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X-TOLE

Q: What were the key findings of the X-TOLE trial?

XEN1101 demonstrated statistically significant and robustly dose-dependent reductions in monthly focal-onset seizure frequency compared to placebo, with the highest dose (25 mg) achieving a 52.8% median reduction versus 18.2% for placebo. The drug was generally well tolerated with adverse effects similar to commonly prescribed ASMs, supporting further clinical development.

Efficacy and Safety of XEN1101, a Novel Potassium Channel Opener, in Adults With Focal Epilepsy: A Phase 2b Randomized Clinical Trial

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Year of Publication: 2023

Authors: Jacqueline A. French, Roger J. Porter, Emilio Perucca, ..., for the X-TOLE Study Group

Journal: JAMA Neurology

Citation: JAMA Neurol. 2023;80(11):1145-1154

PDF: https://pmc.ncbi.nlm.nih.gov/articles/PMC10562989/

Clinical Question

Is the novel Kv7.2/Kv7.3 potassium channel opener XEN1101 effective in reducing monthly seizure frequency in adults experiencing focal-onset seizures despite treatment with 1-3 baseline antiseizure medications?

Study Overview

Objective

XEN1101 - To evaluate the efficacy, safety, and tolerability of XEN1101, a novel selective Kv7.2/Kv7.3 potassium channel opener, as adjunctive therapy for adults with focal-onset seizures

Study Summary

XEN1101 demonstrated robust dose-dependent seizure reduction with median 52.8% reduction at 25 mg vs 18.2% for placebo (P < .001)
50% responder rate was 54.5% for XEN1101 25 mg vs 14.9% for placebo (P < .001)
XEN1101 was generally well tolerated with CNS-related TEAEs similar to other ASMs; no deaths occurred

Intervention

XEN1101 10 mg, 20 mg, or 25 mg once daily with food vs placebo for 8 weeks (no titration required)

Patients per Arm

25 mg: 114; 20 mg: 51; 10 mg: 46; Placebo: 114

Bottom Line

XEN1101 demonstrated statistically significant and robustly dose-dependent reductions in monthly focal-onset seizure frequency compared to placebo, with the highest dose (25 mg) achieving a 52.8% median reduction versus 18.2% for placebo. The drug was generally well tolerated with adverse effects similar to commonly prescribed ASMs, supporting further clinical development.

        Major Points
        XEN1101 is a novel, selective Kv7.2/Kv7.3 potassium channel opener with a long half-life (~10 days) enabling once-daily dosing without titration
Primary efficacy endpoint showed robust dose-response relationship (P < .001 for dose-response test)
Median percent reduction in monthly FOS frequency: 52.8% (25 mg), 46.4% (20 mg), 33.2% (10 mg) vs 18.2% (placebo)
50% responder rates were significantly higher with XEN1101: 54.5% (25 mg), 43.1% (20 mg), 28.3% (10 mg) vs 14.9% (placebo)
Rapid onset of action: 53.6% were responders by end of first week at 25 mg vs 28.1% placebo (P < .001)
Response was sustained throughout the 8-week treatment period at 20 and 25 mg doses
Seizure freedom rates: 6.3% (25 mg), 7.8% (20 mg), 2.2% (10 mg) vs 1.8% (placebo)
Most common TEAEs were CNS-related: dizziness (24.6%), somnolence (15.6%), fatigue (10.9%)
No tissue discoloration observed (unlike predecessor ezogabine)
No deaths occurred; serious AE rate was low and balanced across groups (2.6-4.3%)

      

Design

Study Type: Phase 2b, multicenter, randomized, double-blind, parallel-group, dose-ranging, placebo-controlled adjunctive-therapy clinical trial

Randomization: 1

Blinding: Double-blind. Randomization implemented centrally using Medidata Rave Randomization and Trial Supply Management system with dynamic allocation randomization algorithm (nondeterministic). Stratified by background use of CYP3A4 inducer medications.

Enrollment Period: January 30, 2019 to September 2, 2021

Follow-up Duration: 8-week double-blind treatment phase plus 6-week safety follow-up (for those not entering OLE). Total study duration approximately 26 weeks per patient.

Centers: 97

Countries: North America (39.1%), Europe (60.9%)

Sample Size: 325

Analysis: Modified intention-to-treat analysis (randomized and treated patients with ≥1 seizure diary entry post-treatment). Primary endpoint: ranked analysis of covariance model for monotonic dose-response. Hodges-Lehmann estimate for each dose vs placebo with 90% and 95% CIs. Two-sided tests with significance at P < .05. Sample size of 300 patients provided ≥80% power at 2-sided .05 level for detecting monotonic dose response. SAS version 9.4 or higher.

Inclusion Criteria

Adults aged 18 to 75 years
Diagnosis of focal-onset seizures
≥4 countable focal-onset seizures on average per month recorded during prospective 8-week baseline period
Stable treatment with 1 to 3 antiseizure medications
Written informed consent
Countable seizures: focal aware seizures with motor signs, focal seizures with impaired awareness, focal seizures evolving to bilateral tonic-clonic seizures

Exclusion Criteria

Not explicitly detailed in publication

Baseline Characteristics

Placebo (N=114):

Age, mean (SD), years: 42.9 (13.7)
Age ≥65 years, n (%): 5 (4.4%)
Female, n (%): 61 (53.5%)
Europe, n (%): 67 (58.8%)
North America, n (%): 47 (41.2%)
BMI, mean (SD): 27.3 (5.4)
Age at disease onset, mean (SD), years: 19.2 (14.7)
CYP3A4 inducer use, n (%): 69 (60.5%)
1 background ASM, n (%): 12 (10.5%)
2 background ASMs, n (%): 46 (40.4%)
3 background ASMs, n (%): 56 (49.1%)
Prestudy ASMs failed, median (IQR): 6.0 (4.0-8.0)
Baseline monthly FOS frequency, median (IQR): 13.4 (8.0-30.1)

XEN1101 10 mg (N=46):

Age, mean (SD), years: 40.0 (12.1)
Age ≥65 years, n (%): 2 (4.3%)
Female, n (%): 27 (58.7%)
Europe, n (%): 31 (67.4%)
North America, n (%): 15 (32.6%)
BMI, mean (SD): 26.6 (5.1)
Age at disease onset, mean (SD), years: 19.8 (14.8)
CYP3A4 inducer use, n (%): 25 (54.3%)
1 background ASM, n (%): 4 (8.7%)
2 background ASMs, n (%): 18 (39.1%)
3 background ASMs, n (%): 24 (52.2%)
Prestudy ASMs failed, median (IQR): 5.0 (4.0-9.0)
Baseline monthly FOS frequency, median (IQR): 17.4 (8.0-55.6)

XEN1101 20 mg (N=51):

Age, mean (SD), years: 41.7 (13.6)
Age ≥65 years, n (%): 4 (7.8%)
Female, n (%): 26 (51.0%)
Europe, n (%): 32 (62.7%)
North America, n (%): 19 (37.3%)
BMI, mean (SD): 26.7 (5.0)
Age at disease onset, mean (SD), years: 14.1 (12.1)
CYP3A4 inducer use, n (%): 29 (56.9%)
1 background ASM, n (%): 2 (3.9%)
2 background ASMs, n (%): 20 (39.2%)
3 background ASMs, n (%): 29 (56.9%)
Prestudy ASMs failed, median (IQR): 6.0 (4.0-9.0)
Baseline monthly FOS frequency, median (IQR): 14.5 (7.5-36.4)

XEN1101 25 mg (N=114):

Age, mean (SD), years: 38.7 (13.1)
Age ≥65 years, n (%): 1 (0.9%)
Female, n (%): 54 (47.4%)
Europe, n (%): 68 (59.6%)
North America, n (%): 46 (40.4%)
BMI, mean (SD): 26.5 (5.1)
Age at disease onset, mean (SD), years: 15.3 (12.1)
CYP3A4 inducer use, n (%): 65 (57.0%)
1 background ASM, n (%): 11 (9.6%)
2 background ASMs, n (%): 48 (42.1%)
3 background ASMs, n (%): 55 (48.2%)
Prestudy ASMs failed, median (IQR): 6.0 (3.0-9.0)
Baseline monthly FOS frequency, median (IQR): 12.8 (8.4-24.6)

Total (N=325):

Age, mean (SD), years: 40.8 (13.3)
Age ≥65 years, n (%): 12 (3.7%)
Female, n (%): 168 (51.7%)
White race, n (%): 298 (91.7%)
Europe, n (%): 198 (60.9%)
North America, n (%): 127 (39.1%)
BMI, mean (SD): 26.8 (5.2)
Age at disease onset, mean (SD), years: 17.1 (13.6)
CYP3A4 inducer use, n (%): 188 (57.8%)
1 background ASM, n (%): 29 (8.9%)
2 background ASMs, n (%): 132 (40.6%)
3 background ASMs, n (%): 164 (50.5%)
Prestudy ASMs failed, median (IQR): 6.0 (4.0-9.0)
Overall baseline monthly FOS frequency, median (IQR): 13.5 (7.9-30.3)

Arms

Field	Control	XEN1101 10 mg	XEN1101 20 mg	XEN1101 25 mg
Intervention	Placebo capsule administered once daily with evening meal for 8 weeks	XEN1101 10 mg oral capsule administered once daily with evening meal for 8 weeks. No titration required.	XEN1101 20 mg oral capsule administered once daily with evening meal for 8 weeks. No titration required.	XEN1101 25 mg oral capsule administered once daily with evening meal for 8 weeks. No titration required.
Duration	8 weeks	8 weeks	8 weeks	8 weeks

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Median percent change from baseline in monthly (28-day) focal-onset seizure frequency, assessed using ranked analysis of covariance model for monotonic dose-response relationship	Primary	−18.2% (IQR −37.3% to 7.0%)	25 mg: −52.8% (IQR −80.4% to −16.9%); 20 mg: −46.4% (IQR −76.7% to −14.0%); 10 mg: −33.2% (IQR −61.8% to 0.0%)		Primary dose-response: P < .001; 25 mg vs placebo: P < .001; 20 mg vs placebo: P < .001; 10 mg vs placebo: P = .04
50% responder rate (≥50% reduction from baseline in monthly FOS frequency)	Secondary	14.9%	25 mg: 54.5%; 20 mg: 43.1%; 10 mg: 28.3%	25 mg: OR 7.30 (95% CI 3.77-14.10); 20 mg: OR 4.78 (95% CI 2.18-10.52); 10 mg: OR 2.48 (95% CI 1.05-5.84)	25 mg: P < .001; 20 mg: P < .001; 10 mg: P = .04
Seizure freedom rate (100% reduction) during 8-week treatment period - all observed patients	Secondary	1.8%	25 mg: 6.3%; 20 mg: 7.8%; 10 mg: 2.2%
Seizure freedom rate - completers	Secondary	1.8%	25 mg: 4.5%; 20 mg: 3.9%; 10 mg: 2.2%
Responder rate at end of Week 1 (post hoc)	Secondary	28.1%	25 mg: 53.6%; 20 mg: 47.1%; 10 mg: 43.5%		25 mg: P < .001; 20 mg: P < .05; 10 mg: P < .05
Median weekly FOS percent reduction at Week 1	Secondary	20.2%	25 mg: 55.4%; 20 mg: 41.5%; 10 mg: 39.1%		25 mg: P < .001; 20 mg: P = .04; 10 mg: P < .01
Median time to reach baseline monthly FOS count (exploratory, Figure 2E)	Secondary	4.7 weeks	25 mg: NA (>9 weeks); 20 mg: 7.4 weeks; 10 mg: 5.9 weeks
Clinical Global Impression–Change (CGI-C): At least much improved	Secondary	22.8%	25 mg: 46.4%; 20 mg: 33.3%; 10 mg: 23.9%	25 mg: OR 2.93 (95% CI 1.65-5.21); 20 mg: OR 1.69 (95% CI 0.82-3.51); 10 mg: OR 1.06 (95% CI 0.47-2.38)	25 mg: P < .001; 20 mg: P = .17; 10 mg: P = .96
Patient Global Impression–Change (PGI-C): At least much improved	Secondary	21.9%	25 mg: 42.9%; 20 mg: 37.3%; 10 mg: 34.8%	25 mg: OR 2.67 (95% CI 1.49-4.77); 20 mg: OR 2.11 (95% CI 1.03-4.34); 10 mg: OR 1.90 (95% CI 0.90-4.03)	25 mg: P = .001; 20 mg: P = .04; 10 mg: P = .10
At least 1 TEAE	Adverse	71/114 (62.3%)	10 mg: 31/46 (67.4%); 20 mg: 35/51 (68.6%); 25 mg: 97/114 (85.1%); Any dose: 163/211 (77.3%)
At least 1 serious TEAE	Adverse	3/114 (2.6%)	10 mg: 2/46 (4.3%); 20 mg: 2/51 (3.9%); 25 mg: 3/114 (2.6%); Any dose: 7/211 (3.3%)
TEAEs leading to discontinuation	Adverse	4/114 (3.5%)	10 mg: 1/46 (2.2%); 20 mg: 7/51 (13.7%); 25 mg: 18/114 (15.8%); Any dose: 26/211 (12.3%)
Deaths	Adverse	0 (0%)	0 (0%)
Dizziness	Adverse	8/114 (7.0%)	10 mg: 3/46 (6.5%); 20 mg: 13/51 (25.5%); 25 mg: 36/114 (31.6%); Any dose: 52/211 (24.6%)
Somnolence	Adverse	8/114 (7.0%)	10 mg: 5/46 (10.9%); 20 mg: 11/51 (21.6%); 25 mg: 17/114 (14.9%); Any dose: 33/211 (15.6%)
Fatigue	Adverse	6/114 (5.3%)	10 mg: 5/46 (10.9%); 20 mg: 4/51 (7.8%); 25 mg: 14/114 (12.3%); Any dose: 23/211 (10.9%)
Headache	Adverse	9/114 (7.9%)	10 mg: 6/46 (13.0%); 20 mg: 6/51 (11.8%); 25 mg: 9/114 (7.9%); Any dose: 21/211 (10.0%)
Balance disorder	Adverse	2/114 (1.8%)	10 mg: 2/46 (4.3%); 20 mg: 4/51 (7.8%); 25 mg: 13/114 (11.4%); Any dose: 19/211 (9.0%)
Tremor	Adverse	2/114 (1.8%)	10 mg: 3/46 (6.5%); 20 mg: 3/51 (5.9%); 25 mg: 12/114 (10.5%); Any dose: 18/211 (8.5%)
Confusional state	Adverse	1/114 (0.9%)	10 mg: 1/46 (2.2%); 20 mg: 3/51 (5.9%); 25 mg: 6/114 (5.3%); Any dose: 10/211 (4.7%)
Aphasia	Adverse	1/114 (0.9%)	10 mg: 1/46 (2.2%); 20 mg: 1/51 (2.0%); 25 mg: 8/114 (7.0%); Any dose: 10/211 (4.7%)
Dysarthria	Adverse	0/114 (0%)	10 mg: 1/46 (2.2%); 20 mg: 0/51 (0%); 25 mg: 8/114 (7.0%); Any dose: 9/211 (4.3%)
Gait disturbance	Adverse	1/114 (0.9%)	10 mg: 2/46 (4.3%); 20 mg: 2/51 (3.9%); 25 mg: 8/114 (7.0%); Any dose: 12/211 (5.7%)
Vision blurred	Adverse	1/114 (0.9%)	10 mg: 0/46 (0%); 20 mg: 1/51 (2.0%); 25 mg: 7/114 (6.1%); Any dose: 8/211 (3.8%)
Anxiety	Adverse	6/114 (5.3%)	10 mg: 0/46 (0%); 20 mg: 5/51 (9.8%); 25 mg: 2/114 (1.8%); Any dose: 7/211 (3.3%)
Hallucination	Adverse	0/114 (0%)	10 mg: 0/46 (0%); 20 mg: 3/51 (5.9%); 25 mg: 0/114 (0%); Any dose: 3/211 (1.4%)
Urinary retention	Adverse	0/114 (0%)	2 nonserious events in active treatment groups (both continued treatment; no catheterization required)
Weight increase	Adverse	1/114 (0.9%)	10 mg: 1/46 (2.2%); 20 mg: 2/51 (3.9%); 25 mg: 3/114 (2.6%)
Mean body weight change from baseline, kg (SD)	Adverse	0.2 (2.4)	10 mg: 0.6 (2.3); 20 mg: 1.6 (2.2); 25 mg: 1.9 (2.9)

Subgroup Analysis

Not explicitly reported. Randomization was stratified by background use of CYP3A4 inducer medications (57.8% of patients were taking a CYP3A4 inducer at baseline). XEN1101 is primarily metabolized by CYP3A4, and plasma levels may decrease in the presence of CYP3A4 inducers.

Criticisms

Relatively short 8-week treatment duration limits assessment of long-term efficacy and safety
Unequal group sizes: fewer patients in 10 mg (n=46) and 20 mg (n=51) groups compared to placebo (n=114) and 25 mg (n=114) groups
Unknown impact of COVID-19 pandemic on study outcomes; pandemic restrictions may have contributed to enrollment of a more refractory population
Highly treatment-resistant population (median 6 prior ASMs failed, 50.5% on 3 concomitant ASMs) may limit generalizability to less refractory patients
Phase 2b study requiring confirmation in larger phase 3 trials
Limited diversity: 91.7% identified as White race, limiting generalizability
Extensions of baseline period up to 20 weeks allowed due to COVID-19 restrictions, potentially affecting baseline seizure frequency calculations
No data on specific seizure subtypes (focal aware motor, focal impaired awareness, focal to bilateral tonic-clonic) separately analyzed

Funding

Sponsored by Xenon Pharmaceuticals Inc., the owner and developer of XEN1101. Multiple authors are Xenon Pharmaceuticals employees and/or shareholders. Medical editorial and writing support was funded by Xenon Pharmaceuticals. The paper does not include an explicit trial funding statement beyond the sponsor's role.

Based on: X-TOLE (JAMA Neurology, 2023)