Azetukalner, a Kv7 potassium channel opener, reduced the frequency of focal onset seizures by a placebo-adjusted rate of 42.7%. Xenon Pharmaceuticals believes this is the highest such efficacy “observed in a pivotal epilepsy study,” CEO Ian Mortimer said Monday.
Xenon Pharmaceuticals announced positive data Monday from a Phase 3 trial of its candidate for focal onset seizures, bringing the Vancouver, B.C.–based company one step closer to realizing its first approval after more than 25 years in business.
The Phase 3 data “exceeded expectations and, to our knowledge, show the highest placebo-adjusted efficacy ever observed in a pivotal epilepsy study,” Xenon CEO Ian Mortimer said in a statement on Monday.
Stifel analysts agreed, writing in a Monday morning note that the data from the Phase 3 X-TOLE2 trial “represent [a] best-case scenario--beating the high bar set in ph2b and demonstrating a best-in-class profile.”
Xenon’s stock price jumped nearly 45% to more than $60 in pre-market trading Monday.
Azetukalner, Xenon’s lead asset, is a novel Kv7 potassium channel opener. In the X-TOLE2 study, the drug candidate met the primary endpoint of a change in the frequency of focal onset seizures (FOS) in both the 15-mg and 25-mg dose groups after 12 weeks. Patients given the 25-mg dose of azetukalner saw a 53.2% reduction in this metric while placebo comparators had only a 10.4% change, according to Xenon’s press release. The 15-mg cohort saw a 34.5% reduction versus placebo.
The results are an improvement on Xenon’s Phase 2b X-TOLE study, in which treatment with azetukalner led to a 34.6% placebo-adjusted median percent change (MPC) in the 25-mg dose group over eight weeks compared to X-TOLE2’s 42.7% placebo adjusted rate. The drug’s safety profile was consistent with previous studies, the company reported.
The 43% placebo adjusted median seizure reduction from baseline “was way above investor expectations (25-30%),” Stifel wrote on Monday.
Meanwhile, in an ongoing open-label extension study associated with the X-TOLE trial, 38% of patients were seizure-free after a year or longer, Xenon reported at the American Epilepsy Society Annual Meeting in December.
With these results in hand, Xenon plans to submit a new drug application for azetukalner to the FDA in the third quarter of this year. If approved, it would be the first Kv7 potassium channel opener for epilepsy, according to Monday’s release.
Focal onset seizures are caused by electrical activity in a certain area of the brain. Azetukalner “inhibits neuronal firing by blocking the potassium ion channels, which play a major role in calming down neurons after they fire,” Xenon Chief Medical Officer Chris Kenney told BioSpace prior to the Phase 3 data release.
While there are already around 20 epilepsy drugs on the market, Kenney said azetukalner stands out because of its differentiated mechanism. The most common therapies are SV2A binders and sodium channel blockers, so azetukalner “would be sort of the third leg of the stool.”
In addition to epilepsy, azetukalner is also being studied in Phase 3 for major depressive disorder and bipolar depression.
Kenney said Xenon views azetukalner as a “mechanism in a pipeline because in epilepsy, you have this population of neurons that are hyper-excitable, but in areas like in psychiatry, you also have abnormal circuits in the brain where there are various parts of the circuit where you have hyper-excitable neurons where you can ameliorate symptoms by calming down those neurons.”
A Quarter Century in the Making
This moment has been a long time coming for Xenon, which was founded as a genetics company in November 1996, studying the impact of single gene mutations on human biology, Xenon CEO Ian Mortimer told BioSpace prior to Monday’s release.
Over the past 15–20 years, the company has built up its drug discovery and clinical development capabilities in drugging ion channels in the nervous system, Mortimer added.
Xenon also has three early-stage assets in development for pain: two NaV1.7 sodium channel inhibitors and another Kv7 potassium channel opener
“A huge amount of the focus of the company over the last few years has been on this Kv7 channel,” Mortimer said.
As for azetukalner, Mortimer said in Monday’s statement that the magnitude of effect in X-TOLE2, favorable safety profile, differentiated Kv7 mechanism of action and ease-of-use attributes give the company “great confidence in azetukalner’s potential to become a preferred medication for patients living with uncontrolled seizures.”
