Xenon Pharmaceuticals has paused enrollment in its phase 3 depression studies of azetukalner after seeing adverse events that included a very small number recorded under the broad preferred term of psychosis. The company is still treating participants already enrolled in X-Nova2, in major depressive disorder, and X-Ceed, in bipolar depression, but has voluntarily stopped adding new patients.
Chief Medical Officer Christopher Kenney said on a Thursday analyst call that what Xenon has seen in psychiatry is consistent with its epilepsy experience and includes a small percentage of patients with confusion, aphasia and ataxia. He said most of the adverse events were mild or moderate, and that across the epilepsy and psychiatry programs the neuropsychiatric events have been short in duration, reversible and without long-term sequelae.
The data
Azetukalner is a Kv7 potassium channel opener, and Xenon says it has generated more than 1,500 patient-years of safety and exposure data in epilepsy. Kenney said the phase 3 epilepsy program, which Xenon used this week to file for FDA approval in focal seizures, had one psychosis case in each trial.
The depression interruption affects studies that were already well underway. X-Nova2 had enrolled about 360 participants when Xenon stopped recruitment, which the company said put it about 80% of the way to its target. Xenon now plans to stop that trial early, saying it already has enough patients to show a clinically meaningful improvement. The biotech expects topline X-Nova2 data in the first quarter of next year.
What Xenon is changing
CEO Ian Mortimer said Xenon is using the pause to adjust dosing in a way it believes will improve tolerability. He said the company expects to make those changes over the coming months and has notified the FDA.
Management’s stance is that the setback does not end azetukalner’s path in depression. Kenney told analysts that other depression drugs can also cause serious adverse events, including events along the lines of psychosis, and said Xenon views the pause as temporary rather than as a reason the drug cannot move forward.
William Blair took a similar view but still reduced its probability of success for major depressive disorder to 50% from 60%, noting that it had already considered the indication risky because phase 2 data were somewhat mixed. The firm also said blockbuster antidepressants such as Zoloft and Wellbutrin have similar rates of psychosis.
For investors, the immediate signal is less about the epilepsy filing and more about the difficulty of extending neurology mechanisms into psychiatry. Xenon said nothing in the public domain suggests a connection between its pause and Biohaven’s recent enrollment pause for BHV-7000, another Kv7 activator, and William Blair likewise said the two events are unrelated and do not point to broader class safety issues. Even so, the market reaction showed how quickly sentiment can reset when late-stage psychiatry tolerability becomes uncertain: Xenon shares fell 26% in premarket trading Friday to $42.25 from a Thursday close of $57.35.
