Despite the use of various concurrent antiseizure medications (ASMs), over 30% of patients with focal onset seizures have persistent, uncontrolled seizures.1 Hence, the search for new ASMs with better efficacy and tolerability is continuing. Voltage-gated potassium ion channels (Kv) repolarize neuronal action potentials, thus making potassium channel “openers” potentially attractive targets for the development of a new class of ASMs. In 2011, ezogabine/retigabine (Trobalt© [EU] or Potiga© [USA]) (GlaxoSmithKline, Brentford, London, England and Bausch Health, Laval, Canada respectively) was the first neuronal potassium channel (KCNQ/Kv7) opener approved by the US Food and Drug Administration and the European Medicines Agency.2,3 It had a narrow therapeutic window and was discontinued in 2017, when patients developed lavender skin discolouration and retinal pigment clumping after several years of exposure.4–6 Recently, a positive allosteric modulator of neuronal Kv7.2/7.3 channels, XEN1101, has shown promise in treating focal onset epilepsy.7 XEN1101 is structurally distinct from ezogabine: it has a tertiary rather than a secondary aniline compound, which prevents the formation of chromophoric phenazinium-type dimers, which are associated with ezogabine’s pigmentary clumping. Preclinical studies, the pharmacological profile and a recent phase IIb study of XEN1101 (A study to evaluate XEN1101 as adjunctive therapy in focal epilepsy; ClinicalTrials.gov identifier: NCT03796962) support its development as a potential therapy for focal onset seizures.7–9
XEN1101 pharmacology: Mechanism of action, toxicology, pharmacodynamics and pharmacokinetics
Mechanism of action
XEN1101 is a neuronal Kv7.2–7.5 potassium channel (KCNQ2-5) agonist that is more selective than ezogabine in modulating Kv7 channel subtypes in in vitro cell line studies.7,8 Compared with ezogabine, XEN1101 has a high affinity for the receptor, so it interacts more selectively with Kv7.2/7.3 channels than Kv7.3/7.5 and Kv7.4 channels.8,10 It was not found to affect Kv7.1, hERG and GABA channels in preclinical studies.8,10 XEN1101 was found to be 16 times more potent than ezogabine in the maximal electroshock stimulus screening seizure model.8,10 It was also found to be much more potent than ezogabine in modulating potassium ion channel conductance in patch-clamp studies in human embryonic kidney cells expressing Kv7.2/7.3 channels.8,10
Pharmacokinetics and pharmacodynamics
In single-ascending-dose studies, the effective half-life of XEN1101 is greater than 24 hours, which allows once-a-day dosing.11 Both the absorption and elimination phases of XEN1101 are long.11 The peak serum concentration (Cmax) for 20 mg single doses is 31.5 ng/mL (at time to peak drug concentration [Tmax] 3.69 hours) and a half-life (t1/2) of 41 hours; the Cmax for 30 mg doses is 35.5 ng/mL (at Tmax 3.17 hours) and t1/2 is 63.4 hours (all were mean values from the data of preclinical studies in human subjects). The bioavailability of XEN1101 increases approximately 1.5-times by food intake: in the fed state, a 25 mg dose produces a mean Cmax of 45.8 ng/L and a t1/2 of 97 hours. The terminal elimination profile is long, with a t1/2 of approximately 4–10 days, likely due to its slow release from tissue compartments.11 Near steady-state trough plasma levels were reached about 1 week after dosing.8,11
Drug interactions, safety and toxicology
Based on microsome and transporter screening laboratory assays, drug interactions are not expected for XEN1101.8,10,11 XEN1101 did not inhibit or significantly induce CYP450 enzymes. The compound was not metabolized by most Cytochrome P450 inducers. In vitro studies show that CYP4A4 plays a minor role in the metabolism of XEN1101.8 The major hepatic oxidative metabolite of XEN1101 did not appear to alter the function of KCNQ channels in preliminary studies. However, human drug interaction studies are still needed.
Long-term animal studies have demonstrated a relatively safe, long-term preclinical profile of XEN1101.7,8,10 Dose-limiting sedation and ataxia were observed in monkeys during the initiation of treatment.8 Teratogenic studies in rats and rabbits did not show any embryo-foetal developmental abnormalities at 6 and 10 mg/kg/d dosages.8 The results of carcinogenicity and detailed non-human safety studies have not been reported. In recently completed 6-month and 9-month studies with rats and monkeys, respectively, the daily administration of XEN1101 at maintenance doses of 1, 2.5 or 4 mg/kg/day did not result in major adverse events.8
Ezogabine has a secondary aniline structure that can form chromophoric phenazinium-type dimers causing skin and retinal pigmentation changes.12 Due to its tertiary aniline structure, XEN1101 does not form dimers as ezogabine did, and pigmentary deposits are unlikely to occur.10
XEN1101 clinical trials: Preliminary results
The effects of XEN1101 on a transcranial magnetic stimulation model of cortical excitability in humans
Transcranial magnetic stimulation motor thresholds have been used to define cortical excitability and to probe the effects of ASMs on cortical excitability. In a phase I study of 20 healthy volunteers, XEN1101 increased the participants’ motor thresholds compared with placebo, thus suggesting that it decreases cortical excitability.13–15
The adverse events in the study were mild and included dizziness, fatigue, headache and attention disturbances; there were no serious adverse events in the 20 healthy volunteers.13–15
A phase IIb study of the efficacy and safety of XEN1101 in adults with focal epilepsy
The safety and efficacy of XEN1101 for treating focal onset epilepsy were studied in a multicentre, phase IIb, randomized, double-blind, placebo-controlled study (X-TOLE) with a 3-year open-label extension (OLE) option (ClinicalTrials.gov Identifier: NCT03796962).9,16,17 Adult subjects were randomized to receive placebo or adjunctive XEN11011 therapy at 10 mg, 20 mg and 25 mg doses.9,16,17
The study had baseline and treatment periods of 8 weeks. A total of 530 individuals were screened, with 325 randomly assigned and treated.16,17 The subjects had an average age of 39.8 ± 13 years, and 50.5% of them were women. The study subjects had focal onset epilepsy that was highly resistant to drugs: 91% of them were taking two or three background ASMs. During the study, eight treatment-emergent serious adverse events were reported: severe dizziness (n=1), muscle spasticity (n=1), seizure (n=1), hyponatremia (n=1), confusional state (n=1), psychogenic seizure (n=1), unspecified psychotic disorder (n=1) and somatic delusion (n=1).17 A blinded evaluation of safety labs, vital signs and electrocardiograms showed no safety signals. A total of 12.3% of patients discontinued the study treatment; this discontinuation appeared to be dose dependent: participants receiving placebo had a discontinuation rate of 4.4%, participants receiving 10 mg of XEN1101 had a discontinuation rate of 2.2%, participants receiving a 20 mg dose had a discontinuation rate of 15.7% and participants receiving a 25 mg dose had a discontinuation rate of 22.8%. The most common (>10%) treatment-emergent adverse events were dizziness (24.6%), somnolence (15.6%) and fatigue (10.9%). Six subjects (10 mg: n=1; 20 mg: n=2; 25 mg: n=3) reported
treatment-emergent adverse events of weight increase of ≥7% from baseline. Two subjects developed urinary retention requiring dose reductions. This possible adverse event should be monitored in future studies: voltage-gated K+ channels regulate the bladder detrusor smooth muscle function and ezogabine-produced urinary retention in rodents but had minimal effects in humans.18
At baseline, the subject’s median seizure frequency was ~13 per month (28 days).16,17 During the study treatment, participants in the 25 mg, 20 mg, 10 mg and placebo groups had a median percentage change in monthly seizure frequency of 52.8%, 46.4%, 33.3% and 18.2%, respectively.17 The 50% responder rates (a secondary endpoint) were 54.5%, 43.1%, 28.3% and 14.9% in the 25 mg, 20 mg, 10 mg and placebo groups, respectively.17 There were statistically significant differences between the treatment groups and the placebo group (p<0.05). The >75% seizure responder rates for both the 20 mg and 25 mg doses were 29% (compared with 6.1% for placebo), while 7.8% of participants taking a 20 mg dose of XEN1101 were 100% responders (compared with 1.7% for placebo).17
To date, no pigmentary abnormalities have been recorded during the study’s double-blind phase or early analysis of the continuing OLE.
XEN1101 is a novel ASM that functions as a positive allosteric modulator of neuronal Kv7.2/7.3 channels and shows promise in treating focal onset seizures.7,8 It has higher potency in animal seizure models and in vitro studies than ezogabine. XEN1101 has a tertiary aniline structure that prevents the formation of chromophoric dimers, thus making ezogabine-like pigmentation changes unlikely.10,11 A transcranial magnetic stimulation study was used to identify the optimal tolerated doses that decrease cortical excitability.13 The data from the pharmacokinetics studies support once-a-day dosing. The phase IIb X-TOLE study (ClinicalTrials.gov Identifier: NCT03796962) demonstrated the preliminary safety and a favourable dose-dependent efficacy and tolerability profile.16 The OLE phase of the trial to monitor the safety of XEN1101 is still ongoing.