Xenon halts new enrollment after psychosis adverse events in depression trials; shares plunge

Xenon Pharmaceuticals halted new patient enrollment after psychosis adverse events were reported in depression trials.

According to Fierce Biotech on the 17th (local time), Xenon voluntarily paused new enrollment in its Phase 3 trials XENOVA2 and XCEED, which are studying major depressive disorder (MDD) and bipolar depression. Treatment will continue for existing participants.

The company said it made the decision in response to reports of adverse events that were mostly mild or moderate.

Christopher Kenney, Xenon's chief medical officer (CMO), said on an after-market close conference call with analysts, “What we see in psychiatry, consistent with epilepsy, is that a small number of patients experience confusion, aphasia and ataxia.”

Kenney added, “In a very small number of patients, we observed adverse events that fall under the broad term psychosis.”

Xenon has accumulated safety and exposure data from more than 1,500 people in epilepsy studies of azetukalner, a Kv7 potassium channel opener. In the Phase 3 epilepsy program for focal seizures, for which the company submitted a U.S. Food and Drug Administration (FDA) approval application this week, one case of psychosis occurred in each of two trials, Kenney said.

Across its epilepsy and psychiatry studies, neuropsychiatric adverse events “were short-lived and reversible, with no long-term sequelae,” Kenney said.

Xenon CEO Ian Mortimer said the company plans to use the enrollment pause to adjust the dose. The company expects the changes to improve tolerability and plans to complete them “over the next few months.” It has already notified the FDA.

XENOVA2 had enrolled about 360 participants, reaching 80% of its target, when enrollment was paused. Xenon decided to end the study early because it determined that it had already enrolled enough patients to demonstrate clinically meaningful improvement in the MDD trial. The company plans to announce topline results from XENOVA2 in the first quarter next year.

“Other drugs used for depression can also sometimes cause serious adverse events similar to psychosis,” Kenney said. “This pause is temporary, and we will make adjustments and continue.”

William Blair analysts also said in an investor note that blockbuster antidepressants such as Zoloft and Wellbutrin have similar rates of psychosis. However, they lowered the probability of success in MDD from 60% to 50%.

Investors traded Xenon shares down 26% to $42.25 in premarket trading that day. The previous day's closing price was $57.35.

Xenon's announcement came a week after Biohaven paused enrollment in a focal epilepsy trial of BHV-7000, a selective Kv7.2/7.3 potassium channel activator. Mortimer said publicly available information did not suggest a link between Biohaven's pause and adverse events associated with azetukalner.

William Blair analysts also said the two companies' pauses were unrelated and did not provide evidence of a safety issue across the Kv7 activator class.