BNC210: an investigational α7-nicotinic acetylcholine receptor modulator for the treatment of anxiety disorders

ABSTRACT

Introduction

Anxiety disorders are common, disabling psychiatric conditions associated with excessive worry, irritability, and physiological symptoms of stress. Following insufficient response to psychological therapies, first-line pharmacological treatments for anxiety disorders suffer from inconsistent efficacy, addiction, and intolerable side-effect profiles (e.g. sedation), especially when used inappropriately or contrary to evidence-based guidelines. Developing anxiolytics acting via cholinergic modulation may provide novel options for the treatment of anxiety disorders, without the drawbacks of existing anxiolytics.

Areas covered

We review pharmacological treatment of anxiety disorders and proposed mechanisms of action in relation to the associated neural circuitry. We then consider the mechanism of action, pharmacodynamics, and pharmacokinetics of the negative-allosteric modulator of the alpha7 nicotinic receptor BNC210, an investigational anxiolytic so far employed in studies of those with social anxiety disorder, post-traumatic stress disorder, and agitation in hospitalized elderly. Lastly, we consider the environment of competitor compounds for this indication, and BNC210ʹs place within it, in both the present and near-future.

Expert opinion

: There is a relative paucity of data regarding BNC210, albeit the small amount of mostly non-peer reviewed data indicate it is a well-tolerated, effective anxiolytic. Phase III trials are required for proper appraisal of its utility.

KEYWORDS:

• Anxiety disorders
• social anxiety disorder
• anxiolytic
• nicotinic acetylcholine receptor
• BNC210
• non-sedating

1. Introduction

Anxiety disorders are characterized by feelings of fear and worry that significantly impair function in the social, occupational, and personal realms¹. Symptoms manifest in both mental and physical forms, such as excessive worry and irritability, as well as sweating and trembling [1]. Indeed one of the most common physiological symptoms, heart rate abnormalities, appears to be a driving force behind the conditioning of fear-related behaviors [2,3]. Subtypes of anxiety disorders vary in the specificity of their triggers, from highly specific phobias (e.g. agorophobia), to anxiety in social situations (social anxiety disorder; ‘SAD’), to persistent anxiety not specific to certain situations (e.g. panic disorder, generalized anxiety disorder; ‘GAD’). Although distinct disorders, GAD and SAD have high levels of overlap [4]. As a ‘generalised’ state of anxiety, GAD typically includes anxiety about social situations, which is the hallmark symptom of SAD. Treatment efficacy in GAD and SAD are also typically measured with the same instruments (e.g. the Spielberger State Anxiety Inventory [5]).

Beyond anxiety, there is also considerable overlap between anxiety disorders and other classes of affective disorders, for example, 59% of those with GAD have a lifetime comorbidity with MDD [6]. The overlap between anxiety and depression is thought to result from shared underlying neurobiological mechanisms, i.e. altered serotonergic projections from the raphe nuclei [7] and prefrontonal-limbic pathways [8] (see Chen [9], for review). It is perhaps unsurprising that both depression and anxiety disorders are treated using the same serotonergic medications in the first instance.

Generalized Anxiety Disorder is a common [10], chronic [11], and debilitating [12] psychiatric disorder characterized by ‘anxiety that is generalized and persistent but not restricted to, or even strongly predominating in, any particular environmental circumstances’ [13]. The contribution of hereditary factors is approximately 30% [14], with the remaining 70% attributed to environmental factors, e.g. transmission from parent to child [15]. GAD is more commonly diagnosed in women at a ratio of 3:2 [16], with a mean age at onset of 21 [17]. Much like GAD, SAD chronically impacts everyday functioning, albeit with a higher lifetime prevalence (5.7% for GAD; 12.1% for SAD [18]). The disorder is marked by ‘fear of scrutiny by other people leading to avoidance of social situations’ [13]. Although estimates regarding the heritability of SAD vary in the literature, reported from 13–76% [19], there is a significant, but not exclusive, genetic component to SAD.

The etiology of anxiety disorders is poorly understood, although recent evidence has implicated hyper-reactive functioning in brain areas related to response to threats or otherwise aversive stimuli, such as prefrontal and limbic structures [20–22]. Imaging studies have demonstrated amygdala hyperactivity in response to threatening stimuli across anxiety disorders [23,24] which appears to be regulated through functional connections with the anterior cingulate cortex (ACC) [25,26]. A recent study demonstrated that pharmacological reductions in amygdalar-ACC functional connectivity were associated with significantly reduced amygdala reactivity to fearful faces in GAD patients [21], lending credence to the hypothesis that the prefrontal-limbic system is a relevant substrate in relation to GAD. Crucially, the investigational drug in this study by Wise and colleagues (BNC210) is anticholinergic, raising the prospect of cholinergic modulation as a potential method of action in the pharmacological treatment of GAD.

Clinically, antidepressant serotonergic treatments such as selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs) are favored for anxiety disorders as they carry somewhat tolerable side effect profiles, but typically require 4–8 weeks to be effective. Sertraline, for example, has been shown to significantly reduce anxiety symptoms in both youth and adults in many studies [27]. Benzodiazepines are often offered as second-line treatments for anxiety as they are fast-acting compounds available relatively cheaply, albeit they often carry more debilitating side effects such as addiction and sedation [28]. Effect size analysis has shown benzodiazepines to be moderately effective in treating GAD for up to 8-weeks [29], in addition to treating SAD in those who failed to respond to sertraline [30]. Other treatments in clinic for anxiety disorders include the antiepileptic medications pregabalin and gabapentin, albeit the latter is off-label for anxiety.

The National Institute for Care Excellence (NICE) stepped-care model recommends SSRIs such as sertraline, and then either an SNRI or alternative SSRI, in those who do not respond to low-intensity psychotherapies [31]. Benzodiazepines are not recommended for the treatment of anxiety by NICE in primary or secondary care [31], albeit benzodiazepines are oftentimes used acutely as an augmentation to serotonergic treatments during the 4–8 week period it takes for them to take effect. Recent guidelines from the World Federation of Societies of Biological Psychiatry (WFSBP) concerning various anxiety disorders, including GAD, SAD, and PTSD [32,33] confirmed SSRIs and venlafaxine as first-line treatments, in addition to recommending benzodiazepines as augmentation for SSRIs in the early weeks of treatment for SAD & GAD. Taken together, roughly 50% of patients show a response to the above treatments, with only a third achieving remission [34]. Reasons for insufficient response in many patients varies, although intolerable side-effects such as sedation, and inadequate (i.e. length of trial) or inappropriate use (contrary to evidence-based guidelines) of the treatments are certainly key factors [35]. Clearly, a need exists to develop novel pharmacological compounds that ameliorate anxiety symptoms faster than serotonergic treatments with less severe side effect profiles than benzodiazepines.

Accumulating evidence indicates cholinergic involvement in the etiology and treatment of fear-related behaviors. Nicotinic acetylcholine receptors (nAChRs) are ionotropic ligand-gated receptor polypeptides that are activated by acetylcholine and nicotine [36,37]. The α7 subtype consists entirely of five α7 subunits that are primarily homomeric [38]. NAChRs more broadly are nonselective cation channels, with the α7 subtype particularly permeable to calcium [39], in addition to sodium [40]. Rat studies have highlighted the role of the α⁷ nAChR in anxiolytic behavior. Antagonism of the α⁷ nAChR, of which there is a high concentration in the rat amygdala [41], has been linked to fear-related behavior [42]. SSRIs have been shown to inhibit nicotinic acetylcholine receptors, suggesting that SSRIs may act via cholinergic, alongside serotonergic, modulation [43]. Although not shown in humans, rat models have demonstrated cholinergic inhibition of amygdalar activity following benzodiazepine administration [44], leaving open the possibility that benzodiazepine treatment of anxiety may act via cholinergic inhibition in addition to GABA-ergic effects.

Given the above evidence from pre-clinical models concerning the role of the cholinergic system in fear-related behaviors, it stands to reason that modulation of α⁷ nAChR could serve as an anxiolytic. Bionomics Ltd developed BNC210, a negative-allosteric modulator of the α⁷ nicotinic receptor for this purpose. In pre-clinical models, BNC210 is tolerable, safe, and non-sedating [45] Data published by the developers also appears to demonstrate BNC210 performing effectively as an anxiolytic across various behavioral paradigms, including outperforming placebo on the mouse light dark box and rat elevated plus maze, among others [37]. Encouraging results such as these lead to Bionomics Ltd investing resources investigating the safety and tolerability profile in human studies [46,47], in which it performs well in both without sedating side effects associated with typical anxiolytics. BNC210 is now in phase II trials for the treatment of anxiety disorders, with the first peer-reviewed study suggesting potential efficacy [21]. This review explores the pharmacodynamic and pharmacogenetic profile of BNC210, as well as research data published concerning its efficacy as a treatment for anxiety.

Box: Drug summary box

Drug name: BNC210 Phase: II Indication: Social Anxiety Disorder, Generalized Anxiety Disorder, Post Traumatic Stress Disorder Pharmacology/mechanism of action: Negative-allosteric modulator of the alpha-7 nicotinic receptor. Route of administration: Oral Notable trials: NCT04951076 (Phase II, ongoing); NCT05193409 (Phase II, recently completed)

2. Novel compounds

2.1. Current market

Due to the issues surrounding tolerability and efficacy of currently available anxiolytics outlined above, the necessity of developing novel anti-anxiety compounds is clear. Naturally, the challenging nature of drug development has left many recent development pipelines either stalled or ceased altogether. Table 1 presents a summary of selected competitor compounds recently in development. In addition to these, psychedelic compounds are now being investigated as possible treatments for anxiety alongside their use in depression, with one pre-clinical Lysergic acid diethylamide study indicating efficacy [48]. Overall, there is widespread interest in developing new anxiolytics, which is reflected in a competitive and dynamic market testing various compounds.

Table 1. Overview of selected compounds in development for the treatment of anxiety disorders.

Mechanistic Class	Compound	Target/Pharmacodynamics	Disorder	Developer	Phase	Status
5-HT	CYB004 (DMT)	5-HT2A agonist	GAD, SAD	Cybin	Phase I	Ongoing
Acetylcholine	BNC210	Nicotinic acetylcholine receptor modulator	GAD, SAD	Bionomics	Phase II	Ongoing
Endocannabinoid	JNJ-42165279	Fatty acid amide hydrolase inhibitor	SAD	Janssen	Phase II	No longer under investigation for SAD
Glutamate/GABA	Aloradine	GABAA receptor modulator	SAD	Vistagen	Phase II	Second phase III trial terminated
Melatonin	BHV-0223	Undefined (potential allosteric GABAa agonist)	SAD	Biohaven	Phase II	Ceased development as of 2020

NS = not specified, GAD = Generalized Anxiety Disorder, SAD = Social Anxiety Disorder.

2.2. BNC210: mechanism of action and pharmacodynamics

BNC210 is a negative modulator of the α7 nAChR (see figure 1). BNC210 inhibits α7 nAChR currents in human cell lines with IC50 values in the range of 1.2 to 3 mM. It appears to act as a negative allosteric modulator, as it is neither displaced by alpha-bungarotoxin binding (a neurotoxin that competitively binds to nAChRs), nor are its effects impacted by the concentration of acetylcholine. There are no published data concerning BNC210ʹs off-target (i.e. non-nicotinic) activity. Data published by Wise, Patrick, & Meyer et al. [21], & Perkins, A., Patrick, F., Wise, T., et al. [22], suggest that the response to BNC210 may be hormetic, as low-dose, but not high dose, BNC210 resulted in reduced anxiolytic behaviors and reductions in scores on self-reported state anxiety.

Figure 1. Mechanism of action of BNC210. 1) α7 nAChR in closed position. 2) α7 nAChR in open position following acetylcholine binding. 3) Binding of BNC210 at allosteric site modulates cation flow.

2.3. Pharmacokinetics

BNC210 is a micromolecule initially developed from a quinolone in a medicinal chemistry program with an oral bioavailability of 69.4% [45]. The somewhat slow absorption profile of the liquid suspension requires it to be taken with food, reducing its practical usefulness as a fast-acting treatment for social anxiety disorder. A new tablet formulation circumventing this issue has recently been trialed with SAD outpatients with results yet to be announced (NCT05193409). The developers report that the compound has a half-life of approximately 6.2 hours and low plasma protein binding (70–88%) [45]. Crucially, BNC210 does not interfere with the enzyme CYP450, meaning the metabolism of serotonergic drugs should not be altered [45]. O’Connor and colleagues later claim that repeat dosing of BNC210 produced a 1.8–2.9-fold increase in BNC210 C-max, with T-Max occurring from 2.5–4 hours (T-Half 5.5 hours) [46]. The developers have recently announced that the solid tablet form of BNC210 in use in the SAD trial (NCT05193409) is ‘showing much improved and rapid absorption over the previous liquid suspensions formulation.’

2.4. Clinical data

The relative lack of available clinical data on BNC210 makes its potential efficacy as an anxiolytic difficult to assess, albeit the relevant trials have been outlined below in Table 2. In addition to various safety and pharmacokinetic studies, the manufacturers of the drug have completed three phase 2 studies of BNC210. Two employed BNC210 suspensions (one for PTSD outpatients (NCT02933606) and one for agitated elderly inpatients (NCT03548194)), whereas the most recent study employed a tablet formulation for treating SAD in the acute setting (NCT05193409). All; three of these trials are as-of-yet unpublished in peer-reviewed journals, albeit the developers have announced that neither the PTSD trial nor the agitated elderly inpatient trial reached their primary endpoint. One further trial concerning PTSD outpatients is ongoing (NCT04951076).

Table 2. Overview of completed clinical trials concerning BNC210.

Phase	Description	Participants	n receiving BNC210	Formulation
1	Safety & pharmacokinetics	Healthy volunteers	24	Suspension
1	Safety & pharmacokinetics	Healthy volunteers	3	Suspension
1	Safety & pharmacokinetics	Healthy volunteers	40	Capsule
1	Pharmacokinetics	Healthy volunteers	6	Suspension vs tablet
1	Safety & pharmacokinetics	Healthy volunteers	5	Tablet
1	Safety & pharmacokinetics	Healthy volunteers	10	Tablet
1b	Lorazepam comparison	Healthy volunteers	22	Suspension
1b	CCK-4 Panic attack modeling	Healthy volunteers	59	Suspension
1b	Safety & pharmacokinetics	Healthy volunteers	44	Suspension
2a	Imaging & behavioral study	GAD	25	Suspension
2a	Clinical efficacy	Agitated elderly inpatients	18	Suspension
2	Clinical efficacy	PTSD outpatients	143	Suspension
2	Clinical efficacy	SAD outpatients	Completed – not specified	Tablet
2b	Clinical efficacy	PTSD outpatients	Ongoing	Tablet

GAD = Generalized Anxiety Disorder, SAD = Social Anxiety Disorder, PTSD = Post Traumatic Stress Disorder.

The only peer-reviewed clinical data with respect to BNC210 appears to indicate anxiolytic efficacy. Wise and colleagues [21] administered BNC210 to 24 adults with GAD, returning that low-dose BNC210 reduced amygdalar reactivity to fearful faces at a similar level to lorazepam. BNC210 administration also reduced functional connectivity in fronto-amygdala circuitry involved in anxious responses to aversive stimuli. This study was significant in that it was first to show that cholinergic modulation can beneficially alter the function of anxiety-related fronto-limbic circuitry. Working with the same group of patients, Perkins, A., Patrick, F., Wise, T., et al. [22], found that low-dose BNC210, but not a higher dose, significantly reduced Spielberger state anxiety and flight intensity in the 21 female participants in the cohort, suggesting BNC210 may bind preferentially, but not exclusively, at inhibitory acetylcholine sites.

Regarding safety & tolerability, Bionomics Ltd have reported that BNC210 is safe and well tolerated, reporting no serious adverse events and only mild side effects (e.g. headache) in a small number of participants [46,47]. The lack of reported side effects also extended to behavioral features, with BNC210 resulting in no significant changes in psychomotor, attention, or memory function, which were all impaired following lorazepam administration [47].

3. Current status

BNC210 is a novel anxiolytic compound under investigation for social anxiety disorder, post-traumatic stress disorder, and agitation. Several phase I and II studies, many of which are as-of-yet unpublished in peer-reviewed sources, suggest the compound is safe and well-tolerated. The phase IIa trial conducted by Wise, Patrick, & Meyer et al. [21], indicate efficacy of BNC210 in treating symptoms of anxiety, underlined by functional connectivity changes in anxiety-related front-limbic circuitry [22]. Given phase II trials in SAD and PTSD are yet to be published, and there is an absence of phase III studies, this compound is some way from regulatory review and eventual licensing for this indication.

4. Expert opinion

The rationale behind developing BNC210 is to develop a novel anxiolytic that is both effective against anxiety and lacks the significant side effect profiles and practical drawbacks of current first-line anti-anxiety treatments, such as sedation and addiction. Currently, much of what we know regarding both goals comes from the drug developer, the findings of which have not yet been published following peer-review. Provided this evidence is reliable, then BNC210 is a viable candidate to achieve both goals. Indeed, the only peer-review studies evaluating the efficacy and tolerability of BNC210 appear to reaffirm this, reporting significant reductions on measures of anxious behavior and self-reported state anxiety [22], albeit this was in a small cohort with only 3 male participants and the low dose of BNC210 was more efficacious than the high dose. On a theoretical level, it also stands to reason that if BNC210 goes on to demonstrate efficacy as an anxiolytic in larger trials, this would go some way to further implicate the cholinergic in the etiology of anxiety disorders.

It is too early to say whether BNC210 represents an improvement in currently available therapies, as judgments regarding both efficacy and tolerability require further investigation in clinical trials, in addition to more in-depth critical appraisal in the form of peer-review. There are currently no phase III trials of BNC210 to treat anxiety disorders either completed or underway, meaning BNC210 cannot currently have an impact on treatment strategies as it is some way from being licensed for this indication. This also entails a paucity of data on the cost-effectiveness of BNC210 as a treatment, as the scale of the impact BNC210 could have on clinical practice is undoubtedly inversely related with its cost relative to currently available treatments.

Beyond the general lack of available data on BNC210, the findings available for appraisal require scrutiny. Firstly, without conclusive neuroscientific findings explaining the hormetic dose-dependent response pattern of BNC210 shown in the Wise and Perkins’ studies [21,22], in addition to a total lack of replication, the effect of BNC210 on anxious behaviors and state anxiety being a false positive remains roughly as plausible as BNC210 having true efficacy in treating anxiolytic symptoms. Additionally, although these studies measured anxiety at three separate time points, these were all conducted on the same day. We therefore do not know if this change in anxiety was lasting or fleeting, raising questions as to BNC210ʹs utility as a prescription medication although the pan-methodological convergence between self-report state anxiety and behavioral task results suggests its effects may be non-trivial.

In conclusion, BNC210 is one of several novel anxiolytic compounds under investigation for the treatment of anxiety disorders. The relatively low amount of data on both tolerability and efficacy of BNC210 mean it’s potential as a treatment is hard to currently appraise, meaning it remains some way from being a licensed treatment for anxiety disorders. The currently available data indicate that BNC210 is a good candidate for both an effective and tolerable treatment, albeit this requires replication in larger studies. Ultimately, whilst there is cause of optimism, there is also insufficient data to yet suggest BNC210 constitutes a ‘leading’ candidate with respect to other novel treatments under development for anxiety disorders. If the encouraging results concerning efficacy and tolerability available so far are repeated in larger trials then BNC210 may well end up as a licensed treatment for anxiety disorders, albeit it is unclear if this would be in a stand-alone role or as an augmentation to available therapies.

Article highlights

• The article first discusses recommended pharmacological treatment options in anxiety disorders, followed by the potential role of cholinergic system in fear-related behaviors.

• The article then overviews BNC210; a novel anxiolytic currently under development. This includes a status update regarding the development of BNC210 and rival compounds.

• The article concludes by providing an expert opinion on BNC210 and its place in the wider novel anxiolytic environment both now and in the future.

Declaration of interest

AH Young: Employed by King’s College London; Honorary Consultant South London and Maudsley NHS Foundation Trust (NHS UK)

Editor of Journal of Psychopharmacology and Deputy Editor, BJPsych Open,

Paid lectures and advisory boards for the following companies with drugs used in affective and related disorders: Allegan, AstraZeneca, Bionomics Ltd, Boehringer Ingelheim, COMPASS, Eli Lilly, Janssen, LivaNova, Lundbeck, Neurocentrx, Novartis, Sage, Servier, Sumitomo Dainippon Pharma, Sunovion

Principal Investigator in the Restore-Life VNS registry study funded by LivaNova.

Principal Investigator on ESKETINTRD3004: ‘An Open-label, Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression.’

Principal Investigator on ‘The Effects of Psilocybin on Cognitive Function in Healthy Participants’

Principal Investigator on ‘The Safety and Efficacy of Psilocybin in Participants with Treatment-Resistant Depression (P-TRD)’

UK Chief Investigator for Novartis MDD study MIJ821A12201

Grant funding (past and present): NIMH (USA); CIHR (Canada); NARSAD (USA); Stanley Medical Research Institute (USA); MRC (UK); Wellcome Trust (UK); Royal College of Physicians (Edin); BMA (UK); UBC-VGH Foundation (Canada); WEDC (Canada); CCS Depression Research Fund (Canada); MSFHR (Canada); NIHR (UK). Janssen (UK) EU Horizon 2020

No shareholdings in pharmaceutical companies

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.