Impact of long‐term treatment with cenobamate on concomitant usage of antiseizure medications: A real‐world retrospective study in Spain

Abstract

Objectives

This study explored the safety and effectiveness of adjunctive cenobamate (CNB) in patients with different levels of drug‐resistant epilepsy (DRE) in a real‐world setting, including its impact on the use of co‐antiseizure medication (co‐ASM).

Methods

This was a single‐center, retrospective, observational study. Adults with refractory seizures who had received ≥2 previous ASMs and had been treated with CNB for at least a year were included. Effectiveness and safety endpoints were assessed at 3, 6, 12, and 24 months after CNB was initiated. Co‐ASM use was assessed at every visit.

Results

Ninety‐four patients were included; 23 of 94 (24.5%) had received ≤4 previous ASMs and 70 of 94 (74.5%) had received ≥5 previous ASMs. Patients with ≥5 previous ASMs had a younger age at onset (mean 12 vs 25.9 years) and a longer duration of epilepsy (mean 28.1 vs 16.7 years) compared with patients with ≤4 previous ASMs. The mean CNB daily dose was 310 ± 76.7 mg at 2 years. The mean number of co‐ASMs received by patients was reduced significantly between baseline and all time points (p ≤ .01). The mean defined daily dose (DDD) per patient (not including CNB) was also reduced significantly across all time points (p < .01), falling from 3.2 ± 2.3 at baseline to 1.2 ± 1.9 at the 2‐year follow‐up. At 1 and 2 years after initiation of CNB, 79.6% and 80% of patients had a ≥50% reduction in seizure frequency and 36.6% and 30.9% were seizure‐free, respectively. At 2 years, 73.2% of patients reported their condition to be “Very much better” or “Much better” compared with baseline; 37.5% reported treatment‐related adverse drug reactions at 2 years.

Significance

In patients with DRE, CNB treatment allowed long‐term high seizure‐freedom rates and significant reductions in co‐ASM use, while also achieving both good tolerability and high patient satisfaction scores.

Key points.

• Cenobamate demonstrates sustained seizure freedom and a favorable safety profile in patients with drug‐resistant epilepsy.

• Patients receiving add‐on cenobamate, particularly when started early, show high‐responder and seizure‐freedom rates for up to 2 years.

• Cenobamate optimization allows therapeutic simplification by reducing both the number and dose of concomitant antiseizure medications.

• Optimization of cenobamate enables conversion to monotherapy or biotherapy.

• Cenobamate‐associated reductions in polytherapy can improve tolerability and adherence, contributing to high treatment satisfaction.

1. INTRODUCTION

For patients with epilepsy, the burden of uncontrolled seizures is significant, impacting mortality, seizure‐related injuries, comorbidities, and quality of life. ¹ , ² , ³ , ⁴ , ⁵ Antiseizure medications (ASMs) are the mainstay of early epilepsy treatment, but more than 30% of patients fail to achieve seizure freedom even after treatment with at least two previous ASMs. ⁶ In the last few years, significant progress has been made with the introduction of new, highly effective ASMs with encouraging efficacy and tolerability in patients who have failed two or more previous ASMs. ⁷ , ⁸ , ⁹

Cenobamate (CNB) is a novel ASM with a dual mechanism of action. Through its simultaneous actions as a positive allosteric modulator of γ‐aminobutyric acid A (GABA_A) receptors and a voltage‐gated sodium channel blocker (SCB), CNB reduces excitatory neurotransmission while enhancing signaling through inhibitory pathways. ¹⁰ The efficacy and tolerability of CNB in patients with uncontrolled focal seizures has been demonstrated in randomized, placebo‐controlled clinical trials ⁷ , ¹¹ and in open‐label studies. ¹² , ¹³ In addition, a growing body of real‐world evidence supports the safety and effectiveness of CNB in clinical settings. ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ CNB is now approved by the European Medicines Agency for the adjunctive treatment of focal seizures, with or without secondary generalization, in adult patients with epilepsy who have not achieved adequate seizure control despite treatment with at least two ASMs. ¹⁸

Polypharmacy is a significant issue for patients with epilepsy, increasing the risk of sudden unexpected death in epilepsy (SUDEP) and the likelihood of treatment‐related adverse events (AEs), reducing patient quality of life, and increasing health care costs. ¹⁹ , ²⁰ , ²¹ In a post hoc analysis of a Phase 3 study, CNB treatment showed the potential to reduce concomitant ASM (co‐ASM) use by patients with focal seizures, without impacting the efficacy of CNB. ²² Indeed, once efficacy with CNB is established, most patients may be able to reduce their dose of, or even discontinue, co‐ASMs. ²³ In a recent real‐world study, we demonstrated how optimizing co‐ASM management during the first year of CNB treatment in a highly drug‐resistant patient population could result in high rates of seizure freedom, despite substantial reductions in co‐ASMs. ¹⁷ Here, we present longer‐term outcomes from the same study, with follow‐up extending to 2 years.

2. METHODS

2.1. Study design

This was a single‐center, retrospective, observational study conducted at the Centro de Neurología Avanzada in Seville, Spain. The study was conducted in line with the Declaration of Helsinki and Good Clinical Practice. The protocol was approved by the local institutional review board and health authorities of the Hospitales Universitarios Virgen del Rocío‐Virgen Macarena. Data were obtained from electronic medical records of patients in Centro de Neurología Avanzada.

2.2. Study population

The study population included adults diagnosed with focal seizures who had CNB initiated as part of routine clinical practice between December 2020 and December 2023, and who had taken CNB for more than a year. Participants were at least 18 years of age with diagnosed focal seizures that had not responded to at least two previous ASMs. Exclusion criteria were severe hepatic impairment, end‐stage renal disease, non‐focal seizures, inaccurate or unreliable clinical records according to participating physicians, and initiation of CNB ≤12 months before the closing of the database.

2.3. Study endpoints

Demographic and clinical characteristics of study participants were collected at baseline, including age, age at epilepsy onset, duration of epilepsy, epilepsy type, monogenic etiology, the presence of brain lesions according to magnetic resonance imaging (MRI), previous epilepsy surgery, and the number of previous ASMs. The effectiveness and safety of CNB were assessed at 3, 6, 12, and 24 months after CNB initiation, corresponding to standardized visits. Baseline seizure frequency was recorded as the median number of seizures per month experienced over the 3 months prior to the initiation of CNB.

The main effectiveness endpoints were the evolution in the number of co‐ASMs, the total defined daily dose (DDD) of co‐ASMs, and the CNB daily dose at each time point during the study. Other effectiveness endpoints included seizure frequency and responder rates (≥50%, ≥75%, ≥90%, and 100%; defined as the percentage of subjects with a reduction in the frequency of seizures compared with baseline) at each time point. Seizure freedom was defined as the proportion of patients with no seizures since the previous visit.

Safety and tolerability were assessed at 3, 6, 12, and 24 months based on the incidence of adverse drug reactions (ADRs), defined as AEs considered by the investigator to be related to CNB treatment or to the pharmacokinetic or pharmacodynamic interactions of other ASMs with CNB. The primary safety endpoint was the proportion of patients with ADRs at each time point.

Patients' experiences were assessed using the Patient Global Impression‐Improvement (PGI‐I) scale score at 12 and 24 months of follow‐up. PGI‐I scores were based on a seven‐point Likert scale with answers ranging from 1 (“Much better”) to 7 (“Much worse”) compared with baseline.

Analyses were performed in all subjects enrolled in the study. Data were reported at baseline and at 3, 6, 12, and 24 months after cenobamate initiation if a patient had completed that time point of assessment and had not discontinued cenobamate treatment. Observed data were used in the analysis and no imputations for missing data were performed.

2.4. Statistical analysis

Subject disposition, ADRs, PGI scores, the number of co‐ASMs per patient, DDD of co‐ASMs, CNB dose levels, seizure frequency, and seizure frequency reductions from baseline were summarized using descriptive statistics, including frequency and percentage. The DDD for each reported co‐ASM was calculated using the WHO methodology (https://www.whocc.no/atc_ddd_index/). Changes in the number of co‐ASMs per patient at each visit and DDD were assessed using a paired t test. Differences between subgroups were assessed using Fisher's exact test or the two‐sample t test, as appropriate. Time‐to‐event analysis was conducted using the Kaplan–Meier method, with statistical comparisons between subgroups performed using the log‐rank test. Results are presented graphically.

3. RESULTS

3.1. Patient disposition and baseline characteristics

A total of 94 patients met the inclusion/exclusion criteria and were included in the study. Of these, 23 of 94 (24.5%) had received ≤4 previous ASMs, 70 of 94 (74.5%) had received ≥5 previous ASMs, and 1 of 94 (1.1%) had received an unknown number of previous ASMs.

The mean age of patients was 41.5 years in those with ≤4 previous ASMs and 40.4 years in those with ≥5 previous ASMs. Patients with ≥5 previous ASMs had a younger age at onset (mean age 12 vs 25.9 years; p = .006) and a longer duration of epilepsy (mean duration 28.1 vs 16.7 years; p = .008) compared with patients with ≤4 previous ASMs. More than 90% of patients in both groups had focal epilepsy. The proportion of patients who had previous epilepsy surgery was 8.7% in the group with ≤4 previous ASMs and 22.9% in the group with ≥5 previous ASMs. The mean number of previous ASMs was 2.8 ± 1.2 in the group with ≤4 previous ASMs and 9.7 ± 3.5 in the group with ≥5 previous ASMs (Table 1).

TABLE 1.

Patient demographics and disease characteristics at baseline.

Demographics and characteristics	≤4 previous ASMs (n = 23)	≥5 previous ASMs (n = 70)	p‐Value (≤4 vs ≥5 previous ASMs)	All patients (N = 94)
Age, years
Mean (SD)	41.5 (18.7) a	40.4 (14.8)	NS	40.8 (15.7) b
Median (range)	37 (14–80)	38.5 (12–72)		39 (12–80)
Age at epilepsy onset, years
Mean (SD)	25.9 (21.1)	12 (12.1)	.006	15.7 (16.1)
Median (range)	23 (0–77)	9 (0–56)		10.5 (0–77)
Duration of epilepsy, years
Mean (SD)	16.7 (17.5)	28.1 (15.1)	.008	25.2 (16.3)
Median (range)	9 (2–63)	25.5 (3–67)		23 (2–67)
Epilepsy type
Focal	23 (100)	64 (91.4)	NS	87 (92.6)
Generalized	0	2 (2.9)		2 (2.1)
Combined	0	3 (4.3)		3 (3.2)
Unknown	0	1 (1.4)		2 (2.1)
Monogenic etiology
Yes	1 (4.3)	2 (2.9)	NS	3 (2.9)
No	22 (95.7)	67 (95.7)		90 (95.7)
Not reported	0	1 (1.4)		1 (1.4)
Brain MRI lesion	14 (60.9)	47 (67.1)	NS	62 (66)
Previous epilepsy surgery	2 (8.7)	16 (22.9) c	NS	19 (20.2) c
Previous ASMs
Mean (SD)	2.8 (1.2)	9.7 (3.5)	<.001	8 (4.3)
Median (range)	3 (0–4)	10 (5–18)		7 (0–18)
0	1 (4.3)	0		1
1–3	13 (56.5)	0		13
4–6	9 (39.1)	15 (21.4)		24 (21.4)
7–10	0	31 (44.3)		31 (44.3)
>10	0	24 (34.3)		24 (34.3)
Unknown				1

Abbreviations: ASMs, antiseizure medications; MRI, magnetic resonance imaging; NS, not significant; SD, standard deviation.

^a n = 22.

^b n = 93.

^c 3 patients with missing data.

The retention rate for CNB was 100% (94/94 patients) at the 3‐, 6‐, and 12‐month time points and 98% (56/57 patients) at 24 months. Similar retention rates were observed in patients with ≤4 and ≥5 previous ASMs (Table S1).

3.2. Safety

The proportions of patients reporting at least one ADR at 3, 6, 12, and 24 months were 66%, 47.9%, 45.7%, and 37.5%, respectively (Table S2). Somnolence was the most frequently reported ADR at 3 months (44/94 patients; 46.8%), followed by bradypsychia (16/94 patients; 17.0%), dizziness (15/94 patients; 16.0%), and fatigue (14/94 patients; 14.9%). The proportions of patients with somnolence, bradypsychia, dizziness, and fatigue reduced between 3 months and 2 years of follow‐up. Weight loss was reported in 32 of 94 patients (35.2%) at 1 year and 25 of 56 (48.1%) at 2 years. Similar patterns of ADRs were observed in patients with ≤4 and ≥5 previous ASMs (Table S1).

3.3. Co‐ASM management

The mean number of co‐ASMs received by patients treated with CNB fell significantly from 2.4 ± 0.8 at baseline to 1.3 ± 0.8 at 2 years (p < .0001; Figure 1A). This reduction from baseline was also significant at all other time points (p < .001 at 3 months; p < .0001 at 6 months and 1 year).

FIGURE 1.

Reduction in co‐ASMs during follow‐up. (A) Evolution of the number of co‐ASMs per patient. (B) Mean DDD for patients treated with CNB by study period. (C) Evolution of percentage of patients receiving different numbers of co‐ASMs; differences in height between corresponding shaded areas (i.e., the same color) within the bars and areas immediately to the right of the bars indicate discontinuations or incomplete follow‐up between time points. Bars in A and B indicate 95% confidence intervals. Patients with vagus nerve stimulation were removed from the analysis. p‐Values are based on paired t test vs baseline; **p < .01; ***p < .0001. Co‐ASMs, antiseizure medications co‐administered with CNB. Abbreviations: ASMs, antiseizure medications; Co‐ASMs, concomitant antiseizure medications, DDD, defined daily dose.

Similarly, the mean DDD per patient (not including CNB) was significantly reduced across all time points (p < .0001 at 3 months; p < .0001 at 6 months, 1 year, and 2 years; Figure 1B), falling from 3.2 ± 2.3 at baseline to 1.2 ± 1.9 at the 2‐year follow‐up. The evolution of the percentage of patients receiving different numbers of co‐ASMs is shown in Figure 1C (not including CNB). Although 91.5% of patients were receiving at least two co‐ASMs at baseline, this decreased to only 39.3% at 2 years of follow‐up (Figure 1C).

At 3 and 6 months after the initiation of CNB, both the mean number of co‐ASMs per patient and the mean DDD were significantly higher in patients with ≥5 vs ≤4 previous ASMs (p < .05; Figure 2).

FIGURE 2.

Co‐ASM use and DDD of co‐ASMs according to the number of previous ASMs. Evolution of (A) the mean number of co‐ASMs per patient and (B) the mean DDD of co‐ASMs per patient by period, categorized by those with ≤4 vs ≥5 previous ASMs. Bars indicate 95% confidence intervals; p‐values are based on paired t test for ≤4 vs ≥5 previous ASMs. (C) Evolution of the percentage of subjects receiving different numbers of co‐ASMs by period, categorized by those with ≤4 vs ≥5 previous ASMs (differences in height between corresponding shaded areas [i.e., the same color] within the bars and areas immediately to the right of the bars indicate discontinuations or incomplete follow‐up between time points). *p < .05. Patients with vagus nerve stimulation were removed from the analysis. Co‐ASMs, concomitant antiseizure medications; DDD, defined daily dose.

When co‐ASMs were grouped by mechanism of action (MoA), notable decreases from baseline were observed in the mean number of co‐ASMs per patient for SCBs, synaptic vesicle protein 2A (SV2A) modulators, dual SCBs/GABA modulators, and α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR) antagonists, and these were maintained for at least 2 years (Figure S1A). Similarly, the total DDD per patient reduced between baseline and Year 2 for SCBs, SV2A modulators, GABA modulators, dual SCBs/GABA modulators, and AMPAR antagonists (Figure S1B). For all co‐ASM MoA groups, there was a reduction in mean daily dose between baseline and the 3‐month, 6‐month, 1‐year, and 2‐year follow‐up periods, with SCBs showing the greatest reduction from baseline at early time points (Figure S1C,D).

For patients who were taking specific co‐ASMs at baseline, the mean daily dose and mean DDD for each co‐ASM during follow‐up, and according to the number of previous ASMs, are shown in Table 2 and Table S3. All co‐ASMs showed a reduction in mean daily dose and mean DDD between baseline and Year 1, with the exception of ethosuximide and topiramate. These reductions from baseline were typically maintained throughout the follow‐up period. The greatest reductions in mean daily dose from baseline occurred for the SCBs carbamazepine, eslicarbazepine, lacosamide, oxcarbazepine, and zonisamide.

TABLE 2.

Mean dosage and mean defined daily dose of specific co‐ASMs taken at baseline, by period ^a .

ASM		n	Mean daily dose (mg)	Mean change in dosage from baseline (%)	Mean defined daily dose	Mean change in DDD from baseline (%)
BRV	Baseline	16	195	0	1.95	0
	Month 3	16	175	−7.81	1.75	−10.3
	Month 6	16	135	−30	1.35	−30.8
	Year 1	16	135	−31.2	1.35	−30.8
	Year 2	14	94.6	−51.8	.95	−51.3
CBZ	Baseline	36	1105	0	1.11	0
	Month 3	36	539	−50.5	.54	−51.4
	Month 6	36	244	−77.2	.24	−78.4
	Year 1	36	91.7	−92	.09	−91.9
	Year 2	28	50	−95.5	.05	−95.5
CLB	Baseline	48	26.2	0	1.31	0
	Month 3	48	14.2	−43.3	.71	−45.8
	Month 6	48	8.18	−65.3	.41	−68.7
	Year 1	48	7.45	−68.7	.37	−71.8
	Year 2	30	7.08	−75.3	.35	−73.3
CZP	Baseline	5	31.5	0	3.94	0
	Month 3	5	1.05	−49	.13	−96.7
	Month 6	5	30.7	−48	3.84	−2.5
	Year 1	5	25.5	−73.3	3.19	−19
	Year 2	5	18.5	−78	2.31	−41.4
ESL	Baseline	18	1206	0	1.51	0
	Month 3	18	150	−87.3	.19	−87.4
	Month 6	18	72.2	−93.2	.09	−94
	Year 1	18	22.2	−98.2	.03	−98
	Year 2	7	0	−100	0	−100
ETX	Baseline	2	1125	0	.90	0
	Month 3	2	1125	0	.90	0
	Month 6	2	1000	−8.33	.80	−11.1
	Year 1	2	1125	0	.90	0
	Year 2	1	1250	−16.7	1	11.1
LCM	Baseline	29	386	0	1.29	0
	Month 3	29	167	−57.8	.56	−56.6
	Month 6	29	56.9	−86.7	.19	−85.3
	Year 1	29	22.4	−95.4	.07	−94.6
	Year 2	16	25	−95.8	.08	−93.8
LEV	Baseline	17	2015	0	1.34	0
	Month 3	17	1700	31	1.13	−15.7
	Month 6	17	1015	−34.02	.68	−49.3
	Year 1	17	485	−81.9	.32	−76.1
	Year 2	6	0	−100	0	−100
LTG	Baseline	9	308	0	1.03	0
	Month 3	9	186	−40.2	.62	−39.8
	Month 6	9	117	−63.3	.39	−62.1
	Year 1	9	94.4	−68.4	.31	−69.9
	Year 2	5	80	−73.1	.27	−73.8
OXC	Baseline	2	1500	0	1.50	0
	Month 3	2	300	−75	.30	−80
	Month 6	2	0	−100	0	−100
	Year 1	2	0	−100	0	−100
	Year 2	1	0	−100	0	−100
PB	Baseline	1	300	0	3	0
	Month 3	1	100	−66.7	1	−66.7
	Month 6	1	0	−100	0	−100
	Year 1	1	0	−100	0	−100
PER	Baseline	18	8.56	0	1.07	0
	Month 3	18	5.56	−40.7	.69	−35.5
	Month 6	18	4.78	−50.5	.60	−43.9
	Year 1	18	3.56	−61.6	.44	−58.9
	Year 2	13	3.23	−68.6	.40	−62.6
PHT	Baseline	1	300	0	1	0
	Month 3	1	300	0	1	0
	Month 6	1	150	−50	.50	−50
	Year 1	1	0	−100	0	−100
	Year 2	1	0	−100	0	−100
TPM	Baseline	7	229	0	.76	0
	Month 3	7	286	35.7	.95	25
	Month 6	7	286	35.7	.95	25
	Year 1	7	236	14.3	.79	3.95
	Year 2	5	0	−100	0	−100
VPA	Baseline	14	1050	0	.70	0
	Month 3	14	636	−30	.42	−40
	Month 6	14	521	−32.9	.35	−50
	Year 1	14	571	−39.7	.38	−45.7
	Year 2	7	629	−33.3	.42	−40
ZNS	Baseline	5	380	0	1.90	0
	Month 3	5	60	−80	.30	−84.2
	Month 6	5	60	−80	.30	−84.2
	Year 1	5	0	−100	0	−100
	Year 2	4	0	−100	0	−100

Note: VNS removed from the analysis.

Abbreviations: ASM, antiseizure medication; BRV, brivaracetam; CBZ, carbamazepine; CLB, clobazam; CZP, clonazepam; ESL, eslicarbazepine; ETX, ethosuximide; LCM, lacosamide; LEV, levetiracetam; LTG, lamotrigine; OXC, oxcarbazepine; PB, phenobarbital; PER, perampanel; PHT, phenytoin; TPM, topiramate; VPA, valproic acid; ZNS, zonisamide.

^a Includes only patients who were taking the co‐ASM at baseline.

3.4. Cenobamate dose

According to routine practice, the standard 12‐week titration for CNB was used (i.e., starting dose of 12.5 mg, increasing every 2 weeks to 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg). The mean CNB daily dose was 186 ± 31.2 mg at 3 months, 232 ± 59.9 mg at 6 months, 262 ± 76.6 mg at 1 year, and 310 ± 76.7 mg at 2 years (Table S4). Subjects with ≥5 previous ASMs received consistently higher mean CNB doses than patients with ≤4 previous ASMs across time points (Table S4).

3.5. Effectiveness

Responder rates at the ≥50%, ≥75%, ≥90%, and 100% levels are shown in Figure 3 for all seizures and for focal impaired consciousness (FIC), focal preserved consciousness (FPC), and bilateral tonic–clonic seizures (BTC). At 3 months after initiation of CNB treatment, 67.7% of patients had a ≥50% reduction in the frequency of all seizures, 51.6% had a ≥75% reduction, 44.1% had a ≥90% reduction, and 30.1% were seizure‐free. These reductions in seizure frequency were sustained for at least 2 years.

FIGURE 3.

Responder rates during the study by period, according to seizure type. Bars show the proportions of patients with ≥50%, ≥75%, ≥90%, and 100% reductions in seizure frequency from baseline at all time points, based on (A) all seizures, (B) focal impaired consciousness seizures, (C) focal preserved consciousness seizures, and (D) bilateral tonic–clonic seizures.

A greater proportion of patients with FIC seizures and BTC seizures achieved seizure frequency reductions of ≥50%, ≥75%, ≥90%, and 100% compared with the overall population at all time points. The ≥50%, ≥75%, ≥90%, and 100% responder rates based on all seizures were higher in patients with ≤4 previous ASMs than those with ≥5 previous ASMs (Figure S2A). However, this pattern was not consistent across seizure types, possibly because of low numbers of patients in these subgroup analyses (Figure S2B–D).

At 3 months of CNB treatment, 22% of patients achieved sustained seizure freedom (i.e., seizure freedom that would last at least 6 months), including 35% of patients with ≤4 prior ASMs and 17% of patients with ≥5 prior ASMs (Figure 4A); this rose to 38% of patients (including 43% of patients with ≤4 prior ASMs and 34% with ≥5 prior ASMs) at 24 months. Overall, the proportion of patients achieving sustained seizure freedom was significantly higher in those with ≤4 vs ≥5 prior ASMs (log‐rank test p < .05). Similarly, 34% of patients achieved a sustained ≥90% reduction (i.e., ≥90% reduction which would last at least 6 months) in seizure frequency at 3 months, including 48% of patients with ≤4 prior ASMs and 29% of patients with ≥5 prior ASMs (Figure 4B); this rose to 50% of patients (including 61% of patients with ≤4 prior ASMs and 45% with ≥5 prior ASMs) at 12 months. The proportion of patients achieving a sustained ≥90% reduction in seizure frequency was not significantly different in those with ≤4 vs ≥5 prior ASMs (p = .057).

FIGURE 4.

Time to achievement of sustained (A) seizure freedom and (B) ≥90% reduction in seizure frequency following cenobamate initiation, according to number of prior ASMs. Sustained (i.e., which would last ≥6 months) seizure freedom and ≥90% reduction in seizure frequency was assessed using the Kaplan–Meier method.

At 1 and 2 years of follow‐up, 83% and 73.2% of patients, respectively, reported their condition to be “Very much better” or “Much better” on the PGI‐I scoring system (Table S5). Patient‐reported improvements in condition were similar between patients with ≤4 and ≥5 previous ASMs. However, among those with ≥5 previous ASMs, four patients reported slight worsening of their condition at 1 year and one patient at 2 years, whereas no patients in the ≤4 ASMs group reported worsening at any time point (Table S5).

4. DISCUSSION

This study adds to the growing body of evidence supporting the safety and effectiveness of CNB in patients with drug‐resistant focal epilepsy in real‐world settings. ¹⁵ , ¹⁶ , ¹⁷ , ²⁴ We also show how optimizing co‐ASM management during the first 2 years of CNB treatment allows for substantial reductions in co‐ASMs without jeopardizing the achievement of high seizure‐freedom rates.

Our study underscores the clinical importance of adjusting co‐ASMs during CNB dose escalation to optimize the balance between effectiveness and tolerability. Because the CNB dose was steadily increased between each time point up to 2 years, the proportion of patients receiving three or more co‐ASMs fell from 45% to only 7% over the same period, and there was a parallel reduction in the proportion of patients experiencing ADRs. This was especially apparent in the more treatment‐resistant patients. Among the 75% of individuals in our study who had received at least five previous ASMs, the proportion of patients using multiple co‐ASMs dropped from 96% at baseline to 40% by Year 2, and the proportion of patients experiencing ADRs decreased to 44% by Year 1. The reduction in co‐ASM use in our study was also evidenced by sustained reductions in the number of co‐ASMs per patient and in the mean total DDD per patient. In patients with epilepsy, polytherapy is associated with lower adherence, an increased risk of drug–drug interactions, an increased risk of treatment‐related AEs, reduced quality of life, and higher health care costs. ¹⁹ , ²⁰ , ²⁵ Seizure‐free patients have shown improvements in mood, cognitive function, and overall psychosocial well‐being following discontinuation of ASMs. ¹⁹ The option to gradually increase the CNB dose while tapering co‐ASMs arises because of the biweekly titration schedule of CNB, ¹⁸ combined with its early efficacy. ²⁶ , ²⁷ When initiating CNB treatment in adult patients, dose adjustments of co‐ASMs are recommended either before (for SCBs and GABAergics) or after (for other ASMs) the emergence of AEs. ¹⁷ , ²⁸

The CNB dosing data (Table S4) warrant clarification. In routine practice, we follow the standard 10‐week titration and prioritize simplifying co‐medications to optimize tolerability, rather than slowing titration. Despite this, the mean CNB dose at 3 months was <200 mg. This likely reflects delays between prescription and actual treatment start, which are common in our private setting, since patients tend to wait to acquire prescriptions financed by the Spanish Social Security System. As we defined “initiation” as the prescription date, many patients had only recently begun CNB by the 3‐month visit, leading to heterogeneous exposure and lower recorded doses. This timing artifact diminishes at later assessments and is no longer relevant.

In our study, the use of SCBs, GABA modulators and dual SCBs/GABA modulators was reduced during CNB treatment between baseline and Year 2, as would be expected based on the dual mechanism of action of CNB. ¹⁰ However, consistent with other studies, we also observed reductions in the use of ASMs from other MoA groups, including SV2A modulators and AMPAR antagonists. ¹⁶ , ¹⁷ , ²² , ²⁹ As CNB has potent antiseizure effects, the requirement for additional ASMs across MoA groups to maintain seizure control would be reduced, allowing reductions in dose or withdrawal of these co‐ASMs.

The reduction in co‐ASM use did not come at the expense of seizure control. A high rate of seizure freedom (30%–37%) was sustained for up to 2 years of CNB treatment. These rates compare favorably with those observed in clinical studies ⁷ , ²⁷ and other real‐world studies of CNB. ¹⁶ , ¹⁷ , ²⁴ , ²⁹ In addition, we observed a sustained high rate of patients with at least a 90% reduction in seizure frequency following CNB treatment (44%–56%), which would be expected to provide significant benefits to patients with regard to quality of life.

At first glance, our 3‐month effectiveness results appear to exceed those reported in the pivotal randomized controlled trials (RCTs) of CNB. In the fixed titration, double‐blind dose–response trial, ≥50% responder rates during the 12‐week maintenance phase were 40%, 56%, and 64% for 100, 200, and 400 mg/day, respectively, and seizure freedom occurred in 11% and 21% at 200 and 400 mg/day. ¹¹ The randomized Phase 2 study reported a median seizure reduction of 55.6% with CNB 200 mg/day, a ≥50% responder rate of ~50%, and 28.3% seizure freedom during the 6‐week maintenance phase. ⁷ Several real‐world factors plausibly account for our higher early seizure‐freedom rate while remaining consistent with longer‐term CNB data. First, clinical practice generally applies proactive adjustment of both kinetically and pharmacodynamically interacting co‐ASMs (SCBs and GABAergics mainly), a strategy supported by open‐label CNB studies showing improved tolerability and high retention. ¹² , ¹⁷ , ²² , ³⁰ , ³¹ A recent study by our group also demonstrated that such an approach allows for higher doses of CNB to be reached, and these high doses (much higher than other observational studies published) probably explain, at least partially, the good efficacy results. ¹⁷ Such optimization was restricted in the pivotal RCTs. ⁷ , ¹¹ Second, part of our cohort had CNB initiated earlier in the treatment course, aligning with the well‐described gradient of diminishing returns after successive adequate ASM failures, ⁶ , ³² and with emerging CNB‐specific evidence that earlier use is associated with favorable effectiveness and retention. ³³ Third, methodological differences, including broader eligibility, clinic‐defined outcomes, and longer observation windows, can shift estimates of effectiveness upward compared with strictly protocolized RCT maintenance phases.

Our observation that patients who started on CNB after ≤4 prior ASMs required fewer concomitant ASMs (Figure 2 and Figure S2) and achieved better seizure control (Figure S2) than those who started on CNB after ≥5 prior ASMs aligns with the “accumulating refractoriness” paradigm (i.e., the probability of seizure freedom declines sharply after the first two adequate ASM trials and continues to drop with additional failures). ⁶ , ³³ , ³⁴ Within the CNB program, post hoc analyses indicate that CNB retains efficacy regardless of the extent of prior treatment; however, early, mechanism‐guided de‐escalation of overlapping co‐ASMs (particularly GABAergics and SCBs) improves tolerability, supports retention, and does not compromise seizure control. ¹² , ¹⁷ , ²² , ³¹ Taken together, these data provide a pragmatic rationale to consider CNB before multiple additional regimen failures, not only to increase the likelihood of seizure control but also to enable rational simplification of polytherapy.

Finally, a high proportion of patients in our study expressed long‐term satisfaction with CNB treatment based on PGI‐I scores, with 73% of patients reporting their condition to be “Very much better” or “Much better” after 2 years.

This study has several limitations, including its retrospective, single‐center design, which may contribute to selection bias. Incomplete medical records may also have resulted in missing data. In addition, as this was an observational study, seizure counts may be less accurate than in clinical trials. The relatively small sample size and absence of a control group further limit the generalizability of the findings, and results should therefore be interpreted with caution. In addition, as our analysis included only patients who had completed ≥12 months of CNB treatment, it is vulnerable to survivor (selection) bias. Excluding early discontinuations for lack of efficacy or AEs can inflate observed effectiveness and tolerability (i.e., depletion of susceptibles). Our results should therefore be interpreted as effectiveness among 1‐year survivors on CNB, and not as the average causal effect in all initiators. Nevertheless, similar results (e.g., 25% seizure freedom for 6 months at 1 year of follow‐up in a more refractory cohort than this one) were reported by our group following an intention‐to‐treat analysis, ¹⁷ which supports the reported results in this study.

In conclusion, this study demonstrates the long‐term safety and effectiveness of adjunctive CNB in patients with DRE, providing high rates of seizure freedom while allowing for a significant reduction in the use of co‐ASMs, especially if CNB is initiated early. Thus, CNB can be used effectively to reduce polytherapy in patients with DRE, leading to improvements in tolerability, adherence, and treatment satisfaction.

AUTHOR CONTRIBUTIONS

Juan Jesús Rodríguez‐Uranga led clinical research, data collection, review of the analysis of results, and approved the final version of the manuscript. Juan María Sánchez‐Caro, Roshan Hariramani Ramchandani, and Iratxe Maestro Saiz collected data, reviewed and revised manuscript drafts, and approved the final version.

FUNDING INFORMATION

This study was funded by Angelini Pharma.

CONFLICT OF INTEREST STATEMENT

Juan J. Rodriguez Uranga has been a paid consultant for Eisai Farmacéutica, GW Pharma, Jazz Pharmaceutical Iberia, UCB Pharma, Bial, Novartis, Livanova, Angelini Pharma, Arvelle Therapeutics, GlaxoSmithKline, Pfizer, and Esteve. Juan M. Sánchez Caro has served as a consultant for Angelini Pharma, Eisai, and Nutricia. Roshan Hariramani Ramchandani has carried out consulting work for Eisai. Iratxe Maestro Saiz has no conflicts of interest to disclose.

ETHICS STATEMENT

The protocol was approved by the local institutional review board and health authorities of the Hospitales Universitarios Virgen del Rocío‐Virgen Macarena. The study was conducted in line with the Declaration of Helsinki and Good Clinical Practice.

ETHICAL PUBLICATION STATEMENT

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.

PATIENT CONSENT STATEMENT

As a retrospective study with de‐identified data, patient consent was not required for publication.

Supporting information

Appendix S1.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.