Q3 2023 Xenon Pharmaceuticals Inc Earnings Call
Hello, Thank you for standing by and welcome to Xenon Pharmaceuticals incorporated third quarter 2023 earnings Conference call I would.
Now I'd like to turn the call over to Sherri <unk> our CFO.
We now begin the conference.
Thank you good afternoon, everyone. Thank you for joining us on our call and webcast.
Third quarter 2023 financial and operating results joining me are Ian Mortimer.
Evident and Chief Executive Officer, Dr. Chris Kenny <unk>, Chief Medical Officer, and Dr. Chris One figure and.
Chief commercial officer.
Anne will open today's call with a summary of our progress Chris Kenny will provide an overview of our ongoing <unk>.
Oh, one clinical programs and.
That's one second we'll summarize key findings from our market research around the potential of 11 O. One in the majored in major depressive disorder or M. D D treatment landscape I.
I will summarize our financial results.
Within our partnered programs and anticipated company milestone events before opening the call to your questions. Please.
Please be advised that during this call we will make a number of statements that are forward looking including statements regarding the timing of and potential results from our and our collaborators clinical trials the potential efficacy safety profile future development plans addressable market regulatory success and commercial potential of our and our.
Partnered product candidates the efficacy of our clinical trial designs, our ability to successfully develop and achieve milestones in our <unk> 11 O one and other development programs, the timing and results of our interactions with regulators our ability to successfully develop and obtain regulatory approval a vaccine 11 O one and our other.
Product candidate anticipated enrollment in our clinical trials and the timing thereof, and our expectation that we will have sufficient cash to fund operations into 2026 forward looking statements are subject to numerous risks and uncertainties many of which are beyond our control, including the risks and uncertainties described from time to.
The time in our SEC filings.
Our results may differ materially from those projected on today's call. We undertake no obligation to publicly update any forward looking statement today's press release summarizing on third quarter financial results and the accompanying report on Form 10-Q will be made available under the investors section of our website at www Dot xenon.
Dash pardon my Dot Com and filed with the SEC and on SEDAR now I'd like to turn the call over to Ian.
Thanks, Jerry and good afternoon, everyone and thanks for joining our call today.
I'm excited to share with you the progress we have made this past quarter across under Ology pipeline to begin we remain confident in our ability to execute on our ambitious <unk> 11 O. One phase III program and this includes our export to an X tole III clinical trial in patients with focal onset seizures or off Alaska.
And our exact clinical trial in patients with primary generalized tonic clonic seizure RPG Tcs, we believe our experience with our phase two B X Tole study, which was similar in design to our ongoing ex told two and X Tole III trials provides us with a solid foundation of operational experience and strong.
Existing relationships with leading clinical investigators in the epilepsy space.
As a reminder, we aligned with FDA on key elements of our phase III program.
<unk> plans to submit an NDA upon the successful completion of external to our first actually on 11 O. One phase III clinical trial, along with the existing data package from our phase <unk> clinical trial and additional safety data from other clinical trials to meet regulatory requirements.
And X tole, we screened patients over a period of 26 months from the first quarter of 2019 through the first quarter of 2021 and the next pole too we initiated our first clinical site late last year with our first patient being randomized in Q1 of this year and we expect patient enrollment to complete in the second half of 2024.
So this would be in line or faster the next tool based on our current assumptions and expectations.
And as a reminder, X tole too will recruit more patients. The next hole. So overall, we are pleased with the progress our team has made so far this year.
In addition to ongoing execution in our phase III epilepsy program. We also continue to showcase <unk> 11, O one and connect with leading Epaulet colleges and neurologists.
Including at the 31st International Epilepsy Congress or ITC that took place in Dublin in early September.
We presented data from the ongoing open label extension study from our phase two B X Tole trial.
And the long term efficacy of vaccine at 11 O. One has demonstrated by patients experiencing continued seizure reduction during the OLED and extended periods of seizure freedom and this is translating into overall improvements in patients quality of life Chris.
Chris will provide some more details around the significance of these fine being this later in the call today.
We are also pleased to report that the peer reviewed results from our phase <unk> study of <unk> at 11 O. One in adults with focal epilepsy were recently published in the prestigious Jama Neurology Journal.
Turning now to our program in major depressive disorder, we remain on track to see topline results from our <unk> one phase II <unk> study in late November to mid December.
Given the high unmet need and M. D D and the fact that depression is the most common comorbidity and epilepsy, we are keenly interested in these data.
In September we hosted a well received webinar with leading MDT clinicians, Dr. James Morrow and Dr. Sanjay Matthew who provided their commentary on the mechanistic rationale supporting potassium channel modulation as a potential treatment for M. D D.
Before turning the call over to Chris Kenny I would also like to remind everyone that we have planned for a significant presence at the annual American epilepsy Society meeting or Aes next month with multiple posters and presentations alongside our booth and scientific acceptance and so for those of you who are planning to attend we look.
Forward to connecting with you in Orlando next month.
I'll now pass the call over to Chris Chris.
Let me begin by echoing <unk> acknowledgment of the publication of the phase <unk> data in Jama neurology, the compelling efficacy and safety data from this clinical trials supported further clinical development.
Of exon 11 O one in epilepsy, Andy ambitious phase III program that we're pursuing today.
We also continued to gather data from our ongoing X Tole open label extension study with a cohort of patients now on <unk> 11 O one for more than four years.
To date, we have amassed several hundreds of patient years of safety and efficacy data further supporting exon 11 O one's compelling profile and differentiating from other molecules in development for epilepsy.
We look forward to presenting additional long term data from the extra week open label extension at the American Epilepsy Society next month.
As noted by Ian we recently hosted posters and presentations at the International Epilepsy Congress in Dublin that included interim results from the X Tole open label extension study.
Newly compiled interim data focused on quality of life measures as assessed using a validated tool called the quality of life and epilepsy inventory 31, and the overall open label extension group as well as the subgroup that was seizure free for at least 12 consecutive months at the time of the interim data analysis.
Clinically important improvements in the quality 31, subscales of seizure worry social functioning and medication effects were seen across all patients.
With even greater improvements in the seizure free group, which saw a clinically important improvements in all quality of life subscale as assessed by the quality of <unk> 31.
As a clinician is encouraging to see these quality of life data, which are consistent with the compelling clinical results generated to date and contribute further to the growing evidence that support the promise of exon 11 O. One is a novel differentiated potential treatment for patients with epilepsy.
Turning to our work in major depressive disorder as noted by Ian we remain on track to report ex Nova topline results in late November to mid December while our original trial design plan for 150 subjects with 50 subjects per arm.
Of 10 milligrams Axion 11, O 120 milligrams, <unk> 11, O one or placebo based on patient randomization rates. The ex Nova topline results will include data from more than 160 patients.
As a reminder, within the topline results, we expect to report out on the primary endpoint, which is to assess the efficacy of 10 milligrams and 20 milligrams of <unk> 11, O one compared to placebo on improvement of depressive symptoms using the moderate score change from baseline to week six.
We also intend to report on the secondary objective, which is to assess the efficacy of 10 milligrams and 20 milligram doses of <unk> hundred 11 O one compared to placebo on improvement of anhedonia symptoms using the chaps score change from baseline to week six and.
In addition, we will provide data on the overall safety and Tolerability seen with <unk> hundred one in these patients diagnosed with MTT.
With that summary of our near term data announcement I'd like to turn the call over to Chris <unk>, who will share some of the primary market research conducted by you know in support of our MTT program Chris.
Thanks, Chris.
We used to share information from our market research efforts that have helped us better understand the drivers of clinical decision, making the unmet medical need and MDT and key attributes desired by clinicians in future treatments or.
Our research efforts in both U S key opinion leaders and high volume prescribing psychiatrist with the intended goal of understanding how axion 11 O one would fit into our future treatment paradigm.
With the potential product profile consistent with the Alberta adverse event profile seen in X tole, so understand physicians perspectives pertaining to various product attributes, including efficacy tolerability mechanism of action and ease of use attributes.
Given the antidepressant medications are generally perceived as having non differentiated efficacy. We learned that there are several other key unmet needs that create an opportunity for future products in the <unk> space.
First and foremost physicians are interested in new agents with novel mechanisms of action given.
Given the heterogeneity of depression products with novel mechanisms of action could be used in patients who did not respond initially to generic therapies.
And while the first and second line therapies of choice Ssris and SNRI as we're seeing the offer reasonable efficacy certain safety liabilities were identified as a concern for many patients.
<unk> consistently pointed out challenges with common adverse events, such as sexual dysfunction and significant weight gain when treating patients with M. D D.
In testing the adverse event profile of vaccine on 1100, one seen in next door.
We gathered feedback CNS adverse events, such as dizziness would be acceptable levels observed in X tole.
We also heard interest from physicians about the potential for products that can deliver more rapid relief of symptoms given the delayed therapeutic response with the current standard of care.
Because currently approved therapies do not address Antonia, which represents a common cobra related comorbidity of depression. This was another dimension of interest.
Given that Theres preclinical support for the <unk> seven mechanisms at play a role in addressing in Indonesia.
A unique mechanism of action of <unk> 11, O one could be viewed as an important differentiator in the eyes of these prescribing physicians.
Finally, the ease of use ease of use attributes identified in our epilepsy market research such as once daily dosing with food and no titration are also important to psychiatrist.
In summary, we believe that if approved exon 11 O. One can play a significant role within the MTBE treatment landscape.
<unk> mechanism of action, coupled with a differentiated abbott's event profile that lacks the same liabilities as other mgd therapeutics, such as sexual dysfunction or significant weight gain ease of use attributes and the potential to address anhedonia resulted in a compelling product profile.
Accordingly, if actually on 11 to one shows efficacy and M. D. D. This could be a striking differentiator in epilepsy, given that certain anti seizure medications are associated with unwanted mood symptoms and depression is a common comorbidity in epilepsy patients.
I would now like to turn the call over to Sherri, who will give us a brief update on our partner program with Derek grid before summarizing our third quarter financial results and upcoming milestones.
Ari.
Thanks, very much Craig beginning with our partnered programs our collaborators at Neurocrine are conducting two separate phase III clinical trials evaluating <unk> in 90 135 Q.
One study is focused on adult patients with focal onset seizures and the other study is examining the use of <unk> 90 to 1352 in patients with SDN and <unk> related epilepsy.
Notably Neurocrine has guided the data permits adult focal study are anticipated to be released later this month as a reminder, NBA 91, 352 is a highly selective inhibitor of the sodium channel called NAV, one six which we discovered at xenon and licensed generic line and we're excited to have this hypothesis.
Says at selecting selective sodium channel inhibition can be tested.
Look forward to working with working with Neurocrine on this upcoming data released and the next steps in the program.
Now I'll touch on some highlights from the financial statements and would refer you to our news release and 10-Q report for further details.
Cash and cash equivalents in marketable securities were $639 1 million as of September 30th 2023, compared to $720 8 million as of December 31, 2022.
Based on current operating plans, including the completion of the <unk> 11 O. One phase III epilepsy studies, we anticipate having sufficient cash to fund operations into 2026.
So looking ahead to some important milestone events for xenon.
We expect to important clinical data readouts in the near term first our topline ex Nova M. D. D results are anticipated in late November to mid December. We also expect data from the adult focal onset study conducted by our partner Neurocrine in November.
We look forward to presenting long term longer term X tole open label extension data, including rates of seizure reduction in seizure freedom at the upcoming Aes meeting in December and importantly, we continue to make progress on advancing our <unk> 11 O. One phase III epilepsy program, including our actual two in AG.
<unk> III clinical trials and focal onset seizures and our exact clinical trial.
P G Tcs with patient enrollment in an actual to expected to complete in the second half of 2024.
Our team believes we can make a difference in the lives of patients living with epilepsy and other neurological disorders. We remained focus on executing our clinical development plans and look forward to our near term milestones and reporting on our progress in the months ahead I'll now ask the operator to open the line for any questions operator.
Okay.
Thank you.
At this time I'd like to remind everyone that in order to ask a question. Please.
Please press Star then the number one on your telephone keypad.
We'll pause for just a moment to compile the Q&A roster.
That being said our first question comes from the line of Paul Matisse from Stifel.
Your line is open.
Hey, Thank you for taking my questions and congrats on the progress I had two questions. If you don't mind, one on X salt to Ian Thanks for the color on timing and congrats on the execution can you just give some clarity on once you get to full enrollment what would be the timing for top line data.
And then second I had a question for Chris or really the broader team on ex Nova and I thought some of the commentary Chris you mentioned on an acceptable adverse event profile at the clinician was pretty interesting, especially related to CNS side effects are headed these data how would you draw that line as it relates to a dizziness.
Hey, or discontinuation due to Aes <unk>, where the profile still remains commercially competitive versus a profile, where you think it actually might be more problematic in this population. Thank you.
Okay.
Thanks, Paul Yeah, I'll tackle the first on the second one.
Yes, maybe Chris one second if you can just start and Jeff.
We did it in the prepared remarks, but just to ensure that we're all kind of aligned on what we think about in terms of the AE profile and then Chris can provide perspective on what's acceptable there.
Think about a differentiated profile so in terms of export too Paul.
We've guided today that we think patient enrollment will be completed in the second half of next year. So when the last patient get screened into into the program. There is a two month baseline period, and so we need to count the number of patients or the patients need to count their number sorry patients need to count their number of seizures for a baseline number before those.
Patients are randomized and then it's a three month double blind period. So that's five in total and then there is some follow up before we can be in a position to unblinded data and provide top line results. So it's kind of in that six to eight month range from last patient enrolled to topline data again, just depending on the time.
And a follow up and database lock and data analysis, but in that range. So hopefully that's helpful.
And then Chris and Chris over to you on the AE profile.
Yes happy to address the AE profile, so as we indicated in the prepared remarks what.
What we've done from a profile testing with U S prescribers is.
Present them with an AE profile, that's consistent with what we have seen coming from X tole with both the 10 milligram profile and a 20 milligram profile.
Across the.
The dimension of Aes that were comment from the epilepsy study so that specific profile.
The context of offering efficacy.
That is.
Consistent with what we've seen with other products in the space and then the over arching profile of Axion 11 O. One in terms of once daily dosing.
The ease of use attributes that we mentioned in epilepsy as well so that specifically what's been tested and what we've heard very clearly from physicians is that there's a role for a product that looks like.
The <unk> profile in the future treatment paradigm.
MTBE, assuming that the product gets approved and.
And there was an appreciation for every product has a risk benefit.
<unk>.
And the lack of very concerning Aes that are seen with ssris and SNRI specifically sexual dysfunction.
Gabe was viewed to be compelling from our clinicians point of view.
As a potential driver for utilization.
Yeah, I'll, just add a little bit I think I'd really like to kind of underscore the phrase it's Chris just used a risk benefit because I understand the question in the context of.
Of the safety and what's what's acceptable from an adverse event perspective, but the totality of that safety data will be relevant right. So whatever your sort of your dizziness is.
Whatever that rate ends up being if youre, not really causing serious any serious sexual side effects. That's that's an upside.
Also if you are not having any serious safety issues like a dress or siri.
Serious rash or anything like that I think that also puts the safety signal into context, and then of course I mean, the question is focused on safety, which makes sense I get it but really it's it needs to be taken in the context of the overall risk benefit of the drug because.
Think back to the Zagha being controlled trial with the separation of seven nine points between active and placebo, if youre seeing that sort of separation and your what youre willing to sort of accept in terms of adverse events goes up substantially compared to something where there is just a couple of points separation between active and placebo.
Okay.
Fair enough thanks, very much thanks.
Thanks.
Okay.
Thank you.
Our next question comes from the line of Brian Abrams from RBC capital markets.
Line is open.
Hi, good afternoon, and thanks for taking my question Congrats on the continued progress.
On the efficacy side for M D D.
Now that you've done the market research and we are getting closer to data could you talk a little bit more about the scenarios.
From a both mattress and shops that might prompt you to explore our registrational program focused on <unk>.
To focus more on anhedonia or to focus more on.
Building out the mood signal in the epilepsy indication.
And then just secondarily.
Could you give the timeline update on next 12, two can you just clarify I guess, how far behind X totaled three is timeline wise and how much of a rate limiter that study is for future filing or that could that could those safety data to be submitted as a safety update during the review.
Thanks, Brian.
I will tackle these and then if anyone.
Has anything to add on our side please jump in.
Yes.
We've kind of really talked about.
The different outcomes in <unk>, if there is potentially multiple paths forward right. Obviously, if we don't see separation and activity there and I think that's clear.
And then the two paths in terms of seeing activity I think if we see a separation and we believe.
That we are seeing an antidepressant effect, but we believe that there is still risk in terms of our registration program that I think that's a good opportunity for us to continue to differentiate <unk> in the epilepsy space, we didn't focus on it on our remarks today, but I think everybody knows it.
And I'll remind.
Remind everyone on the call that not only do we have very compelling efficacy.
In Appalachia, but with a novel mechanism QD no titration and we're seeing early onset to efficacy at week. One are all things that we think is a very compelling product profile in epilepsy. It. If we can add moved to that in terms of medical communication and education, I think that could be even stronger. So that's obviously an option.
And then although we're not going to put specific numbers around it and I think risk benefit that we just spoke about in the previous question. I think is important if we think that the risk benefit overall is compelling in depression, and we are comfortable moving ahead with registration work and the primary indication of major depressive disorder. So there has to really be a clear bar there.
<unk> that we believe that we can replicate the data in larger studies in phase III.
In terms of your second question on export to in the next 12 three.
<unk> export too is on the critical path to filing an NDA. So it's not X tole three or exact obviously any patient that goes through <unk> III or exact can go into open label extension and we can use the safety data from those other studies as part of the requirements in terms of the overall safety database.
But we're really focused on export too on the critical path to filing because as we discussed with FDA at our end of phase two meeting we will be filing on the export data combined with the X tole data that we have obviously previously published and we've shared with the FDA as well so.
At some point in the future, we'll give guidance on <unk> III, an exact but to answer your specific question not on the critical path in terms of registration and filings.
Really helpful clarity. Thank you Ian.
Yes.
Right.
Okay.
Thank you.
Again, just a reminder, if you'd like to ask a question. Please press star one.
So that you may join the queue.
The next question comes from the line of tests from Maryland from J P. Morgan.
Your line is open.
Good afternoon, guys. Thank you for taking our questions.
So with enrollment expected to complete in the second half of next year and next door to what are the key levers to being on the sooner versus the later end of that enrollment guidance.
And there was a little bit alluded to on the prior question, but what is the latest thinking on the cadence of the pivotal datasets for ex told two X two or three and X Act shall we expect Xbox before actual free or how should we be thinking about that thank you.
You.
Thanks tests.
Sorry, Chris can provide.
Provide your perspective as well.
So I don't think Theres any from my perspective specific lever.
Paul too.
For patient enrollment to be completed earlier in the second half of 2024 versus later in the second half of 2024.
We are executing well against the plan of a site initiation and patient screening patient randomization. So will you feel confident where we are we do our best to predict and as we have guidance that is out.
So we're going to put some error bars, there based on our best assumptions and expectations as we get closer we'll be able to narrow those but I don't think theres any specific lever in terms of trying to make that go faster I think we have from the very beginning and we want to run.
A good study and we will go as quickly as we can while maintaining the integrity and the conduct of the study.
Chris I don't know if you have anything to add specifically, there and then I'm happy to jump in on the on the second question on the cadence of data events.
No I don't have anything to add just.
For every patient gets enrolled in any clinical trial. There are so many different variables and so many different variables at each site and variables that each country and so.
It's complicated to the extent that it's hard to sort of put my finger on one or two things and say this is what's going to drive the timeline one way or another.
Yeah.
And then your second question in terms of cadence. So obviously <unk> has been our focus and we've talked often with investors that we've tried to leverage an X talk to as many of those relationships that we had an extra also investigators that have experience with the drug in clinical sites that we've worked with in the past.
And quite frankly investigators that still have patients.
That are being treated with <unk> in an open label extension from the asphalt study. So we're doing all of that in <unk> two.
When we have guidance on <unk> III, an exact that in test we can come back to the guidance on which one is going to read out first of those two separate phase III clinical trials thats pretty much hard to do that today.
Thanks for taking our questions.
Yeah.
Yes.
Thank you.
Our next question comes from the line of Andrew Tsai from Jefferies.
Your line is open.
Hey, good afternoon. Thanks for taking my question just one on MDT reading out.
We understand the AE profile.
11, <unk> hundred one can be different from between MDI and in epilepsy I think you've mentioned previously how you are.
Monitoring.
Monitoring blinded safety. So how are the blinded aes in the HDD discontinuation rates.
Looking compared to your internal expectations is there anything out of the ordinary to relative to what you guys assumed going on in the study or maybe said another way Directionally speaking are you seeing lower rates in the <unk> study compared to your epilepsy study. Thanks.
Thanks, Andrew.
Sure.
Maybe the first of other questions just on some of the details of the <unk> study I'm sure you can appreciate and others, Ken as well as the study is now complete we're very close to.
Unwinding the data and we will have data in the coming weeks as we guided in late November to mid December So we're not going to make any specific comments around what we're seeing in the data we have said previously.
Obviously as we run any clinical study, we're going to monitor it along the way.
And we're going to do a safety review committees that are that are required and based on those previous safety Review Committee is there hasnt, we need to be any adjustments in the study.
But we're not going to talk about specifics on the blinded data and we're looking forward to sharing our full data set in the near term.
Thanks very much.
Yeah.
Thank you.
Our next question comes from the line of Jason <unk> from Bank of America. Your line is open.
Hi, Good afternoon. This is dana on for Jason.
Congrats on the progress this quarter and thank you for taking our question.
So he has had a question on the on X know the top line that we'll be seeing very shortly.
I guess, if we if we don't see a positive trial.
Does that add any risk or uncertainty in your view to being able to generate additional data.
For 11 O one anti depressant effect in epilepsy patients.
And then just wanted to sort of follow up on that.
M D D market research on <unk>.
No one's safety profile.
Given that this is in safety as kind of a major driving force.
M D D space.
The lack of serious aes that come with that as the horizon or is that you mentioned earlier.
The sexual dysfunction weight gain.
Did kols pointed out.
Any part about 11 O ones AE profile that could be sort of a positive differentiator and mgd patient. Thank you so much.
Thanks Dana.
Got there so all of that I think we've got them all down here, but if we miss one just jump back in.
So.
Maybe I'll make one kind of global comment around the <unk> study.
I'll pass it to Chris Kenny just to talk about.
The population that is in epilepsy patients that has comorbid depression, which is different than the primary obviously the patient that has major depressive disorder.
So Chris maybe you can just comment about that and obviously, we are looking not stratify them by looking at some of those data in the phase III and then.
And then Chris I'm talking to and we can talk about the 1100, one AE profile and M. D D I think.
You started your question with yes.
<unk> <unk> hundred one doesn't work in an ex Nova.
I think if it if we don't see a separation.
We're very confident in saying that we don't think theres any read through into the epilepsy program. So I just wanted to be absolutely clear with that.
We're very confident in.
Ken.
The consistency and reproducibility across epilepsy studies and the compelling profile, we have from X tall, and the ability to execute and export to a next door three so.
I think this is a really interesting and important readout in the near term. The next node, but I don't think the outcome of that has any read through into into our epilepsy program, but why don't we go a little deeper Chris Kenny just in looking at that co morbid.
Are the patient that has come our depression, that's in epilepsy patients.
Yes, I mean, what I would say is that.
The underlying pathophysiology of the depressive symptoms can be different depending on whether youre looking.
I had a patient who has a different psychiatric issue or neurodegenerative issue or epilepsy. So just because the drug is behaving in a certain way and one of those population doesn't mean, it's going to behave exactly the same in the other and just to be a little more concrete in the in the phase III program are epilepsy.
Patients obviously were focused on developing an anti seizure drug and that's the focus but we are.
Looking at mood using skills in that population. So once once those phase III studies are done we're going to have this enormous body of information about how those patients respond to the drug.
From the standpoint of their depressive symptoms now the downside is we're not purposely enriching for depressive symptoms that way we are in <unk>. So there are some limitations but.
We're going to let the data guide us for both studies.
Just acknowledged the fact that depression isn't the same as epilepsy.
A little bit more on the MDT, our AE profile of 11 O N and M D.
Yeah, absolutely. So just just to remind folks that if.
If we take a step back and think about the profile that mercury emerge from <unk> with the 20 milligram and the 10 milligram profile.
The majority of the Aes that are reported.
My old and when you think about the difference between 20 milligrams and 10 milligrams. The 10 milligram dose was highly comparable if not indistinguishable from placebo as it pertains to the AE profile. So.
And then the 20 milligram profile highly consistent with other CNS.
CNS active.
Uh huh.
Anti seizure medications with dose limiting our really aes that emerged at the high end of the dose paradigm, but.
But still appropriate for that patient population, so I'm trying to book at.
In the context of the MTBE market research. So are there. Other specific question was around are there other aes that can be seen as a positive differentiator well I think the.
The cleaner the profile looks the.
Better Axion 11 O one emerges in the eyes of clinicians so that very well could be a positive differentiator. If one sees in AE profile that is similar to the 10 milligram profile that emerged from external but to be clear. We also spent time in our market research diving deep into that perspective.
<unk> on it.
Any such as dizziness, which is a little less comment on the current standard of care, but in the context of it being a mild and potential potentially transient.
It was something that clinicians viewed in the totality of the risk benefit profile to be.
Within the reason within reason and would ultimately result in the product being used in their armamentarium.
And maybe I would just add.
One other point Christmas comments.
If we have a huge body of data on next Gen 11, one now just as a reminder, Chris kind of his comments earlier, we have our first patients out more than four years of dosing, we have hundreds and hundreds of patient years of exposure now and we're seeing this consistency and profile and we know that not all patients are going to tolerate.
These drugs are the same so as we in our epilepsy experience as we move from X and X 12 from 10 to 20 to 25 milligrams do you get a step up in efficacy and you get a step up in some of the CNS adverse events based on.
The potency and activity of this drug.
And we know that when we think about epilepsy, or we think about depression, there would be multiple doses dosages available and so if you don't tolerate a certain dose there is an opportunity for you to move to a lower dose.
Which can address some of the tolerability so.
I think we have when we think about <unk> 11 O. One we know a tremendous amount about it and we have that flexibility because we know patients well tolerate the drug differently from patient to patient.
Great. Thank you so much I appreciate all the color.
Thank you.
Our next question comes from the line of.
Paul Choi from Goldman Sachs Your line.
One is open.
Hi, Thank you and thanks for taking our questions I have two.
First for the team.
With regard to the pace of enrollment and ex told two I appreciate your comment that it's.
Tracking faster than X tole, but could you maybe just comment on if youre seeing any competition for recruiting patients and whether any of your clinical trial sites overlap with others developing potassium channel drugs for epilepsy.
And my second question is.
Under a scenario where ex Nova a readout positively can you maybe comment on how the recent.
FDA rejection of Saran alone.
Has or hasnt affected your thinking on potential future development and MDT. Thank you.
Yes.
Thanks, Paul.
<unk>.
Yes, so I'll, maybe I'll make a couple of comments first on exon two and Chris Kenny you're very close to the investigators and the sites. So please add your perspective.
And then we can get to the extra out of the question.
So as we think about X tole too I mean, I think one of the messages. We're communicating today is that obviously, we have a lot of experience in running global epilepsy studies I think if we look back over the last few years, we have run the largest number of significant epilepsy studies.
When we compare ourselves to any other sponsor so I think theres a huge amount of experience that we're gathering.
Often we don't find that a.
Clinical site will take on two competing studies at all focused on one but I'll, let Chris provide his perspective, there and then when we just look at the recruitment rates in X tole too when we look at other companies over the last number of years that have run.
Epilepsy studies I believe that our recruitment rate in our ability to complete these studies have outperformed others.
And so obviously, we're very proud of the work that the team has done but Chris any other.
Specific comments that youre seeing at individual sites on competition.
Okay.
Yes, I mean, the challenges that are that have come up probably the number one challenge at the sites is more about making sure that each site has the appropriate resources to be able to support this study.
And.
And the issue of competition with other anti seizure medications hasnt slowed down to my knowledge, even a single site.
So if you think about the timing in terms of I believe your when you say <unk> seven drugs I believe youre alluding to the.
The public information that bio <unk> is going to start phase III by the end of this year.
<unk>.
We went out we were going out to sites quite a while ago.
So we've locked in those sites already that we were most focused on so.
So that really competition with other TV <unk> has not had any rule in terms of slowing us down to date.
Okay.
Thanks, Chris and then Paul you other question on ex Nova and maybe the regulatory environment.
We haven't had.
We haven't had regulatory interaction with the psychiatry division obviously with.
Now if it's positive and we move into late stage clinical development, we'd do an end of phase II meeting.
So I think maybe we'll just pause on that question until we have more interaction when we look at the Saar around alone summary basis of approval and we've looked at the regulatory information Thats publicly available we don't see any read through to the work that we're doing.
With <unk> hundred one in major depressive disorder with the caveat as I mentioned earlier that we still need to have.
Detailed regulatory interaction is what you would think about our late stage program.
Okay, great. Thanks for all the color.
Sure.
Right.
Thank you.
Our next question comes from the line of Joseph Tung from TD Cowen.
Your line is open.
Hi, there good evening and thank you for taking my questions maybe the first one on the upcoming Neurocrine data.
How are you thinking about potentially moving forward with that co fund option. What are some considerations you have and can you remind us when you have to make that decision as it immediately after data is that after the end of phase two with the FDA or is there a time on that and then for the the one little one NDA filing can you just remind us what kind of safety.
Database is required to initiate that is having patients through that totally double blind period sufficient or will you need some additional time, but after the data readout before you could start the filing thank you.
Great. Thanks, Joe Sherry do you want to tackle the first one on co fund and then Chris and I can provide perspective on safety database.
Yeah, absolutely so as a reminder, our collaboration and we.
We have a tiered royalty structure, so ultimately drive progressive we weren't eligible for royalties based on sales.
So the co fund option allows for us to opt in to take four or 550%.
Development costs and in return, we would get an incremental step up as well, which at the highest tier what amount with 20 royalty.
We're going to have the benefit of having a lot more information in hand, that's why we have to make the decisions around.
On the coupon.
Importantly, we're going to have data from this upcoming phase two study.
Which will be to evaluate them. In addition to all of that information around the phase III development program. So agreed upon protocol with FDA phase III, a full budget around what the phase III development program will look like and we'll be able to make a decision based on that that totality of that information.
Want to point out I think you know given our experience in this space, we are very well positioned to be able to review all of that and make a very informed and educated decision.
Also I will say that at this AGM neurocrine.
Neurocrine is driving that development.
The 35 acute program.
And ultimately we'll have to see what their next steps are so it is possible that from them.
He is a signal finding study they may decide to proceed.
Larger phase <unk> study rather than directly into phase three.
In which case the timelines around that.
Our longer and so don't expect that is the decision that we need to in the near term I'd say you know at the fastest if they are going straight into phase III, probably you know.
At least 12 months, maybe more like 18 months until they have regulatory interaction and all of that information I I discussed.
Thanks, Gerry and then Joe I think your question on.
NDA and safety database when you specifically sat around after the double blind period, Im assuming that youre kind of referring more to long term exposure.
So.
I'll answer that one and then if you have a follow up letter let us know so this is a large market opportunity. So we think about ICA ICH guidelines in terms of exposure is the long term exposures that are required are 300 subjects or this is the guidance is 300 subjects of six months of exposure on a 100 subjects with 12 months of exposure.
And as I'm sure you can appreciate we have.
A significant amount of long term data actually I think that's one of the things that is continuing to differentiate us versus even though it is in the competitive space is that we now have so much experience with this molecule that long term safety is not going to be gating to to an NDA filing by any means.
Okay perfect that is very helpful. Thank you so much.
Thank you.
Yeah.
Thank you.
The next question comes from the line of Danielle Brill from Raymond James.
Your line is open.
Hey, guys. Thanks, so much for the question.
I was wondering if you could talk about the decision to permit enrollment of patients with PTSD next now that we ask the sense on PTSD can be associated with lower treatment response rates just march traditional antidepressants.
Specifically curious it'd be stratified enrollment and if you plan to breakout treatment response rates with patients and patients with or without PTSD or other comorbid anxiety.
Thanks, so much.
Chris Kenny can you.
Good perspective there.
Well the topline analysis of <unk> was going to focus on the madrasah.
The chaps topline safety et cetera, so it's not part of the topline the second round of data. We can look at those sorts of things, but that that isn't a major looking at PTSD. It's not stratified in this study and looking at whether those patients are responding differentially isn't part of the plan.
Daniel I don't know the numbers off the top of my head, but I think we're talking about relatively small numbers and so I think that in the context of a study of this size I think even doing that may have limited utility.
Understood. Thanks for the question sure.
Okay.
Thank you.
Our next question comes from the line of Marc Goodman from Leerink partners.
Your line is open hi, thanks.
Hi, Thanks. This is rather on the line from Mark could.
Could you just give us an update on your pediatric formulation of <unk> 11 O. One and also your second Gen molecules that are in preclinical development and could we expect to see any data from these candidates in the near term. Thanks.
Okay.
Thanks for the question, Yes, we are we have as we stated I think in previous calls we've we've got alignment from regulators on what the pediatric plan is for exon 11 O. One.
So there is some layers to this.
In terms of focal onset seizures, we have an ability in the U S to take advantage of the what's called the PK extrapolation role, where we can do open open label work and younger cohorts of patients will start without a license and then move into children.
With our exact study of our primary generalized tonic clonic seizure study.
We have based on feedback from regulators move the lower bound of the age 12 and above for that study. So we'll be enrolling some of those patients in the phase III program.
And then in terms specifically on a pediatric formulation. So obviously an oral capsule can go down to a certain age group and then when we get into much younger age groups, we're going to need to work on a pediatric formulation. So that work is ongoing internally.
In terms of next generation <unk> drugs.
We've communicated.
You know a number of times that we have a number of different chemistries and different molecules that we're interested in pre clinically.
Target the potassium channels in the CNS.
We don't talk a lot about kind of stage of development, where we are a publicly with those but we would expect over the next year or two we would have molecules that will transition into clinical development and that's probably an appropriate time to start sharing some of the preclinical data publicly as well.
Okay.
Okay.
Operator, we can move to the next question.
I apologize and thank you.
Our next question comes from the line of Laura Chico from Wedbush.
Your line is open.
Hi, this is anchored on for Laura Chico.
If you could speak at all to any efforts to close working late 11 O. One wouldn't with another eight ASN. This would be something that could be explored in focal epilepsy space I realize.
It may be challenging to dose optimized but would there be any advantages to this type of approach.
Thank you.
Hi, Thanks, Congrats a really interesting question, Chris one second and I know you've done some time thinking about this and obviously.
The types of anti seizure medicines that have been developed over time. So maybe you can start and then Chris kind of if you have anything to add as well.
Yeah, what I can say is what we expect from our commercial use standpoint and in the focal onset seizure.
Market is most certainly combination use with other commonly used anti seizure medications.
And there are a handful of those products, which are used quite frequently early in lines of therapy limit your assets and lamotrigine and increasingly you'll close or products that would be potentially ideal candidates for thinking about.
Co formulation opportunities.
Something that's been on our radar for consideration, although there are technical complexities to consider when you think about the range of doses that exist as well as the requirement for other products to be titrated to full efficacy.
One of the key advantages of <unk> 11 O wanted the treatment of <unk> that we don't require titration and that gets us to a therapeutic dose with the.
The initial dose selected so theres a little bit more technical complexity to that question then the obvious desire to think about co formulation with other commonly used anti seizure medication something that still needs to be explored.
Yeah.
Chris anything to add.
Nothing to add.
Yes, okay.
As Chris said, there is a real challenge. There is you have a lot of these drugs that are titrated and not everyone gets the same dose and so that provides some inherent technical challenges on co formulation.
Okay.
Okay.
Thank you.
Our next question comes from the line of Mohit Bansal from Wells Fargo.
Your line is open.
Hi, This is <unk> on for Mohit, Thanks for taking my question.
So I have two the first is that is a.
The monotherapy study and MDT doesn't work or even if it does is there a possibility of studying <unk> as an adjunct and DTE to see if there's any synergistic effects.
Then my second question is if you can help us understand why it there are no treatment specifically approved for Antonia when it looks like some antidepressants.
Have shown a benefit and have tonia scores.
Yeah.
Yeah.
Sure Thanks for the questions Chris.
Chris do you want to start on them.
And then maybe I'll start with a global comment and then maybe you can provide your perspective on monotherapy and potentially future development in the adjunctive setting as well and any perspective, you have I think both you and Chris can weigh in on it.
Yeah.
I think if just turning to your very first part of your question on <unk>.
Ex no there isn't.
Isn't positive would we move ahead with adjunctive <unk> studies I think that that's unlikely.
That if we don't see a signal in this study that we would be running an adjunctive study separately to this I think in the scenario where X. Gen 11 O. One is positive in X number and were moving ahead, then I think it's a question that we'd definitely thought about it and it'll be somewhat jurisdictional dependent also based on interact.
And with regulators, but Chris why don't you provide your perspective, there and then we can move to the and I know in your question.
I think you covered it I don't have anything to add to that.
Okay.
And so yes, I mean, maybe just at a different way if if we're positive then.
And then we're moving ahead into registration studies, then I think we would look at both potentially monotherapy or adjunctive studies and future development.
On the anhedonia side, either Chris or Chris Your perspective on maybe why we haven't seen I know anhedonia is definitely showing up as an endpoint and a lot more studies now, but we haven't seen.
That used as a primary endpoint in development.
I'll start off and then I'll hand, it off to Chris.
If you take a look at the patients who meet the criteria for having moderate to severe depression, which is the case in the <unk> study.
Then it's very difficult to find a complete lack of anhedonia and in fact, that's a key feature of the getting to the.
The diagnosis of M. D D. So they tend to work together pretty closely and.
As Ian just said I mean, there's been this increasing interest in Indonesia I think your observation is more driven I think by people not just not focusing on it in the past.
Now, it's become clear that its something worthy of.
Of treatment.
Chris.
Yeah. The only thing I can add there is that when when we go out and do market research. There is very clear consistency with primary efficacy endpoints around MA address in that space and.
One can only assume that in order to avoid.
Deviating from a regulatory perspective on what gets ultimate FDA approval, but we have seen two to Ian and Chris's point increased interest in Indonesia as.
<unk> of the efficacy profile for these products given the fact that it's a core coke comorbidity associated with depression and.
We're here to see how this unfolds in the coming years.
Great. Thank you so much.
Thank you.
Last question will come from Tim Lugo from William Blair.
Your line is open.
Thanks for squeezing me in for X Tole, two and three I know, they're designed very similarly to a store.
However.
Well the defining feature vector with how many therapies those patients have failed and.
<unk> is an unknown out there.
One is a very well known company within the community can you just talk maybe how the baseline profiles of two and three are aligning up versus actual and maybe how that could.
What will eventually be able to both coming from the study.
Yeah. Thanks, Tim I think that's a.
A really interesting question that we're absolutely monitoring.
I don't think we have a lot to say on it today, but something that won't be tracking so I'll give my perspective, and then Chris can.
Provide yards as well, yes, so there's a good opportunity and maybe just to take a step back and confirmed some of the comments that you've made what share on point, which is ex told to an ex told three are designed after extra all obviously about the naming convention there was very deliberate. So it is the same inclusion exclusion criteria.
For our full two and three as compared to X tall, but as you suggest Jerry next to all 11 O. One with an unknown molecule at that time and also we know that X tole was run at least part of <unk> was run during the pandemic and we got a quite a severe patient population and when we look at the literature.
Can't find another study where it was as severe a population as we trialed.
And then ex tall and we look at three different measures. We look at the number of drugs that patients had failed prior to study the number of background therapies. They were on coming into the study as well as the baseline seizure burden.
So there is a hypothesis that maybe an extra one two and three we will get a less severe patient population.
Yeah, well look at that Jim we're not at a point right now to be able to comment on that it's always difficult when youre running a study because those.
Baseline characteristics are changing every day as youre enrolling more patients, but as we get closer to completing these studies I think that would be something that would be irrelevant for us to comment on.
Chris anything to add to that.
Wanted to sort of emphasize the importance of keeping an eye on the baseline characteristics of these studies as we go forward. So it's something that.
We always do because we want to make sure that the population is somewhat in keeping with what we're expecting and if not then we wanted to be able to pivot and not wait till the end of the study to realize that so that's something that we follow.
Very closely I think it's hard to imagine a scenario, where we're going to end up with patients who are more impaired.
And so I think it's more likely to Ann's point that we end up with patients who are less impaired and as we tease out the data from X tole. It suggests that those patients actually respond better.
So we would have to confirm that in phase III of course, but so I think that's all I'll say it remains to be seen exactly how the populations compare.
Thank you so much.
Thanks, Tim.
Thank you.
With that this concludes today's conference call. Thank you for joining you may now disconnect. Okay.
Thanks, everyone.
Yeah.
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