 2.75 (ALOGPS) and 3.3 (Chemaxon).[6] These values indicate a favorable balance between lipid and aqueous solubility, suggesting the molecule can readily cross biological membranes like the intestinal wall and the blood-brain barrier, a prerequisite for an orally active CNS drug.
• Drug-Likeness Rules: The compound's properties align well with established guidelines used in medicinal chemistry to predict oral bioavailability. It adheres to Lipinski's Rule of Five and the Ghose Filter, two widely used filters for assessing drug-likeness.[6] It does, however, violate Veber's Rule, likely due to its number of rotatable bonds, which can influence conformational flexibility and receptor binding.[6]
• Safety Classification: A critical attribute identified from its chemical profile is a Globally Harmonized System (GHS) classification of H361: "Suspected of damaging fertility or the unborn child" (Reproductive toxicity, Category 2).[1] This warning, derived from preclinical toxicology data, represents a significant safety flag that profoundly influences the drug's development trajectory. It necessitates stringent exclusion criteria in clinical trials, such as enrolling only women who are postmenopausal or surgically sterile, and imposes limitations on its potential use in wider patient populations should it ever reach the market.[7]

The composite physicochemical profile of JNJ-42165279 points to a rational drug design process aimed at creating an orally active, CNS-penetrant molecule. However, the low aqueous solubility and the significant reproductive toxicity warning highlight inherent challenges that must be managed throughout its development lifecycle.

Property	Value	Source(s)
IUPAC Name	N-(4-chloropyridin-3-yl)-4-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]piperazine-1-carboxamide	1
CAS Number	1346528-50-4	1
DrugBank ID	DB15173	1
Molecular Formula	$C_{18}H_{17}ClF_{2}N_{4}O_{3}$	3
Average Molecular Weight	410.8 g/mol	1
Monoisotopic Mass	410.0957244 Da	1
Predicted Water Solubility	0.141 mg/mL	6
Predicted logP	2.75 - 3.3	6
Hydrogen Bond Acceptors	5	6
Hydrogen Bond Donors	1	6
Rotatable Bond Count	3	6
Rule of Five Compliance	Yes	6
GHS Classification	Repr. 2 (H361): Suspected of damaging fertility or the unborn child	1

II. Mechanism of Action and Pharmacological Target

This section deconstructs the molecular mechanism by which JNJ-42165279 exerts its effects, focusing on its interaction with the target enzyme, FAAH, and the subsequent physiological consequences that form the basis of its therapeutic hypothesis.

2.1. The Endocannabinoid System and Fatty Acid Amide Hydrolase (FAAH)

The endocannabinoid system is a crucial neuromodulatory system involved in the homeostatic regulation of numerous physiological processes, including fear and anxiety responses, pain perception, mood, and immune function.[14] It primarily consists of cannabinoid receptors (CB1 and CB2), endogenous ligands (endocannabinoids), and the enzymes responsible for their synthesis and degradation.

One of the most well-characterized endocannabinoids is N-arachidonoylethanolamine, commonly known as anandamide (AEA).[14] Anandamide is synthesized "on demand" in postsynaptic neurons and acts as a retrograde messenger, binding to presynaptic CB1 receptors to inhibit neurotransmitter release.[14] This feedback mechanism is a key way the brain modulates neuronal activity.

The signaling of anandamide and other related fatty acid amides (FAAs)—such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA)—is terminated by enzymatic hydrolysis after they are taken back up into cells.[9] The principal enzyme responsible for this degradation is Fatty Acid Amide Hydrolase (FAAH). FAAH is an integral membrane enzyme that is highly expressed throughout the brain and in various peripheral tissues, positioning it as a key regulator of endocannabinoid tone.[6] By inhibiting FAAH, it is possible to prevent the breakdown of these signaling lipids, thereby increasing their concentration and prolonging their action at their respective receptors. This strategy forms the therapeutic rationale for the development of FAAH inhibitors.[15]

2.2. Molecular Interaction with FAAH: A Slowly Reversible Covalent Inhibitor

JNJ-42165279 is a potent and selective inhibitor of FAAH, designed to amplify endogenous cannabinoid signaling.[1] Its mechanism of inhibition is sophisticated and represents a deliberate choice in its molecular design.

The compound acts as a substrate for the FAAH enzyme. This interaction leads to the formation of a covalent bond between the drug molecule and the catalytic serine residue (Ser241) located within the enzyme's active site.[9] This covalent modification, a process known as carbamylation for urea-based inhibitors like JNJ-42165279, effectively inactivates the enzyme and prevents it from hydrolyzing its natural substrates.[9]

A critical feature of this mechanism is that the inhibition is slowly reversible, rather than permanent or irreversible.[3] Over time, the covalent bond between the drug fragment and the enzyme undergoes slow hydrolysis, which regenerates the active, functional FAAH enzyme.[14] This kinetic profile offers a significant therapeutic advantage: the rate of reversal is slow enough that the inhibitory effect persists long after the parent drug has been cleared from circulation, providing a durable pharmacodynamic effect that supports a convenient once-daily dosing regimen.[14]

This "slowly reversible" covalent mechanism is a key differentiator from truly irreversible inhibitors. Irreversible inhibitors permanently inactivate the target enzyme, requiring the cell to synthesize new protein to restore function. While effective, this carries a higher theoretical risk of cumulative toxicity, particularly if the inhibitor binds covalently to off-target proteins. The slowly reversible nature of JNJ-42165279's interaction with FAAH provides a built-in safety feature, offering prolonged target engagement without permanent enzyme modification. This distinction became particularly salient following the 2016 clinical trial tragedy involving BIA 10-2474, another FAAH inhibitor. The ability of JNJ-42165279's developers to articulate its potentially safer, non-permanent mechanism of action was likely a crucial factor in the decision by regulators and the company to resume its clinical trials, distinguishing it from compounds with a higher risk profile.

2.3. Downstream Effects on Endogenous Fatty Acid Amides

The direct pharmacological consequence of FAAH inhibition by JNJ-42165279 is the prevention of FAA degradation. This leads to a significant and measurable accumulation of anandamide (AEA), PEA, and OEA in both the periphery (plasma) and the central nervous system (brain and cerebrospinal fluid).[9]

The central therapeutic hypothesis for JNJ-42165279 and other FAAH inhibitors rests on this biochemical outcome. By elevating the levels of endogenous cannabinoids like anandamide, the drug is intended to potentiate their natural, physiological signaling at cannabinoid receptors, primarily CB1.[14] This approach is thought to produce therapeutic effects—such as anxiolysis, analgesia, and mood elevation—in a more nuanced and localized manner than directly stimulating cannabinoid receptors with an exogenous agonist (like THC from cannabis). The goal is to enhance the body's own regulatory system, thereby achieving therapeutic benefit while avoiding the undesirable side effects commonly associated with direct CB1 receptor agonists, such as cognitive impairment, motor deficits, and psychoactive effects.[16]

III. Preclinical Pharmacology and Toxicology

This section details the foundational in vitro and in vivo studies that established the initial profile of JNJ-42165279's potency, selectivity, efficacy, and safety, which collectively provided the justification for its advancement into human clinical trials. The preclinical data package for JNJ-42165279 was robust, demonstrating the characteristics of a promising drug candidate, while also highlighting key areas for consideration during clinical translation.

3.1. In Vitro Potency and Selectivity Profile

In vitro assays are essential for determining a compound's intrinsic activity at its molecular target and for assessing its potential for off-target effects. JNJ-42165279 was characterized as a potent inhibitor of FAAH with an excellent selectivity profile.

• Potency: The inhibitory potency of JNJ-42165279 was quantified using recombinant FAAH enzymes, revealing a notable difference between species.
• Human FAAH (hFAAH): The half-maximal inhibitory concentration ($IC_{50}$) was determined to be 70 nM.[3] This value indicates potent activity against the human form of the enzyme.
• Rat FAAH (rFAAH): The IC50​ was 313 nM.4 The observation that JNJ-42165279 is approximately 4.5-fold more potent against the human enzyme than the rat enzyme is a critical piece of translational information. It implies that the effective doses observed in rat models may not be directly proportional to the doses required in humans, necessitating careful pharmacokinetic and pharmacodynamic modeling to guide dose selection for clinical trials.
• Selectivity: A hallmark of a well-designed drug candidate is high selectivity for its intended target, which minimizes the risk of off-target side effects. JNJ-42165279 demonstrated exceptional selectivity.
• In a comprehensive screening panel against 50 other biologically relevant targets—including other enzymes, G-protein coupled receptors, transporters, and ion channels—JNJ-42165279 did not produce greater than 50% inhibition at a high concentration of 10 μM.[9]
• Crucially, the compound showed no inhibitory activity against key cytochrome P450 (CYP) enzymes (1A2, 2C8, 2C9, 2C19, 2D6, and 3A4) or the hERG potassium channel at 10 μM.[9] Lack of activity at these targets is a significant de-risking factor, as it indicates a low potential for causing common drug-drug interactions or drug-induced cardiac arrhythmias (QT prolongation).

3.2. In Vivo Pharmacodynamic Effects and Efficacy in Animal Models

In vivo studies in animal models are used to confirm that a drug can reach its target after administration, produce the intended biological effect, and demonstrate efficacy in a model of human disease.

• Target Engagement: JNJ-42165279 was confirmed to be orally active and capable of blocking FAAH activity in both the brain and peripheral tissues of rats. This target engagement resulted in the expected downstream effect: a significant elevation of the FAAH substrates AEA, OEA, and PEA.[4] More detailed investigation using in vivo microdialysis in the amygdala—a brain region critical for processing fear and anxiety—confirmed that oral administration of JNJ-42165279 selectively increased extracellular levels of anandamide without affecting the levels of 2-arachidonoylglycerol (2-AG), another major endocannabinoid degraded by a different enzyme (MAGL). This result elegantly demonstrated the compound's specific action on the FAAH pathway within a functionally relevant brain circuit.[2]
• Efficacy in a Neuropathic Pain Model: The therapeutic potential of JNJ-42165279 was tested in the spinal nerve ligation (SNL) model in rats, a widely used model of neuropathic pain. In this model, a single oral dose of 60 mg/kg of JNJ-42165279 effectively and dose-dependently reversed tactile allodynia (pain response to a non-painful stimulus). The maximum pain-relieving effect was observed 30 minutes post-dose and was maintained for at least two hours.[4] This finding provided strong preclinical proof-of-concept for the drug's efficacy, at least in the context of pain. While the primary clinical development path for JNJ-42165279 focused on psychiatric disorders, this robust efficacy signal in a pain model underscores the broad therapeutic potential of FAAH inhibition.

3.3. Preclinical Toxicology and Safety Pharmacology

The overall preclinical safety profile of JNJ-42165279 was favorable, characterized by excellent ADME properties and high selectivity, which together supported its progression into human trials.[9] However, specific toxicology studies revealed a notable concern.

• Reproductive Toxicology: In embryo-fetal development studies conducted in Sprague-Dawley rats, administration of high doses of JNJ-42165279 (100 mg/kg, once daily for 11 days) was found to induce fetal lens fiber hypertrophy and degeneration, with nuclear cataracts observed in some animals.[12] This specific finding is the likely basis for the GHS classification of reproductive toxicity [1] and represents the most significant safety liability identified in the preclinical program.

In summary, the preclinical data for JNJ-42165279 presented a compelling case for clinical development, characterized by potent and selective on-target activity, oral bioavailability, CNS penetration, and efficacy in a relevant disease model. This strong foundation was tempered by translational considerations regarding inter-species potency and a clear reproductive toxicology signal that would require careful management in human studies.

Assay Type	Model / System	Key Parameter	Result	Source(s)
In Vitro Potency	Recombinant human FAAH (hFAAH)	$IC_{50}$	70 nM	3
In Vitro Potency	Recombinant rat FAAH (rFAAH)	$IC_{50}$	313 nM	4
In Vitro Selectivity	Panel of 50 receptors, enzymes, transporters, ion channels	% Inhibition	<50% at 10 μM for all targets	9
In Vitro Safety	CYP enzymes (1A2, 2C8, 2C9, 2C19, 2D6, 3A4), hERG channel	% Inhibition	No significant inhibition at 10 μM	9
In Vivo Efficacy	Spinal Nerve Ligation (SNL) rat model of neuropathic pain	Reversal of tactile allodynia	59% maximum pain relief at 60 mg/kg (p.o.)	12
Preclinical Toxicology	Embryo-fetal development model in Sprague-Dawley rats	Fetal effects	Lens fiber hypertrophy, degeneration, and cataracts at 100 mg/kg/day	12

IV. Human Pharmacokinetics and Pharmacodynamics

This section details the critical studies that translated the preclinical findings into humans, linking the administered dose of JNJ-42165279 to its concentration in the body (pharmacokinetics) and its biological effect at the target enzyme (pharmacodynamics). The data from Phase I studies provided exceptionally clear and powerful evidence that the drug robustly engages its target in the human central nervous system.

4.1. Absorption, Distribution, Metabolism, and Excretion (ADME) Profile

Phase I studies, including a single ascending dose study (NCT01650597) and a multiple ascending dose study (NCT01964651), were conducted in healthy volunteers to characterize the human ADME profile of JNJ-42165279.[15]

• Administration and Absorption: The compound is orally bioavailable, consistent with its design and preclinical data.[1] Pharmacokinetic analyses showed that plasma concentrations of the drug generally increased with the dose, although a high degree of inter-individual variability in exposure was noted.[15]
• Distribution: A key question for any CNS drug is its ability to cross the blood-brain barrier. JNJ-42165279 demonstrated successful CNS penetration. After seven days of daily administration, drug concentrations were measured in the cerebrospinal fluid (CSF). These CSF concentrations were approximately 3% of the peak plasma values, a ratio consistent with the drug's high degree of binding to plasma proteins (the unbound, free fraction in human plasma was estimated to be only 6.4–7.5%).[15] Only the unbound fraction of a drug is typically able to cross the blood-brain barrier.
• Metabolism: JNJ-42165279 was identified as a substrate for the cytochrome P450 3A (CYP3A) enzyme system. This is a common metabolic pathway for many drugs, and this finding indicates a potential for drug-drug interactions when co-administered with strong inhibitors or inducers of CYP3A.[15]
• Elimination Half-life: The plasma half-life of JNJ-42165279 is approximately 8–14 hours.[14] This, combined with its slowly reversible mechanism of action, provides pharmacokinetic and pharmacodynamic support for a once-daily dosing schedule.

4.2. Evidence of Peripheral Target Engagement

To confirm that JNJ-42165279 was inhibiting FAAH in the human body, its pharmacodynamic (PD) effects were measured in peripheral tissues. FAAH activity was assessed in leukocytes (white blood cells) isolated from blood samples, and the concentrations of FAAH substrates were measured in plasma.[15]

• FAAH Activity in Leukocytes: Administration of JNJ-42165279 resulted in potent inhibition of FAAH activity. After 10 days of once-daily dosing with 10–100 mg, the remaining FAAH activity in leukocytes was reduced to a mean trough of just 0.58–10.5% of pre-dose levels, indicating near-complete and sustained peripheral enzyme inhibition.[15]
• Plasma Fatty Acid Amides: This profound enzyme inhibition produced the expected downstream biochemical consequence: a dramatic increase in the plasma concentrations of FAAs. Single doses of JNJ-42165279 led to peak anandamide (AEA) concentrations that were 5.5 to 10-fold higher than those seen with placebo. Similarly, peak concentrations of OEA and PEA were 4.3 to 5.6-fold higher. These substantial increases confirmed robust peripheral target engagement.[15]

4.3. Evidence of Central Target Engagement and Brain Occupancy

While peripheral data are important, the ultimate test for a CNS drug is demonstrating that it engages its target within the brain. The development program for JNJ-42165279 employed state-of-the-art techniques to provide definitive evidence of central target engagement.

• Cerebrospinal Fluid (CSF) Biomarkers: The most direct biochemical evidence of central FAAH inhibition was obtained from CSF samples. After seven days of daily dosing, JNJ-42165279 produced a profound increase in the levels of endocannabinoids within the CSF, a proxy for the brain environment.
• Mean CSF anandamide (AEA) concentrations increased by an astonishing ~41-fold to ~77-fold relative to pre-dose values.
• Mean CSF oleoylethanolamide (OEA) concentrations increased by ~5.8-fold to ~7.4-fold.15 This massive elevation of the primary FAAH substrate in the CNS provided incontrovertible proof that the drug was potently inhibiting the enzyme at its site of action.
• Positron Emission Tomography (PET) Imaging: To directly visualize and quantify the binding of JNJ-42165279 to FAAH in the living human brain, a PET imaging study (NCT02169973) was conducted using the specific FAAH radiotracer [¹¹C]MK3168.[15] This technique is considered the gold standard for confirming CNS target occupancy.
• The study demonstrated significant, dose-dependent blocking of the tracer's binding to brain FAAH after administration of JNJ-42165279.
• Critically, the results showed that saturation of brain FAAH occupancy occurred at doses of 10 mg and above.[15] A single 10 mg dose was sufficient to achieve approximately 80% occupancy of the FAAH enzyme in the brain.[15]

The human PK/PD data for JNJ-42165279 is arguably the strongest component of its entire development profile. The combination of PET imaging demonstrating near-complete target saturation in the brain and CSF measurements showing a massive downstream increase in anandamide provides unambiguous and powerful evidence of target engagement. This robust dataset establishes that the drug performs its intended mechanistic function flawlessly in humans. Consequently, any subsequent failures to demonstrate clinical efficacy cannot be attributed to a lack of target engagement; the explanation must lie either in the therapeutic hypothesis itself or in other aspects of the clinical trials.

V. Clinical Development and Efficacy Assessment

Following the successful demonstration of safety and robust target engagement in Phase I, JNJ-42165279 advanced into a series of Phase II clinical trials to evaluate its efficacy in several psychiatric disorders. This section critically evaluates the design and outcomes of these trials, which represent the ultimate test of the therapeutic hypothesis that enhancing endocannabinoid tone via FAAH inhibition can alleviate symptoms of these conditions. The results have been mixed, revealing a complex picture of a drug with a clear biological effect but an elusive clinical benefit.

Trial Identifier (NCT)	Indication	Phase	Participants (N)	Dose	Duration	Primary Endpoint	Outcome Summary
NCT02432703	Social Anxiety Disorder (SAD)	IIa	149	25 mg QD	12 weeks	Change in LSAS Total Score	Not Met
NCT03664232	Autism Spectrum Disorder (ASD)	II	61	25 mg BID	12 weeks	Change in ABI Scores	Not Met
NCT02498392	Major Depressive Disorder (MDD) with Anxious Distress	IIa	161	25 mg QD	6 weeks	Change in HDRS17 Total Score	Not Published
Eudra-CT 2020-001965-36	Post-Traumatic Stress Disorder (PTSD)	II	100	25 mg BID	12 weeks	N/A	Negative

5.1. Indication: Social Anxiety Disorder (SAD) - Trial NCT02432703

The first major test of JNJ-42165279's efficacy was in patients with Social Anxiety Disorder, a condition for which the endocannabinoid system's role in fear and anxiety regulation provides a strong therapeutic rationale.

5.1.1. Study Design and Endpoints

This was a Phase 2a, multicenter, randomized, double-blind, placebo-controlled, parallel-group proof-of-concept study.[7] A total of 149 participants with a DSM-5 diagnosis of SAD and a baseline Liebowitz Social Anxiety Scale (LSAS) score of ≥70 were randomized in a 1:1 ratio to receive either JNJ-42165279 at a dose of 25 mg once daily (QD) or a matching placebo for 12 weeks.[14]

• Primary Endpoint: The pre-specified primary outcome measure was the change in the LSAS total score from baseline to the end of the 12-week treatment period.[7]
• Secondary Endpoints: Key secondary measures included a responder analysis (defined as the percentage of participants achieving a ≥30% improvement from baseline in LSAS total score), the Clinical Global Impression-Improvement (CGI-I) scale, the Hamilton Anxiety Scale (HAM-A), and the Hamilton Depression Rating Scale (HDRS17).[14]

5.1.2. Analysis of Efficacy Results

The trial yielded a complex and nuanced set of results, failing on its primary endpoint but showing statistically significant effects on important secondary measures.

• Primary Endpoint: NOT MET. At week 12, the mean reduction from baseline in the LSAS total score was numerically larger in the JNJ-42165279 group (-29.4) compared to the placebo group (-22.4). However, due to high variability in the response, this difference did not achieve statistical significance.[14]
• Secondary Endpoints: MET. Despite the failure of the primary endpoint, the study demonstrated statistically significant and clinically meaningful effects on two key secondary outcomes:
• Responder Rate: The percentage of participants who met the criteria for a clinical response (≥30% LSAS improvement) was significantly higher for those treated with JNJ-42165279 (42.4%) compared to placebo (23.6%), with a p-value of 0.04.[25] This indicates that a patient taking the drug was nearly twice as likely to experience a meaningful reduction in their symptoms as a patient taking placebo.
• CGI-I Scale: The percentage of participants who were rated by their clinician as "much or very much improved" on the CGI-I was also significantly higher in the JNJ-42165279 group (44.1%) versus the placebo group (23.6%), with a p-value of 0.02.[14] This corroborates the responder analysis, showing that clinicians observed a substantial global improvement in a significantly larger proportion of drug-treated patients.

The investigators concluded that while the 25 mg dose appeared to elicit an anxiolytic effect, it might have been suboptimal. They hypothesized that trough drug concentrations at the end of the 24-hour dosing interval may have been insufficient to maintain complete FAAH inhibition, potentially leading to a blunted overall effect.[14]

This discrepancy between the primary and secondary outcomes is a classic clinical trial scenario that suggests a heterogeneous treatment effect. The failure on the continuous primary endpoint (mean change) could be driven by a large number of non-responders diluting the average effect. In contrast, the success on the categorical secondary endpoints (responder rates) strongly indicates that the drug is highly effective for a specific subpopulation of patients. This pattern suggests that JNJ-42165279 is not a universally effective treatment for SAD, but it may offer significant benefit to a definable group of "responders." The key challenge for future development would be to prospectively identify these individuals through predictive biomarkers.

Efficacy Outcome (Week 12)	Placebo (N=75)	JNJ-42165279 (N=74)	p-value
Mean Change in LSAS Total Score (SD)	-22.4 (23.57)	-29.4 (27.47)	Not Significant
% Responders (≥30% LSAS Improvement)	23.6%	42.4%	0.04
% "Much/Very Much Improved" on CGI-I	23.6%	44.1%	0.02

5.2. Indication: Autism Spectrum Disorder (ASD) - Trial NCT03664232

Based on the role of the endocannabinoid system in social behavior and anxiety, JNJ-42165279 was evaluated in adolescents and adults with ASD.

5.2.1. Study Design and Endpoints

This was a Phase 2, double-blind, placebo-controlled study involving 61 participants aged 13-35 years with a confirmed diagnosis of ASD.[29] Participants were randomized to receive JNJ-42165279 at a dose of 25 mg twice-daily (BID) or placebo for 12 weeks.[29]

• Primary Endpoints: The primary endpoints were the change from baseline to day 85 in scores on the Autism Behavior Inventory (ABI), including the Core Domain (ABI-CD), Social Communication (ABI-SC), and Repetitive/Restrictive Behavior (ABI-RB) subscales.[29]

5.2.2. Analysis of Efficacy Results

Similar to the SAD trial, the study in ASD failed to meet its primary objectives but revealed intriguing signals in secondary and exploratory analyses.

• Primary Endpoints: NOT MET. At day 85, there was no statistically significant difference between the JNJ-42165279 and placebo groups on any of the primary ABI endpoints. The p-values ranged from 0.231 to 0.290, indicating a clear lack of effect on these measures.[29]
• Secondary Endpoints: Several secondary outcomes showed small to moderate changes that directionally favored JNJ-42165279. Notably, a statistically significant improvement was seen on the Repetitive Behavior Scale-Revised (RBS-R, p = 0.006), and a trend towards improvement was observed on the Social Responsiveness Scale 2 (SRS, p = 0.064).[29]
• PK/PD Correlation: A crucial exploratory finding emerged from this study: a positive correlation was observed between the magnitude of the pharmacodynamic effect and clinical improvement. Participants treated with JNJ-42165279 who achieved higher plasma concentrations of FAAs (indicating more robust target engagement) also experienced the greatest reduction in their SRS total scores.[29] This finding provides evidence that the drug's biological effect is linked to clinical outcome, further supporting the idea of a "responder" subpopulation.

5.3. Indication: Major Depressive Disorder (MDD) - Trial NCT02498392

JNJ-42165279 was also investigated as an adjunctive treatment for patients with MDD with anxious distress who had not responded adequately to standard antidepressant therapy (SSRIs or SNRIs).[30]

5.3.1. Study Design and Status

This was a Phase 2a, randomized, double-blind, placebo-controlled study in which participants received either JNJ-42165279 (25 mg QD) or placebo in addition to their ongoing antidepressant for 6 weeks.[30] The primary endpoint was the change from baseline in the Hamilton Depression Rating Scale (HDRS17) total score.[30] The trial enrolled 161 participants and is listed as completed.[2] However, as of this report, no results from this study have been published in peer-reviewed literature or presented at scientific conferences.[33] In the pharmaceutical industry, the absence of a public disclosure of results for a completed trial is often interpreted as an indication that the study failed to meet its primary endpoint.

5.4. Other Investigational Uses and Outcomes

The therapeutic hypothesis was also tested in Post-Traumatic Stress Disorder (PTSD). In a Phase 2 trial (Eudra-CT 2020-001965-36), JNJ-42165279 was studied as an adjunct to internet-delivered cognitive behavioral therapy (CBT). The study concluded that FAAH inhibition with JNJ-42165279 did not enhance the effects of CBT and was not a suitable adjunct treatment for PTSD.[34]

VI. Safety and Tolerability Profile

The safety and tolerability of an investigational drug are paramount, and this aspect of JNJ-42165279's development is particularly noteworthy. It has maintained a favorable safety profile throughout human testing, a critical feature that has distinguished it within a drug class that has faced significant safety challenges.

6.1. Summary of Safety Findings from Human Clinical Trials

Across its entire clinical program, from Phase I studies in healthy volunteers to Phase II studies in patient populations, JNJ-42165279 has been consistently reported as safe and well-tolerated.

• In Phase I multiple-ascending dose and PET studies involving healthy volunteers, no safety concerns were identified.[15]
• In the Phase IIa study in 149 participants with Social Anxiety Disorder, the official publication stated that the drug was "well tolerated".[14]
• In the Phase II study in 61 adolescents and adults with Autism Spectrum Disorder, the investigators concluded that JNJ-42165279 "demonstrated an acceptable safety profile".[29]

This consistent record of good tolerability is a significant asset for the compound, especially given the CNS indications it targets, where side effects can often limit the utility of approved medications.

6.2. The BIA 10-2474 Incident and its Impact on JNJ-42165279 Development

The development landscape for all FAAH inhibitors was irrevocably altered in early 2016. A Phase I clinical trial for a different FAAH inhibitor, BIA 10-2474, being developed by the company Bial, resulted in a series of severe adverse neurological events in healthy volunteers, including one death.[3] This tragedy immediately cast a dark shadow over the entire drug class and raised urgent questions about whether FAAH inhibition was a safe therapeutic strategy.

In response to this event, Janssen Research & Development took a swift and responsible "precautionary measure." The company voluntarily suspended dosing in its two ongoing Phase II trials of JNJ-42165279 (NCT02432703 in SAD and NCT02498392 in MDD).[3] At the time of the suspension, Janssen was emphatic in stating that no serious adverse events had been reported in any of the clinical trials conducted with JNJ-42165279 to date.[3]

The clinical hold remained in effect until more information about the BIA 10-2474 incident became available. The trials for JNJ-42165279 were later resumed, a decision that would have required extensive review and discussion with regulatory agencies.[3] The ability to restart the program suggests that the company successfully argued that the toxicity observed with BIA 10-2474 was specific to that molecule and not an inherent, class-wide effect of FAAH inhibition.

6.3. Comparative Safety within the FAAH Inhibitor Class

Subsequent investigations into the BIA 10-2474 tragedy suggested that its severe toxicity may have been caused by off-target effects on other serine hydrolase enzymes, rather than its intended action on FAAH.[36] This hypothesis is supported by the fact that other FAAH inhibitors that have entered clinical trials have not produced similar adverse events. For instance, Pfizer's FAAH inhibitor, PF-04457845, was reported to be well-tolerated in its clinical trials, even though it ultimately failed to demonstrate efficacy for osteoarthritis pain.[20]

The favorable safety profile of JNJ-42165279 can likely be attributed to key features of its molecular design. Its high preclinical selectivity, with minimal activity against a wide range of other biological targets, reduces the risk of unintended off-target pharmacology.[9] Furthermore, its slowly reversible covalent mechanism of action may offer a safer profile than truly irreversible inhibitors, avoiding permanent enzyme modification.[3]

The demonstrated safety and tolerability of JNJ-42165279 is therefore not just a passive feature but a key strategic asset. It was the primary enabler of its continued development in the wake of the BIA 10-2474 incident. By successfully decoupling itself from the toxicity concerns that halted other programs, JNJ-42165279, along with other well-tolerated compounds, helped to validate that FAAH can be targeted safely in humans. This has kept the therapeutic hypothesis for this enzyme class alive, even as the path to demonstrating clear clinical efficacy remains challenging.

VII. Integrated Analysis and Future Perspectives

This final section synthesizes the comprehensive data presented in this report to provide a holistic assessment of JNJ-42165279. It directly addresses the central paradox of its development—the disconnect between its powerful biological activity and its inconsistent clinical results—and offers an expert perspective on its remaining therapeutic potential and possible future directions.

7.1. Synthesizing the Disconnect Between Target Engagement and Clinical Efficacy

The core conundrum of the JNJ-42165279 development program is the stark contrast between its pharmacodynamic success and its clinical efficacy failures. The evidence is unequivocal that the drug potently and selectively inhibits its target, FAAH, in the human brain, leading to a massive increase in the concentration of its primary substrate, anandamide.[15] Yet, this profound biological effect has not translated into a clear and consistent therapeutic benefit in well-controlled Phase II trials for SAD, ASD, MDD, or PTSD. Several potential explanations for this disconnect must be considered.

1. The FAAH Inhibition Hypothesis: The foundational premise may be overly simplistic. The hypothesis that simply increasing the global tone of anandamide and other FAAs is sufficient to treat complex neuropsychiatric disorders might be flawed. The brain possesses powerful homeostatic mechanisms to maintain equilibrium. It is plausible that in the face of sustained, pharmacologically-induced elevation of endocannabinoids, the system adapts through mechanisms such as receptor downregulation or changes in other neurotransmitter systems, ultimately neutralizing the therapeutic effect over time. The negative result in the PTSD trial, where the drug failed to augment a proven therapy like CBT, lends some weight to this possibility.[34]
2. Dosing and Exposure: The investigators of the SAD trial hypothesized that the 25 mg once-daily dose was suboptimal, as trough concentrations might have allowed for partial recovery of FAAH activity before the next dose.[14] The PET imaging data showed that a 10 mg dose was sufficient to achieve ~80% FAAH occupancy at peak concentrations.[15] While this is high, it is possible that for a clinical effect, near-complete (>95%) and continuous, sustained inhibition throughout the entire dosing interval is required. The twice-daily dosing in the ASD trial was an attempt to address this, but it still failed to meet primary endpoints, suggesting that dosing frequency alone may not be the complete answer.
3. Trial Design and Endpoint Selection: The choice of primary endpoints may not have been sensitive enough to detect the drug's true effect. In the SAD trial, the drug failed on the mean change in LSAS but succeeded on responder rates and clinician global impressions.[25] This pattern suggests that the drug has a significant effect, but perhaps only in a subset of the population, an effect that is more easily detected by categorical "responder" endpoints than by a continuous measure of central tendency like the mean.
4. Patient Heterogeneity: This is perhaps the most compelling explanation and is supported by data from multiple trials. The finding from the ASD study that clinical improvement on the SRS scale correlated with the magnitude of the pharmacodynamic response (i.e., the level of FAA elevation) is a crucial clue.[29] It strongly implies that the drug's effect is real but is dependent on individual biological factors. It is plausible that FAAH inhibition is only effective in individuals who have a pre-existing deficit or dysregulation in their endocannabinoid system. In individuals with a normally functioning system, elevating endocannabinoids further may have little to no therapeutic benefit.

7.2. Critical Assessment of Therapeutic Potential and Challenges

Based on the currently available data, the therapeutic potential of JNJ-42165279 as a broad-spectrum, first-line treatment for disorders like SAD or ASD appears low. The repeated failure to meet primary endpoints in well-designed trials makes a path to approval for a general patient population exceptionally difficult.

However, a potential niche may exist for the treatment of a specific subpopulation of "responders," if such a group could be prospectively identified. The statistically significant result on the Repetitive Behavior Scale-Revised (p=0.006) in the ASD trial is intriguing and may represent a more specific symptom domain where the drug has a tangible effect.[29]

The primary challenge for the JNJ-42165279 program is the lack of a clear path forward. Without a validated biomarker to enrich a clinical trial population with likely responders, initiating a large, expensive Phase III study would be a high-risk gamble with a low probability of success. The fundamental scientific work to understand the biological basis of the response heterogeneity observed in Phase II has yet to be completed.

7.3. Recommendations for Future Research and Development Pathways

To salvage the potential of JNJ-42165279 or to inform the development of future FAAH inhibitors, several research avenues should be pursued.

• Biomarker Discovery: A comprehensive, retrospective analysis of the biological samples collected during the Phase II trials is essential. This should include genetic analysis to look for correlations between clinical response and polymorphisms in genes related to the endocannabinoid system (e.g., the FAAH C385A polymorphism, rs324420, which is known to affect FAAH protein levels).[35] In addition, baseline levels of endocannabinoids and related lipids in plasma or CSF should be correlated with treatment outcomes to determine if a "low-tone" endocannabinoid state predicts response.
• Dose Optimization: To definitively test the "suboptimal dose" hypothesis from the SAD trial, a new, carefully designed dose-ranging study could be considered. This study should include higher doses and/or twice-daily dosing and should incorporate intensive PK/PD sampling to correlate drug exposure and continuous FAAH inhibition with clinical effects.
• Indication Re-evaluation: Given the strong preclinical efficacy signal in a neuropathic pain model [12], a re-evaluation of pain indications may be warranted. While another FAAH inhibitor, PF-04457845, failed in osteoarthritis pain (a condition with a significant inflammatory component) [9], conditions with a more centralized pain mechanism, such as fibromyalgia or specific types of neuropathy, could be more promising targets.

Conclusion

JNJ-42165279 stands as a well-characterized, potent, and selective FAAH inhibitor with an excellent safety profile and definitive proof of central target engagement in humans. It represents a triumph of medicinal chemistry and early-phase clinical pharmacology. However, its story also serves as a cautionary tale about the complexities of translating a powerful biological mechanism into a reliable clinical therapy. The failure to consistently demonstrate efficacy despite robustly modulating its target suggests that the underlying therapeutic hypothesis—that global enhancement of endocannabinoid tone is sufficient to treat complex neuropsychiatric disorders—may be incomplete. The future of JNJ-42165279, and perhaps the entire class of FAAH inhibitors, hinges on the ability of researchers to unravel the biological heterogeneity of these disorders and to identify the specific patient populations for whom this elegant mechanism of action can provide true therapeutic benefit.

Works cited

1. N-(4-Chloro-3-pyridinyl)-4-((2,2-difluoro-1,3-benzodioxol-5-yl)methyl)-1-piperazinecarboxamide | C18H17ClF2N4O3 | CID 54576693 - PubChem, accessed October 20, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/54576693
2. JNJ-42165279 - Drug Targets, Indications, Patents - Patsnap Synapse, accessed October 20, 2025, https://synapse.patsnap.com/drug/167fd931400c47a1a505a86b7defa3ca
3. JNJ-42165279 - Wikipedia, accessed October 20, 2025, https://en.wikipedia.org/wiki/JNJ-42165279
4. JNJ-42165279 (CAS Number: 1346528-50-4) | Cayman Chemical, accessed October 20, 2025, https://www.caymanchem.com/product/19987/jnj-42165279
5. JNJ-42165279 | JNJ-5279 | Amides - Ambeed.com, accessed October 20, 2025, https://www.ambeed.com/products/jnj-42165279.html
6. JNJ-42165279: Uses, Interactions, Mechanism of Action | DrugBank ..., accessed October 20, 2025, https://go.drugbank.com/drugs/DB15173
7. NCT02432703 | A Safety and Efficacy Study of JNJ-42165279 in Participants With Social Anxiety Disorder | ClinicalTrials.gov, accessed October 20, 2025, https://clinicaltrials.gov/study/NCT02432703
8. JNJ 42165279 - AdisInsight - Springer, accessed October 20, 2025, https://adisinsight.springer.com/drugs/800036911
9. Preclinical Characterization of the FAAH Inhibitor JNJ-42165279 ..., accessed October 20, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4677372/
10. JNJ-42165279 | Ligand page - IUPHAR/BPS Guide to PHARMACOLOGY, accessed October 20, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9012
11. JNJ-42165279 | 1346528-50-4 - Sigma-Aldrich, accessed October 20, 2025, https://www.sigmaaldrich.com/US/en/product/achemblock/advh14dbe696?context=bbe
12. JNJ-42165279 | FAAH Inhibitor - MedchemExpress.com, accessed October 20, 2025, https://www.medchemexpress.com/JNJ-42165279.html
13. JNJ-42165279 dihydrochloride | FAAH Inhibitor | MedChemExpress, accessed October 20, 2025, https://www.medchemexpress.com/jnj-42165279-dihydrochloride.html
14. The effects of inhibition of fatty acid amide hydrolase (FAAH) by JNJ-42165279 in social anxiety disorder - eScholarship.org, accessed October 20, 2025, https://escholarship.org/content/qt9366n0qk/qt9366n0qk.pdf
15. Fatty Acid Amide Hydrolase Inhibition by JNJ‐42165279: A Multiple‐Ascending Dose and a Positron Emission Tomography Study in Healthy Volunteers - PubMed Central, accessed October 20, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6039207/
16. Fatty Acid Amide Hydrolase (FAAH) Inhibitor – an enzyme with novel therapeutic potential, accessed October 20, 2025, https://www.delveinsight.com/blog/fatty-acid-amide-hydrolase-faah
17. (PDF) Fatty Acid Amide Hydrolase Inhibition by JNJ-42165279: A Multiple-Ascending Dose and a Positron Emission Tomography Study in Healthy Volunteers - ResearchGate, accessed October 20, 2025, https://www.researchgate.net/publication/324002135_Fatty_Acid_Amide_Hydrolase_Inhibition_by_JNJ-42165279_A_Multiple-Ascending_Dose_and_a_Positron_Emission_Tomography_Study_in_Healthy_Volunteers_Fatty_Acid_Amide_Hydrolase_Inhibition_by_JNJ-42165279
18. Preclinical Characterization of the FAAH Inhibitor JNJ-42165279 | ACS Medicinal Chemistry Letters - ACS Publications, accessed October 20, 2025, https://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.5b00353
19. The effects of inhibition of fatty acid amide hydrolase (FAAH) by JNJ-42165279 in social anxiety disorder: a double-blind, randomized, placebo-controlled proof-of-concept study (2020) - Reddit, accessed October 20, 2025, https://www.reddit.com/r/neuroscience/comments/xc2ivn/the_effects_of_inhibition_of_fatty_acid_amide/
20. FAAH inhibitors in the limelight, but regrettably - Semantic Scholar, accessed October 20, 2025, https://pdfs.semanticscholar.org/964c/d52e71ca5bb6011f88242fb8e4449d833195.pdf
21. JNJ-42165279 | FAAH inhibitor | Mechanism | Concentration - Selleck Chemicals, accessed October 20, 2025, https://www.selleckchem.com/products/jnj-42165279.html
22. Preclinical Characterization of the FAAH Inhibitor JNJ-42165279. - SciSpace, accessed October 20, 2025, https://scispace.com/pdf/preclinical-characterization-of-the-faah-inhibitor-jnj-2slm3w55m8.pdf
23. Healthy Subjects (HS) Completed Phase 1 Trials for JNJ-42165279 (DB15173) - DrugBank, accessed October 20, 2025, https://go.drugbank.com/indications/DBCOND0132512/clinical_trials/DB15173?phase=1&status=completed
24. Fatty Acid Amide Hydrolase Inhibition by JNJ-42165279: A Multiple-Ascending Dose and a Positron Emission Tomography Study in Healthy Volunteers - PubMed, accessed October 20, 2025, https://pubmed.ncbi.nlm.nih.gov/29575526/
25. The effects of inhibition of fatty acid amide hydrolase (FAAH) by JNJ-42165279 in social anxiety disorder: a double-blind, randomized, placebo-controlled proof-of-concept study - PubMed Central, accessed October 20, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8115178/
26. NCT02432703 - Clinical Trials, accessed October 20, 2025, https://cdn.clinicaltrials.gov/large-docs/03/NCT02432703/SAP_001.pdf
27. The effects of inhibition of fatty acid amide hydrolase (FAAH) by JNJ-42165279 in social anxiety disorder: a double-blind, randomized, placebo-controlled proof-of-concept study, accessed October 20, 2025, https://scholars.okstate.edu/en/publications/the-effects-of-inhibition-of-fatty-acid-amide-hydrolase-faah-by-j
28. The effects of inhibition of fatty acid amide hydrolase (FAAH) by JNJ-42165279 in social anxiety disorder: a double-blind, randomized, placebo-controlled proof-of-concept study - eScholarship.org, accessed October 20, 2025, https://escholarship.org/uc/item/9366n0qk
29. Efficacy and safety of JNJ-42165279, a fatty acid amide hydrolase ..., accessed October 20, 2025, https://pubmed.ncbi.nlm.nih.gov/39414987/
30. NCT02498392 | An Efficacy, Safety and Tolerability Study of JNJ-42165279 in Participants With Major Depressive Disorder With Anxious Distress | ClinicalTrials.gov, accessed October 20, 2025, https://clinicaltrials.gov/study/NCT02498392
31. Efficacy & Safety of JNJ-42165279 in Subjects with MDD & Anxiety, accessed October 20, 2025, https://www.hra.nhs.uk/planning-and-improving-research/application-summaries/research-summaries/efficacy-safety-of-jnj-42165279-in-subjects-with-mdd-anxiety/
32. An Efficacy, Safety and Tolerability Study of JNJ-42165279 in Participants With Major Depressive Disorder With Anxious Distress - ClinicalTrials.Veeva, accessed October 20, 2025, https://ctv.veeva.com/study/an-efficacy-safety-and-tolerability-study-of-jnj-42165279-in-participants-with-major-depressive-dis
33. Elevated Brain Fatty Acid Amide Hydrolase Induces Depressive-Like Phenotypes in Rodent Models: A Review - MDPI, accessed October 20, 2025, https://www.mdpi.com/1422-0067/22/3/1047
34. jnj-42165279 / j&j - larvol delta, accessed October 20, 2025, https://delta.larvol.com/Products/?ProductId=90893003-7c43-419a-a553-b02f5fee3f14
35. Fatty-acid amide hydrolase 1 - Wikipedia, accessed October 20, 2025, https://en.wikipedia.org/wiki/Fatty-acid_amide_hydrolase_1
36. EVALUATION OF THE POTENCY AND SELECTIVITY OF THE NOVEL FAAH INHIBITOR BIA 10‐2474 IN COMPARISON WITH PF‐04457845 AND JNJ‐42165279 | Request PDF - ResearchGate, accessed October 20, 2025, https://www.researchgate.net/publication/352605811_EVALUATION_OF_THE_POTENCY_AND_SELECTIVITY_OF_THE_NOVEL_FAAH_INHIBITOR_BIA_10-2474_IN_COMPARISON_WITH_PF-04457845_AND_JNJ-42165279
37. J&J halts a depression program in the shadow of a fatal French trial | Fierce Biotech, accessed October 20, 2025, https://www.fiercebiotech.com/r-d/j-j-halts-a-depression-program-shadow-of-a-fatal-french-trial