Darigabat (CVL-865, PF-06372865): A Comprehensive Profile of an Investigational GABAA Receptor Modulator

1. Introduction to Darigabat

1.1. Overview and Background

Darigabat is an investigational small molecule pharmaceutical agent currently undergoing clinical evaluation for its potential therapeutic applications in a range of neurological and psychiatric conditions.[1] It is classified as a GABAergic medication, operating specifically as a positive allosteric modulator (PAM) of the gamma-aminobutyric acid type A (GABAA) receptor.[1] The development of Darigabat is centered on the hypothesis that it can deliver the established therapeutic benefits of GABAergic modulation, such as anxiolytic and anticonvulsant actions, while offering an improved side-effect profile. A key objective is the minimization of sedation, a common limiting side effect of older, non-selective GABAergic compounds like benzodiazepines. This anticipated improvement is attributed to Darigabat's selective interaction with specific subtypes of the GABAA receptor.[2]

1.2. Chemical Identity and Synonyms

The officially recognized generic name for this investigational compound is Darigabat.[1] Throughout its research and development phases, Darigabat has been identified by several internal developmental code names. The most prominent of these are CVL-865, utilized by Cerevel Therapeutics, and PF-06372865 (sometimes cited as PF-6372865), used during its initial development by Pfizer.[1] The International Nonproprietary Name (INN) "darigabat" was formally adopted for the compound previously designated CVL-865.[6]

1.3. Therapeutic Class

Darigabat is categorized within the broad class of GABAergic agents. Its more precise pharmacological classification is a GABAA Receptor Positive Allosteric Modulator (PAM).[1] A defining feature of Darigabat's mechanism of action is its selective positive allosteric modulation of GABAA receptors that incorporate α2 (alpha-2), α3 (alpha-3), and α5 (alpha-5) subunits. It is reported to exhibit minimal functional activity at GABAA receptors that contain the α1 (alpha-1) subunit.[1]

1.4. Developmental History and Current Developers

The initial discovery and early-phase development of Darigabat were undertaken by Pfizer Inc..[2] Subsequently, Cerevel Therapeutics assumed a significant role in advancing its clinical development, often through licensing agreements or collaborations built upon Pfizer's foundational work.[3]

A pivotal event in Darigabat's developmental trajectory occurred on August 1, 2024, when AbbVie Inc. finalized its acquisition of Cerevel Therapeutics. This strategic acquisition, valued at approximately $8.7 billion, integrated Darigabat, along with other pipeline assets from Cerevel, into AbbVie's expanding neuroscience portfolio.[7] This transition is noteworthy as it places the future development of Darigabat under the aegis of a major pharmaceutical corporation with substantial resources. Such backing can significantly influence the compound's path forward, including the capacity to fund and manage large-scale, late-stage clinical trials and navigate the complexities of regulatory approval and potential commercialization. Reports from the time of acquisition confirmed Darigabat's ongoing Phase 2 development status for treatment-resistant epilepsy and panic disorder as part of the acquired assets.[20]

The consistent emphasis on Darigabat's selectivity for GABAA receptors containing α2, α3, and α5 subunits, while sparing the α1 subunit, points to a deliberate and sustained strategy in central nervous system (CNS) drug development.[2] This strategy is rooted in the pursuit of a "safer GABAergic" agent, aiming to dissociate the therapeutic effects from the common adverse effects associated with non-selective GABAA modulators like benzodiazepines. The α1 subunit, in particular, is widely believed to mediate the sedative, amnesic, and ataxic effects of these older drugs. By minimizing interaction with α1-containing receptors, Darigabat is designed to retain or enhance desired anxiolytic effects (primarily linked to α2 and α3 subunits) and other potential CNS benefits, while reducing the burden of these limiting side effects.

The acquisition by AbbVie, a major pharmaceutical entity, despite Darigabat's earlier discontinuations for indications such as Generalized Anxiety Disorder (GAD) and chronic low back pain, underscores a persistent industry belief in the therapeutic potential of this subtype-selective modulation approach.[2] This suggests that the perceived advantages for specific, perhaps more mechanistically aligned or high-unmet-need indications like drug-resistant epilepsy and panic disorder, are considered to outweigh the risks observed in broader applications. Classical benzodiazepines, while effective, are hampered by significant side effects like sedation and dependence, largely attributed to their non-selective GABAA receptor modulation, especially α1 agonism. Darigabat's design explicitly targets α2/3/5 selectivity to spare α1, theoretically separating desired therapeutic actions from these undesired effects. Although development for GAD and pain was halted, indicating that this "safer GABAergic" profile may not be universally applicable or easily realized across all CNS disorders, the continued investment and advancement for epilepsy and panic disorder suggest these conditions might represent a more suitable therapeutic niche. AbbVie's multi-billion dollar acquisition of Cerevel, including Darigabat, post these setbacks, strongly implies that the core scientific rationale—subtype selectivity for improved tolerability in targeted CNS conditions—remains highly valued and holds commercial promise for major pharmaceutical organizations. This acquisition provides substantial resources for further, potentially more focused, development, indicating the industry's ongoing commitment to finding GABAergic modulators with superior risk-benefit profiles, with subtype selectivity as a key strategy.

The evolution of Darigabat's targeted therapeutic indications also reflects a common pattern in drug development: iterative refinement based on accumulating clinical experience. Initial explorations into broader conditions like GAD and chronic pain were followed by a strategic pivot towards more specific neurological and psychiatric disorders, such as drug-resistant focal epilepsy and panic disorder.[1] The "negative" outcomes in the GAD and pain trials [2], while disappointing for those specific uses, likely furnished invaluable data. This information would have helped to delineate the compound's actual clinical pharmacological profile, guiding its subsequent development towards areas where its unique mechanism of action might offer a more favorable therapeutic window or address a more precisely defined unmet medical need. The specific subtype modulation of Darigabat (α2/3/5) might be more critically involved or offer a better therapeutic index in the neurocircuitry of epilepsy or acute panic responses compared to the more complex, chronic state of GAD or neuropathic pain. For instance, α2/α3 subunits are strongly linked to anxiolysis, which is highly relevant for panic disorder. This demonstrates a data-driven refinement process, where early clinical trial results, even if not meeting primary endpoints for an initial indication, are instrumental in understanding a drug’s true clinical effects and redirecting resources towards more promising therapeutic avenues.

2. Chemical and Physical Properties

2.1. Chemical Structure

Darigabat is a complex organic molecule. Its systematic IUPAC (International Union of Pure and Applied Chemistry) name is 7-ethyl-4-[3-(4-ethylsulfonyl-2-methoxyphenyl)-4-fluorophenyl]imidazo[4,5-c]pyridazine.[6] An alternative, structurally consistent systematic name also reported is 7-ethyl-4-(4'-(ethylsulfonyl)-6-fluoro-2'-methoxybiphenyl-3-yl)-7H-imidazo[4,5-c]-pyridazine.[1]

The structural formula can be represented by the following identifiers:

• SMILES (Simplified Molecular Input Line Entry System): CCN1C=NC2=C(C=NN=C12)C1=CC=C(F)C(=C1)C1=CC=C(C=C1OC)S(=O)(=O)CC [12] or CCN1C=NC2=C1N=NC=C2C3=CC(=C(C=C3)F)C4=C(C=C(C=C4)S(=O)(=O)CC)OC.[10] These two SMILES strings describe the same molecular structure.
• InChI (IUPAC International Chemical Identifier): InChI=1S/C22H21FN4O3S/c1-4-27-13-24-21-18(12-25-26-22(21)27)14-6-9-19(23)17(10-14)16-8-7-15(11-20(16)30-3)31(28,29)5-2/h6-13H,4-5H2,1-3H3.[1]
• InChIKey (Hashed version of InChI): PTTQXDBPTFOCMT-UHFFFAOYSA-N.[1]

2.2. Molecular Formula and Molecular Weight

• Molecular Formula: C22H21FN4O3S.[1]
• Average Molecular Weight: Approximately 440.49 g/mol or 440.5 g/mol.[1]
• Monoisotopic Mass: 440.131839889 Da [1] or 440.13183988 Da.[10]

2.3. CAS Number

The Chemical Abstracts Service (CAS) registry number assigned to Darigabat is 1614245-70-3.[1]

2.4. Other Physical Properties

Selected physicochemical properties are summarized in Table 1. These properties are crucial for understanding the drug's behavior, including its absorption, distribution, and potential for oral bioavailability.

Table 1: Chemical and Physical Properties of Darigabat

Property	Value	Source Snippet(s)
IUPAC Name	7-ethyl-4-[3-(4-ethylsulfonyl-2-methoxyphenyl)-4-fluorophenyl]imidazo[4,5-c]pyridazine	6
Synonyms	CVL-865, PF-06372865, PF-6372865	1
Molecular Formula	C22H21FN4O3S	1
Molecular Weight (Average)	~440.49 g/mol or 440.5 g/mol	1
Molecular Weight (Monoisotopic)	440.13183988 Da	10
CAS Number	1614245-70-3	1
InChI	InChI=1S/C22H21FN4O3S/c1-4-27-13-24-21-18(12-25-26-22(21)27)14-6-9-19(23)17(10-14)16-8-7-15(11-20(16)30-3)31(28,29)5-2/h6-13H,4-5H2,1-3H3	1
InChIKey	PTTQXDBPTFOCMT-UHFFFAOYSA-N	1
SMILES	CCN1C=NC2=C1N=NC=C2C3=CC(=C(C=C3)F)C4=C(C=C(C=C4)S(=O)(=O)CC)OC	10
XLogP3	2.9	10
Hydrogen Bond Donor Count	0 (PubChem computed)	10
Hydrogen Bond Acceptor Count	7 (PubChem computed); 6 6	6
Rotatable Bond Count	6 (PubChem computed); 4 6	6
Topological Polar Surface Area	95.4 Ų (PubChem computed); 86.97 Ų 6	6
Solubility	In DMSO: 30 mg/mL (68.11 mM), sonication recommended	13
Storage Conditions	Powder: -20°C for 3 years. In solvent: -80°C for 1 year. Keep from light.	13

Discrepancies in computed values for properties like hydrogen bond donor/acceptor counts, rotatable bond count, and TPSA from different sources (e.g., PubChem vs. CDK) are not uncommon and often depend on the specific algorithms and parameters used in the calculations.

The physicochemical profile of Darigabat, including a reported XLogP3 value of 2.9 [10] and a molecular weight of approximately 440.5 g/mol [1], generally aligns with characteristics favorable for orally bioavailable drugs, often assessed by criteria such as Lipinski's Rule of Five. The topological polar surface area (TPSA) of around 95.4 Ų [10] further suggests a potential for reasonable membrane permeability. This overall profile is consistent with its intended development as an orally active agent targeting the central nervous system [4], as oral administration is the planned route and penetration of the blood-brain barrier (BBB) is essential for its action. Indeed, preclinical data indicate that Darigabat does cross the BBB.[13] The reported solubility in dimethyl sulfoxide (DMSO) is a common characteristic for compounds used in preclinical and in vitro experimental settings.[13]

The molecular architecture of Darigabat, featuring a fluoro-substituted biphenyl core linked to an ethylsulfonyl methoxy phenyl group and an ethyl-imidazo-pyridazine moiety, indicates a degree of structural complexity.[1] While detailed synthetic pathways are beyond the scope of this profile, the mention of specific synthetic strategies such as Buchwald-Hartwig amination and Suzuki coupling in related research [14] implies that the synthesis of this multi-ring, heteroatom-rich structure is a non-trivial chemical endeavor. Such complexity often translates to multi-step synthetic processes, which can have implications for manufacturing scalability and cost, factors relevant to the overall drug development lifecycle.

3. Pharmacology

3.1. Mechanism of Action

Darigabat exerts its pharmacological effects as a positive allosteric modulator (PAM) of the GABAA receptor.[1] This means it binds to a site on the GABAA receptor distinct from the GABA binding site and enhances the effect of GABA, the principal inhibitory neurotransmitter in the mammalian CNS. Specifically, Darigabat is designed to selectively target GABAA receptors that incorporate α2 (alpha-2), α3 (alpha-3), and α5 (alpha-5) subunits. A crucial aspect of its design is its minimal functional activity at GABAA receptors containing the α1 (alpha-1) subunit.[1] Reports indicate that α1 subunit-containing GABAA receptors may be largely unaffected by Darigabat at therapeutic concentrations.[2]

This subtype selectivity is central to Darigabat's therapeutic hypothesis. Non-selective benzodiazepines, which also act as GABAA receptor PAMs, modulate receptors containing α1, α2, α3, and α5 subunits more broadly.[2] The α1 subunit is widely believed to mediate many of the undesirable side effects of benzodiazepines, such as sedation, amnesia, and ataxia.[2] In contrast, the anxiolytic effects of benzodiazepines are thought to be primarily mediated through α2 and α3 subunit-containing receptors, while α5 subunits have been implicated in cognitive processes, including memory (though the role of α5 modulation is complex and can be associated with memory impairment by some agents). By preferentially modulating α2, α3, and α5 subunits and sparing α1, Darigabat aims to achieve therapeutic benefits, such as anxiolysis and anticonvulsant activity, with a reduced burden of α1-mediated side effects.[2] It has been reported that a dose of Darigabat achieving over 80% receptor occupancy demonstrated no somnolence with dose titration in one study context, whereas benzodiazepines typically produce significant somnolence at receptor occupancies of only 10-15%.[2] However, it is important to note that somnolence has been reported as an adverse event in some Darigabat trials, such as the GAD trial.[11]

3.2. Pharmacodynamics

The pharmacodynamic profile of Darigabat is characterized by its interaction with GABAA receptor subtypes and its subsequent physiological effects.

Receptor Binding Affinities and Functional Activity:

Darigabat demonstrates high binding affinity for GABAA receptors containing α1, α2, α3, or α5 subunits.9 However, a critical distinction lies between binding affinity and functional efficacy. While Darigabat binds with high affinity to α1-containing GABAA receptors (Ki values reported in the range of 0.18-0.28 nM) 13, it is characterized by minimal functional activity or efficacy at these α1 subunits (relative efficacy reported as 0.11 or ≤20% modulation).9 This means that although the drug can occupy the binding site on α1-containing receptors, it does not significantly enhance GABA's inhibitory effect through these particular receptor subtypes. This "binding without strong functional modulation" at the α1 subunit is a cornerstone of its differentiated pharmacological profile and the basis for its hypothesized improved tolerability.

The binding affinities (Ki values) for various GABAA receptor subunit combinations are summarized in Table 2. It is important to note that Ki values can vary depending on the assay conditions and specific recombinant receptor systems used. Some sources also report Ki values for positive allosteric modulation (PAM Ki), which may differ from direct binding Ki values and reflect the concentration required for a modulatory effect.[13]

Table 2: GABAA Receptor Subunit Binding Affinities (Ki) and Functional Activity of Darigabat

GABAA Subunit Combination	Binding Affinity (Ki, nM)	Functional Efficacy/Activity	Source Snippet(s)
α1 (general)	0.28	Minimal functional efficacy (relative efficacy = 0.11)	9
α1β3γ2	0.18 (functional Ki with GABA)	Low allosteric modulation (≤20%)	9
α1 PAM	21 (PAM Ki)		13
α2 (general)	2.4 or 2.9	Significant positive allosteric modulation (90-140% at α2/3/5)	9
α2β2γ2	2.9 (functional Ki with GABA)		13
α2 PAM	134 (PAM Ki)		13
α3 (general)	2.8	Significant positive allosteric modulation (90-140% at α2/3/5)	9
α3β3γ2	1.1 (functional Ki with GABA)		13
α5 (general)	7.2	Significant positive allosteric modulation (90-140% at α2/3/5)	9
α5β2γ2	18 (functional Ki with GABA)		13

Note: Ki values can vary based on experimental conditions. PAM Ki refers to the affinity for producing positive allosteric modulation.

Preclinical Evidence of Anxiolytic and Anticonvulsant Activity:

Preclinical studies have provided evidence for Darigabat's anxiolytic and anticonvulsant properties. It has demonstrated anxiolytic activity in animal models.13 Its anticonvulsant potential has been shown in several established epilepsy models:

• Maximal Electroshock Seizure (MES) Model (Rats): Doses of 3 and 10 mg/kg significantly increased hindlimb withdrawal latency, indicating anticonvulsant effect.[13]
• Pentylenetetrazole (PTZ) Seizure Model (Mice): Doses of 0.3, 3, and 10 mg/kg significantly increased seizure onset latency.[13]
• Mesial Temporal Lobe Epilepsy (MTLE) Mouse Model (Drug-Resistant Focal Seizures): Darigabat dose-dependently reduced hippocampal paroxysmal discharges (HPDs), with efficacy comparable to diazepam at doses of 3 and 10 mg/kg.[17]
• Amygdala-Kindled Rat Model (Focal Seizures): Oral doses of 1 and 10 mg/kg demonstrated antiseizure activity.[15]
• Genetic Absence Epilepsy Rats from Strasbourg (GAERS) Model: Oral doses of 0.3–10 mg/kg dose-dependently reduced spike-and-wave discharges, with a 10 mg/kg dose achieving complete suppression 30 minutes post-administration, suggesting broad-spectrum antiseizure activity.[15]

Physiological Responses and Biomarkers:

The development of Darigabat has utilized a translational pharmacology approach, employing biomarkers to bridge preclinical findings with human responses. In preclinical rat studies, Darigabat induced an occupancy-dependent increase in quantitative EEG (qEEG) beta frequency, a known marker of GABAergic drug activity. Furthermore, in drug-discrimination assays, rats did not generalize the Darigabat cue to a GABAA α1-selective cue, providing further support for its lack of significant α1 modulation in vivo.9

In Phase 1 studies involving healthy human volunteers, Darigabat administration led to a robust increase in saccadic peak velocity (SPV), which is considered a pharmacodynamic marker of α2/α3 GABAA receptor subunit pharmacology. Increases in qEEG beta frequency were also observed in humans, alongside a slight, saturating increase in body sway.[9] The use of these objective biomarkers (qEEG, SPV) is crucial in early clinical development for confirming target engagement and for attempting to differentiate the effects of α2/3/5 modulation from potential α1-mediated effects in humans. This approach provides a more rigorous assessment of the drug's mechanism of action in vivo than relying solely on subjective reports or behavioral outcomes in initial human trials.

3.3. Pharmacokinetics (Absorption, Distribution, Metabolism, Excretion - ADME)

The pharmacokinetic profile of Darigabat has been investigated in healthy volunteers, and key parameters are summarized in Table 3.

Table 3: Key Pharmacokinetic Parameters of Darigabat (Healthy Volunteers)

Parameter	Value	Condition	Source Snippet(s)
Route of Administration	Oral	Single and Multiple Doses	2
Tmax (Time to Peak Plasma Conc.)	Median 1–2 hours	Single and Multiple Doses	14
Elimination Half-life (t1/2)	~11 hours (multiple dose); 6.0–8.9 hours (single dose range)	Multiple Dose; Single Dose	2
Bioavailability	Orally active, crosses blood-brain barrier		13
Volume of Distribution (Vd/F)	194–260 L (apparent, single dose)	Single Dose	15
Clearance (CL/F)	17.4–26.9 L/h (apparent oral clearance, single dose)	Single Dose	15
Primary Metabolism Route	Extensively metabolized, primarily via Cytochrome P450 3A4 (CYP3A4)		2
Excretion Details	Low urinary recovery of unchanged drug (<0.6%)		14

• Absorption: Darigabat is orally active.[3] Following oral administration, it is rapidly absorbed, with the median time to reach peak plasma concentration (Tmax) being approximately 1 to 2 hours in healthy volunteers after both single and multiple doses.[14] Plasma exposure (Cmax and AUC) appeared to increase dose-proportionally within the investigated dose ranges.[15]
• Distribution: Darigabat is known to cross the blood-brain barrier, a prerequisite for its action on CNS targets.[13] The apparent volume of distribution following a single oral dose in healthy subjects ranged from 194 to 260 liters, suggesting extensive distribution into tissues.[15]
• Metabolism: Darigabat undergoes extensive metabolism, with the primary enzyme responsible being Cytochrome P450 3A4 (CYP3A4).[2] The significance of this metabolic pathway is underscored by a dedicated clinical trial (NCT05824143; CVL-865-HV-1003) designed to evaluate the effect of carbamazepine, a strong CYP3A4 inducer, on the pharmacokinetics of Darigabat in healthy adult participants.[16] This study has been completed.[16] Another Phase 1 trial (CVL-865-HV-1004) was planned to assess the absorption, metabolism, excretion, and mass balance of radiolabeled ([14C]) Darigabat in healthy male participants.[16] The primary metabolism by CYP3A4 makes Darigabat susceptible to a well-defined set of potential drug-drug interactions. Co-administration with strong CYP3A4 inhibitors could lead to increased Darigabat plasma concentrations and an elevated risk of adverse effects, while co-administration with strong CYP3A4 inducers could decrease Darigabat concentrations, potentially reducing its efficacy. The proactive investigation of the interaction with carbamazepine is critical, especially considering epilepsy as a target indication where enzyme-inducing antiepileptic drugs are commonly used.
• Excretion: The mean terminal elimination half-life (t1/2) of Darigabat in healthy adult subjects is approximately 11 hours following multiple oral doses.[2] After single doses, the half-life ranged from 6.0 to 8.9 hours.[15] The urinary recovery of unchanged Darigabat is low (less than 0.6%), indicating that the majority of the drug is eliminated as metabolites.[14] The mean apparent oral clearance for single doses ranged from 17.4 to 26.9 L/h.[15]

4. Clinical Development Program

Darigabat's clinical development has encompassed several indications, with a strategic refinement of focus over time based on emerging data.

4.1. Investigational Therapeutic Indications (Current Focus)

• Epilepsy:
• Photosensitive Epilepsy (PSE): An early Phase 2a single-dose, proof-of-concept study in patients with photosensitive epilepsy demonstrated robust anticonvulsant activity. Six out of seven patients treated with Darigabat (single doses of 17.5 mg or 52.5 mg, tablet formulation) experienced complete suppression of the photoparoxysmal EEG response to intermittent photic stimulation (IPS).[8] This effect was reported to be comparable to that of lorazepam (2 mg) but, importantly, Darigabat did not cause sedation in this context.[14]
• Focal Onset Seizures (Drug-Resistant): The REALIZE trial (NCT04244175; CVL-865-SZ-001) was a Phase 2 study evaluating Darigabat as an adjunctive therapy in adult participants with drug-resistant focal onset seizures.[8] This trial was completed in May 2024 [16], with data readout anticipated around mid-2024.[18] The primary endpoint was the change from baseline in focal onset seizure frequency per week over the maintenance phase (up to Day 71).[26] Key secondary endpoints included the 50% responder rate, percentage of seizure-free participants, and changes in quality of life (QOLIE-31) and global impression scales (PGIC, CGI-S, CGI-I).[26] An open-label extension trial (NCT04686786; CVL-865-SZ-002) was also conducted and is listed as completed as of December 2024.[4] As of early 2025, specific efficacy results from the REALIZE trial have not been detailed in the available information. The outcome of this trial is highly anticipated and will be pivotal for Darigabat's future in epilepsy.
• Panic Disorder:
• A Phase 1 proof-of-principle trial in healthy volunteers, utilizing a CO2 inhalation challenge model to induce panic-like symptoms, demonstrated clinically meaningful and statistically significant anxiolytic activity for Darigabat at doses of 7.5 mg twice daily (BID) and 25 mg BID compared to placebo.[8] The primary endpoint was the change in the Panic Symptoms List (PSL-IV) total score after eight days of dosing. Both Darigabat doses showed significant improvements (3.9 points for 7.5 mg BID, p=0.036; 4.5 points for 25 mg BID, p=0.008, placebo-adjusted). The positive control, alprazolam 1 mg BID, showed a non-significant 1.6-point improvement (p=0.286).[22] On the secondary endpoint, Fear Visual Analog Scale (VAS Fear score), the 7.5 mg BID Darigabat dose also showed a significant placebo-adjusted improvement (12.8 points, p=0.026).[22]
• Following these positive Phase 1 results, the ADAPT trial (NCT05941442; CVL-865-PA-2001), a Phase 2 study, was initiated to evaluate the efficacy, safety, and tolerability of Darigabat in participants with panic disorder.[1] This trial investigated Darigabat 25 mg BID (following a 2-week titration period up to 12.5 mg BID, then 12 weeks of maintenance at 25 mg BID) compared with placebo.[31] The primary endpoint was the change from baseline in the Panic Disorder Severity Scale (PDSS) total score at Week 14.[31] The ADAPT trial is reported as completed as of March 31, 2025.[4] Specific efficacy results from this trial are not yet available in the provided information.
• Other Anxiety Disorders (Preclinical): As of January 2023, Darigabat was also reported to be in preclinical development for other anxiety disorders beyond panic disorder.[2]

The differing outcomes between the GAD trial and the acute anxiety models (PSE, CO2 challenge) suggest that Darigabat's efficacy may be indication-specific. The neurobiological underpinnings of GAD, a chronic condition, may differ substantially from those involved in acute panic responses or the generation of seizures. Alternatively, the adjunctive design of the GAD trial, the specific patient population (inadequate responders to standard of care), or the limited dose range explored could have contributed to the lack of efficacy observed.[11] The α2/3/5 selectivity, while theoretically beneficial for anxiety, might not be optimally effective or dosed for the complexities of chronic GAD, especially in the context of concomitant standard treatments. This highlights the challenges in translating receptor-specific modulation into broad clinical efficacy across the diverse spectrum of anxiety disorders.

4.2. Discontinued Indications

• Generalized Anxiety Disorder (GAD): A Phase 2 trial (NCT02310568) evaluating Darigabat (PF-06372865) as an adjunctive treatment for outpatients with GAD who had an inadequate response to standard of care was terminated prematurely.[1] The study, which compared two doses of Darigabat (2.5 mg BID and 7.5 mg BID) with placebo, was stopped after 90 of the planned 384 subjects were randomized. The decision was based on the failure of either Darigabat dose to differentiate from placebo on the primary endpoint (change in Hamilton Anxiety Inventory total score at week 4) or the key secondary endpoint (Sheehan Disability Scale total score).[11] Contributing factors cited included the limited sample size at termination and the failure to explore a broader range of doses.[11] A 2024 review also noted that PF-06372865 (Darigabat) did not achieve efficacy endpoints in patients in proof-of-concept studies for anxiety, referring to the GAD trial.[7]
• Chronic Lower Back Pain (CLBP): Development of Darigabat for CLBP was also discontinued following a Phase 2 trial that did not demonstrate efficacy.[1]

4.3. Overview of Clinical Trials

Darigabat has been investigated in numerous clinical trials, spanning Phase 1 studies in healthy volunteers to Phase 2 studies in patient populations for various indications.[1] As of early 2021, it was reported that Darigabat had been evaluated in 289 patients and healthy volunteers across nine clinical trials.[8] A summary of major clinical trials is presented in Table 4.

Table 4: Summary of Major Clinical Trials for Darigabat

NCT ID / Trial ID	Phase	Indication(s)	Intervention(s)	Key Endpoints (Primary & Major Secondary)	Participants	Key Efficacy Results Summary	Status (as of early 2025) / Latest Update	Source Snippet(s)
NCT02564029 (Phase 2a PSE)	2a	Photosensitive Epilepsy	Darigabat (17.5 mg, 52.5 mg single doses, tablet) vs. Placebo, Lorazepam	Reduction in photoparoxysmal EEG response	7	Darigabat significantly reduced EEG response; 6/7 complete suppression of IPS; comparable to lorazepam without sedation.	Completed	8
NCT04244175 (REALIZE / CVL-865-SZ-001)	2	Drug-Resistant Focal Onset Seizures (Adjunctive)	Darigabat (dose not specified in overviews) vs. Placebo	Change in focal onset seizure frequency/week; 50% responder rate; seizure-freedom	~150-154	Results pending (data readout expected mid-2024)	Completed (May 2024)	3
NCT04686786 (CVL-865-SZ-002 OLE)	2	Focal Onset Seizures (Open-Label Extension)	Darigabat	Safety, Tolerability, Long-term seizure control	~120	Results not detailed	Completed (Dec 2024)	4
Phase 1 Acute Anxiety (CO2 Challenge)	1	Acute Anxiety (Healthy Volunteers)	Darigabat (7.5 mg BID, 25 mg BID) vs. Placebo, Alprazolam (1 mg BID)	Change in Panic Symptoms List (PSL-IV) total score; VAS Fear score	N/A (HV study)	Darigabat 7.5mg & 25mg BID significantly improved PSL-IV vs. placebo; 7.5mg improved VAS Fear.	Completed (Results Feb 2022)	8
NCT05941442 (ADAPT / CVL-865-PA-2001)	2	Panic Disorder	Darigabat (25 mg BID after titration) vs. Placebo	Change in Panic Disorder Severity Scale (PDSS) total score; Panic attack frequency	80	Results pending	Completed (Mar 2025)	1
NCT02310568 (GAD)	2	Generalized Anxiety Disorder (Adjunctive)	Darigabat (PF-06372865, 2.5 mg BID, 7.5 mg BID) vs. Placebo	Change in Hamilton Anxiety Inventory (HAM-A) total score; Sheehan Disability Scale	90 (of 384 planned)	No differentiation from placebo on primary or secondary endpoints.	Terminated	1
Phase 2 CLBP	2	Chronic Lower Back Pain	Darigabat vs. Placebo	Pain reduction	N/A	Lack of efficacy.	Discontinued	1
NCT03351751 (Multiple Dose PK/Safety HV)	1b	Healthy Volunteers	Darigabat (25 mg BID, 42.5 mg BID maintenance after titration) vs. Placebo	PK parameters, Safety, Tolerability	18-19	Dose-proportional PK; t1/2 ~11h; well-tolerated; no withdrawal symptoms.	Completed	14
NCT05824143 (CVL-865-HV-1003 DDI Study)	1	Healthy Volunteers	Darigabat + Carbamazepine	PK of Darigabat	13-15	Results not detailed	Completed (Jun 2023)	16

4.4. Formulations, Dosage, and Administration in Clinical Trials

• Route of Administration: Darigabat has been consistently administered orally in clinical trials.[2]
• Dosage Forms:
• Tablets: Used in the photosensitive epilepsy trial (17.5 mg and 52.5 mg single doses) [15] and generally implied for other patient trials.[3]
• Oral Suspension: Utilized in early Phase 1 single ascending dose studies in healthy volunteers (dose range 0.04–100 mg).[15]
• Concentrations/Dosages Investigated:
• Epilepsy (Photosensitive): Single doses of 17.5 mg and 52.5 mg.[15]
• Epilepsy (Focal Onset, REALIZE): Specific maintenance doses are not consistently detailed in the provided overviews, but adjunctive BID dosing was employed.[26] Preclinical models used 0.3–10 mg/kg PO.[17]
• Panic Disorder (Phase 1, CO2 Challenge): 7.5 mg BID and 25 mg BID.[22]
• Panic Disorder (Phase 2, ADAPT): A titration period (up to a maximum of 12.5 mg BID for two weeks) followed by a maintenance dose of 25 mg BID for 12 weeks.[31]
• GAD (Phase 2, terminated): 2.5 mg BID and 7.5 mg BID.[11]
• Healthy Volunteers (Multiple Dose PK/Safety, NCT03351751): Maintenance doses of 25 mg BID and 42.5 mg BID, achieved after a 7-day titration period.[14]
• Duration of Use in Studies:
• Photosensitive Epilepsy: Single dose administration.[8]
• Focal Onset Seizures (REALIZE): Maintenance phase up to Day 71 (approximately 10 weeks), with an open-label extension trial also conducted.[16]
• Panic Disorder (Phase 1, CO2 Challenge): 8 days of treatment.[22]
• Panic Disorder (Phase 2, ADAPT): Total treatment duration of 14 weeks (2 weeks titration + 12 weeks maintenance).[31]
• GAD (Phase 2, terminated): Planned for 8 weeks; however, the study was terminated early for some participants.[11]
• Healthy Volunteers (NCT03351751): 21 days of treatment (7 days titration followed by 14 days maintenance).[15]

The consistent mention of dose titration in healthy volunteer studies [2] and its incorporation into the ADAPT panic disorder trial protocol [31], coupled with the observation that somnolence was reduced after titration in healthy volunteer studies [23], strongly suggests that managing initial CNS side effects through gradual dose escalation is a key component of Darigabat's administration strategy. This approach is common for CNS-active medications, as it allows the body to acclimate, thereby improving overall tolerability and adherence. Rapid initiation at target therapeutic doses might otherwise lead to a higher incidence or severity of adverse events.

5. Safety and Tolerability Profile

5.1. Adverse Events

Across various clinical trials, Darigabat has generally been described as well-tolerated.[2]

Common Adverse Events:

The most frequently reported adverse events, primarily emerging from studies in healthy volunteers and trials for GAD and panic disorder, include 2:

• Dizziness: Often cited as the most frequently reported adverse event in some studies.[14]
• Somnolence: Typically described as mild-to-moderate and often reported to diminish or be manageable with dose titration.[2]
• Fatigue.[2]
• Headache.[2]
• Bradyphrenia (slowness of thought).[2]
• Modest memory impairment / mild cognitive impairment: The 7.5 mg dose in the GAD trial demonstrated some impairment on the Digit Symbol Substitution test.[2]
• Balance impairment / Disturbance in attention.[2]
• Feeling abnormal.[2]

Most of these adverse events were characterized as mild in severity.[14] Table 5 summarizes common adverse events.

Table 5: Common Adverse Events Reported in Darigabat Clinical Trials

Adverse Event	Frequency/Severity Indications	Relevant Trial(s)/Population	Source Snippet(s)
Dizziness	Most frequently reported (mild)	Healthy Volunteers (HV), GAD, Panic (Phase 1)	2
Somnolence	Mild-to-moderate, often reduced with titration	HV, GAD, Panic (Phase 1)	2
Fatigue	Common, mild	HV, Panic (Phase 1)	2
Headache	Common, mild	HV, GAD	2
Bradyphrenia (Slowness of thought)	Common	HV, Panic (Phase 1)	2
Cognitive/Memory Impairment (mild/modest)	Reported; DSST impairment at 7.5mg in GAD trial	HV, GAD	2
Balance Impairment / Disturbance in Attention	Common	HV, Panic (Phase 1)	2

Serious Adverse Events (SAEs):

No serious adverse events were reported in the Phase 1 trial for acute anxiety.22 The multiple-dose Phase 1 study in healthy volunteers (NCT03351751) also reported no clinically significant safety findings.23 Detailed information regarding SAEs from the larger, more recently completed Phase 2 trials in epilepsy (REALIZE) and panic disorder (ADAPT) is not yet available in the provided documentation.

Withdrawal Symptoms:

An important observation from the Phase 1 multiple-dose study in healthy volunteers was the lack of reported withdrawal symptoms upon discontinuation of Darigabat treatment.14 This is a potentially significant differentiating factor from traditional benzodiazepines, which are known for dependence and withdrawal syndromes. The formal assessment of withdrawal symptoms, using tools like the Penn Physician's Withdrawal Checklist (PWC), was included as a secondary endpoint in the ADAPT Phase 2 panic disorder trial (NCT05941442), indicating that this aspect is being systematically investigated.31 Confirmation of a low withdrawal liability in larger patient populations and over longer treatment durations would represent a major clinical advantage for Darigabat.

Suicidality:

The assessment of suicidality, typically using instruments like the Columbia Suicide Severity Rating Scale (C-SSRS), has been a standard component of safety monitoring in Darigabat clinical trials, including NCT05824143 (DDI study), NCT05941442 (ADAPT panic disorder), and NCT04244175 (REALIZE epilepsy).25 No specific concerns regarding suicidality have been highlighted in the available results summaries.

While Darigabat is designed to minimize α1-mediated sedation and is generally reported as "well-tolerated," the consistent reporting of dizziness and somnolence as common adverse events, even if often mild or manageable with dose titration, suggests that a complete separation of therapeutic effects from all CNS depressant effects is challenging.[2] The GAD trial, for instance, noted impairment on the Digit Symbol Substitution test with the 7.5 mg dose, alongside reports of somnolence.[11] This indicates that either the α2/3/5 modulation itself contributes to these effects at therapeutically relevant doses, or that the "sedation window" (the dose range providing efficacy without unacceptable sedation) is narrower than ideally hoped for in some contexts. The α1-sparing strategy may reduce the severity or incidence of sedation compared to non-selective benzodiazepines, but it does not appear to eliminate these CNS effects entirely, particularly at doses required for certain therapeutic outcomes. This nuance is important for managing expectations and for patient counseling should Darigabat eventually reach the market.

5.2. Contraindications

The provided research materials do not list any specific contraindications for Darigabat.[1] It is important to note that [34], and [35] discuss contraindications for other medications (dabigatran, darifenacin, general antiepileptics) or general classes of drugs [38], but these are not directly attributable to Darigabat without specific data. As an investigational drug, formal contraindications would be established by regulatory authorities upon review of comprehensive safety and efficacy data, and would be detailed in the official prescribing information if the drug is approved. General contraindications for other GABA modulators, such as known hypersensitivity to the compound or components of its formulation, might be considered, but their direct applicability to Darigabat remains speculative without specific supporting evidence.

5.3. Warnings and Precautions

Similar to contraindications, specific warnings and precautions for Darigabat are not extensively detailed in the available snippets, beyond general statements regarding its investigational status and the observed adverse event profile.[2]

Based on its mechanism of action as a GABAA PAM and its observed CNS effects (dizziness, somnolence, potential cognitive effects), general precautions applicable to CNS-active drugs would likely be relevant. These would typically include:

• Caution regarding activities requiring mental alertness and motor coordination, such as driving or operating heavy machinery, particularly during initial treatment or after dose increases.
• The need for dose titration, as discussed, to manage initial CNS effects and improve tolerability.[2]
• Potential for additive CNS depression if used concomitantly with other CNS depressant substances (see Drug Interactions). General precautions for the broader class of GABA modulators can include risks of sedation, dizziness, and, for some agents, potential for dependence and effects on psychomotor performance.[38] While Darigabat is designed to mitigate some of these, particularly dependence and severe sedation, the reported adverse events still warrant caution.

5.4. Drug Interactions

The potential for drug interactions with Darigabat primarily stems from its metabolism and its pharmacodynamic effects on the CNS.

Metabolic Interactions:

• Darigabat is primarily metabolized by the cytochrome P450 3A4 (CYP3A4) enzyme system.[2]
• CYP3A4 Inducers: Co-administration with strong CYP3A4 inducers (e.g., carbamazepine, rifampin, phenytoin, St. John's Wort) could potentially decrease plasma concentrations of Darigabat, leading to reduced efficacy. The clinical trial NCT05824143 specifically investigated the interaction with carbamazepine, highlighting the recognized importance of this pathway.[16] The proactive nature of this DDI study is crucial for informing dosing guidelines if Darigabat is used adjunctively with enzyme-inducing antiepileptic drugs or other CYP3A4 inducers.
• CYP3A4 Inhibitors: Conversely, co-administration with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir, clarithromycin) could increase plasma concentrations of Darigabat, potentially increasing the risk and/or severity of adverse events.

Pharmacodynamic Interactions:

• CNS Depressants: As a GABAA PAM with known CNS effects such as dizziness and somnolence, Darigabat has the potential for additive CNS depressant effects if used concomitantly with other substances that depress the CNS. This includes alcohol, benzodiazepines, opioids, sedative-hypnotics, and certain antidepressants or antipsychotics. Such combinations could lead to excessive sedation, cognitive impairment, and impaired motor function.

Table 6: Known or Potential Drug Interactions with Darigabat

Interacting Drug/Class	Potential Mechanism of Interaction	Potential Clinical Consequence	Source/Rationale
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin, phenytoin, St. John's Wort)	Increased metabolism of Darigabat via CYP3A4 induction	Decreased plasma concentrations of Darigabat, potentially leading to reduced efficacy	2; General PK principles
Strong CYP3A4 Inhibitors (e.g., ketoconazole, ritonavir, clarithromycin, grapefruit juice)	Decreased metabolism of Darigabat via CYP3A4 inhibition	Increased plasma concentrations of Darigabat, potentially leading to increased risk/severity of adverse events	2; General PK principles
Other CNS Depressants (e.g., alcohol, benzodiazepines, opioids, sedative-hypnotics)	Additive pharmacodynamic effects on CNS depression	Increased risk of sedation, dizziness, cognitive impairment, respiratory depression (depending on agent)	General pharmacology of GABAergic agents; 2 (observed AEs)

6. Use in Specific Populations

Information regarding the use of Darigabat in specific populations such as pregnant or lactating women, children, and the elderly is limited, as is typical for investigational drugs in relatively early stages of clinical development.

• Pregnancy: There is no specific clinical data available from the provided snippets concerning the use of Darigabat in pregnant women.[39] General pharmacological principles dictate caution with CNS-active agents during pregnancy, and use would typically be considered only if the potential benefit to the mother clearly justifies the potential risk to the fetus. Animal reproduction studies, if conducted, would provide initial insights, but human data is paramount.
• Lactation: Similarly, no specific clinical data on Darigabat's use during breastfeeding or its excretion into human milk are available in the provided documents.[43] The potential for excretion into breast milk and subsequent effects on the nursing infant would need to be evaluated.
• Pediatric Use: The provided research snippets do not contain specific information on clinical trials or the established safety and efficacy of Darigabat in pediatric populations.[46] While some GABAA modulators are used in pediatric epilepsy (e.g., diazepam for seizure clusters in children older than 6 years [46]), this does not directly inform Darigabat's potential pediatric application without dedicated studies.
• Geriatric Use: Specific clinical trial data focusing on geriatric populations for Darigabat are also absent from the provided materials.[50] General pharmacological principles for CNS-active drugs in older adults—such as increased sensitivity to side effects like dizziness, somnolence, cognitive impairment, and an increased risk of falls—would likely apply.[51] If Darigabat were to be used in this population, cautious dosing, potentially starting at lower doses with slow titration, and careful monitoring would be essential.

The absence of specific data on Darigabat in these special populations represents a significant information gap. While this is standard for drugs in earlier phases of development, it underscores major areas requiring future research should Darigabat progress towards regulatory approval. Regulatory agencies like the FDA and EMA typically mandate such data or provide clear justification for its absence (e.g., waivers or deferrals for pediatric investigation plans). Given Darigabat's CNS effects, such as dizziness and somnolence [2], and the known heightened sensitivity of geriatric patients to such effects from other CNS-active medications [51], it can be reasonably inferred that if Darigabat were to be used in elderly individuals, it would necessitate careful dose selection and vigilant monitoring to mitigate risks such as falls, confusion, and excessive sedation. This would be a particularly important consideration if Darigabat were explored for conditions with a higher prevalence in older age groups.

7. Regulatory Status and Future Outlook

7.1. Orphan Drug Designation (ODD)

Based on the available information, there is no indication that Darigabat (or its developmental codes CVL-865, PF-06372865) has received Orphan Drug Designation (ODD) from either the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for any of its investigated indications.[4] One source explicitly states "FDA Designation: None *" for Darigabat under Pfizer's development.[4] While some forms of epilepsy can qualify for ODD if they meet the prevalence criteria for rare diseases, Darigabat does not currently appear to have this status.

7.2. Current Stage of Development and Projected Timelines

As of early 2025, Darigabat is in the late stages of Phase 2 clinical development for its primary target indications:

• Focal Onset Seizures (Epilepsy): The REALIZE trial (NCT04244175) was completed in May 2024, with data readout anticipated around mid-2024.[16]
• Panic Disorder: The ADAPT trial (NCT05941442) was completed in March 2025.[4]

The acquisition of Cerevel Therapeutics by AbbVie in August 2024 means that AbbVie now oversees the continued development of Darigabat.[7] AbbVie's Q4 2024 financial results, reported in early 2025, did not provide specific updates on the Darigabat REALIZE trial results but reaffirmed the company's commitment to its neuroscience pipeline.[69]

Darigabat is at a critical juncture following AbbVie's acquisition and the recent completion of key Phase 2 trials. The forthcoming results from the REALIZE (epilepsy) and ADAPT (panic disorder) studies will be decisive for its progression into more extensive and costly Phase 3 programs. Positive data under AbbVie's stewardship could significantly accelerate its development, while negative or equivocal findings might lead to reprioritization or discontinuation, particularly given its past discontinuations for GAD and chronic pain.

7.3. Discussion of Potential and Future Directions

Darigabat holds the potential to become a novel therapeutic option for individuals with drug-resistant focal epilepsy and panic disorder, provided that the ongoing and upcoming Phase 2 and subsequent Phase 3 trials demonstrate a favorable efficacy and safety profile.[3] Its primary differentiating feature lies in its α2/3/5 GABAA receptor subtype selectivity, which theoretically offers an advantage over non-selective benzodiazepines by potentially reducing side effects such as sedation, cognitive impairment, and the risks of dependence and withdrawal.[2]

The future development of Darigabat will be heavily influenced by the outcomes of the REALIZE and ADAPT Phase 2 trials. Positive and clinically meaningful results would likely pave the way for Phase 3 programs. Further research might also explore its utility in other anxiety spectrum disorders or specific types of epilepsy where its unique modulatory mechanism could be particularly relevant. However, significant data gaps concerning long-term safety and efficacy, as well as its effects in special populations (pediatric, geriatric, pregnant/lactating women), will need to be addressed.

The quest for a "non-sedating anxiolytic" or a GABAergic agent with a significantly improved therapeutic window is a long-standing challenge in neuroscience. A December 2024 review [7] contextualized Darigabat (as PF-06372865) within this broader search, noting its progression to proof-of-concept studies but also mentioning that it, along with other subtype-selective GABAA PAMs like TPA-023 and AZD7325, "did not achieve efficacy endpoints in patients" (referring specifically to the GAD indication). This perspective suggests that the path for Darigabat, particularly in anxiety disorders, may still be demanding. For Darigabat to succeed, especially in panic disorder, it must demonstrate not only statistically significant efficacy but also a clearly superior and clinically meaningful side-effect profile compared to existing treatments (such as SSRIs, SNRIs, or even the judicious use of benzodiazepines). The positive results from the Phase 1 CO2 challenge model for panic symptoms [22] are encouraging, but the results from the larger Phase 2 ADAPT trial will be crucial in determining its viability for this indication.

The development timeline for CNS drugs is notoriously lengthy and fraught with high attrition rates. Despite being in development for several years under different pharmaceutical stewardship (Pfizer, then Cerevel, now AbbVie), Darigabat remains in Phase 2 for its lead indications.[1] This underscores the inherent challenges in bringing novel CNS therapies to market. The acquisition by AbbVie may provide the necessary resources and expertise to navigate the expensive and complex late-stage development phases, but even with successful trial outcomes, market approval is likely still several years away.

8. Conclusion

Darigabat (CVL-865, PF-06372865) is an orally active, investigational GABAA receptor positive allosteric modulator, distinguished by its selectivity for receptors containing α2, α3, and α5 subunits, while aiming to minimize activity at α1-containing subunits. This profile is designed to reduce α1-mediated side effects commonly associated with non-selective benzodiazepines, such as sedation, while preserving or enhancing therapeutic effects like anxiolysis and anticonvulsant activity. Pharmacokinetically, it is primarily metabolized by CYP3A4 and possesses an elimination half-life of approximately 11 hours after multiple doses.

Preclinical studies and early clinical trials have provided evidence of its anxiolytic and anticonvulsant potential. Clinical development, now under the stewardship of AbbVie following its acquisition of Cerevel Therapeutics, is currently focused on drug-resistant focal epilepsy and panic disorder, with key Phase 2 trials (REALIZE for epilepsy and ADAPT for panic disorder) having recently completed or with data readouts imminent. Earlier development for Generalized Anxiety Disorder and chronic low back pain was discontinued due to a lack of efficacy.

Darigabat has generally been reported as well-tolerated in clinical studies to date. Common adverse events include dizziness and somnolence, which are often characterized as mild and may be managed with dose titration. Encouragingly, early data from a healthy volunteer study suggested a low potential for withdrawal symptoms upon discontinuation, a significant potential advantage over traditional benzodiazepines.

The therapeutic potential of Darigabat hinges on the forthcoming results from its Phase 2 trials in epilepsy and panic disorder. Positive outcomes demonstrating a clear and clinically meaningful benefit, coupled with a superior safety and tolerability profile compared to existing therapies, would be crucial for its advancement into Phase 3 development and eventual regulatory consideration. Significant data gaps remain, particularly concerning long-term efficacy and safety, as well as its use in special populations (pediatric, geriatric, pregnant, and lactating individuals). The journey of Darigabat underscores both the promise of targeted GABAA receptor modulation and the inherent complexities of developing novel treatments for CNS disorders. Its future trajectory will be significantly shaped by the upcoming clinical data and AbbVie's strategic decisions for its neuroscience pipeline.

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