Comprehensive Report on Bavisant (DB12299): An Investigational Histamine H3 Receptor Antagonist

I. Executive Summary

Bavisant (DrugBank ID: DB12299), also known by its research codes JNJ-31001074 and BEN-2001, is an investigational small molecule drug. Its primary mechanism of action is as a potent and selective antagonist or inverse agonist of the histamine H3 (H3R) receptor, a target predominantly expressed in the central nervous system (CNS).[1] By modulating H3R activity, Bavisant was hypothesized to increase the release of several key neurotransmitters, including histamine, acetylcholine, norepinephrine, and dopamine, thereby promoting wakefulness and enhancing cognitive functions.[2]

Initially developed by Johnson & Johnson (Janssen), Bavisant showed promise in preclinical models for disorders related to cognition and wakefulness.[6] This led to a broad clinical development program investigating its utility in Attention Deficit Hyperactivity Disorder (ADHD) in both adult and pediatric populations, narcolepsy, and alcoholism, alongside extensive Phase 1 pharmacokinetic and drug interaction studies.[8] However, a key Phase 2 study (NCT00880217) in adults with ADHD failed to demonstrate significant clinical efficacy compared to placebo, even though active comparators (atomoxetine and OROS methylphenidate) showed clear benefits.[11] This lack of efficacy led to the discontinuation of Bavisant's development for ADHD and subsequently for narcolepsy by Johnson & Johnson.[13]

Following these discontinuations, Bavisant (re-designated BEN-2001) was investigated by BenevolentAI for the treatment of Excessive Daytime Sleepiness (EDS) in patients with Parkinson's Disease (PD).[2] A Phase 2b dose-finding study (CASPAR, NCT03194217) was completed, and while trial registry information indicates "results posted" [15], external research commentary suggests these results were negative.[16]

Currently, Bavisant remains an investigational compound. Its development for ADHD and narcolepsy has been formally discontinued. The future of its development for EDS in Parkinson's Disease by BenevolentAI is contingent on the full analysis and interpretation of the CASPAR study data, with recent pipeline updates from BenevolentAI not prominently featuring Bavisant.[17] The journey of Bavisant underscores the significant challenges in translating preclinical promise for CNS-active compounds, particularly H3R modulators, into clinically meaningful therapeutic benefits.

II. Introduction to Bavisant

A. Overview, DrugBank ID (DB12299), and Synonyms

Bavisant is an investigational small molecule pharmaceutical agent identified by the DrugBank accession number DB12299.[8] It has been primarily recognized under the research code JNJ-31001074 during its initial development phase by Johnson & Johnson (specifically, Janssen Pharmaceutical Research & Development, L.L.C.).[6] More recently, in its development by BenevolentAI, it has been referred to as BEN-2001.[2] The compound has been explored for a variety of CNS indications, leveraging its unique mechanism of action.

The development history of Bavisant reflects a common trajectory for many pharmaceutical candidates, involving initial discovery and broad investigation by a major pharmaceutical company, followed by potential repurposing or further development by other entities. Johnson & Johnson conducted extensive Phase 1 and Phase 2 trials across several indications, including ADHD, narcolepsy, alcoholism, and various pharmacokinetic and drug interaction studies.[8] After Johnson & Johnson discontinued development for ADHD and narcolepsy [13], BenevolentAI took interest in the compound, focusing on its potential for treating Excessive Daytime Sleepiness (EDS) in Parkinson's Disease.[2]

B. Chemical Properties

Bavisant is classified as a small molecule drug.[8] The primary Chemical Abstracts Service (CAS) number for the free base form of Bavisant is 929622-08-2.[6] A dihydrochloride salt form is also documented with CAS number 929622-09-3 [3], and a dihydrochloride monohydrate form also exists.[14]

The International Union of Pure and Applied Chemistry (IUPAC) name for Bavisant is (4-cyclopropylpiperazin-1-yl)-[4-(morpholin-4-ylmethyl)phenyl]methanone.[8] Its molecular formula as a free base is C19​H27​N3​O2​, corresponding to a molecular weight of approximately 329.44 g/mol.[6] The dihydrochloride monohydrate form has a molecular formula of C19​H27​N3​O2​⋅2HCl⋅H2​O and a molecular weight of 420.374 g/mol.[14]

Physically, Bavisant is a solid, typically appearing as a light yellow to brown powder.[6] In terms of solubility, it is readily soluble in dimethyl sulfoxide (DMSO), with concentrations of 100 mg/mL achievable (often requiring sonication).[6] Its water solubility is reported as 2.46 mg/mL based on ALOGPS prediction.[18] Key physicochemical parameters relevant to its drug-like properties include a LogP value of 1.76 (ALOGPS) or 1.31 (Chemaxon), and a strongest basic pKa of 7.11 (Chemaxon).[18] These properties are generally consistent with those of an orally administered drug candidate intended for CNS penetration, which is critical given its target, the histamine H3 receptor, is predominantly located in the brain. The existence of various salt forms is a common strategy in pharmaceutical development to optimize properties such as solubility, stability, and bioavailability.

Table 1: Key Identifiers and Chemical Properties of Bavisant

Property	Value	Source(s)
DrugBank ID	DB12299	User Query, 8
Synonyms	JNJ-31001074, BEN-2001	2
CAS Number (Free Base)	929622-08-2	User Query, 6
CAS Number (Dihydrochloride)	929622-09-3	3
Molecular Formula (Free Base)	C19​H27​N3​O2​	6
Molecular Weight (Free Base)	329.44 g/mol	6
IUPAC Name	(4-cyclopropylpiperazin-1-yl)-[4-(morpholin-4-ylmethyl)phenyl]methanone	8
Appearance	Solid; Light yellow to brown	6
Solubility (Water, ALOGPS)	2.46 mg/mL	18
Solubility (DMSO)	100 mg/mL (requires sonication)	6
LogP (ALOGPS / Chemaxon)	1.76 / 1.31	18
pKa (Strongest Basic, Chemaxon)	7.11	18

This table summarizes the fundamental chemical and identifying information for Bavisant, providing a concise reference for its basic characteristics.

III. Pharmacology

A. Mechanism of Action

1. Histamine H3 Receptor Antagonism/Inverse Agonism:

Bavisant is characterized as a potent and highly selective antagonist or inverse agonist of the histamine H3 (H3R) receptor.1 The histamine H3 receptors are G protein-coupled receptors predominantly located in the central nervous system, where they function as presynaptic autoreceptors on histaminergic neurons and as heteroreceptors on non-histaminergic neurons.2 As autoreceptors, H3Rs regulate the synthesis and release of histamine itself.4 A key characteristic of H3 receptors is their high level of constitutive (agonist-independent) activity.4

Bavisant, by acting as an antagonist, blocks the binding of endogenous histamine to the H3R. More specifically, its action as an inverse agonist means it reduces this basal, constitutive activity of the H3 receptor.[2] The consequence of this antagonism/inverse agonism is an increased synthesis and release of histamine in the brain, as the negative feedback loop normally mediated by H3 autoreceptors is disinhibited.[2] The differentiation between simple antagonism and inverse agonism is pharmacologically significant; an inverse agonist actively reduces receptor signaling below its basal level, which is particularly relevant for receptors like H3R that exhibit substantial spontaneous activity. This suggests Bavisant may more actively suppress H3R signaling pathways rather than merely preventing histamine from binding.

2. Modulation of Neurotransmitter Systems:

Beyond its effects on histamine, Bavisant's mechanism involves the modulation of other critical neurotransmitter systems. H3Rs are also present as heteroreceptors on various non-histaminergic neurons.2 By blocking these H3 heteroreceptors, Bavisant is thought to disinhibit the release of other neurotransmitters crucial for wakefulness, attention, learning, memory, and overall cognitive function.2 The neurotransmitters reported to be upregulated by H3R antagonism include acetylcholine, norepinephrine (noradrenaline), dopamine, serotonin, and glutamate, while potentially decreasing the release of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).2 This broad-spectrum modulation of central neurotransmission underpins the rationale for investigating Bavisant across a range of CNS disorders characterized by deficits in arousal, attention, and cognitive processing. However, such widespread effects also carry the potential for a complex side effect profile if the drug's actions are not precisely targeted or if homeostatic balances are unduly perturbed.

3. Implications for Wakefulness and Cognition:

The primary intended pharmacological outcome of H3R antagonism or inverse agonism with Bavisant is the promotion of wakefulness and the enhancement of various cognitive functions, including attention, learning, memory, and a reduction in impulsivity.2 This profile formed the scientific basis for its clinical investigation in conditions such as Attention Deficit Hyperactivity Disorder (ADHD), narcolepsy, and Excessive Daytime Sleepiness (EDS) associated with Parkinson's Disease.2

B. Pharmacodynamics

1. Preclinical Findings:

Preclinical studies provided initial support for Bavisant's proposed mechanism and therapeutic potential. In vivo studies in rats demonstrated that Bavisant administration leads to an increase in acetylcholine levels in the frontal cortex.6 This elevation of acetylcholine, a neurotransmitter critically involved in learning and memory, is consistent with the expected downstream effects of H3R antagonism and supports its potential as a cognitive enhancer. Furthermore, preclinical efficacy was reported in various experimental models targeting wakefulness, attention, cognitive performance, and even alcohol consumption, although specific details for Bavisant in all these models are not uniformly available in the provided materials.7 The breadth of these preclinical investigations justified the subsequent exploration of Bavisant in diverse human clinical conditions.

2. Human Pharmacodynamic Data:

Direct human pharmacodynamic data, such as receptor occupancy studies using Positron Emission Tomography (PET) or direct measurement of neurotransmitter changes in cerebrospinal fluid (CSF) following Bavisant administration, are not extensively detailed in the available research snippets. A PET study (NCT00708701) was conducted to assess H3 receptor occupancy by Bavisant in healthy subjects, which would be highly informative for confirming target engagement in humans.9 However, the results of this PET study have not been published within the provided resources.

Consequently, the pharmacodynamic effects of Bavisant in humans are largely inferred from the clinical outcomes observed in therapeutic trials, such as changes in ADHD rating scales (e.g., ADHD-RS-IV) or scales measuring sleepiness.[11] The CASPAR study (NCT03194217), which investigated Bavisant for EDS in Parkinson's Disease, would represent the most recent source of human pharmacodynamic information via its clinical endpoints, but detailed results beyond "posted" or "negative" are sparse in the snippets.[15] The absence of detailed human pharmacodynamic biomarker data represents a gap in fully elucidating the direct effects of Bavisant on its target and downstream neurotransmitter systems in humans, beyond the assessment of clinical symptoms.

IV. Pharmacokinetics (ADME)

A. Absorption, Distribution, Metabolism, and Excretion in Humans

A comprehensive understanding of Bavisant's absorption, distribution, metabolism, and excretion (ADME) profile in humans is crucial for its development and safe use. However, detailed quantitative human ADME data are largely unavailable in the provided research materials, with DrugBank noting "Not Available" for most specific parameters.[1]

1. Oral Bioavailability and Brain Penetration:

Bavisant is consistently described as an orally active and brain-penetrating compound in preclinical contexts.6 These characteristics are essential for a drug targeting CNS H3 receptors and intended for oral administration. Specific human oral bioavailability figures (e.g., %F) are not provided in the snippets. While pharmacokinetic data from rat studies exist for structurally related compounds, showing variable bioavailability 25, this does not directly translate to humans. The successful progression to Phase 1 and 2 human trials implies adequate oral absorption and likely CNS distribution were achieved, but quantitative details are missing.

2. Metabolism:

The specific metabolic pathways of Bavisant in humans, including the roles of cytochrome P450 (CYP) enzymes or other conjugation pathways, are not detailed in the provided information.1 General statements indicate that ADME properties guided the optimization of H3 antagonists 7, but Bavisant's specific routes of biotransformation remain undefined from these sources.

The undertaking of drug-drug interaction (DDI) studies, such as NCT00915746 with ketoconazole (a strong CYP3A4 inhibitor) and NCT01210593 with oral contraceptives (primarily metabolized by CYP3A4), suggests that CYP3A4-mediated metabolism or interaction was a consideration during its development.[6] However, without the results of these studies or a dedicated human radiolabeled ADME study [6], the precise contribution of CYP3A4 or other enzymes to Bavisant's metabolism is speculative.

3. Half-life, Clearance, and Volume of Distribution:

Specific human pharmacokinetic parameters such as elimination half-life (t1/2​), clearance (CL), and volume of distribution (Vd​) are not detailed in the provided snippets.1 Numerous Phase 1 studies were conducted in healthy volunteers, including specific populations like Japanese subjects (NCT00708688) and the elderly (NCT00766238), which would have aimed to characterize these parameters.7 However, the results from these studies are not available in the provided material. Preclinical data in rats for related compounds show a range of half-lives and clearances, but these are not directly applicable to Bavisant in humans.25

4. Excretion:

The routes and extent of Bavisant and its metabolites' excretion in humans (e.g., renal, fecal) are not specified in the available information.1

B. Pharmacokinetics in Special Populations

Johnson & Johnson conducted a standard battery of Phase 1 studies to evaluate Bavisant's pharmacokinetics in special populations. While these studies are noted as completed, their detailed findings are not present in the provided snippets.

• Pediatric Patients (ADHD trials): Single-dose pharmacokinetic, safety, and tolerability studies were completed in children aged 6-11 years (NCT00890240) and adolescents aged 12-17 years (NCT00890292) with ADHD.[6]
• Elderly Subjects: A Phase 1 study assessing pharmacokinetics and safety in healthy elderly subjects (NCT00766238) was completed.[9]
• Patients with Hepatic Impairment: A Phase 1 study was conducted in subjects with hepatic impairment (NCT01180050).[9]
• Patients with Renal Impairment: A Phase 1 study was conducted in subjects with renal impairment (NCT01180063).[9] The completion of these studies indicates a systematic approach to characterizing Bavisant's pharmacokinetics. However, the absence of published results limits the ability to define specific dosage adjustments or precautions for these populations based on the provided information.

C. Drug-Drug Interaction Studies

Several DDI studies were completed for Bavisant, primarily to assess its potential as a victim or perpetrator of metabolic interactions.

• Interaction with Ketoconazole (NCT00915746): This open-label study assessed the effect of ketoconazole, a strong inhibitor of CYP3A4, on the pharmacokinetics of Bavisant in healthy subjects.[6] The results would clarify the clinical relevance of CYP3A4 in Bavisant's clearance.
• Interaction with Oral Contraceptives (NCT01210593): This study evaluated the effect of Bavisant on the pharmacokinetics of an oral contraceptive (a CYP3A4 substrate) in healthy female subjects.[6] This study would indicate whether Bavisant induces CYP3A4.
• Food Effect Study (NCT00659123): The effect of food on Bavisant pharmacokinetics was assessed in healthy subjects.[9] The results of these critical DDI studies are not available in the provided snippets. One source mentions that Bavisant was "previously withdrawn from clinical trials due to drug-drug interactions".[22] This statement, if directly applicable to Bavisant and not a general comment on H3R inverse agonists, would be a significant finding. However, the primary documented reason for the discontinuation of Bavisant for ADHD was lack of efficacy.[11] Without the full DDI study reports, a definitive conclusion on Bavisant's DDI profile cannot be drawn from the available materials.

V. Clinical Development and Efficacy

A. Overview of Investigational Indications

Bavisant has been investigated across a range of conditions, primarily targeting CNS disorders where modulation of histamine and other neurotransmitters via H3R antagonism was deemed potentially beneficial. The main indications explored include Attention Deficit Hyperactivity Disorder (ADHD) and Attention Deficit Disorders With Hyperactivity, Alcoholism, Narcolepsy, and Excessive Daytime Sleepiness (EDS) in Parkinson's Disease.[2] Additionally, numerous Phase 1 studies focused on pharmacokinetics and drug interactions.[6]

B. Clinical Trials for Attention Deficit Hyperactivity Disorder (ADHD)

1. Adult ADHD (NCT00880217 - "A Safety and Efficacy Study of JNJ-31001074 in Adults With ADHD"):

This pivotal Phase 2 trial, sponsored by Johnson & Johnson Pharmaceutical Research & Development, L.L.C., was central to Bavisant's development for ADHD.6 The study, completed in January 2010, was a randomized, double-blind, placebo- and active-controlled, parallel-group, multicenter investigation conducted at 37 US study centers.9 It enrolled 430 adult men and women (aged 18-55 years) with ADHD, of whom 424 received at least one dose of study medication.9 Participants were randomized to receive Bavisant at doses of 1 mg/day, 3 mg/day, or 10 mg/day, placebo, atomoxetine hydrochloride (80 mg/day), or osmotic-release oral system (OROS) methylphenidate hydrochloride (54 mg/day) for a 42-day double-blind treatment phase.9

The primary efficacy endpoint was the mean change from baseline in the total score on the ADHD Rating Scale, Version IV (ADHD-RS-IV) at Day 42.[9] The results, published by Weisler et al. in CNS Drugs (2012), are summarized in Table 3.[9]

Table 3: Efficacy Outcomes in Adult ADHD Trial (NCT00880217 - Weisler et al., 2012)

Treatment Arm	N (Randomized)	Baseline Mean ADHD-RS-IV Total Score (approx.)	Mean Change from Baseline in ADHD-RS-IV at Day 42	p-value vs. Placebo
Placebo	73	~36-38	-8.8	N/A
Bavisant 1 mg/day	68	~36-38	-9.3	Not statistically tested (due to step-down procedure)
Bavisant 3 mg/day	68	~36-38	-11.2	Not statistically tested (due to step-down procedure)
Bavisant 10 mg/day	67	~36-38	-12.2	0.161
Atomoxetine 80 mg/day	74	~36-38	-15.3	<0.005
OROS Methylphenidate 54 mg/day	68	~36-38	-15.7	<0.005

Data adapted from Weisler et al., 2012.[9] Baseline scores are approximate based on typical trial populations.

None of the Bavisant doses demonstrated a statistically significant improvement over placebo on the primary endpoint. The 10 mg/day dose showed a numerical trend towards improvement, but this did not reach statistical significance (p=0.161). Due to a pre-specified step-down closed testing procedure, the lower doses (1 mg and 3 mg) were not formally tested against placebo for superiority as the highest dose failed to meet significance.[9] In contrast, both active comparators, atomoxetine and OROS methylphenidate, showed statistically significant and clinically meaningful improvements over placebo (p<0.005 for both).[9] Secondary efficacy assessments mirrored this pattern, showing a non-significant trend towards improvement with Bavisant.[9] The study concluded that Bavisant did not display significant clinical effectiveness in the treatment of adults with ADHD.[9] This failure to differentiate from placebo, particularly in a trial where standard ADHD medications demonstrated their expected efficacy, was a critical negative finding for Bavisant in this indication.

2. Pediatric ADHD:

Johnson & Johnson also pursued development in pediatric ADHD populations.

• NCT00890292: A completed Phase 1 study evaluated the pharmacokinetics, safety, and tolerability of a single dose of Bavisant in adolescents (12-17 years) with ADHD.[6]
• NCT00890240: A similar completed Phase 1 study was conducted in children (6-11 years) with ADHD.[6] The results of these pediatric PK studies are not detailed in the provided snippets. Several other Phase 1 and Phase 2 trials in pediatric and adolescent ADHD, including studies in Japan (NCT01233441, NCT01233454) and open-label extension studies (NCT01601222, NCT01601248), were also part of the development program but were ultimately discontinued by Johnson & Johnson by July 2022.[9] This broad discontinuation suggests that the lack of efficacy seen in adults, or other unstated findings from the pediatric program, led to the cessation of ADHD development. An earlier Phase 2 study, NCT00566449, titled "A Safety and Effectiveness Study of JNJ-31001074 in Adults With Attention-Deficit/Hyperactivity Disorder," was also conducted by Johnson & Johnson, but its specific outcomes beyond being a Phase 2 trial are not detailed.[9]

C. Clinical Trial for Alcoholism (NCT01362699)

A Phase 2 trial, NCT01362699, titled "A Single Center, Randomized, Double Blind, Placebo Controlled, Parallel Group Study of the Efficacy of JNJ 31001074 on Cue Induced Craving for Alcohol in Adult Subjects With Alcohol Dependence," was planned by Janssen Research & Development, LLC, in collaboration with The Scripps Research Institute.[6] The rationale was based on preclinical studies suggesting that H3R antagonists might decrease alcohol drinking behaviors.[35] However, this trial was withdrawn prior to enrollment.[9] The decision to withdraw may have been influenced by emerging data from other Bavisant trials or strategic portfolio considerations by the sponsor.

D. Clinical Trial for Excessive Daytime Sleepiness in Parkinson's Disease (NCT03194217 - CASPAR Study)

Following the discontinuation of Bavisant (JNJ-31001074) for ADHD and narcolepsy by Johnson & Johnson, BenevolentAI acquired or licensed the compound, renaming it BEN-2001, and initiated the CASPAR study (NCT03194217).[2] This was a Phase 2b, multicenter, multinational, randomized, double-blind, parallel-group, placebo-controlled dose-finding study.[15] The trial aimed to evaluate the efficacy and safety of three fixed doses of Bavisant (0.5 mg, 1 mg, and 3 mg per day) compared to placebo for the treatment of EDS in subjects with Parkinson's Disease.[15] The study enrolled 244 patients aged 50 to 80 years.[15] The rationale for this indication was based on Bavisant's known wakefulness-promoting properties, with insomnia being a noted side effect, particularly at higher doses.[14]

The CASPAR study is listed as completed, and results are indicated as "posted" on clinical trial registries like Veeva CTV.[15] However, specific efficacy and safety data from these posted results are not detailed in the provided snippets. Significantly, a research publication discussing treatments for EDS in PD mentions "negative results" for Bavisant (NCT03194217) in this indication.[16] This discrepancy between "results posted" (a neutral statement of availability) and an interpretation of "negative results" creates uncertainty about the outcome of this repurposing effort.

E. Clinical Trials for Narcolepsy

Johnson & Johnson also pursued Bavisant for narcolepsy, an indication with a strong mechanistic rationale for an H3R antagonist. Two Phase 2 trials, NCT01073501 and NCT01072773, were conducted in several countries including the UK, Spain, USA, Germany, and the Czech Republic.[9] However, similar to the ADHD program, development for narcolepsy was discontinued by Johnson & Johnson, with the latest update indicating this discontinuation as of July 2022.[13] The reasons for discontinuation are not explicitly stated but likely relate to insufficient efficacy or unfavorable risk-benefit assessments.

F. Other Pharmacokinetic and Basic Science Studies

A comprehensive suite of Phase 1 studies was conducted by Johnson & Johnson. These included trials in healthy volunteers to assess single and multiple dose safety and pharmacokinetics (e.g., NCT00499082), food effect (NCT00659123), pharmacokinetics in healthy Japanese (NCT00708688) and elderly subjects (NCT00766238), studies in patients with hepatic (NCT01180050) and renal impairment (NCT01180063), and drug-drug interaction studies (NCT00915746 with ketoconazole; NCT01210593 with an oral contraceptive).[6] A PET study (NCT00708701) was also conducted in healthy subjects to assess H3 receptor occupancy.[7] The detailed results of these foundational Phase 1 studies are generally not available in the provided snippets.

Table 2: Summary of Key Clinical Trials for Bavisant (JNJ-31001074/BEN-2001)

NCT Number	Trial Title/Indication	Phase	Status	Sponsor(s)	Participants (Approx.)	Results/Key Outcome Summary (from snippets)
NCT00880217	Adult ADHD	2	Completed	Johnson & Johnson	430	Did not meet primary efficacy endpoint; not statistically superior to placebo. Active controls (atomoxetine, methylphenidate) were superior. 11
NCT01362699	Alcohol Dependence (Cue-Induced Craving)	2	Withdrawn	Janssen R&D, Scripps Research Institute	0 (Withdrawn)	Trial withdrawn prior to enrollment. 6
NCT03194217	Excessive Daytime Sleepiness in Parkinson's Disease (CASPAR)	2b	Completed	BenevolentAI Bio Ltd.	244	"Results posted" on registries.15 However, 16 indicates "negative results."
NCT01073501	Narcolepsy	2	Discontinued	Johnson & Johnson	N/A	Development discontinued by J&J (July 2022). 13
NCT01072773	Narcolepsy	2	Discontinued	Johnson & Johnson	N/A	Development discontinued by J&J (July 2022). 13
NCT00915746	DDI: Bavisant + Ketoconazole (Healthy Volunteers)	1	Completed	Johnson & Johnson	N/A	Results not detailed in snippets. 6
NCT01210593	DDI: Bavisant + Oral Contraceptive (Healthy Volunteers)	1	Completed	Johnson & Johnson	N/A	Results not detailed in snippets. 8
NCT00890292	Pediatric ADHD (Adolescents 12-17 yrs) - PK/Safety	1	Completed	Johnson & Johnson	N/A	Results not detailed in snippets. 10
NCT00890240	Pediatric ADHD (Children 6-11 yrs) - PK/Safety	1	Completed	Johnson & Johnson	N/A	Results not detailed in snippets. 10

N/A: Not available in provided snippets.

Table 5 (Summary of CASPAR Study - NCT03194217 for EDS in Parkinson's Disease)

(Renamed from original outline for clarity and focus)

Feature	Details	Source(s)
Sponsor	BenevolentAI Bio Ltd.	9
Phase	Phase 2b	9
Status	Completed	9
Participants	244 patients with Parkinson's Disease and Excessive Daytime Sleepiness (EDS), aged 50-80 years	15
Design	Multicenter, multinational, randomized, double-blind, parallel-group, placebo-controlled, dose-finding	15
Bavisant Doses	0.5 mg/day, 1 mg/day, 3 mg/day	15
Primary Outcome	Efficacy (e.g., Epworth Sleepiness Scale) and safety in treating EDS in PD	15 (Specific primary endpoint measure details like ESS are from participant info sheet context 40)
Stated Result Summary	Registries indicate "Results posted." However, 16 (a research publication) states "negative results."	15

VI. Safety and Tolerability

A. Overview of Safety Profile from Clinical Trials

The safety and tolerability of Bavisant have been evaluated across its clinical development program, primarily through the assessment of treatment-emergent adverse events (TEAEs), laboratory parameters, and electrocardiogram (ECG) readings.[9] Data from the adult ADHD trial (NCT00880217) provide the most detailed insights available from the provided snippets. Generally, lower doses of Bavisant (1 mg and 3 mg daily) were better tolerated than the 10 mg daily dose in this population.[9]

B. Common and Serious Adverse Events (Primarily from Adult ADHD Trial NCT00880217)

The abstract by Weisler et al. (2012) for the NCT00880217 trial provides overall incidences of TEAEs and discontinuations due to TEAEs but does not detail specific common or serious adverse events for Bavisant.[9] Insomnia has been noted as a potential side effect of H3 antagonists generally, and for Bavisant in the context of its investigation for EDS in Parkinson's Disease, where dose-dependent insomnia was considered a factor.[14] A comprehensive list of TEAEs would require access to the full study publication or more detailed trial results. The available data on TEAE incidence are presented in Table 4.

C. Dose-Dependent Adverse Effects

A clear dose-dependent trend in tolerability was observed in the adult ADHD trial (NCT00880217). The incidence of total TEAEs and the rate of discontinuations due to TEAEs were notably higher with the 10 mg/day dose of Bavisant compared to the 1 mg/day and 3 mg/day doses, and also higher than placebo.[9] This suggests that while higher doses might offer a slight numerical trend towards better efficacy, they come at the cost of reduced tolerability, narrowing the potential therapeutic window. As mentioned, insomnia is a characteristic adverse effect linked to H3R antagonists due to their wakefulness-promoting mechanism, and this was reportedly dose-dependent for Bavisant in the context of its PD EDS investigation.[14]

D. Reasons for Discontinuation in Clinical Trials

Discontinuation rates due to TEAEs in the NCT00880217 adult ADHD study were as follows:

• Bavisant 1 mg/day: 4.4%
• Bavisant 3 mg/day: 7.4%
• Bavisant 10 mg/day: 19.2%
• Placebo: 2.7%
• Atomoxetine 80 mg/day: 10.8%
• OROS methylphenidate 54 mg/day: 8.8%.[9] The markedly higher discontinuation rate for the 10 mg Bavisant dose (19.2%) compared to placebo (2.7%) and even the active controls (10.8% for atomoxetine, 8.8% for methylphenidate) underscores the tolerability challenges at this dose level. This dose-limiting toxicity, coupled with insufficient efficacy at lower, better-tolerated doses, likely contributed significantly to the decision to halt development for ADHD.

Table 4: Key Safety and Tolerability Findings in Adult ADHD Trial (NCT00880217 - Weisler et al., 2012)

Treatment Arm	N (Received Study Med)	Incidence of Total TEAEs (%)	Discontinuations due to TEAEs (%)
Placebo	~68-73 (estimated)	58.9	2.7
Bavisant 1 mg/day	68	61.8	4.4
Bavisant 3 mg/day	68	82.4	7.4
Bavisant 10 mg/day	67	89.0	19.2
Atomoxetine 80 mg/day	74	83.8	10.8
OROS Methylphenidate 54 mg/day	68	82.4	8.8

Data adapted from Weisler et al., 2012.[9] N for placebo estimated based on randomization ratios and total N.

VII. Regulatory and Development Status

A. Initial Development by Johnson & Johnson (Janssen)

Bavisant, then JNJ-31001074, was initially developed by Johnson & Johnson (Janssen Pharmaceutical Research & Development, L.L.C.).[6] The primary focus of their extensive clinical program was on CNS disorders, including ADHD and narcolepsy, based on the drug's H3R antagonist mechanism and its potential to enhance wakefulness and cognition.[2]

B. Discontinuation for ADHD and Narcolepsy

Despite a comprehensive development effort, Johnson & Johnson discontinued the development of Bavisant for ADHD. This decision was primarily driven by the lack of significant clinical effectiveness observed in the Phase 2 adult ADHD study (NCT00880217), where Bavisant failed to separate from placebo on the primary efficacy endpoint.[9] Subsequently, development for narcolepsy, which had reached Phase 2 (trials NCT01073501, NCT01072773), was also discontinued by Johnson & Johnson, with this information reported as of July 2022.[9] One source [22] mentions that Bavisant was "previously withdrawn from clinical trials due to drug-drug interactions." While the primary reported reason for ADHD discontinuation was lack of efficacy, it is possible that unpublicized DDI concerns or an overall unfavorable risk-benefit profile considering all factors contributed to the broader discontinuation decisions by Johnson & Johnson.

C. Subsequent Development by BenevolentAI (as BEN-2001)

Following its discontinuation by Johnson & Johnson, Bavisant was acquired or licensed by BenevolentAI and re-designated as BEN-2001.[2] BenevolentAI initiated a Phase 2b clinical trial (CASPAR study, NCT03194217) to investigate BEN-2001 for the treatment of Excessive Daytime Sleepiness (EDS) in patients with Parkinson's Disease.[9] The rationale for this repurposing effort was to leverage Bavisant's known wakefulness-promoting effects, and potentially its dose-dependent side effect of insomnia, to address the significant unmet need of EDS in this patient population.[14]

D. Current Overall Status and Future Outlook

The CASPAR study (NCT03194217) for EDS in Parkinson's Disease has been completed, and trial registries indicate that results have been posted.[15] However, a crucial piece of information from a research publication [16] suggests "negative results" for Bavisant in this trial. This discrepancy between the neutral "results posted" status and a specific interpretation of "negative results" casts significant doubt on the success of this indication.

The future development of Bavisant by BenevolentAI hinges on the full analysis and strategic interpretation of the CASPAR study data. Recent pipeline updates from BenevolentAI (e.g., a December 2024 press release focusing on BEN-8744 [17]) do not prominently feature BEN-2001/Bavisant, which may suggest it is not currently a lead asset or that its development is paused or terminated pending further review. A May 2025 pipeline snapshot for BenevolentAI shows a Phase 2 asset but does not explicitly name it as Bavisant.[46] The overall trajectory of Bavisant, from broad initial investigation to multiple discontinuations and a potentially unsuccessful repurposing attempt, highlights the substantial challenges inherent in CNS drug development, particularly for novel mechanisms like H3R modulation.

VIII. Conclusion and Expert Insights

A. Summary of Bavisant's Profile:

Bavisant (JNJ-31001074 / BEN-2001) is an orally active, brain-penetrant small molecule designed as a selective histamine H3 receptor antagonist/inverse agonist. Its mechanism aimed to enhance wakefulness and cognitive functions by increasing the release of histamine and other key neurotransmitters like acetylcholine, norepinephrine, and dopamine in the CNS. Despite a strong preclinical rationale and extensive early-phase clinical investigation by Johnson & Johnson for ADHD and narcolepsy, Bavisant failed to demonstrate significant clinical efficacy in these indications, leading to their discontinuation. A subsequent attempt by BenevolentAI to repurpose Bavisant for Excessive Daytime Sleepiness in Parkinson's Disease (CASPAR study, NCT03194217) has also reportedly yielded negative results, despite trial registries indicating "results posted."

The safety profile of Bavisant appears to be dose-dependent, with lower doses (1 mg, 3 mg) being generally well-tolerated in adult ADHD studies, while higher doses (10 mg) were associated with a significantly increased incidence of adverse events and treatment discontinuations, with insomnia being a characteristic effect. Detailed human pharmacokinetic (ADME) data, particularly regarding its metabolic pathways and specific parameters like half-life and clearance in humans, remain largely unpublished in the provided materials, representing a notable gap in its publicly available profile.

B. Assessment of Therapeutic Potential and Unmet Needs

The initial therapeutic rationale for targeting the H3 receptor for CNS disorders such as ADHD and narcolepsy was robust, given the receptor's role in regulating arousal and cognitive neurotransmitter systems. However, Bavisant's clinical development illustrates the profound difficulty in translating this preclinical promise into tangible clinical benefits for patients. The failure in ADHD, despite the trial including effective active comparators, strongly suggests a true lack of efficacy for Bavisant in that complex disorder.

Excessive Daytime Sleepiness in Parkinson's Disease represents a significant unmet medical need, and the attempt to repurpose Bavisant for this indication was mechanistically plausible. However, if the reported negative results of the CASPAR study are confirmed, it would further underscore the challenges in finding effective treatments for this symptom and for Bavisant itself.

C. Critical Analysis of Development Failures and Future Directions

The lack of efficacy of Bavisant in ADHD, despite its intended mechanism, could be attributed to several factors. These may include insufficient target engagement at doses that were well-tolerated, a more complex pathophysiology of ADHD than can be addressed by H3R modulation alone, or perhaps issues related to the specific pharmacological profile of Bavisant, such as its interaction with various H3R isoforms which are known to have different pharmacological properties and distributions.4 The field of H3R antagonism has seen multiple clinical development failures for various CNS indications 49, suggesting that either the human pharmacology of H3Rs is not yet fully understood, preclinical models lack sufficient predictive validity for human efficacy, or identifying the precise patient populations and optimal therapeutic window for this class of drugs is exceptionally challenging.

The future of Bavisant itself appears highly uncertain, particularly if the CASPAR study results are indeed confirmed as negative. The journey of Bavisant serves as a salient example of the high attrition rates in CNS drug development and the complexities of targeting neurotransmitter systems like the histaminergic pathway. While the H3 receptor remains a theoretically attractive target for disorders of wakefulness and cognition, Bavisant's story emphasizes the critical need for better translational models and a deeper understanding of human receptor pharmacology to guide future drug discovery efforts in this domain. Further research into specific H3R isoforms and their differential roles might offer new avenues, but for Bavisant, the path forward seems limited based on the currently available information.

Works cited

1. Bavisant: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed June 5, 2025, https://www.drugbank.ca/drugs/DB12299
2. Bavisant: Histamine H3 Receptor Inverse Agonist - Ontosight.ai, accessed June 5, 2025, https://ontosight.ai/glossary/term/bavisant-histamine-h3-receptor-inverse-agonist--67a1e05c6c3593987a5c5203
3. Bavisant HCl | CAS#929622-09-3 | H3 receptor antagonist | MedKoo, accessed June 5, 2025, https://www.medkoo.com/products/57110
4. Full article: Histamine H3 receptor antagonists/inverse agonists: a patent review (October 2017 – December 2023) documenting progress, accessed June 5, 2025, https://www.tandfonline.com/doi/full/10.1080/13543776.2024.2446227?af=R
5. Pitolisant and Other Histamine-3 Receptor Antagonists—An Update on Therapeutic Potentials and Clinical Prospects - MDPI, accessed June 5, 2025, https://www.mdpi.com/2305-6320/7/9/55
6. Bavisant (JNJ-31001074) | H3 Receptor Antagonist | MedChemExpress, accessed June 5, 2025, https://www.medchemexpress.com/bavisant.html
7. Novel Benzamide-Based Histamine H3 Receptor Antagonists: The Identification of Two Candidates for Clinical Development | Request PDF - ResearchGate, accessed June 5, 2025, https://www.researchgate.net/publication/275217485_Novel_Benzamide-Based_Histamine_H3_Receptor_Antagonists_The_Identification_of_Two_Candidates_for_Clinical_Development
8. Bavisant | C19H27N3O2 | CID 16061509 - PubChem, accessed June 5, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Bavisant
9. Bavisant - Drug Targets, Indications, Patents - Patsnap Synapse, accessed June 5, 2025, https://synapse.patsnap.com/drug/dad20b3b1a854c7abd3ca9bc9cc827e5
10. Bavisant Completed Phase 1 Trials for Attention Deficit Hyperactivity Disorder (ADHD) Basic Science - DrugBank, accessed June 5, 2025, https://go.drugbank.com/drugs/DB12299/clinical_trials?conditions=DBCOND0041782&phase=1&purpose=basic_science&status=completed
11. Randomized clinical study of a histamine H3 receptor antagonist for the treatment of adults with attention-deficit hyperactivity disorder - PubMed, accessed June 5, 2025, https://pubmed.ncbi.nlm.nih.gov/22519922/
12. Randomized Clinical Study of a Histamine H3 Receptor Antagonist for the Treatment of Adults with Attention-Deficit Hyperactivity Disorder | Request PDF - ResearchGate, accessed June 5, 2025, https://www.researchgate.net/publication/224808598_Randomized_Clinical_Study_of_a_Histamine_H3_Receptor_Antagonist_for_the_Treatment_of_Adults_with_Attention-Deficit_Hyperactivity_Disorder
13. Bavisant - BenevolentAI/Johnson & Johnson - AdisInsight - Springer, accessed June 5, 2025, https://adisinsight.springer.com/drugs/800031762
14. BAVISANT DIHYDROCHLORIDE - Inxight Drugs - ncats, accessed June 5, 2025, https://drugs.ncats.io/drug/C1H7H5X3RE
15. BEN-2001 in Parkinson Disease Patients With Excessive Daytime Sleepiness (CASPAR), accessed June 5, 2025, https://ctv.veeva.com/study/ben-2001-in-parkinson-disease-patients-with-excessive-daytime-sleepiness
16. Randomized trial of modafinil for treating subjective daytime sleepiness in patients with Parkinson's disease | Request PDF - ResearchGate, accessed June 5, 2025, https://www.researchgate.net/publication/10868902_Randomized_trial_of_modafinil_for_treating_subjective_daytime_sleepiness_in_patients_with_Parkinson's_disease
17. BenevolentAI announces positive topline safety and pharmacokinetic data from the Phase Ia clinical study of BEN-8744 in healthy volunteers, accessed June 5, 2025, https://www.benevolent.com/news-and-media/press-releases-and-in-media/benevolentai-announces-positive-topline-safety-and-pharmacokinetic-data-phase-ia-clinical-study-ben-8744-healthy-volunteers/
18. Bavisant: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed June 5, 2025, https://go.drugbank.com/drugs/DB12299
19. D0M8OC - Drug Information | Therapeutic Target Database, accessed June 5, 2025, https://idrblab.net/ttd/data/drug/details/d0m8oc
20. Bavisant | CAS NO.:929622-08-2 | GlpBio, accessed June 5, 2025, https://www.glpbio.com/gc35471.html
21. Bavisant dihydrochloride (JNJ-31001074 dihydrochloride) | H3 Receptor Antagonist, accessed June 5, 2025, https://www.medchemexpress.com/bavisant-dihydrochloride.html
22. Time course of receptor occupancy of 18 b and bavisant (10 mg kg⁻¹... - ResearchGate, accessed June 5, 2025, https://www.researchgate.net/figure/Time-course-of-receptor-occupancy-of-18b-and-bavisant-10mgkg-po-in-male_fig3_332272672
23. JNJ-31001074 | Histamine Receptor | CAS 929622-08-2(free base) - InvivoChem, accessed June 5, 2025, http://www.invivochem.com/jnj-31001074.html
24. Bavisant Completed Phase 2 Trials for Parkinson's Disease (PD) / Excessive Daytime Sleepiness Treatment - DrugBank, accessed June 5, 2025, https://go.drugbank.com/drugs/DB12299/clinical_trials?conditions=DBCOND0033391%2CDBCOND0053495&phase=2&purpose=treatment&status=completed
25. Novel Benzamide-Based Histamine H3 Receptor Antagonists: The Identification of Two Candidates for Clinical Development, accessed June 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4394347/
26. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583) - PubMed, accessed June 5, 2025, https://pubmed.ncbi.nlm.nih.gov/15020604/
27. Drug Drug Interaction (DDI) (DBCOND0106607) | DrugBank Online, accessed June 5, 2025, https://go.drugbank.com/conditions/DBCOND0106607
28. Pharmacokinetics (DBCOND0031919) | DrugBank Online, accessed June 5, 2025, https://go.drugbank.com/conditions/DBCOND0031919
29. Bavisant | JNJ31001074 | H3 antagonist | Axon 4233, accessed June 5, 2025, https://www.axonmedchem.com/product/4233
30. (PDF) Serotonergic Drugs for the Treatment of Attention-Deficit/Hyperactivity Disorder: A Review of Past Development, Pitfalls and Failures, and a Look to the Future - ResearchGate, accessed June 5, 2025, https://www.researchgate.net/publication/383980311_Serotonergic_Drugs_for_the_Treatment_of_Attention-DeficitHyperactivity_Disorder_A_Review_of_Past_Development_Pitfalls_and_Failures_and_a_Look_to_the_Future
31. Bavisant | JNJ-31001074 | Histamine Receptor | Ambeed.com, accessed June 5, 2025, https://www.ambeed.com/products/929622-08-2.html
32. National Library of Medicine 8600 Rockville Pike, Bethesda, MD 20894 - Error | ClinicalTrials.gov, accessed June 5, 2025, https://clinicaltrials.gov/search?term=NCT00566449%20NCT00880217%20NCT00890240%20NCT00890292
33. Bavisant - PharmaKB, accessed June 5, 2025, https://www.pharmakb.com/drug-report/bavisant
34. WO2022113008A1 - Histamine h3 receptor antagonists/inverse agonists for the treatment of autism spectrum disorder - Google Patents, accessed June 5, 2025, https://patents.google.com/patent/WO2022113008A1/en
35. Histamine, histamine H3 receptor and alcohol use disorder - Helda - University of Helsinki, accessed June 5, 2025, https://helda.helsinki.fi/bitstreams/91917aa3-9d9e-4575-a1be-fde6ed7c6dfb/download
36. Histamine H3 Receptor: A Novel Therapeutic Target in Alcohol Dependence? - PMC, accessed June 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3355329/
37. Results from a Phase 2 Study of Induction Docetaxel and Carboplatin Followed by Maintenance Rucaparib in the Treatment of Patients with Metastatic Castration-resistant Prostate Cancer with DNA Homologous Recombination Repair Deficiency - PubMed, accessed June 5, 2025, https://pubmed.ncbi.nlm.nih.gov/40413129/
38. One-year results of a clinical trial of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency - PubMed, accessed June 5, 2025, https://pubmed.ncbi.nlm.nih.gov/33875845/
39. Histamine H3 receptor antagonists | Request PDF - ResearchGate, accessed June 5, 2025, https://www.researchgate.net/publication/232046304_Histamine_H3_receptor_antagonists
40. Dose finding phase IIb study of Bavisant to evaluate its safety and effiCacy in treAtment of exceSsive daytime slee - Parkinson's UK, accessed June 5, 2025, https://www.parkinsons.org.uk/sites/default/files/2018-12/Participant%20information%20sheet%20(200KB).pdf
41. Comments to ADHD Therapeutic Class Scan (OSU Drug Use Research & Management Program / Oregon Health Authority) Background, accessed June 5, 2025, https://www.orpdl.org/durm/meetings/meetingdocs/2013_07_25/finals/2013_07_25_WrittenTestimony.pdf
42. MEMoRIA AnuAl - Sacyl, accessed June 5, 2025, https://www.saludcastillayleon.es/investigacion/es/memorias-investigacion-2018.ficheros/1437880-Memoria%20Investigaci%C3%B3n%20CAUBU2018.pdf
43. Human Absorption, Distribution, Metabolism, and Excretion Studies: Origins, Innovations, and Importance - PubMed, accessed June 5, 2025, https://pubmed.ncbi.nlm.nih.gov/36973000/
44. Guidance Snapshot: Clinical Pharmacology Considerations For Human Radiolabeled Mass Balance Studies - FDA, accessed June 5, 2025, https://www.fda.gov/media/181634/download
45. The Importance of the Human Mass Balance Study in Regulatory Submissions - PMC, accessed June 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6916658/
46. BenevolentAI Ltd. - Drug pipelines, Patents, Clinical trials - Patsnap Synapse, accessed June 5, 2025, https://synapse.patsnap.com/organization/f02a65f713fc5962002bc215917d1e79
47. BenevolentAI Annual Report 2022, accessed June 5, 2025, https://www.benevolent.com/application/files/9816/7939/1282/BenevolentAI_Annual_Report_2022.pdf
48. A Brief History of BenevolentAI – CanvasBusinessModel.com, accessed June 5, 2025, https://canvasbusinessmodel.com/blogs/brief-history/benevolentai-brief-history
49. Histamine H3 receptors and its antagonism as a novel mechanism for antipsychotic effect: a current preclinical & clinical perspective - PubMed, accessed June 5, 2025, https://pubmed.ncbi.nlm.nih.gov/27833522/
50. Randomized Controlled Study of the Histamine H3 Inverse Agonist MK-0249 in Adult Attention-Deficit/Hyperactivity Disorder | Request PDF - ResearchGate, accessed June 5, 2025, https://www.researchgate.net/publication/230696514_Randomized_Controlled_Study_of_the_Histamine_H3_Inverse_Agonist_MK-0249_in_Adult_Attention-DeficitHyperactivity_Disorder