Bexicaserin for the treatment of seizures in developmental and epileptic encephalopathies: A phase 1b/2a trial (PACIFIC)

Abstract

Objective

This randomized, double‐blind, phase 1b/2a clinical trial was designed to evaluate the safety, tolerability, and efficacy of oral bexicaserin versus placebo for the treatment of seizures in adolescents and adults with developmental and epileptic encephalopathies (DEEs).

Methods

Eligible participants had a DEE diagnosis, were aged 12–65 years, and were taking 1–4 concomitant antiseizure medications. Randomization to treatment groups (4:1 bexicaserin:placebo) was stratified by type of DEE (Dravet syndrome [DS], Lennox–Gastaut syndrome [LGS], or DEE Other). Following a 28‐day baseline period, the treatment period consisted of a 15‐day flexible uptitration period (6, 9, or 12 mg three times daily, 5 days each) and a 60‐day maintenance period on the highest tolerated dose. Primary end points were safety (adverse events) and change from baseline in countable motor seizure frequency.

Results

Forty‐three and nine participants were assigned to bexicaserin treatment and placebo, respectively, and received ≥1 dose (safety set); 35 bexicaserin and nine placebo participants completed titration, entered the maintenance period, and had ≥1 seizure measurement during the maintenance period (full analysis set). Twenty‐eight of 43 bexicaserin‐treated participants (65.1%) and three of nine (33.3%) in the placebo group reported drug‐related treatment‐emergent adverse events (TEAEs); seven of 43 participants (16.3%) discontinued bexicaserin due to a TEAE during titration and two of 43 (4.7%) during maintenance, most frequently due to somnolence. Median reductions in countable motor seizure frequencies were −59.8% with bexicaserin and −17.4% with placebo; reductions with bexicaserin were observed across DEEs (DS, −74.6%; LGS, −50.8%; DEE Other, −65.5%). The proportion of participants achieving ≥50% reductions during the treatment period (responder analysis) was 60.0% with bexicaserin versus 33.3% with placebo.

Significance

Bexicaserin was well tolerated and associated with clinically relevant reductions in countable motor seizure frequencies in participants with a variety of DEEs. This novel trial design may expand treatment access to patients previously excluded from clinical trials.

Key points.

• Bexicaserin, a highly selective 5HT_2C receptor superagonist, is an investigational molecule in clinical development that has progressed to phase 3 for the treatment of seizures associated with DEEs.

• In this phase 1b/2a clinical trial (PACIFIC), bexicaserin exhibited a favorable safety and tolerability profile in adolescents and adults with any type of DEE.

• Bexicaserin treatment reduced countable motor seizure frequency by −59.8% from baseline, with 60.0% of participants experiencing a ≥50% reduction in countable motor seizures.

• Reductions in countable motor seizure frequency were observed across DEEs (DS, −74.6%; LGS, −50.8%; DEE Other, −65.5%).

• Results support the evaluation of bexicaserin in patients with etiologically heterogenous DEEs in one trial.

1. INTRODUCTION

Developmental and epileptic encephalopathies (DEEs) comprise the most severe group of epilepsies, characterized by treatment‐resistant seizures, developmental slowing or regression, and frequent epileptiform activity on electroencephalography. ¹ , ² , ³ , ⁴ However, many patients with a DEE do not fit criteria for any of the known epilepsy syndromes. ² DEEs are etiologically heterogeneous and can be of genetic, structural, immune, or acquired etiology, or the etiology may be unknown. ¹ , ² , ⁴ , ⁵ , ⁶ A genetic cause is currently identified in 50% of patients, with more than 1000 genes implicated to date. ² , ⁷ Regardless of etiology, DEEs are associated with significant morbidities and substantially reduced quality of life. ² , ⁸ Individuals with treatment‐resistant epilepsies such as DEEs are also at greater risk of status epilepticus (SE) or death (including sudden unexpected death in epilepsy [SUDEP]). ² , ⁹ With improved seizure control, the risk of SE and SUDEP, and the ongoing cognitive or behavioral disruption driven by the epileptic encephalopathy, may be ameliorated, which will significantly improve quality of life for patients, their families, and caregivers. ⁴ , ¹⁰ , ¹¹ , ¹²

Despite the diverse etiologies that underlie DEEs, clinical trials have historically focused on Dravet syndrome (DS), CDKL5 deficiency disorder (CDD), tuberous sclerosis complex (TSC), and Lennox–Gastaut syndrome (LGS). ³ , ¹³ Although 11 different antiseizure medications (ASMs) are currently approved in the United States for the treatment of seizures in patients with DS, CDD, TSC, or LGS ¹⁴ (with additional ASMs applied to treat specific seizure types), most patients with these disorders do not achieve seizure control. This unmet need necessitates the development of new treatments. In addition, the exclusion of individuals with the remaining DEEs from rigorous, randomized controlled trials leaves a large portion of this vulnerable population with the most severe group of epilepsies without novel, proven options to treat seizures. In the absence of controlled safety and efficacy data in patients with DEEs other than the aforementioned, ASMs are prescribed off‐label, making it challenging to make informed decisions around the treatment of seizures in the wider group of DEEs. ¹⁵

With the array of comorbid conditions associated with DEEs and the complex polypharmacy that is typically required to manage patients, ³ , ¹³ the adverse effect burden and potential drug–drug interactions (DDIs) must be carefully considered. Certain DDIs associated with ASMs can further contribute to cognitive and functional impairment for individuals with DEEs, adding to the challenges of treating these patients. ¹⁶ Health care providers could greatly improve patient care with treatment options that not only improve seizure control, but also minimize the potential for adverse effects or DDIs. ¹⁶ , ¹⁷

Bexicaserin is an investigational molecule in development for the treatment of seizures associated with DEEs. It is an oral, centrally acting, highly selective superagonist of the 5‐hydroxytryptamine 2C (5‐HT_2C) receptor subtype, a member of the serotonin receptor family. ¹⁸ , ¹⁹ 5‐HT_2C receptors are widely expressed on inhibitory neurons in epileptogenic regions of the brain, including the cortex and hippocampus, where they are hypothesized to modulate excitatory tone. ²⁰ In support of their utility as an antiepileptic target, preclinical and clinical data have shown that 5‐HT_2C receptor activity modulates the frequency and threshold of seizure onset. ¹⁹ , ²¹ , ²² , ²³ Bexicaserin was effective at reducing motor seizures and brain epileptiform activity in animal models of seizures produced by excess excitatory activity, reduced inhibitory activity, and/or various genetic mutations, suggesting the potential for broad efficacy in DEEs stemming from diverse etiologies. ¹⁹ Through its novel selectivity for 5‐HT_2C, bexicaserin may reduce seizures by increasing the activity of inhibitory interneurons within epileptogenic cortex, while minimizing potential adverse effects associated with (off‐target) engagement of other serotonin receptor subtypes (e.g., 5‐HT_2B receptors in cardiovascular tissue, 5‐HT_2A receptors producing hallucinogenic activity). ²⁴ , ²⁵

Herein, we report the primary results from the randomized, double‐blind, placebo‐controlled phase 1b/2a clinical trial of bexicaserin, which was designed to evaluate the safety, tolerability, and efficacy of bexicaserin in the treatment of seizures for patients with any type of DEE.

2. MATERIALS AND METHODS

2.1. Participants

Eligible participants were aged ≥12 and ≤65 years, had a DEE diagnosis (DS, LGS, or any other type of DEE [“DEE Other”]), and had an average of ≥4 countable motor seizures per 4‐week period during the 12 weeks before screening and ≥4 during the 4‐week screening period. Participants were taking 1–4 concomitant ASMs at stable doses for ≥4 weeks before screening (or 30 days for cannabidiol‐based drugs). Current or prior use of fenfluramine or lorcaserin was prohibited due to their potentially confounding activity at 5‐HT_2C receptors. Participants were also prohibited from taking topiramate (unless stable for ≥6 months before screening), anorectic agents, monoamine oxidase inhibitors, or serotonin agonists or antagonists. Individuals with a history of cardiovascular or cerebrovascular disease (e.g., pulmonary arterial hypertension, cardiac valvulopathy, myocardial infarction, or stroke) were ineligible. Diagnostic eligibility criteria specific to each DEE (DS, LGS, DEE Other) are provided in Table S1. Additional diagnostic information collected for participants in the DEE Other group can be found in Supplemental Methods in Appendix S2.

2.2. Study design

PACIFIC (NCT05364021; registered March 22, 2022) was a randomized, double‐blind, placebo‐controlled, parallel‐group, dose‐escalation phase 1b/2a clinical trial of bexicaserin for the treatment of seizures in DEEs (Figure S1). Enrollment took place across 34 sites in the United States and Australia (study dates: March 3, 2022 to November 20, 2023). Eligible participants were randomly assigned 4:1 to receive bexicaserin or placebo as a liquid either orally or through a G‐tube/percutaneous endoscopic gastrostomy tube; doses were administered ≥6 h apart. Randomization was stratified by type of DEE using a randomization schedule generated by an Interactive Web Response System in a manner that could include 10 participants with DS (bexicaserin, n = 8; placebo, n = 2), 10 with LGS (bexicaserin, n = 8; placebo, n = 2), and 30 with DEE Other (bexicaserin, n = 24; placebo, n = 6). Epilepsy syndromes and classification of seizure types for all participants were reviewed and confirmed by the Epilepsy Study Consortium. ²⁶ The investigators, clinical site staff, participants and their caregivers, clinical site monitors, study management team at the sponsor, and clinical research organization involved in the study were blinded to the assigned treatment throughout the study. Treatment was provided in 8‐oz amber polyethylene terephthalate bottles labeled “LP352‐Oral Solution 3 mg/mL or Placebo.”

Potential participants first underwent a 7‐day initial screening period to confirm inclusion and exclusion criteria. This was followed by a 28‐day baseline period during which they were further screened for eligibility based on an observation of ≥4 countable motor seizures, with a minimum of 2 countable motor seizures during the first 14 days and 2 during the second 14 days. The participant could not be seizure‐free for >21 consecutive days, to mitigate confounding seizure clustering.

Following the 5‐week screening/baseline period, eligible participants entered a 15‐day flexible uptitration period to determine the maximum tolerated dose they would receive during the maintenance period (6 mg, 9 mg, or 12 mg three times daily [TID]; increased every 5 days, as tolerated). Study drug or placebo were administered while the participant's ASM dosing regimen at enrollment remained stable. After completing the 60‐day maintenance period, participants could elect to enter the 52‐week open‐label extension (OLE); otherwise, participants underwent a 5–15‐day taper (depending on the maintenance dose, which was reduced every 5 days) and were followed for an additional 30 days.

2.3. Assessments

To collect seizure data, caregivers recorded seizure frequency and type(s) in a daily diary throughout the screening period and clinical trial. Each site completed a Seizure Identification and Diagnostic Review Form for every participant. This information was submitted to the Epilepsy Study Consortium after the screening visit for review and approval and used to ensure seizures were classified accurately and the participant's enrollment was appropriate; subsequently, it was used to help confirm diagnostic eligibility criteria. Countable motor seizures were defined in accordance with the international seizure classification as a means of reflecting a clear, formalized end point to appropriately capture any countable seizure with a motor component. Difficult‐to‐count seizures were analyzed using the best estimate of seizure frequency reported by caregivers. SE occurred when a participant had a seizure lasting >5 min or had >1 seizure within a 5‐min period without returning to a baseline level of consciousness between episodes; these seizures were considered a medical emergency and were documented as adverse events. For additional information regarding seizure classifications (e.g., countable motor seizures, nonmotor seizures), refer to Supplemental Methods in Appendix S2.

2.4. End points

The primary safety end point was the incidence and severity of treatment‐emergent adverse events (TEAEs). The primary efficacy end point was the median percentage change from baseline in observed countable motor seizure frequency during the treatment period (titration and maintenance).

Additional end points in the protocol included the highest tolerated dose achieved and maintained; median percentage change from baseline in observed countable motor seizure frequency during the maintenance period; median percentage change from baseline in total seizure frequency during the treatment period; and proportion of participants with ≥50% reduction in frequency of countable motor seizures and total seizures during the treatment period.

2.5. Statistical analysis

Random assignment of 50 participants was planned, with the aim of enrolling 10 with DS, 10 with LGS, and 30 with DEE Other (i.e., any other type of DEE); no formal sample size calculation was performed for this phase 1b/2a trial. For continuous variables, data are summarized as the number of participants, mean, SD, median, minimum, and maximum by treatment group, with two‐sided 95% confidence intervals unless otherwise noted. For categorical variables, data are presented as the number and proportion of patients for each category by treatment group. No formal hypothesis testing was carried out; therefore, any p‐values generated were considered nominal and were not adjusted for multiple testing. Given the early phase and small size of this study, there was no formal hierarchy established for statistical testing, and individual datapoints are presented instead of variance estimates. For seizure frequency end points (defined as the percentage change from baseline in seizure frequency), the Wilcoxon–Mann–Whitney test was used to compare the distributions of the percentage change from baseline in seizure frequency. The median percentage change in each group was used to summarize the results. All end points in the protocol were defined as proportions (percentage of participants) and were analyzed using Fisher exact test. Change from baseline in countable motor seizures was evaluated post hoc using a two‐sample t‐test comparing the means in the placebo and bexicaserin groups.

Safety end points were assessed in all participants who received ≥1 dose. Efficacy end points were evaluated in the full analysis set, which included all participants who completed the titration period and who had ≥1 postbaseline seizure measurement available during the maintenance phase.

2.6. Standard protocol approvals, registrations, and patient consents

This trial was registered with ClinicalTrials.gov (NCT05364021). It was conducted in accordance with the Declaration of Helsinki and relevant federal regulations, in compliance with the International Council for Harmonisation good clinical practice guidelines and according to the appropriate regulatory requirements in the countries where the study was conducted. The clinical study protocol, protocol amendments, informed consent forms, and other study‐related documents were reviewed and approved by independent ethics committees and institutional review boards for each study center. Prior to entering the study, informed consent was obtained from the parents or legal guardians of all participants.

3. RESULTS

3.1. Participants

Fifty‐two participants were enrolled across 34 sites (LGS, n = 29; DS, n = 4; DEE Other, n = 19; Figure 1). Demographics and baseline characteristics were largely comparable between treatment groups, considering the small number of participants assigned to receive placebo (Table 1). Seizure types reported in ≥20% of participants, based on seizure history taken at baseline (safety set, n = 52), were generalized tonic–clonic (n = 33 [63.5%]), absence (n = 28 [53.8%]), tonic (n = 28 [53.8%]), focal (n = 25 [48.1%]), myoclonic (n = 22 [42.3%]), focal to bilateral tonic–clonic (n = 12 [23.1%]), and atonic seizures (n = 11 [21.2%]) based on 2025 classification terms from the International League Against Epilepsy ²⁷ (see Appendix S2, Supplemental Methods for details on seizure classification). All participants had a history of countable motor seizures at enrollment and screening. The median (range) number of baseline countable motor seizures observed during the 28‐day screening period was 31.5 (18–70) for participants with DS, 51.5 (5–389) for LGS, and 20.8 (6–325) for DEE Other. All participants had ≥1 concomitant ASM, the most common of which were clobazam, valproate, levetiracetam, cannabidiol, and lamotrigine.

FIGURE 1.

Summary of treatment disposition in the phase 1b/2a trial of bexicaserin for developmental and epileptic encephalopathies (DEEs; PACIFIC). Safety was assessed in all participants who received ≥1 dose of bexicaserin or placebo (n = 52); efficacy was evaluated in the full analysis set, which included all participants who completed titration and had ≥1 postbaseline seizure measurement during maintenance (n = 44). DS, Dravet syndrome; LGS, Lennox–Gastaut syndrome.

TABLE 1.

Demographics and baseline characteristics.

Characteristic	Placebo, n = 9	Bexicaserin, n = 43	Overall, N = 52
Age, years
Mean (SD)	26.7 (7.7)	23.8 (9.6)	24.3 (9.3)
Median	23	23	23.0
Minimum, maximum	19, 41	12, 55	12, 55
Sex, n (%)
Male	7 (77.8)	21 (48.8)	28 (53.8)
Female	2 (22.2)	22 (51.2)	24 (46.2)
Race, n (%)
Asian	2 (2.22)	3 (7.0)	5 (9.6)
Black or African American	0	1 (2.3)	1 (1.9)
Native Hawaiian or other Pacific Islander	0	2 (4.7)	2 (3.8)
White	6 (66.7)	33 (76.7)	39 (75.0)
Other	1 (11.1)	4 (9.3)	5 (9.6)
BMI, kg/m2
Median	28.1	22.4	23.0
Minimum, maximum	19.0, 34.0	17.0, 35.0	17.0, 35.0
Countable motor seizures (4‐week baseline period), n a
Median (minimum, maximum)	24.1 (6, 80)	40.0 (5, 389)	38.2 (5, 389)
Concomitant ASMs, n (%)
Clobazam	2 (22.2)	21 (48.8)	23 (44.2)
Valproate	6 (66.7)	17 (39.5)	23 (44.2)
Levetiracetam	1 (11.1)	16 (37.2)	17 (32.7)
Cannabidiol b	3 (33.3)	14 (32.6)	17 (32.7)
Lamotrigine	4 (44.4)	13 (30.2)	17 (32.7)
DEE type, n (%)
DS	0	4 (9.3)	4 (7.7)
LGS	5 (55.6)	24 (55.8)	29 (55.8)
DEE Other	4 (44.4)	15 (34.9)	19 (36.5)

Abbreviations: ASM, antiseizure medication; BMI, body mass index; DEE, developmental and epileptic encephalopathy; DS, Dravet syndrome; LGS, Lennox–Gastaut syndrome.

^a Baseline countable motor seizures were calculated from the full analysis set (bexicaserin, n = 35; placebo, n = 9; total, n = 44).

^b Participants receiving cannabidiol were prescribed Epidiolex; in addition, one participant (in the bexicaserin group) was using cannabis sativa.

Forty‐three participants were randomly assigned to receive bexicaserin and nine to receive placebo, and each received ≥1 dose of study drug; among these participants, 35 of 43 and nine of nine, respectively, continued into the maintenance period. Of the 35 participants who received bexicaserin, 30 (85.7%) received the highest dose (12 mg TID) and 27 (77.1%) received and tolerated the highest dose through the maintenance period (Table S2). Eleven of 52 participants (21.2%) had ≥1 major protocol deviation (bexicaserin, n = 10; placebo, n = 1); most (observed in ≥2%) were related to the study procedure/missed procedure (n = 6/52 [11.5%]), study drug/dosing (n = 2/52 [3.8%]), and study procedure/visit missing (n = 2/52 [3.8%]).

Thirty‐two bexicaserin‐treated participants and nine receiving placebo completed the trial (Figure 1). All 41 participants who completed the titration and maintenance phases entered the OLE.

3.2. Safety

Safety was assessed in all participants who received ≥1 dose of study drug (safety population). Thirty‐five of 43 participants (81.4%) receiving bexicaserin and eight of nine participants (88.9%) receiving placebo reported ≥1 TEAE; 28 of 43 (65.1%) and three of nine (33.3%) experienced TEAEs that were considered drug‐related (Table 2). The most common TEAEs reported were somnolence, decreased appetite, constipation, and diarrhea. Four treatment‐related serious TEAEs were reported in three participants receiving bexicaserin (two ankle fractures [in one participant], constipation [n = 1], and change in seizure presentation [increasing seizures; n = 1]), but none led to discontinuation or dose modification; no serious treatment‐related TEAEs were reported in the placebo group.

TABLE 2.

Summary of TEAEs.

	TEAE, n (%)
	Placebo, n = 9	Bexicaserin, n = 43	Overall, N = 52
Participants with ≥1 TEAE	8 (88.9)	35 (81.4)	43 (82.7)
Drug‐related TEAE	3 (33.3)	28 (65.1)	31 (59.6)
Serious TEAE	0	3 (7.0)	3 (5.8)
Drug‐related serious TEAE	0	2 (4.7)	2 (3.8)
TEAE leading to study discontinuation a	0	9 (20.9)	9 (17.3)
TEAE leading to dose modification	1 (11.1)	10 (23.3)	11 (21.2)
TEAE leading to death	0	0	0
TEAEs by SOC b
Nervous system disorders
Somnolence	1 (11.1)	12 (27.9)	13 (25.0)
Lethargy	0	4 (9.3)	4 (7.7)
Tremor	0	3 (7.0)	3 (5.8)
Gastrointestinal disorders
Constipation	0	6 (14.0)	6 (11.5)
Diarrhea	0	5 (11.6)	5 (9.6)
Infections and infestations
Urinary tract infection	0	3 (7.0)	3 (5.8)
General disorders and administration site conditions
Fatigue	0	3 (7.0)	3 (5.8)
Pyrexia	0	3 (7.0)	3 (5.8)
Metabolic and nutritional disorders
Decreased appetite	0	9 (20.9)	9 (17.3)
Psychiatric disorders
Agitation	0	3 (7.0)	3 (5.8)
Vascular disorders
Hypotension	0	3 (7.0)	3 (5.8)

Abbreviations: SOC, system organ class; TEAE, treatment‐emergent adverse event.

^a Seven participants discontinued during titration; two discontinued during maintenance.

^b ≥5% of participants receiving bexicaserin and greater than placebo.

TEAEs leading to dose reductions were reported in 10 of 43 participants (23.3%) who received bexicaserin and one of nine participants (11.1%) who received placebo (Table 2). Nine of 43 participants in the bexicaserin group (and none in the placebo group) experienced a total of 16 TEAEs leading to study discontinuation, with discontinuations occurring more commonly during the 15‐day titration period (7/43 [16.3%]) than the 60‐day maintenance period (2/43 [4.7%]). The most frequent TEAE leading to discontinuation was somnolence (five participants receiving bexicaserin). There were no deaths or episodes of SE reported during the trial.

A review of hematology, chemistry, coagulation, urinalysis, other laboratory parameters, vital signs, electrocardiograms, and physical examination parameters revealed no clinically concerning or meaningful changes.

Potential DDIs with concomitant ASMs were evaluated based on dose‐normalized concentration geometric mean ratios after bexicaserin administration compared with baseline values. The analysis was conducted with the inclusion of participants in the placebo group and then again with the exclusion of participants in the placebo group. The data demonstrated no apparent clinically meaningful effect of bexicaserin on the pharmacokinetics of coadministered ASMs in this trial (Figure S2); concentrations remained stable across all visits.

3.3. Efficacy

Efficacy end points were evaluated in the full analysis set: those who completed the titration period and had ≥1 postbaseline seizure measurement during the maintenance phase. The primary efficacy end point—change in countable motor seizure frequency from baseline during the treatment period (uptitration and maintenance, days 1–75)—showed a median reduction of −59.8% relative to baseline among participants receiving bexicaserin and −17.4% in participants receiving placebo (Δ = 42.4%, p = .0538; Figure 2A, Table 3). Countable motor seizure frequency during the maintenance period alone demonstrated a median reduction of −58.5% with bexicaserin and −15.6% with placebo (Δ = 42.9%, p = .1040; Table 3). In an exploratory post hoc analysis, treatment with bexicaserin produced a significant placebo‐adjusted mean reduction in countable motor seizure frequency of −52.0% (p = .0206) during the treatment period. Across the DEEs (DS, LGS, DEE Other), median countable motor seizure frequency reductions were comparable, with the overall pattern of response in LGS appearing highly similar to DEE Other (Figure 2B, Table 3).

FIGURE 2.

Median change from baseline in countable motor seizure frequency during the treatment period in (A) the overall population and (B) by developmental and epileptic encephalopathy (DEE). (A) Box‐and‐whisker plots show median, quartiles 1 and 3, and range of percentage change from baseline in countable motor seizures with bexicaserin versus placebo, with individual participant values overlaid and color‐coded by their diagnosed DEE. (B) Bar plots showing median percentage change from baseline with bexicaserin versus placebo for each DEE; by chance, there were no participants with Dravet syndrome (DS) assigned to receive placebo. LGS, Lennox–Gastaut syndrome; NA, not applicable.

TABLE 3.

Seizure frequency end points.

End point subgroup	Placebo, n = 9	Bexicaserin, n = 35	Difference (p)
Median percentage change in countable motor seizures: treatment period [primary end point]	−17.4%	−59.8%	42.4% (p = .0538)
DS [bexicaserin: n = 3; placebo: n = 0]	N/A	−74.6%	N/A
LGS [bexicaserin: n = 17; placebo: n = 5]	−17.4%	−50.8%	33.4% (p = .1636)
DEE Other [bexicaserin: n = 15; placebo: n = 4]	−32.2%	−65.5%	33.3% (p = .3070)
Median percentage change in countable motor seizures: maintenance period	−15.6%	−58.5%	42.9% (p = .1040)
Median percentage change in total seizures: treatment period	−21.0%	−51.0%	30.0% (p = .2493)
Median percentage change in total seizures: maintenance period	−20.7%	−48.2%	27.5% (p = .3464)
Participants with ≥50% response in countable motor seizures: treatment period, n (%)	3 (33.3%)	21 (60.0%)	26.7% (p = .2607)
Participants with ≥50% response in total seizures: treatment period, n (%)	3 (33.3%)	18 (51.4%)	18.1% (p = .4618)

Note: No formal sample size calculation was performed for this phase 1b/2a trial, and no statistical hierarchy was prespecified; reported p‐values are nominal.

Abbreviations: DEE, developmental and epileptic encephalopathy; DS, Dravet syndrome; LGS, Lennox–Gastaut syndrome; N/A, not applicable.

In addition to changes in countable motor seizure frequency, bexicaserin‐treated participants experienced a greater median reduction in total seizure frequency during the treatment period (−51.0%) versus the placebo group (−21.0, Δ = 30.0%; Table 3); when considering the maintenance period alone, median reductions in total seizure frequencies were −48.2% with bexicaserin compared with −20.7% with placebo (Δ = 27.5%; Table 3).

A 50% responder analysis of the full analysis set demonstrated that 21 of 35 participants (60.0%) treated with bexicaserin exhibited a ≥50% reduction in frequency of countable motor seizures compared with three of nine participants (33.3%) receiving placebo (Figure 3, Table 3). Similar responses were experienced for total seizures, with 18 of 35 participants (51.4%) and three of nine participants (33.3%), respectively, achieving a ≥50% reduction in frequency of total seizures (Table 3).

FIGURE 3.

Proportion of participants with ≥50% reductions in frequency of countable motor seizures and total seizures during the treatment period (responder analysis).

4. DISCUSSION

The term “DEE” was established in 2017 to describe a large group of individually rare and universally severe epilepsies. ¹ Although these epilepsies occur due to a myriad of underlying causes, they share common symptoms. ⁴ Patients with DEEs are desperately in need of therapeutic options for treatment of their severe disorder including seizures and associated morbidities. ² However, they face several challenges, including complex polypharmacy, that can lead to DDIs or adverse side effects, and many have not had access to clinical trials of ASMs. ³ , ¹³ The phase 1b/2a clinical trial of bexicaserin was the first to investigate treatment of seizures in patients with any type of DEE to address the treatment gap for individuals who were previously excluded from clinical trials, which historically focused on participants with DS, CDD, TSC, and LGS. ³ , ¹³

Throughout the 75‐day treatment period, a favorable safety and tolerability profile was observed for bexicaserin. The most common TEAE leading to discontinuation was somnolence—a frequently observed side effect with ASMs. ²⁸ Notably, discontinuations of bexicaserin were more frequent during the 15‐day uptitration period (n = 7) compared with the maintenance period (n = 2), suggesting a flexible, slower titration strategy would likely mitigate dose‐related side effects. Furthermore, all 41 participants who completed the randomized controlled trial elected to enroll in the OLE. In the subset of participants newly exposed to bexicaserin in the OLE (placebo‐to‐bexicaserin cohort), no TEAEs led to discontinuation, indicating bexicaserin was well tolerated in the context of a more flexible titration process. ²⁹

Substantial reductions in countable motor seizure frequency and total seizure frequency were reported with bexicaserin treatment. Comparable reductions in countable motor seizure frequency were observed across all DEEs (DS, LGS, DEE Other). Notably, more than half of the participants receiving bexicaserin experienced ≥50% reductions in frequency of countable motor seizures and total seizures, a common end point used in ASM clinical trials and an accepted regulatory outcome for clinical efficacy. ³⁰ These data therefore reflect clinical relevance, particularly considering they were observed while the participants' baseline ASM regimen remained stable and in a small trial primarily designed to assess preliminary safety and tolerability. Although additional measures of treatment impact have been proposed for evaluating efficacy, ³¹ reduction in seizure frequency is a widely accepted outcome measure for ASM clinical trials. ²⁸ To support these end points, the International League Against Epilepsy and Pediatric Epilepsy Research Consortium 2019 consensus statement posited that caregiver‐documented seizures via seizure diaries are a practical and valid measure for determining the efficacy of ASMs. ³²

Seizure counting for the purposes of clinical trials can still be challenging, and some seizure types common in patients with DEEs are considered “uncountable” (e.g., myoclonic and atypical absence seizures). For this reason, most trials in LGS used “drop seizures” (defined as any seizure associated with a potential drop or fall) as the primary measure of evaluating change in seizure frequency. This approach is less than ideal because (1) many “countable” seizures that have the potential for impacting quality of life are not included in this definition; (2) not all DEEs are associated with tonic or atonic seizures, which are the most common seizure types resulting in “drop seizures”; and (3) using only “drop seizures” reduces the number of eligible trial patients, as not all DEEs have seizures associated with a “drop.” Also, nonambulant patients in wheelchairs may not be able to drop but can still have disabling tonic and atonic seizures. Therefore, several more recent ASM clinical trials have used different, broader definitions of “drop seizures” in their methodologies. ³³ However, to perform a trial across DEEs, a more inclusive measure, such as countable motor seizures, is required.

The incorporation of “countable motor seizures” as the primary measure of efficacy and the novel clinical development approach of including patients with any type of DEE in this phase 1b/2a clinical trial offers a potential regulatory path in evaluating the treatment of seizures for individuals who have the most severe forms of epilepsy. Although DS is relatively homogenous from an etiological perspective, both the LGS and DEE Other groups are etiologically heterogenous. ⁴ Notably, LGS is a well‐accepted DEE syndrome for drug development and has multiple approved ASMs. ² The comparable efficacy, safety, and etiological heterogeneity observed in LGS and DEE Other provide objective evidence that aggregating patients with any type of DEE can also serve as a viable study population, allowing far greater access and assessment of efficacy to address the urgent unmet need in these individuals. Furthermore, these results support the phase 3 clinical trial program where, for the first time, a regulatory body has endorsed this broader approach.

Taken together, the clinically relevant reductions in seizure frequencies and the limited potential for adverse effects support the potential use of bexicaserin in the treatment of seizures associated with DEEs across adolescent and adult age groups, with the possibility of treating individuals earlier in childhood, when treatment effects may be even more impactful. Because DEEs often present in infancy, participants as young as 2 years are being enrolled in the phase 3 trials of bexicaserin. Notably, and in line with preclinical studies, there was low DDI potential with bexicaserin and ASMs administered during the trial, in part due to its minimal dependency on cytochrome P450 metabolism, being a substrate instead for metabolism via UDP‐glucuronosyltransferase. ³⁴ , ³⁵ In addition, the unprecedented selectivity of bexicaserin for 5‐HT_2C over other serotonin receptor subtypes as well as (nonserotonin) molecular targets ³⁵ may offer advantages in improving seizure control, while at the same time reducing the potential for adverse effects or DDIs. ²⁴ , ²⁵ As most patients with DEEs are taking multiple ASMs, ⁴ these data convey a greater understanding of the underlying mechanism of bexicaserin while imparting confidence in how it may fit into a treatment regimen for individuals with DEEs. ³⁶

The small sample size of the entire study and the lack of a control group among participants with DS are limitations to this pilot clinical trial, preventing well‐powered and direct head‐to‐head comparisons, which are being investigated in subsequent studies. The favorable safety and efficacy results reported here are supportive of the clinical development of bexicaserin, which has since progressed with the initiation of a global phase 3 program to evaluate the efficacy and safety of bexicaserin for the treatment of seizures associated with DEEs.

Using a novel approach that included patients with all types of DEEs, results from this phase 1b/2a clinical trial (PACIFIC) suggest bexicaserin has a favorable safety and tolerability profile, and placebo‐adjusted reductions in countable motor and total seizures frequencies are attainable. The comparable efficacy and safety observed across the DEEs further support the inclusion of patients with etiologically heterogenous DEEs in one trial. This approach offers an equitable opportunity for patients with all types of DEEs to participate in pharmaceutical trials, thereby contributing valuable safety and efficacy data during drug development, with the potential for patients to gain access to a new effective medication(s). Based on these data, the US Food and Drug Administration granted bexicaserin Orphan Drug Designations for DS and LGS, Rare Pediatric Disease designation for DS, and Breakthrough Therapy designation for the treatment of seizures associated with DEEs. These will serve to further accelerate the evaluation of bexicaserin for the treatment of DEEs and potentially bring new hope to patients and their families.

FUNDING INFORMATION

Longboard Pharmaceuticals, now a part of H. Lundbeck A/S, supported this study.

CONFLICT OF INTEREST STATEMENT

D.J.D. receives research salary support from the Epilepsy Study Consortium for consulting work and/or attending scientific advisory boards with Beacon Biosignals, Biohaven Pharmaceuticals, Encoded Therapeutics, Grin Therapeutics, GW Pharma, Jazz Pharmaceuticals, Longboard Pharmaceuticals, Marinus, Neurelis, Neurocrine, Praxis, Rapport Therapeutics, SK Life Sciences, Stoke, Takeda, UCB, Xenon Pharmaceuticals, and Zogenix, and has received travel reimbursement for research advisory/scientific meetings from the Epilepsy Study Consortium, Epilepsy Foundation of America, Lennox Gastaut Foundation, France Foundation, Thomas Jefferson University, and Ministry of Health of the United Arab Emirates. I.E.S. has served on scientific advisory boards for BioMarin, Chiesi, Eisai, Encoded Therapeutics, GlaxoSmithKline, Knopp Biosciences, Nutricia, Takeda Pharmaceuticals, UCB, Xenon Pharmaceuticals, and Longboard Pharmaceuticals, has received speaker honoraria from GlaxoSmithKline, UCB, BioMarin, Biocodex, Chiesi, LivaNova, Nutricia, Zuellig Pharma, Stoke Therapeutics, Eisai, Akumentis, and Praxis, has received funding for travel from UCB, Biocodex, GlaxoSmithKline, BioMarin, Encoded Therapeutics, Stoke Therapeutics, Eisai, and Longboard Pharmaceuticals, has served as an investigator for Anavex Life Sciences, Cerevel Therapeutics, Eisai, Encoded Therapeutics, EpiMinder, Epygenyx, ES‐Therapeutics, GW Pharma, Longboard Pharmaceuticals, Marinus, Neurocrine BioSciences, Ovid Therapeutics, SK Life Science, Takeda Pharmaceuticals, UCB, Ultragenyx, Xenon Pharmaceuticals, Zogenix, and Zynerba, has consulted for Care Beyond Diagnosis, Epilepsy Consortium, Atheneum Partners, Ovid Therapeutics, UCB, Zynerba Pharmaceuticals, BioMarin, Encoded Therapeutics, Biohaven Pharmaceuticals, Stoke Therapeutics, and Praxis, is a Non‐Executive Director of Bellberry and a Director of the Australian Academy of Health and Medical Sciences, may accrue future revenue on pending patent WO61/010176 (filed: 2008): Therapeutic Compound, has a patent for SCN1A testing held by Bionomics and licensed to various diagnostic companies, and has a patent molecular diagnostic/theranostic target for benign familial infantile epilepsy (PRRT2) 2011904493 & 2012900190 and PCT/AU2012/001321 (TECH ID: 2012–009). D.G.V. was a principal investigator on the PACIFIC study and has received payments to his institution for research conducted for Longboard Pharmaceuticals (now a part of H. Lundbeck A/S), as well as for UCB Pharma, SK Life Science, and Xenon Pharmaceuticals; he has acted as a research consultant for Longboard, Praxis, SK Life Science, and Xenon Pharmaceuticals, serves on the speakers bureau for SK Life Science, and is a member of the Epilepsy Study Consortium and a member of the Board of Directors of the American Epilepsy Society. J.A.F. has served as an investigator for Praxis, UCB, Praxis, Xenon Pharmaceuticals, Biohaven, and Equilibre, received research funding from One‐8 Foundation, UCB, Eisai, GW/Jazz, Pfizer, and Lundbeck, performed consulting work and/or attended scientific advisory boards for Acadia Pharmaceuticals, Access Industries, Acuta Capital Partners, AFASCI, Agrithera, Alterity Therapeutics Limited, Angelini Pharma, Arvelle Therapeutics, Autifony Therapeutics Limited, Axonis, Baergic Bio, Bain Capital, Beacon Biosignals, Biogen, Biohaven Pharmaceuticals, Bloom Science, BridgeBio Pharma, Bright Minds Biosciences, Camp4 Therapeutics Corporation, Capsida Biotherapeutics, Cerebral Therapeutics, Cerecin, Cerevel, Ceribell, Coda Biotherapeutics, Cognizance Biomarkers, Cowen and Company, Crossject, EcoR1 Capital, EG 427, Eisai, Eliem Therapeutics, Encoded Therapeutics, Engrail, Epalex, Epihunter, Epiminder, Epitel, Equilibre BioPharmaceuticals, Genentech, Grin Therapeutics, GW Pharma, Harmony/Epygenix, Ionis Pharmaceuticals, iQure Pharma, IQVIA RDS, Janssen Pharmaceutica, Jazz Pharmaceuticals, Knopp Biosciences, Korro Bio, Leal Therapeutics, Lipocine, LivaNova, London Research & Pharmaceuticals, Longboard Pharmaceuticals, Lundbeck, Maplight Therapeutics, Marinus, Medscape/Web MD, Modulight.bio, Mosaica Therapeutics, Neumirna Therapeutics, Neurelis, Neurocrine, Neuroelectrics USA Corporation, Neurona Therapeutics, Neuronetics, Neuropace, NeuroPro Therapeutics, Neuroventis, Neurvati, Noema Pharma, Ono Pharmaceutical Co., Otsuka Pharmaceutical Development, Ovid Therapeutics, Paladin Labs, Pfizer, Praxis, PureTech, Rafa Laboratories, Rapport Therapeutics, Receptor Holdings, Rivervest Venture Partners, Sage Therapeutics, SK Life Sciences, Stoke, Stream Neuroscience, Supernus, Takeda, Taysha Gene Therapies, Third Rock Ventures, UCB, uniQure, Ventus Therapeutics, Vida Ventures Management, Xenon Pharmaceuticals, and Zogenix, received payment or honoraria for presenting on behalf of Angelini and Praxis, received support for meeting attendance from the Epilepsy Study Consortium, the Epilepsy Foundation, Angelini Pharma, Biohaven Pharmaceuticals, Cerebral Therapeutics, Ceribell, Cowen and Company, Harmony Biosciences, LivaNova, Longboard Pharmaceuticals, Maplight Therapeutics, Neumirna Therapeutics, Neurelis, Neurocrine, NeuroPace, Neurvati, Praxis, Rapport, SK Life Science, Takeda, Ventus, and Xenon Pharmaceuticals, served on advisory boards for Agrithera, Angelini, Beacon Biosciences, Biogen, Biohaven Pharmaceuticals, Bloom Sciences, Brightminds Biosciences, Cerevel, EcoR1capital, Ionis Pharmaceuticals, Jazz Pharmaceuticals, London Research, Longboard Pharmaceuticals, Marinus, Neumirna, Grin/Neurvati, Noema Pharma, Ovid Therapeutics, Rapport Therapeutics, Sage Therapeutics, Stoke, Stream Neuroscience, UCB Pharma, Ventus Therapeutics, and Xenon Pharmaceuticals, receives payment as a member of the Epilepsy Foundation and the Epilepsy Study Consortium, and is a volunteer for the American Brain Foundation. C.O. was a shareholder and employee at Longboard Pharmaceuticals (now a part of H. Lundbeck A/S) at the time of study conduct. Shikha Polega is an employee at H. Lundbeck A/S. Randall Kaye was a shareholder and employee at Longboard Pharmaceuticals (now a part of H. Lundbeck A/S) at the time of study conduct. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Supporting information

Appendix S1–S2

Dlugos DJ, Scheffer IE, French JA, Vossler DG, Orevillo C, Polega S, et al. Bexicaserin for the treatment of seizures in developmental and epileptic encephalopathies: A phase 1b/2a trial (PACIFIC). Epilepsia. 2026;67:646–659. 10.1111/epi.18689

DATA AVAILABILITY STATEMENT

Lundbeck is committed to sharing the data from this clinical trial when the product is approved in Europe and/or the United States. Please visit www.lundbeck.com for more information about our clinical data sharing policy and processes.