2023-11-28 13:49:13 ET
Summary
- Xenon Pharmaceuticals Inc.'s XEN1101 is being advanced in two identical phase 3 studies known as X-TOLE2 and X-TOLE3 for patients with focal onset seizure; Completion of recruitment for XTOLE-2 expected end of 2024.
- The global epilepsy market size will grow to $4.7 billion by 2030; focal seizures occur in up to 60% of patients with epilepsy.
- Major Depressive Disorder patients given XEN1101 achieved a statistically significant MADRS week 1 score implying a rapid onset of action in helping these patients.
- XEN1101 would not only be effective in reducing monthly seizure frequency in patients with focal onset seizure, but could also possibly help them with respect to depression as well.
Xenon Pharmaceuticals Inc. (XENE) has been making great progress with its pipeline, that's because it was able to report some positive data from its phase 2 X-NOVA study, which used its drug XEN1101 for the treatment of patients with major depressive disorder [MDD]. Even though the primary endpoint of this mid-stage study was not met MADRS at week 6, the drug still showed an early onset of efficacy of a statistically significant change of MADRS at week 1 when MDD patients were given XEN1101. The thing is that this program for future development in MDD remains in consideration, along with the possibility of targeting other indications. Not only that, but this data bodes well for the main clinical program it has in its pipeline, which is the use of this drug for the treatment of patients with focal onset seizures [FOS]. That's because such patients have a co-morbidity of depression.
Thus, XEN1101 does not only reduce seizure frequency but could have a major impact on depression that these patients experience as well. Xenon Pharmaceuticals is focusing on two late-stage studies for its main FOS program, which are X-TOLE2 and X-TOLE3. Besides this phase 3 program, there is another. This would be with respect to a late-stage study known as X-ACKT, which is exploring the use of this very same drug for the treatment of patients with primary generalized tonic-clonic seizures.
The bottom line is that this drug provides reduced seizure frequency in a shorter time period [week 1], plus other attractive attributes such as no titration being required like other epilepsy drugs. Enrollment for one of the late-stage studies as part of the FOS program, known as X-TOLE2, is expected to be completed by the 2nd half of 2024. This is important because the company expects to have an NDA submission of XEN1101 for FOS only based on prior phase 2b X-TOLE and phase 3 X-TOLE2 data.
XEN1101 For The Treatment Of Patients With Focal Onset Seizures
The first and main clinical program to go over in the pipeline would be the use of XEN1101, which is being developed for the treatment of patients with focal onset seizures [FOS]. Such seizures are typically seen in people with epilepsy, which is a type of neurological disorder characterized by random and unpredictable seizures. Focal seizures are highly common, and I state that because they account for approximately 60% of seizures that occur in new cases of epilepsy. As you can see, focal seizures are highly common in patients with epilepsy. It is expected that the global epilepsy market size will grow to $4.7 billion by 2030 .
Even if only accounting for 60% of focal seizures are observed here, this would still be a large market opportunity. As the name implies, the term "focal" means that such seizures begin in one portion of the brain. After that, it is quite possible that the seizure could spread to another part of the brain or cross over into another hemisphere of it. Xenon has already initiated a phase 3 study for this program, which I described above. The two late-stage studies initiated using XEN1101 for the treatment of patients with FOS are X-TOLE2 and X-TOLE3 respectively. These trials are expected to each recruit up to 360 patients who are to be randomized 1:1:1 to receive one of the following doses:
- 15 mg of XEN1101
- 25 mg of XEN1101
- Placebo.
The thing is that this phase 3 trial won't recruit just any patient, it is going to recruit specific age groups and baseline statistics. Patients to be recruited must be between the ages of 18 to 75 and must also be taking at least 1 to 3 current anti-seizure medications.
Not only that, but they must have a seizure frequency of at least ?4 seizures per month at baseline. Why the need to be taking such anti-seizure medications? That's because the goal of this late-stage trial is not just to test the use of XEN1101 alone as a treatment. This drug is being tested as an adjunctive one, in that it is being given to patients along with their current anti-seizure medication. Thus, XEN1101 is being tested as an adjunctive therapy for the treatment of these patients with FOS.
In order to see if either of these studies will be successful, the primary endpoint is going to be evaluated. The primary endpoint is going to be the median percent change in monthly seizure frequency from baseline through the 12-week period. Both doses of XEN1101 are going to be compared to the placebo over this double-blind period of 12 weeks. This program still has a bit of a ways to go as enrollment completion is not expected until the following year. It is expected that completion of enrollment for the first of two phase 3 studies, known as TOLE-2 , will occur by the end of 2024. It is quite possible that data from this late-stage study could be released by 2025.
The reason why I say that is because the primary completion date is expected by April 2025. Thus, it is highly likely that results from this study are to be released later on during that year. The phase 3 program was only initiated because of positive results from a prior phase 2b study known as X-TOLE. With respect to this study, it was noted that the primary endpoint of percent reduction from baseline in monthly FOS frequency of 52.8% was achieved. Thus, the statistical significance of this primary endpoint of XEN1101 versus placebo was achieved with a p-value of p <.001.
XEN1101 Achieved Great 1-week Efficacy In Patients With MDD
As I stated above, it was shown that the primary endpoint from the phase 2 proof-of-concept X-NOVA study , which evaluated the use of XEN1101 for the treatment of patients with major depressive disorder [MDD] was not met. This mid-stage proof-of-concept study recruited a total of 168 patients with moderate to severe MDD. Patients were given either 10 mg or 20 mg of XEN1101 whereby they were evaluated for the primary endpoint compared to placebo. The primary endpoint was the change in the Montgomery-Asberg Depression Rating Scale [MADRS] at week 6. The primary endpoint was not met, because a statistically significant difference of either doses of XEN1101 was not achieved compared to placebo with respect to this primary endpoint. The mean reductions observed were as follows:
- 15.61 average reduction score observed in 10 mg XEN1101 treated group
- 16.94 average reduction score observed in 20 mg XEN1101 treated group
- 13.90 average reduction observed in placebo treated group.
As you can see, patients who took XEN1101 had a better trend towards reduction of MADRS at week 6 compared to placebo, but a statistically significant difference was not achieved. Despite not meeting the primary endpoint, the stock still traded higher by 16%. I think that the stock was not punished because of one major outcome in the trial which was noted. This was with respect to the fact that statistical significance was achieved in term of MADRS at week 1. An average reduction of 4.88 points in MADRS was observed in the placebo group, whereas the patients in the 20 mg XEN1101 treatment group achieved a 7.54-point reduction. This difference was statistically significant , with a p-value of p=0.047.
While it is disappointing that the primary endpoint was not met, this has implications that this drug at least helps these patients with depression achieve a rapid onset of efficacy in a 1-week period. Believe it or not, this outcome has implications for Xenon Pharmaceuticals' lead program, which is the use of XEN1101 for FOS. How so? Well, a major co-morbidity of epilepsy would be depression or MDD. Thus, this drug would not only have an impact on monthly seizure reductions for these FOS patients but would also help with rapid onset of action in targeting the depression that occurs as well.
Financials
According to the 10-Q SEC Filing , Xenon Pharmaceuticals had cash and cash equivalents and marketable securities of $639.1 million as of September 30, 2023. Despite having several late-stage studies in place, it believes that this is going to be enough cash to fund its operations into 2026. This is likely to give it plenty of time to reach several milestones in the coming years. Especially, with enrollment completion of the phase 3 TOLE-2 study, which is expected by the end of 2024. With plenty of cash to reach several milestones in the coming years, there is no near-term risk of dilution.
Risks To business
There are several risks that investors should be aware of before investing in Xenon Pharmaceuticals. The first risk to consider would be with respect to the recently announced phase 2 proof-of-concept X-NOVA clinical trial, which used XEN1101 for the treatment of patients with major depressive disorder [MDD]. That's because even though there is encouraging data established, there is no guarantee that management will decide to move this drug forward towards MDD in further testing or any other indication for that matter.
A second risk to consider would then be with respect to the ongoing phase 3 XTOLE-2 and XTOLE-3 studies. That's because there is no guarantee that the primary endpoint of median percent change in monthly seizure frequency from baseline through 12 weeks is going to be achieved in either of these studies.
Not only that, but the goal is to file an NDA of XEN1101 for FOS with the phase 2b X-TOLE and first phase 3 XTOLE-2 studies. Even upon a clinical submission with data from both of these studies, there is no guarantee that the FDA will accept the regulatory application nor that this drug will ultimately be approved to treat this specific indication.
The third and final risk to consider would be with respect to a possible label expansion of XEN1101. There is another phase 3 program going, which is exploring the use of this drug to treat primary generalized tonic clonic seizures [PGCTS]. The use of this drug for the treatment of this seizure patient population is being explored in the phase 3 X-ACKT trial. One thing to note though is that only a single late-stage trial is being done for this program.
Conclusion
Xenon Pharmaceuticals has made great progress in being able to advance its pipeline. While it is quite disappointing that the phase 2 proof-of-concept X-NOVA study didn't achieve statistical significance in patients with MDD with respect to the primary endpoint, there was such a difference observed in MADRS in the first week of treatment. This at least bodes well for patients with FOS, who also have a co-morbidity of MDD to deal with.
With this drug providing several bonuses, it might be enough to make headway into the seizure market. It has no titration being required for starters, plus it has demonstrated an exceedingly well rapid onset of action in terms of seizure reduction.
Not only that but there is another aspect to consider, which is that despite the currently available anti-seizure medications in place, up to 50% of patients have a difficult time controlling their seizures or are refractory. Thus, the addition of XEN1101 might be a great alternative for those who don't achieve help from current medications.
For further details see:
Xenon: MDD Data Provides Rationale For XEN1101 Advancement Towards FOS