Trial Enrolment Paused Over Neuropsychiatric Adverse Events
Xenon Pharmaceuticals has stopped enrolling patients in its phase 3 depression trials after reporting adverse events such as psychosis.
The biotech is continuing to treat current patients in X-Nova2 and X-Ceed, phase 3 trials of azetukalner that are under way in major depressive disorder (MDD) and bipolar depression, respectively. But the company has voluntarily withdrawn from enrolling new patients in the studies due to reporting of adverse events which were mostly mild or moderate.
When compared to epilepsy, what’s happening in psychiatry is a small percentage of patients with confusion, aphasia and ataxia, Xenon Chief Medical Officer Christopher Kenney said on a post-market call to analysts.
In a small number of patients, we’ve observed an adverse event that we’ve grouped under the umbrella term of “psychosis,” Kenney added.
Xenon has over 1,500 patient-years of safety and exposure experience with azetukalner, a Kv7 potassium channel opener, in epilepsy. The biotech that used this week to submit the phase 3 epilepsy data for FDA approval in focal seizures had one case of psychosis in each of the trials in the program, Kenney said.
Kenney said there were no long-term sequelae with neuropsychiatric adverse events in either of the epilepsy or psychiatric studies.
The biotech will take advantage of the enrollment pause to tweak dosing, which it thinks will make its products more tolerable, CEO Ian Mortimer told analysts. The alterations will be “over the coming months,” Xenon said, and the company has informed the FDA.
X-Nova2 Target Reached and Timelines Intact
Xenon stopped enrollment of X-Nova2, with approximately 360 participants. At the time of the pause, X-Nova2 was 80% recruited for its target. The biotech halted the study early because, according to Xenon, the trial already has enough patients to prove a clinically meaningful improvement. The company is set to announce topline X-Nova2 data in the first quarter of next year and believes it has a future with 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 believe this is an obstacle for this drug to progress; this is a pause, we’re going to make some adjustments and then we will progress.”
Analyst Perspectives and Class Comparisons
William Blair analysts came to the same conclusion in a note to investors. Analysts said that blockbuster antidepressants such as Zoloft and Wellbutrin are equally likely to cause psychosis. Despite that, the analysts reduced their chance of success in MDD from 60% to 50% and noted they had always considered the indication a “risky” one based on results in phase 2, which were “somewhat mixed.”
Xenon’s update came a week after Biohaven halted enrollment in clinical trials of its selective activator of Kv7.2/7.3 potassium channels, BHV-7000, for focal epilepsy. Biohaven has limitedly shared information on the pause. Given the information in the public domain, there is no indication that Biohaven’s pause is related to the azetukalner adverse events, Mortimer said.
William Blair analysts said the Xenon and Biohaven pauses have nothing to do with each other and are not a sign of any cross-class issues with safety of Kv7 activators. The analysts also backed Xenon’s expectations that the setback in psychiatry won’t have an impact on the prospects of azetukalner in epilepsy. Psychosis events in epilepsy were already known as part of the risk/benefit profile in the indication, the analysts said.
Xenon Pharmaceuticals has temporarily paused new patient enrollment in its Phase 3 clinical studies evaluating azetukalner for major depressive disorder and bipolar depression. The decision followed a review of neuropsychiatric adverse events, including a small number of events recorded under the broad category of psychosis.
The affected studies include X-NOVA2 for major depressive disorder and X-CEED for bipolar depression. According to Xenon, patients who are already enrolled will continue participating in the studies while the company evaluates potential changes to dosing designed to improve tolerability.
Xenon Assesses Neuropsychiatric Safety
The reported events included confusion, speech difficulties and problems with motor coordination, along with a small number of psychosis cases. Xenon has characterized the events as generally mild or moderate, short in duration and reversible. The company said the events had not previously been observed in its Phase 2 X-NOVA study in major depressive disorder.
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