Xenon shares climb despite Phase II depression drug miss
27 Nov 2023
Phase 2Clinical Result
Xenon Pharmaceuticals reported that a Phase II trial of its depression drug candidate XEN1101 failed to significantly alleviate symptom severity in patients with major depressive disorder (MDD). However, company shares nevertheless jumped as much as 16% after the X-NOVA trial readout was released Monday, with the company touting a strong efficacy trend at the higher dose as well as significance achieved on a key secondary endpoint.
"We are encouraged by the data we have generated with XEN1101 in this proof-of-concept study where we see clinically meaningful, dose-dependent drug activity and early onset of efficacy in depression," remarked chief medical officer Christopher Kenney, adding that the results "also support our belief that XEN1101, through its unique Kv7 mechanism of action, has the potential to play an important role in addressing anhedonia, a common co-morbidity in depression."
The randomised X-NOVA study involved 168 patients with moderate-to-severe MDD and was designed to assess the safety and efficacy of 10mg or 20mg of XEN1101, a novel potassium channel opener administered as monotherapy. The primary objective compared XEN1101 to placebo based on Montgomery-Åsberg Depression Rating Scale (MADRS) score change through week six. According to top-line results, the mean reduction was 15.61 in the XEN1101 10mg group and 16.94 in the XEN1101 20mg group, versus 13.90 for placebo. "A clear dose response and a clinically meaningful, but not statistically significant, 3.04 difference between placebo and the XEN1101 20mg group was observed," Xenon reported.
Benefit on reducing anhedonia
The company said statistical significance was nevertheless achieved on the pre-specified endpoint of the Hamilton Depression Rating Scale (HAM-D17) at week 6, where the mean reduction was 13.26 with the 20mg dose of the drug, compared to a reduction of 10.18 in the placebo arm. Xenon noted that on the key secondary endpoint of Snaith-Hamilton Pleasure Scale (SHAPS) measuring anhedonia at week 6, there was also a significant reduction of 7.77 in the XEN1101 20mg group versus a change of 5.30 for placebo.
Meanwhile, there were no serious adverse events reported at either of the two XEN1101 doses tested, while discontinuation rates due to treatment-emergent adverse events were "low" with three patients in the XEN1101 20mg versus two in the placebo group. XEN1101 was also not associated with clinically meaningful weight gain or sexual dysfunction.
Building on epilepsy programme
"Based on the totality of data from this study, including clinically meaningful drug activity in depression and anhedonia, we are actively exploring the future development of XEN1101 in MDD and potentially other indications as we believe this mechanism has potential broad applicability," commented CEO Ian Mortimer. He said the X-NOVA results in depression build on XEN1101's profile in the ongoing Phase III programme in epilepsy.
Last month, results from the Phase IIb X-TOLE trial published in JAMA Neurology found that XEN1101 reduced monthly frequency of focal onset seizures (FOS) by a median 52.8% versus placebo. "We believe the new clinical data we have generated through X-NOVA further support the potential of XEN1101 to have a highly differentiated profile in the treatment of epilepsy given the significant co-morbidity of depression in epilepsy patients," Mortimer added.
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