Xenon Pharmaceuticals has paused enrollment in phase 3 depression trials after seeing adverse events, including psychosis.
The biotech continues to treat existing participants in X-Nova2 and X-Ceed, phase 3 trials that are testing azetukalner in major depressive disorder (MDD) and bipolar depression, respectively. However, the company has voluntarily stopped enrolling new patients in the studies in response to reports of mostly mild or moderate adverse events.
“What we’re seeing in psychiatry, which is consistent with epilepsy, is a small percentage of patients with confusion, aphasia, ataxia,” Xenon Chief Medical Officer Christopher Kenney, M.D., explained on a conference call with analysts after the market closed Thursday.
“In a very small number of patients, we have seen an adverse event captured under the broad preferred term of psychosis,” Kenney added.
Xenon has generated more than 1,500 patient-years of safety and exposure data on azetukalner, a Kv7 potassium channel opener, in epilepsy. The phase 3 epilepsy program, which the biotech used this week to file for FDA approval in focal seizures, featured one psychosis case in both trials, Kenney said.
Across the epilepsy and psychiatry studies, neuropsychiatric adverse events have been “short in duration and reversible, without any long-term sequelae,” Kenney said.
The biotech will use the enrollment pause to adjust dosing, which Xenon believes will improve tolerability, CEO Ian Mortimer told analysts. Xenon expects to make the changes “over the coming months” and has notified the FDA, the CEO added.
X-Nova2 had enrolled about 360 participants when Xenon paused enrollment, putting it 80% of the way toward its recruitment target. Xenon calculated that the MDD trial already has enough patients to show a clinically meaningful improvement, leading the biotech to stop the study early. The company plans to report topline X-Nova2 data in the first quarter of next year and sees a future for the asset in depression.
“If you look at other drugs that are used for depression, they do cause serious adverse events, sometimes in keeping with this along the lines of psychosis, sometimes other issues,” Kenney said on the call. “We don't think that this is something that prevents this drug [from] moving forward—we view this pause as temporary. We’re going to make some adjustments and then go forward.”
William Blair analysts reached a similar conclusion in a note to investors. Blockbuster antidepressants like Zoloft and Wellbutrin have similar rates of psychosis, the analysts noted. Even so, the analysts lowered their probability of success in MDD from 60% to 50% while pointing out that they had always viewed the indication as risky given phase 2 data were “somewhat mixed.”
Investors sent Xenon’s stock down 26% to $42.25 in pre-market trading Friday from a Thursday closing price of $57.35.
Xenon’s update arrived one week after Biohaven paused enrollment in focal epilepsy trials of BHV-7000, a selective activator of Kv7.2/7.3 potassium channels. Biohaven has provided limited information on the pause. Based on the details in the public domain, Mortimer said nothing suggests a connection between Biohaven’s pause and the azetukalner adverse events.
William Blair analysts agreed the Xenon and Biohaven pauses are unrelated and not evidence of broader Kv7 activator class safety issues. The analysts also supported Xenon’s view that azetukalner’s prospects in epilepsy are unaffected by the psychiatry setback. Psychosis events in epilepsy were already known as part of the risk/benefit profile in the indication, the analysts said.