Q1 2024 Xenon Pharmaceuticals Inc Earnings Call

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Thank you for standing by my name is lives and I'll be your conference operator today at this time I'd like to welcome everyone to the first quarter 2024, and in Pharmaceuticals incorporated earnings Conference call. All lines have been placed on mute to prevent any background noise. After the speakers' remarks, there will be a question and answer.

Liz: Thank you for standing by. My name is Liz, and I'll be your conference operator today. At this time, I'd like to welcome everyone to the first quarter 2024 Xenon Pharmaceuticals Incorporated Earnings Conference Call. All lines have been placed on mute to prevent any background noise.

Liz: She says if.

Liz: If you'd like to ask a question. During this time simply press star followed by the number one on your telephone keypad.

Liz: If you'd like to withdraw your question. Please press star one again, thank you I'd now like to turn the call over to Chad Fisher VP Investor Relations. Please go ahead.

Liz: After the speaker's remarks, there will be a question and answer session. If you'd like to ask a question during this time, simply press star followed by the number one on your telephone keypad. If you'd like to withdraw your question, please press star one again. Thank you. I'd now like to turn the call over to Chad Bejerre, BP Investor Relations. Please go ahead.

Chad Bejerre: Thank you operator, and good afternoon, and thank you for joining us on our call and webcast to discuss its first quarter 2024 financial and operating results.

Chad Bejerre: Thank you for joining us on our call and webcast to discuss Xenon's first quarter 2024 financial and operating results. Joining me today are Ian Mortimer, Xenon's President and Chief Executive Officer, Dr. Chris Kenney, Xenon's Chief Medical Officer, Dr. Chris von Seggern, Xenon's Chief Commercial Officer, and Sherry Aulin, Xenon's Chief Financial

Chad Bejerre: Joining me today are Ian Mortimer.

Chad Bejerre: <unk> Chief Executive Officer.

Chad Bejerre: Doctor, Chris Kenny <unk>, Chief Medical Officer, Dr. Chris One second xenon as Chief commercial officer.

Speaker Change: Sure Alan.

Chad Bejerre: He announced chief financial Officer.

Chad Bejerre: Ian will begin with a summary of our recent progress, Chris Kenney will provide an overview of our ongoing clinical stage programs, including our plans for major depressive disorder or MDD, Chris von Segern will summarize key findings from recently completed market research, and Sherry Aulin will close with a summary of our financial results and anticipated milestone events before opening the call to your questions. 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 clinical trials.

Christopher John Kenney: And we will begin with a summary of our recent progress Chris Kenny will provide an overview of our ongoing clinical stage programs.

Chad Bejerre: Leading our plans in major depressive disorder or M D.

Chad Bejerre: First of all I will summarize key findings from recently completed market research and Sherry Allen will close with a summary of our financial results and anticipated milestone events before opening the call up to your questions.

Chad Bejerre: Please be advised that during this call.

Chad Bejerre: We'll make a number of statements that are forward looking including statements regarding the timing of potential results from clinical trials.

Chad Bejerre: The potential efficacy safety profile future development plans and current and anticipated indications addressable market regulatory success and commercial potential of our and our partners' product candidates the efficacy of our clinical trial designs, our ability to successfully develop and achieve milestones in a club.

Chad Bejerre: The development programs.

Chad Bejerre: The timing and results of our interactions with regulators our ability to successfully develop and obtain regulatory approvals anticipated enrollment in our clinical trials.

Chad Bejerre: And the timing thereof.

Chad Bejerre: And our expectation that we will have sufficient cash to fund operations into 2027.

Chad Bejerre: Today's press release summarizing the announced first quarter 2024 financial results and the accompanying quarterly report on Form 10-Q will be made available under the investors section of our website at xenon Dash pharma dot com and filed with the SEC.

Chad Bejerre: Cedar plus now I would like to turn the call over to Ian.

Chad Bejerre: product candidates, the efficacy of our clinical trial design, our ability to successfully develop and achieve milestones in our clinical development program, the timing and results of our interactions with regulators, our ability to successfully develop and obtain regulatory approvals, anticipated enrollment in our clinical trials, and the timing thereof, and our expectation that we will have sufficient cash to fund operations in 2027. Today's press release summarizing Xenon's first quarter 2024 financial results and the accompanying quarterly report on form 10-Q will be made available under the investor section of our website at xenon-pharma.com and filed with the SEC and on CDER Plus. Now, I would like to turn the call over to Ian. Ian?

Ian C. Mortimer: Thank you, Chad, and good afternoon, everyone, and thanks for joining us on our call today. Before I provide an update on our pipeline, I'm excited to announce that we have received approvals from the United States Adopted Names, or USAN, Council and the World Health Organization International Nonproprietary Names, or INN, Expert Committee for the use of ezetucalinor as the nonproprietary or generic name for XCN 1101. Notably, the calinor suffix refers to the molecule's novel KV7 mechanism of action.

Ian: Thank you Chad and good afternoon, everyone and thanks for joining us on our call today.

Ian C. Mortimer: If ultimately approved for use in patients, ezetucalinor would become the first medicine with a calinor suffix to be launched commercially. This is an important milestone for Xenon and represents another step forward as we advance Zetu Calendar towards commercialization. Moving now to our pipeline.

Ian C. Mortimer: Before I provide an update on our pipeline I am excited to announce that we have received approvals from the United States adopted names or <unk> Council and the World Health organization International non proprietary names are INR and expert committee for the use of is that two calendar as the non proprietary or generic name for <unk>.

Ian C. Mortimer: <unk> 11 of one <unk>.

Ian C. Mortimer: Notably the calendar suffix refers to the molecules novel TV Southern mechanism of action. If ultimately approved for use in patients is that your calendar would become the first medicine with a calendar suffix to be launched commercially. This is an important milestone for xenon and represents another step forward as we advance is that two calendar.

Ian C. Mortimer: <unk> towards commercialization.

Ian C. Mortimer: This past quarter, we continued to make strong progress. Our team remains focused on three key areas. Number one, the continued execution of our AZETU calendar phase three epilepsy program. Number two, the expansion of AZETU beyond epilepsy with our MDD program. And three, the continued advancement of our discovery portfolio. First, in our Epilepsy Program, patient enrollment continues to progress in our XTOL-2 and XTOL-3 clinical trials in Focal Onset Seizures, or FOS, and our exact clinical trial in primary generalized tonic-clonic seizures, or PGTC. We continue to anticipate that patient enrollment for the first of these trials, XTOL 2, will complete in late 2024 to early 2025.

Ian C. Mortimer: Moving now to our pipeline this past quarter, we continued to make strong progress our team remains focused on three key areas number one the continued execution of our is that two calendar phase III epilepsy program.

Ian C. Mortimer: Second, we made important advancements in our AZETU calendar MDD program over this past quarter, including reaching alignment with the FDA through end-to-phase 2 interactions on key components of our phase 3 program, which we look forward to initiating in the second half of this year. We are also continuing to evaluate additional opportunities for ZETU calendar, focusing specifically on other potential neuropsychiatric indications where a scientific rationale exists, as well as a commercial fit with epilepsy and MDD. Later in the call, Chris Kenney will provide additional details on the next steps in our MDD program.

Ian C. Mortimer: Two the expansion or is that too calendar beyond epilepsy with our M. D. D program and three the continued advancement of our discovery portfolio.

Ian C. Mortimer: First in our epilepsy program patient enrollment continues to progress and our ex told two and X tole, three clinical trials and focal onset seizures or F O S.

Ian C. Mortimer: And our exact clinical trial in primary generalized tonic clonic seizures RPG Tcs.

Ian C. Mortimer: We continue to anticipate the patient enrollment for the first of these trials ex told two will complete in late 2024 to early 2025.

Ian C. Mortimer: Second we made important advancements in our is that two calendar M. D. D program over this past quarter, including reaching alignment with the FDA through end of phase II interactions on key components of our phase III program, which we look forward to initiating in the second half of this year.

Ian C. Mortimer: We are also continuing to evaluate additional opportunities for that to counter focusing specifically on other potential neuropsychiatric indications, where a scientific rationale exists as well as the commercial fed with epilepsy and M. D D.

Christopher John Kenney: Later in the call Chris Kenny will provide additional details on next steps in our <unk> program.

Ian C. Mortimer: And third, we are continuing to progress our early stage discovery efforts. As a reminder, Zetucalnir is the most clinically validated and advanced KV7 therapeutic in development across multiple indications, and we see the mechanism as having broad potential applicability. The breadth and depth of potential therapeutic indications for the mechanism provides a compelling strategic rationale for the development of additional KV7 product candidates that are chemically diverse from the ZETU calendar and could provide additional development opportunities.

Christopher John Kenney: And third we are continuing to progress our early stage discovery efforts. As a reminder is that your calendar is the most clinically validated and advanced kv seven therapeutic in development across multiple indications and we see the mechanism is having broad potential applicability.

Ian C. Mortimer: The breadth and depth of potential therapeutic indications for the mechanism provides a compelling strategic rationale for the development of additional kv seven product candidates that are chemically diverse from is that two calendar and could provide additional development opportunities.

Ian C. Mortimer: For that reason, we are excited to continue to leverage our ion channel expertise with the goal of progressing multiple KV7 molecules forward into clinical development in order to extend the reach of this promising and differentiated mechanism to more patients in need. Beyond our robust potassium channel development efforts, we continue to evaluate and advance development candidates targeting sodium channels, including NAV1.1 and NAV1.7, which may have utility in treating seizure disorders and pain, respectively.

Ian C. Mortimer: For that reason, we are excited to continue to leverage our ion channel expertise with the goal of progressing multiple kv seven molecules forward into clinical development in order to extend the reach of this promising and differentiated mechanism to more patients in need.

Ian C. Mortimer: Beyond our robust potassium channel development efforts, we continue to evaluate and advance development candidates targeting sodium channels, including that 1.1, and NAV, one seven which may have utility in treating seizure disorders and pain respectively.

Ian C. Mortimer: We expect multiple candidates to move through GLP toxicology studies and into clinical development over the next few years. During the first quarter, we also continued our outreach efforts to key opinion leaders and leading physicians. At the recent annual meeting of the American Academy of Neurology, or AAN, we hosted two oral presentations related to our X-Toll Epilepsy Program, and we engaged with neurologists and epileptologists who continue to express significant excitement about Z2Calendar's unique and compelling profile in both epilepsy and MD.

Ian C. Mortimer: We expect multiple candidates to move through GOP toxicology studies and into clinical development over.

Ian C. Mortimer: Over the next few years.

Ian C. Mortimer: During the first quarter. We also continued our outreach efforts to key opinion leaders and leading physicians at the recent annual meeting of the American Academy of Neurology or AAN, we hosted two oral presentations related to our X tole epilepsy program, and we engage with neurologists and Apple apologist, who can.

Ian C. Mortimer: To express significant excitement about is that your calendars unique and compelling profile in both epilepsy and MDT.

Ian C. Mortimer: We look forward to continuing to showcase the ZETU Calendar at upcoming medical conferences throughout the remainder of this year, and Chris will note some of the near-term conferences where Xenon will have a presence. So we're off to a great start to the year, and I'm proud of the continued progress across Xenon's pipeline, including both clinical and preclinical efforts. Now I'll turn the call over to Chris Kenney, who will provide some additional details on the progress within our ZETU clinical programs. Chris, it's over to you.

Ian C. Mortimer: We look forward to continuing to showcase as that two calendar at upcoming medical conferences throughout the remainder of this year and Chris will note. Some of the near term conferences, where xenon, we will have a presence.

Christopher John Kenney: So we're off to a great start to the year and I'm proud of the continued progress across the non pipeline, including both clinical and preclinical efforts. So now I'll turn the call over to Chris Kenny who will provide some additional details on the progress within our is that two calendar clinical programs Chris over to you.

Christopher John Kenney: Okay, thanks a lot Ian. Before summarizing our clinical development programs, I'd like to touch on our recent presence at AAN in March. Importantly, our abstracts focused on a Zetu calendar and epilepsy. We were selected for two oral presentations, and we're grateful to our epilepsy opinion leaders, both Drs. Jackie French and Roger Porter, for presenting these data on our behalf.

Christopher John Kenney: Okay. Thanks, a lot Ian.

Christopher John Kenney: Summarizing our clinical development programs I'd like to touch on our recent presence.

Christopher John Kenney: In March importantly, our abstracts focused on is that two calendar in epilepsy were selected for two oral presentations and we're grateful to our epilepsy opinion leaders, both doctors, Jackie French and Doctor Roger Porter for are presenting presenting data on our behalf and particular, we hire.

Christopher John Kenney: In particular, we highlighted results from our ongoing EXTOL open-label extension study, which demonstrated impressive seizure freedom rates, including one in four patients who were on treatment for two years or more achieving at least 12 months of consecutive seizure freedom. In addition, we have now generated more than 600 patient years of safety data, with some patients having been on a Zetu calendar for more than four years, supportive of a well-tolerated drug Turning to an update on our clinical development efforts, within our Phase III Epilepsy Program, our three clinical trials, EXTOL-2 and EXTOL-3 in focal-onset seizures and EXACT in primary generalized tonic-clonic seizures, continue to progress. As Ian mentioned, we continue to anticipate completion of XTOL-2 patient enrollment later this year or early 2025.

Christopher John Kenney: <unk> results from our ongoing X Tole open label extension study, which demonstrated impressive seizure freedom rates, including one in four patients who were on treatment for two years or more achieving at least 12 months of consecutive seizure freedom.

Christopher John Kenney: In addition, we have now generated more than 600 patient years of safety data with some patients having been on has that two calendar for more than four years supportive of a well tolerated drug profile.

Christopher John Kenney: Turning to an update on our clinical development efforts within our phase III epilepsy program. Our three clinical trials ex told two and X toll free and focal onset seizures and exact and primary generalized tonic clonic seizures continue to progress as Ian mentioned, we continue to anticipate.

Christopher John Kenney: Completion of ex told to patient enrollment later this year or early 2025 as a reminder, we intend to submit an NDA. Upon the successful completion of ex told to our first phase III clinical trial, along with the existing data package from our phase <unk> X tole clinical.

Christopher John Kenney: As a reminder, we intend to submit an NDA upon the successful completion of XTOL-2, our first Phase 3 clinical trial, along with the existing data package from our Phase 2b XTOL clinical trial and additional safety data from other clinical trials to meet regulatory requirements. Within our MDD program, we've made significant progress towards advancing our Phase 3 development plans based on the encouraging top-line data generated from our Phase 2 proof-of-concept Ex Nova study.

Christopher John Kenney: While and additional safety data from other clinical trials to meet regulatory requirements.

Christopher John Kenney: Within our MDT program, we've made significant progress towards advancing our phase III development plans.

Christopher John Kenney: Just on the encouraging topline data generated from our phase II proof of concept study.

Christopher John Kenney: Earlier this year, we submitted to the FDA our end of phase II briefing package, which included our draft phase III protocol synopsis and preparation for an April in person meeting prior to the meeting we received preliminary written feedback from the FDA in response to our briefing package.

Christopher John Kenney: Earlier this year, we submitted to the FDA our end of phase two briefing package, which included our draft phase three protocol synopses in preparation for an April in-person meeting. Prior to the meeting, we received preliminary written feedback from the FDA in response to our briefing. The feedback was comprehensive and fully addressed our questions to the FDA. As a result, the in-person portion was determined not to be necessary.

Christopher John Kenney: Feedback was comprehensive and fully addressed our questions to FDA.

Christopher John Kenney: As a result, the in person portion was determined not to be necessary. We're pleased to have been able to efficiently achieve alignment with FDA, enabling us to continue progressing our MDT program into late stage development.

Christopher E. Von Seggern: We're pleased to have been able to efficiently achieve alignment with FDA, enabling us to continue progressing our MDD program into late-stage development. Broadly, our development plans include three phase three clinical trials in MDT, each with one active drug on, or 20 Milligrams Versus Placebo, using the Hamilton Depression Rating Scale or HAM-D17 as the primary endpoint, assessing efficacy in depression and continuing to assess the efficacy of the Z2 calendar on improvements in anhedonia as well as HAM-D17 at week one with hopes to confirm the compelling data we generated around the rapidity of onset in the Ex Nova study.

Christopher E. Von Seggern: Broadly our development plans include three phase III clinical trials and MDT.

Christopher E. Von Seggern: Each with one active drug arm for 20 milligrams versus placebo using the Hamilton depression rating scale or <unk> 17, as the primary endpoint assessing efficacy in depression and continuing to assess the efficacy of the Z two calendar on improvements and anhedonia as well.

Christopher E. Von Seggern: <unk> 17 at week, one we hope to confirm the compelling data we generated around the rapidity of onset in the Nova study.

Christopher E. Von Seggern: Having now reached alignment with FDA on key design elements of the Phase 3 program, we've all selected our CROs and are working to finalize our protocols. Once the final protocols are filed, we intend to provide additional details around the design of our MDD studies and look forward to initiating the first of these phase three clinical trials in the second half of this year. As Ian noted, we recognize the importance of continuing to educate the healthcare community about the potential benefits of the Z2 count.

Christopher E. Von Seggern: Having now reached alignment with the FDA on key design elements of the Phase III program. We've also elected our CRO.

Christopher E. Von Seggern: And are working to finalize our protocols.

Christopher E. Von Seggern: Once the final protocols of style.

Christopher E. Von Seggern: We intend to provide additional details around the design of our MDT studies and look forward to initiating the first of these phase III clinical trials.

Christopher E. Von Seggern: In the second half of this year as Dan noted, we recognize the importance of continuing to educate the health care community about the potential benefits or is that too calendar.

Christopher E. Von Seggern: This week, the Xenon team attended the annual meeting of the American Psychiatric Association, or APA, in New York. We're also pleased to announce that we will present the Ex Nova top-line data at the annual meeting of the American Society of Clinical Psychopharmacology, or ASCP, taking place in Miami from May 28th to 31st. This will be the first time these promising results are presented at a major medical meeting and will represent yet another opportunity to raise awareness of the Zetu calendar's differentiated profile and potential impact within the MDD population. I'll now turn the call over to Chris von Seggern, who will summarize findings from recent market research outlining the AZETU calendar value proposition. Chris.

Christopher E. Von Seggern: This week the xenon team attended the annual meeting of the American Psychiatric Association or <unk> in New York.

Speaker Change: We're also pleased to announce that we will present, the ex Nova topline data at the <unk>.

Speaker Change: Annual meeting of the American Society of clinical Psychopharmacology or <unk>, taking place in Miami from May 28 to 31.

Speaker Change: This will be the first time. These promising results are presented at a major medical meeting and will represent yet another opportunity to raise awareness of <unk> calendar is differentiated profile and potential impact within the MDT population.

Speaker Change: I'll now turn the call over to Chris <unk>, who will summarize findings from recent market research outlining the is that two calendar value proposition Chris.

Speaker Change: Thanks, Chris on last quarters call, we discussed our market research findings that have informed our clinical development and commercial plans and depression.

Christopher E. Von Seggern: Chris, on last quarter's call, we discussed our market research findings that have informed our clinical development and commercial plans in depression. To recap, we conducted primary research with 150 high-volume prescribing physicians who expressed interest in the statute calendar's potential profile with ease-of-use properties, such as once-daily dosing without the need for titration, rapid onset of effect, novel mechanism of action, differentiated safety profile compared to standard-of-care agents like SSRIs and SNRIs, and ability to address anhedonia, a common comorbidity of depression.

Christopher E. Von Seggern: To recap we conducted primary research with 150 hydraulic prescribing physicians, who expressed interest in such a calendar as potential profile with ease of use properties such as once daily dosing without the need for titration rapid onset of effect novel mechanism of action differentiated safety profile compared to standard of care agents.

Christopher E. Von Seggern: Like Ssris and S N arise and ability to address an hotelier a common comorbidity of depression.

Christopher E. Von Seggern: These findings suggest there could be a compelling product fit for azethucaloner in the MDD treatment landscape, particularly for patients with a remaining unmet medical need resulting from an inadequate response to initial therapies or those that experience common adverse events such as significant weight gain or sexual dysfunction.

Christopher E. Von Seggern: These findings suggest there could be a compelling product set for us that the calendar and the tree LGD treatment landscape, particularly for patients where the remaining unmet medical needs, resulting from inadequate response to initial therapies are those that experienced common adverse events, such as significantly gain or sexual dysfunction.

Christopher E. Von Seggern: This past quarter, we conducted further market research with practicing epileptologists and neurologists in the U.S. to better understand the unmet medical need associated with depression in epilepsy patients. As we have mentioned previously, we believe the data generated in major depressive disorder to date add to our already clearly differentiated profile in epilepsy. Past research has indicated that depression is a common comorbidity in epilepsy and that the condition is often underappreciated and potentially undiagnosed, particularly in more difficult-to-treat patient populations.

Christopher E. Von Seggern: This past quarter, we conducted further market research with practicing <unk> and neurologists in the U S to better understand the unmet medical need associated with depression in epilepsy patients as.

Christopher E. Von Seggern: As we have mentioned previously we believe the data generated in major depressive disorder to date add to our already clearly differentiated profile in epilepsy.

Christopher E. Von Seggern: Our past researches indicate a depression is a common comorbidity in epilepsy and.

Christopher E. Von Seggern: And that the condition is often underappreciated and potentially undiagnosed, particularly in more difficult to treat patient populations.

Christopher E. Von Seggern: We also know that comorbid depression is associated with worse compliance and poorer outcomes for patients suffering from epilepsy. Thus, our recent research supports a clear need for a novel medicine that offers potent seizure reduction while potentially addressing mood-related conditions. Past research has reinforced the value proposition of Zetecaliner and FOS, with physicians indicating significant interest in a novel KB7 mechanism that will require titration and demonstration of rapid efficacy at one week. Potential benefit in depression further enhances the profile that's at the counter in epilepsy, and physicians cited Lamotrigine as an analog that offers mood benefit in this patient population. Our recent research serves to strengthen our conviction around the highly differentiate I will now turn the call over to Sherry to summarize our financial results and upcoming milestones. Okay, Sherry? Thanks, Chris.

Christopher E. Von Seggern: We also know the comorbid depression is associated with worse compliance and poorer outcomes for patients suffering from epilepsy.

Sherry: Our recent research supports a clear need for a novel Medicine and offers post potent seizure reduction while potentially addressing mood related conditions.

Sherry: Past research has reinforced the value proposition of it is after calendar and fos with.

Sherry: <unk>, indicating significant interest in the novel <unk> seven mechanism Morgan Stanley.

Sherry: It will require titration and demonstration of rapid efficacy at one week.

Sherry: Essential benefit in depression further enhances the profile does that to calendar in epilepsy and physicians cited lamotrigine is an analog that offers mood benefit.

Sherry: Patient population.

Sherry: Our recent research serves to strengthen our conviction around the highly differentiated profile that is emerging for us that to calendar or Pos and we believe that if approved is that the talent there will be a mainstay of treatment for patients with focal onset seizures.

Sherry: I will now turn the call over to Sherri to summarize our financial results and upcoming milestones Gary.

Sherry: Thanks, Chris beginning briefly with our financial results beyond is well positioned with a strong balance sheet to support our plans for that to counter and other earlier stage programs in our pipeline.

Sherry Aulin: Thanks, Chris. Beginning briefly with our financial results, Xenon is well-positioned with a strong balance sheet to support our plans for Rosetta Kellner and other earlier stage programs in our pipeline. As of March 31, 2024, cash and cash equivalents and marketable securities were $885.4 million, compared to $930.9 million as of December 31, 2023. Based on current operating plans, including the completion of Ezekielner Phase III epilepsy studies and fully supporting late-stage clinical development of Ezekielner and MDD, we anticipate having sufficient cash to fund operations into 2027.

Sherry Aulin: As of March 31, 2024, our cash and cash equivalents in marketable securities were 885 4 million compared to $930 9 million as of December 31, 2023 based.

Sherry Aulin: Based on current operating plans, including the completion does that keep calendar phase III epilepsy studies and fully supporting late stage clinical development Thats affected calendar in MTBE, we anticipate having sufficient cash to fund operations into 2027.

Sherry Aulin: I would refer you to our news release and 10-Q report for further details on our financial results. We remain focused on our goal to improve outcomes for patients in areas of high unmet medical need. Looking ahead, we anticipate a number of important milestones, events, and goals. We will continue to advance our ZETU calendar phase 3 epilepsy program, including our XTOL 2 and XTOL 3 clinical trials in FOS, and our exact clinical trial in PGTCS, with patient enrollment in XTOL 2 expected to complete in late 2024 to early 2025.

Sherry Aulin: I would refer you to our news release and 10-Q report for further details around our financial results.

Sherry Aulin: We remain focused on our goal to improve outcomes for patients in areas of high unmet medical need looking ahead, we anticipate a number of important milestones and events and golf.

Sherry Aulin: We'll continue to advance our is that two calendar phase III epilepsy program <unk>.

Sherry Aulin: Including our <unk> Nx tool III clinical trials, and fos and our exact clinical trial in PT Tcs with patient enrollment in actual to expected to complete in late 2024 to early 2025.

Sherry Aulin: We expect to initiate the first of three phase three clinical trials in MDD in the second half of 2024. We will continue to explore other development opportunities for Zetu-CalNER, and we will continue to advance our early stage preclinical ion channel programs with the goal of advancing multiple candidates into IND-enabling studies in 2024 and 2025. Our strong belief in azethucalonar's potential to play a role in epilepsy, major depressive disorder, and potentially other indications is centered around its unique mechanism of action and attractive product profile, supported by the clinical data generated to date. We look forward to keeping you updated on our progress. I'll now ask the operator to open the line for any questions.

Sherry Aulin: We expect to initiate the first of three phase III clinical trials and mbd in the second half of 2024.

Sherry Aulin: We'll continue to explore other development opportunities for Etsy calendar and we will continue to advance our early stage preclinical ion channel programs with the goal of advancing multiple candidates into IND, enabling studies in 2024 and 2025.

Sherry Aulin: Our strong belief is that good calendar has potential to play a role in epilepsy major depressive disorder and potentially other indications is centered around its unique mechanism of action and attractive product profile.

Sherry Aulin: By the clinical data generated to date, we look forward to keeping you updated on our progress.

Sherry Aulin: Now I'll ask the operator to open the line for any questions.

Sherry Aulin: Operator.

Speaker Change: Thank you and at this time I'd like to remind everyone in order to ask a question Press Star then the number one on your telephone keypad.

Operator: And at this time, I'd like to remind everyone, in order to ask a question, press star then the number one on your telephone keypad. We'll pause for just a moment to compile the Q&A list, and your first question comes from the line of Paul Matteis from Stifo. Please go ahead.

Operator: Lastly, just a moment to compile the Q&A roster.

Paul Andrew Matteis: And your first question comes from the line of.

Paul Andrew Matteis: From Stifel. Please go ahead.

Paul Andrew Matteis: I have an ex-toll question and just one quick NAV 1.7 question. For ex-toll 2, Ian, I was wondering if you could just give a little bit more granularity on where you are with enrollment, how things are tracking relative to the last quarter, and sort of your comfort that the guidance is intact. I know you reiterated that today. And then on 1.7, in doing a little bit more digging around the target, we came across an example of another compound in this space running to issues with syncope and hypotension, and there had been some question around the expression of this target in the autonomic nervous system.

Paul Andrew Matteis: I have an X tole question I'm, just one click NAV one seven question on on X Tole Kiwi and I was wondering if you could just give a little bit more granularity on where you are with enrollment.

Paul Andrew Matteis: How things are tracking relative to the last quarter and sort of your comfort that.

Paul Andrew Matteis: But the guidance is intact I know you reiterated it today and then on $1 seven.

Paul Andrew Matteis: And given a little bit more digging around the target. We came across an example of another compound in this space.

Paul Andrew Matteis: Running into issues with syncope and hypertension and there had been some question around the expression of this targeted in the autonomic nervous system and so I was just kind of curious people always talk about selectivity with $1 seven but how do you think about beyond target margin and sort of where are you with the compounds that youre working on right now thank you.

Paul Andrew Matteis: And so I was just kind of curious, people always talk about selectivity with 1.7, but how do you think about the on-target margin and sort of where you are with the compounds that you're working on right now? Thank you.

Paul Andrew Matteis: Yes.

Ian C. Mortimer: Great. Thanks, Paul.

Paul Andrew Matteis: Thanks, Paul.

Speaker Change: So all I can answer your question on external too and I can give some comments on one seven and then if anyone else wants to jump Venezuela on our side. So yes as you mentioned on exon two we reiterated guidance today.

Ian C. Mortimer: Yeah, so I can answer your question on XTOL 2, and I can give some comments on 1.7. And then if anyone else wants to jump in as well on our side. So, yeah, as you mentioned on XTOL 2, we reiterated guidance today. You know, I think we all use some comments that we've used with investors and on previous calls as well. You know, we're targeting 360 subjects randomized in these Phase 3 studies, so a little bit larger than the Phase 2 program. And we need to go to about 80 to 100 medical centers to get the studies complete. And so you can just kind of do the math.

Ian C. Mortimer: I think we all I'll use some comments that we've used with investors and on previous calls as well.

Ian C. Mortimer: We're we're targeting 360 subjects randomized in these phase III studies, so a little bit larger than the phase II program, we need to go to about 80 to 100 medical centers to get the study is complete and so you can just kind of do the math, there's a handful of patients on average you get per center and so we do naturally see some.

Ian C. Mortimer: There's a handful of patients, on average, you get per center. And so we do naturally see some ups and downs and ebbs and flows of screening and enrollment. You know, we're reiterating guidance today because it's the best information we have based on where we are. So we've made good progress since our last update, and guidance remains the same that we expect to complete patient enrollment later this year or early

Ian C. Mortimer: Some ups and downs and ebbs and flows of SKU.

Ian C. Mortimer: Greening and enrollment.

Ian C. Mortimer: We reiterated guidance today and so the best information we have based on where we are so we've made good progress since our last update and guidance is remains the same that we expect to complete patient enrollment later this year or early next year.

Ian C. Mortimer: On 1.7, you know, obviously, in any target that we work on, whether it be potassium channels or sodium channels, whether it be 1.1 or 1.7, we're always looking at potential on-target or off-target effects. We're doing a lot of screening in panels, and then obviously, we're looking at safety margins in non-GLP studies, and then we will as these move into GLP toxicology studies. So, you know, often when we think about some of the potential risks of these targets, they can be hitting other targets or, as you say, potentially even on-target.

Ian C. Mortimer: On one seven.

Ian C. Mortimer: Obviously in any target that we work on whether it be potassium channels or sodium channels, whether it be one one or one seven were always looking at potential on target or off target effects, we're doing a lot of screening.

Ian C. Mortimer: And panels and then obviously, we're looking at safety margins and non DLP and then we will be as we move into <unk> toxicology studies. So.

Ian C. Mortimer: Often when we think about some of the potential risks of these targets.

Ian C. Mortimer: They can be hitting other targets or as you say potentially even on target I mean, we do know that the genetic population that are the homozygous loss of function. So you kind of think about that is.

Ian C. Mortimer: I mean, we do know that the genetic population that is the homozygote loss of function, so you kind of think about that as, you know, very difficult to recapitulate in a human, but 100% receptor occupancy. These people, other than not feeling pain, regardless of noxious stimuli, other than that, are normal. Sometimes there is a sense of smell based on some 1.7 expression in the olfactory. But for most people, other than that, we don't see other concerns when they have one in that genetic population that is a complete loss of function.

Ian C. Mortimer: Very difficult to recapitulate in a human but 100% receptor occupancy these people other than not feeling pain, regardless of noxious stimuli other than that are normal sometimes there is a sense of smell based on some one seven.

Ian C. Mortimer: <unk> and the older factory, but for the most other than that.

Ian C. Mortimer: We don't see other concerns when they have when that genetic population that has a complete loss of function. So I do think overall when we compare one seven to some of the sodium and potassium channels and we look at in the CNS that we do have we believe we're going to have larger margins and we see that pre clinically.

Ian C. Mortimer: So I do think overall, when we compare 1.7 to some of the sodium and potassium channels that we look at in the CNS, that we do have, we believe we're going to have larger margins, and we see that preclinically. But whether, as you mentioned, things like syncope, we would continue to look at those in all of our preclinical work, as well as in healthy volunteers. But right now, we believe that these molecules should have really good therapeutic indices. Chris, do you have anything to add to either of those points? I mean, there are many.

Chris: But whether as you mentioned things like syncope, we would continue to look at those in all of our preclinical work as well as in healthy volunteers, but right now we believe that these molecules should have really good therapeutic indices.

Ian C. Mortimer: Chris do you have anything to add on either of those points.

Chris: I mean, there are there are literature.

Christopher John Kenney: I mean, there are mentions in the literature of hypotension and the now 1.7 loss of function. So, fortunately, that's pretty easy to keep track of in the clinic in terms of following vital signs, following blood pressure, and seeing if it's dropping as patients change position, from lying to standing. So it's something we'll keep a close eye on, but it's easy to follow.

Christopher John Kenney: Mentions of hypotension in that that now one seven.

Christopher John Kenney: Loss of function.

Christopher John Kenney: So I mean, Fortunately, that's pretty easy to keep track of and the clinic in terms of following vital signs following blood pressure.

Christopher John Kenney: Dropping as patients change position position.

Christopher John Kenney: Lying to standing so it's something we'll keep a close eye on but it's easy to follow.

Speaker Change: Alright, Thank you guys.

Speaker Change: Thank you Ann as a reminder, please limit yourself to one question and re enter the queue for additional questions.

Christopher John Kenney: And.

Operator: Thank you, and as a reminder, please limit yourself to one question and re-enter the queue for additional questions. The next question comes from the line of Brian Abrahams from RBC Capital Markets.

Christopher John Kenney: Next question comes from the line of Brian Abrahams from RBC capital markets.

Operator: Hi, guys. This is Leo on for Brian and Thanks for taking our question I wanted to ask one maybe just on the nature of the discussions with the FDA you had I mean, it sounded like those were very positive, but I'm curious if you can maybe talk about some of the key questions. You had in the answers you receive in particular curious if you've got any more clarity on whether you can leverage safety.

Brian Abrahams: Database across the indications.

Brian Abrahams: Maybe how youre thinking about.

Brian Abrahams: Study enrollment split across the U S versus ex U S geographies. Thanks.

Brian Abrahams: Thanks, Leo. Yeah, I can start, and Chris can jump in.

Brian Abrahams: Thanks, Leo Yes, I can start and Chris can jump in yeah, I think really good progress on the team so I do want to.

Brian Abrahams: When you go from the top line Phase two data late in Q4, and then have an end of phase two meeting booked in <unk>.

Brian Abrahams: April and and not have to go ahead with the meeting I mean, thats actually incredible progress in that period of time, So that's kudos to.

Brian Abrahams: The internal team had seen on moving that very quickly. So we had mentioned before we had a number of questions in front of the agencies.

Brian Abrahams: In.

Brian Abrahams: Front of FDA in terms of the overall clinical program as Chris mentioned, we share our phase III protocol synopsis with FDA and and also as you say kind of leveraging the safety database. So I think the nice thing is as we can leverage a huge amount of the work that we've done in epilepsy. So that's clinical pharmacology CMC toxicology.

Brian Abrahams: <unk>.

Brian Abrahams: Then we can leverage into the <unk> program and <unk>, we are going to run as we mentioned three phase III clinical trials Youre question did ask about jurisdiction, we havent nailed all of that down in terms of all of the clinical trial sites. So as we said there is kind of more details to come on the phase III program, we'll have more details there.

Brian Abrahams: And obviously, we're going to have a lot of safety data from epilepsy that we can leverage and then specifically we're going to have a lot of data in Mds given that we're going to be running the three phase III clinical trials and then there is the ex Nova data and as you know there is an ISP ongoing as well. So I think we're going to have lots of information.

Brian Abrahams: That's available for FDA. So I think we feel really comfortable there as we mentioned we got everything we need it in the written response and so the meeting wasn't required I'm, Chris any other details you want to add.

Brian Abrahams: Sure. Thanks, Ian Yes.

Ian C. Mortimer: Yeah, I think really good progress for the team. So I do want to, you know, when you go from top line phase two data late in Q4 and then have an end of phase two meeting booked in April, and not have to go ahead with the meeting. I mean, that's actually incredible progress in that period of time.

Ian C. Mortimer: Terms of the clarity that we were seeking with the FDA wanted to make sure that the development program on a high level was acceptable.

Ian C. Mortimer: So that's kudos to the internal team at Xenon moving that very quickly. So as we mentioned before, we had a number of questions in front of the agencies, in front of the FDA, in terms of the overall clinical program. As Chris mentioned, we share our phase three protocol synopses with FDA and also, as you say, kind of leverage the safety database. So, I think the nice thing is that we can leverage a huge amount of the work that we've done in epilepsy. So that's clinical pharmacology, CMC, and toxicology that we can leverage into the MDD program. In MDD, we are going to run, as we mentioned, three phase three clinical trials. Your question did ask about jurisdiction.

Ian C. Mortimer: We haven't nailed all of that down in terms of all of the clinical trial sites. So, as we said, there's kind of more details to come on the phase three program. We'll have more details there, and obviously, we're going to have a lot of safety data from epilepsy that we can leverage. And then specifically, we're going to have a lot of data in MDD given that we're going to be running three phases, three clinical trials.

Ian C. Mortimer: Particularly the number of studies.

Ian C. Mortimer: They needed to be done we've already done an amazing amount of or a large amount of work pre clinically and in terms of clinical pharmacology and so we just wanted to make sure.

Ian C. Mortimer: Then there's the data, and as, you know, there's an ongoing process as well. So I think we're going to have lots of information that's available for FDA. So I think we feel really comfortable there. As we mentioned, we got everything we needed in the written response. And so the meeting wasn't required. Chris, any other details you want to add? Sure. Thanks, Ian. Yeah, I mean, in terms of the, you know, clarity that we were seeking with FDA one.

Christopher John Kenney: Sure, thanks, Ian. Yeah, I mean, in terms of the, you know, clarity that we were seeking with FDA, we wanted to make sure that the development program at a high level was acceptable. So the, particularly the number of studies that needed to be done, we've already done an amazing amount of, or a large amount of work preclinically and in terms of clinical pharmacology. And so we just wanted to make sure. You know, from the time of the last end of phase two meeting a couple of years ago for epilepsy, to make sure that all of that was still addressing everything that they wanted us to. And so we confirmed that.

Chris: From the time of the last end of Phase two meeting a couple of years ago for epilepsy make sure that all of that we're still addressing everything that they wanted us to and so we confirm that and then getting into more detail. Ian has already alluded to this but you kind of get into the design elements and making sure that if there is agreement on the primary endpoint and the statistical hierarchy, we've been very clear.

Christopher John Kenney: And then getting into more detail, Ian's already alluded to this, but you kind of get into the design elements, making sure that there is agreement on the primary endpoint and the statistical hierarchy. We've been very clear with what we think will be the differentiating features for Z2 calendar and MDD, and we want to make sure that that's included in the statistical hierarchy so we have a chance to actually promote it if this drug is approved. Make sure the size of the study is appropriate and those sorts of things.

Christopher John Kenney: With what we think will be differentiating features for is that your calendar in MTBE and we want to make sure that thats included in the statistical hierarchy. So we have a chance to actually promote on this drug is approved make sure. The size of the study is appropriate those sorts of things as far as leveraging the safety database question absolutely yes.

Christopher John Kenney: As far as leveraging the safety database question, absolutely, yes. We have, you know, if you look at ICH guidelines in terms of the exposures that you need, we're going to be well over that with this compound. So we're going to definitely leverage the work done in epilepsy and then continue to address all the safety data that FDA has asked for us, specifically in the major depressive disorder population. And then as far as geography is concerned, we don't think that we can pull off three large studies in MDD solely in the U.S., and so we're looking into all those options. But to Ian's point, we haven't drilled it down completely just yet, and... Thank you. And your next question comes from the line of...

Christopher John Kenney: If you look at ICA guidelines in terms of the exposures that you need we're going to be well over that with this compound. So we're going to definitely leverage the work done in an epilepsy and then continue to address all the safety data that the FDA has asked for us in the specifically in the major depressive disorder population and then as far as the only thing.

Christopher John Kenney: I'll say about geography is that we don't think that we can pull off three large studies in mds solely in the U S and so we're looking into all of those options, but to <unk> point, we haven't drilled it down completely just yet.

Christopher John Kenney: Okay.

Christopher John Kenney: Okay.

Speaker Change: Thank you and your next question comes from the line of Jason.

Operator: Thank you. And your next question comes from the line of Jason Gerberry from Bank of America. Please go ahead.

Jason Matthew Gerberry: Jason <unk> from Bank of America. Please go ahead.

Jason Matthew Gerberry: Hey, good evening, Thanks for taking my question.

Jason Matthew Gerberry: I'm just curious in your FDA meeting on M D D.

Speaker Change: And to the extent that you're willing to talk about this.

Speaker Change: Any feedback.

Jason Matthew Gerberry: Is your confidence that perhaps you could interrogate the impact on <unk>.

Jason Matthew Gerberry: In a unique way versus how studies have been done in the past or to potentially generate.

Speaker Change: Our unique and differentiated label claims around amazonia.

Jason Matthew Gerberry: So that's my question.

Operator: Yes.

Jason Matthew Gerberry: Thanks, Jason. Chris, do you want to address maybe we should go through a little bit of the rationale and the mechanism and what we saw in ExNova, and obviously we'll be looking at that in Phase 3 as well.

Operator: Thanks.

Jason Matthew Gerberry: Jason Chris do you want to address maybe we should go through a little bit of the rationale and the mechanism and what we saw in.

Jason Matthew Gerberry: And obviously it will be we will be looking at that in phase III as well.

Chris: Yes, I mean, the anhedonia story is such an interesting one and such an unmet need because not only is it an issue in terms of on the surface people are unable to enjoy the things in life that they normally would have and idonia is closely linked with suicidality as well and so this is a meaningful thing.

Christopher John Kenney: Yeah, I mean, the anhedonia story is such an interesting one and such an unmet need, because not only is it an issue in terms of, on the surface, people are unable to enjoy the things in life that they normally would, but anhedonia is closely linked to suicidality as well. And so this is a meaningful thing to go after. To answer your question more specifically about, you know, leveraging anhedonia in a unique way in the label, I sort of already alluded to that. I guess I was being a bit cryptic in the last answer.

Christopher John Kenney: To go after to answer your question more specifically about leveraging and Idoneous unique way in the label I sort of already alluded to that I guess I was a bit cryptic in the last answer, but but just to be clear. We're really interested in an <unk>. There was the earlier study with the <unk> compound that showed improvements in anhedonia.

Christopher John Kenney: But just to be clear, we're really interested in anhedonia. There was an earlier study with the KB7 compound that showed improvements in anhedonia, and ZF2 calendar has done the same.

Christopher John Kenney: Is that through calendar has done the same we believe that this may be a real signal that needs to be confirmed in phase III and so.

Christopher John Kenney: We believe that this may be a real signal that needs to be confirmed in Phase 3. And so the manner in which we're assessing anhedonia will be included within the statistical hierarchy. And, you know, if it works at the end of the day, and we check a couple of other boxes, we're hoping to be able to have that on the label, and to have the sales reps speaking with physicians about that, assuming the drug is approved.

Christopher John Kenney: Entering which we're assessing and have tonia will be included within the statistical hierarchy.

Christopher John Kenney: Sure.

Christopher John Kenney: If it works at the end of the day and we check a couple of other boxes, we're hoping to be able to.

Christopher John Kenney: To have that in the label and to help the sales reps speaking with physicians about that assuming the drugs approved.

Speaker Change: Okay, Thanks, Chris and maybe yeah, and maybe Jason we can even expand this a little bit Chris one second I can talk about when we've done I know the market research that Chris was referring to in the prepared remarks was actually looking at.

Christopher John Kenney: Thanks, Chris. And maybe, yeah, and maybe, Jason, we can even expand this a little bit. Chris von Seggern can talk about when we've done, I know, the market research that Chris was referring to in the prepared remarks was actually looking at the opportunity to address comorbid depression and epilepsy, but we had done previously a lot of work with psychiatrists as well. I think, you know, the opportunity as a differentiating feature, as you mentioned, is that to counter anhedonia is important. Chris, maybe you want to provide your perspective there. Ian, I was going to come in and say exactly that when we conducted our...

Christopher John Kenney: The the opportunity of addressing comorbid depression in epilepsy, but we had done previously a lot of work with psychiatrists as well I think.

Christopher John Kenney: The the opportunity has a differentiating feature as you mentioned or is that too calendar with antonio's embark Chris maybe you want to provide your perspective there.

Christopher E. Von Seggern: Yeah, Ian, I was going to come in and say exactly that. When we've conducted market research in the past, thinking about the profile of the Z2 calendar, physicians clearly latch on to a number of elements, the novel mechanism of action, the lack of sexual dysfunction or weight gain, but we hear very clearly the unmet medical need that exists with anhedonia and really the desperation for alternatives that offer a compelling efficacy profile in this component of the disease, and that's driven because SSRIs and SNRIs don't offer benefit along that dimension.

Christopher John Kenney: It's going to come in and say exactly that when we've conducted market research in the past.

Christopher E. Von Seggern: Thinking about the profile of this action calendar physicians clearly latch on to you.

Christopher E. Von Seggern: A number of elements the novel mechanism of action and the lack of.

Christopher E. Von Seggern: Sexual dysfunction or weekend, but we hear very clearly unmet medical need that exists with an agility and really the desperation for alternatives and offer a compelling efficacy profile of <unk>.

Christopher E. Von Seggern: In this component of the disease, and driven because ssris and Ssris don't offer benefit along that dimension. So we view it as a really important component of the commercial differentiation for us at your caller in MTBE and and we're hopeful as Chris.

Christopher E. Von Seggern: So, we view it as a really important component of the commercial differentiation for a Z2 calendar and MDD, and we're hopeful, as Chris and Ian have both mentioned, that this is something that will ultimately be incorporated in the labels when we move forward.

Christopher E. Von Seggern: Mentioned that this is something ultimately will be incorporated in the label as we move forward.

Speaker Change: Great. Thanks, guys.

Christopher E. Von Seggern: Great. Thanks, guys. Thank you. Thank you. And your next question...

Speaker Change: Thank you.

Christopher E. Von Seggern: Thank you and your next question comes from Brian Brian <unk> from Baird. Please go ahead.

Operator: Thank you. And your next question comes from the line of Brian Skorney from Barrett. Please go ahead. All right.

Operator: Hi, This is Luke on for Brian.

Brian Peter Skorney: We're just wondering were there any notable changes that FDA suggested for the phase III <unk> program endpoints enrollment criteria or any other aspects.

Brian Peter Skorney: Largely onboard with your proposed design.

Brian Peter Skorney: Yes, Thanks, Luke yes, they were largely on where they are on board with our design.

Brian Peter Skorney: Yeah, thanks, Luke. Yeah, they were largely on board with our design. Actually, if you go back to our Q4 results script of a couple of months ago, and the prepared remarks there, we kind of walked through, at least at the high level, how we were thinking about it, and Chris did it again today, in terms of the design, the primary endpoint, other things that we would be looking at. So, you'll have seen in today's remarks, when you compare them to our remarks last time, nothing' So, as we mentioned, we have good alignment with the agency, and no major adjustments are needed as we move forward.

Brian Peter Skorney: Actually if you go back to our Q4 results script of a couple of months ago in the prepared remarks, there we kind of walked through at least the high level. How we were thinking about it and did it again today in terms of the design the primary endpoint and other things that we would be looking at so youll see youll have seen in today's remarks, when you compare.

Luke: Sure Charlie.

Brian Peter Skorney: Our remarks last time nothing's changed there so as we mentioned we have good alignment with the agency and had no.

Brian Peter Skorney: Major adjustments needed as we move forward.

Speaker Change: Okay. Thank you.

Speaker Change: Thank you again next question comes from the line of cost scenario from Jpmorgan. Please go ahead.

Operator: Thank you. And your next question comes from the line of Tess Romero from J.P. Morgan. Please go ahead.

Tessa Thomas Romero: Hey, good afternoon, Ian and team thanks for taking our questions. So first one is probably a fairly quick one.

Tessa Thomas Romero: Hey, good afternoon, Ian and team. Thanks for taking our questions. So the first one is probably a fairly quick one. Just wanted a little bit of clarity on whether the ASCP presentation is more of an encore of what we've already seen, or are there new analyses that we should be preparing for? And then the second one is, when you might think you will be able to come and more definitively outline where you might like to take Exeon 1101 and what types of internal work you are doing to decide on where the most de-risked or compelling potential opportunities might be? Thanks.

Tessa Thomas Romero: Just wanted a little bit of clarity on.

Tessa Thomas Romero: Is the <unk>.

Tessa Thomas Romero: CPE presentation more of an encore Nf what we've already seen or are there new analyses that we should be preparing for.

Tessa Thomas Romero: Then second line is when you might think you will be able to comment more definitively outline where you might like to take <unk> line and what types of internal work you are doing to decide on where the most of the rest are compelling potential opportunities might be thanks.

Ian C. Mortimer: Tess, just for clarification, so there's a second question on indication expansion outside of epilepsy and MDD. That's right, exactly. Okay, great. Chris, do you want to answer the first question on the data that we're going to be presenting from Xnova later this month? And then I'm happy to just talk about indication expansion.

Tessa Thomas Romero: Tests just for clarification. So the second question on indication expansion outside of epilepsy and M D.

Speaker Change: Right exactly okay.

Chris: Okay great.

Ian C. Mortimer: Chris do you want to answer the first question on <unk>.

Chris: The data that we're going to be presenting from ex Nova later this month, and then I'm happy to just talk about indication expansion.

Chris: Yeah, Hi, Jess Yeah, so regarding Asap.

Christopher John Kenney: Yeah, hi Tess. Yeah, so regarding ASCP, if you're referring to the poster that was shared in the scientific exhibit at AES, it will be largely an encore. There will be one set of new analyses in there.

Christopher John Kenney: You're referring to the poster that was shared in a scientific exhibit.

Chris: Yes, it will be largely an on core there will be one set of new analyses in there.

Christopher John Kenney: Thanks, Chris. And then, Tess, in terms of indication expansion, I mean, we did, and we've talked about it on prior calls, we did a really significant life-cycle management project between our medical team and our commercial team last year, a lot of really great ideas on where we could potentially take both azethucalaner and other KV molecules, and we've made really good progress on some of those preclinical assets.

Speaker Change: Thanks, Chris and then in terms of indication expansion.

Christopher John Kenney: I mean, we've we did and we've talked about it in prior calls we did a really significant lifecycle management project between our medical team and our commercial team last year, a lot of really great ideas on where we could potentially take both is that two calendar, but also other <unk> molecules.

Christopher John Kenney: And we've made really good progress on some of those preclinical assets as we've talked about it.

Christopher John Kenney: So, you'll hear from us later this year. Obviously, we're committed to the Phase III program in epilepsy and the Phase III program in major depressive disorder. We think there is an opportunity to expand additionally for azethucalaner in other neuropsych areas, and so I'm sure you can kind of think about the ones that bubble up to the top of that list, but we've done a fair bit of work. We want to do a little bit more, and then we'll come back with a plan that's more fully fleshed out. Thank you. And your next question comes from the line of Paul Choi from Goldman Sachs.

Tess: So you'll hear from US later this year. So obviously, we're committed to the phase III program in epilepsy in the phase III program in major depressive disorder. We think there is an opportunity to expand additionally for us out to calendar and other.

Paul Choi: And other neuroscience areas and so I'm sure you can kind of think about the ones that the bubble up to the top of that and last but we've done a fair bit of work, we want to do a little bit more and then we'll come back with with a plan that's more fully flushed out.

Paul Choi: Thank you.

Christopher John Kenney: Yes.

Christopher John Kenney: And your next question comes from the line of Paul Choi from Goldman Sachs.

Christopher John Kenney: Yes.

Paul Choi: Hi, Tim Thanks for taking our question. This is <unk>, calling in for Paul.

Paul Choi: I guess a quick one for me if you could just provide a little bit of color on.

Paul Choi: Your phase III <unk> study in <unk>, sorry, excuse me PGE Tcs.

Paul Choi: Has that study completed enrollment and do you have any color on the timing of when you expect that to read out and thank you so much.

Paul Choi: Thanks <unk>.

Operator: Thanks, Khalil. Sherry, do you want to address the milestones for the exact study?

Christopher John Kenney: Sharon do you want to address milestones for the exact study.

Sherry Aulin: Yeah, absolutely. So the exact study is ongoing. We started it last year, and we're actively recruiting patients in that study. As a reminder, we're actually leveraging the sites from X-Tol2 and X-Tol3 for the exact study, so investigators can actually, you know, epileptologists or neurologists who have patients who have the primary diagnosis of PGTCS can be directed into the exact study. PGTCS, just to take a step back, is less prevalent than FOS. So the patient population overall is smaller and just has a different phenotype. Patients have more severe seizures but generally a lower seizure burden.

Sherry Aulin: Yes, absolutely.

Sherry Aulin: So these <unk> studies ongoing.

Sherry Aulin: We started that last year and we are actively recruiting patients in that study.

Sherry Aulin: As a reminder, we're actually leveraging the sites from <unk> III for the exact study investigators.

Sherry Aulin: Investigators can actually on Apple apologist for neurologists, who have patients and to have the primary diagnosis of PTA Tcs can be directed into the exact study.

Sherry Aulin: Yes.

Sherry Aulin: Yes, just to take a step back is less prevalent than fos.

Sherry Aulin: So the patient population overall is smaller and just has a different phenotype right patients have more severe seizures, but generally a lower seizure burden and so on.

Sherry Aulin: So, in general, if you think about just fewer patients in this PGTCS population versus FOS, these studies do take a little bit longer to recruit and enroll, and that's very consistent with what we've seen historically with PGTCS studies from other study sponsors. So, you know, we're continuing to make progress, again, leveraging the sites from XTOL 2 and XTOL 3. XACT is continuing to actively recruit patients. We will absolutely give guidance on this study.

Sherry Aulin: General, Yes, if you think about just keep our patients and this and this PGE tcs population versus the <unk>.

Sherry Aulin: <unk> take a little bit longer to recruit and enroll.

Sherry Aulin: Very consistent with what we've seen historically with PTT CF studies from others to any sponsors so we're continuing to make progress again.

Sherry Aulin: Leveraging our <unk> and in fact is continuing to actively recruit patients we will absolutely give guidance on this study, we're just not quite there yet today.

Sherry Aulin: We're just not quite there yet today.

Christopher E. Von Seggern: And Sherry, just to add, you know, this was already stated in the prepared remarks. But yeah, I think it's really important to keep in mind that we're positioning XTOL as the first pivotal trial in focal onset seizures. And it's really the completion of XTOL-2 that will drive the initial NDA submission. So, not to be dismissive of the PGTS question, but I just want to be clear that we're, you know, where the priority is in the short term. Thanks.

Speaker Change: Sure got it okay Chris.

Christopher E. Von Seggern: To add this was already stated.

Christopher E. Von Seggern: In the prepared remarks, but yes, I think it's really important to keep in mind that we're positioning <unk> as the first pivotal trial and focal onset seizures and it's really the completion of ex told two that will drive the initial NDA submission so not to be dismissive of the Pts question, but I just wanted to be clear that we're.

Christopher E. Von Seggern: Where the priority is.

Christopher E. Von Seggern: In the short term.

Operator: Absolutely. Thanks, Chris. And your next question comes from the line of Danielle Abril from Raymond James. Please go ahead. Hey guys, this is Alex on behalf of Danielle.

Sherry Aulin: Thanks, Chris.

Speaker Change: And your next question comes from Ryan Spohn Europeans from Raymond James. Please go ahead.

Operator: And your next question comes from the line of Danielle Abril from Raymond James. Please go ahead.

Operator: Hey, guys. This is Alex on for Danielle.

Danielle Abril: Thanks, Alex. Chris, I can start.

Danielle Abril: Just another question on MVP could you walk us through your rationale for running three distinct phase III trials as opposed to say to potentially larger more well powered trials and is it your intention that these trials will be philosophically identical and trial design.

Speaker Change: Thanks, so much.

Ian C. Mortimer: You can add in. So we haven't given, Alex, we haven't given sample size numbers for the phase three program yet. That's to come. But I think when we do have those numbers out, you'll see that we believe each of these phase three studies is well-powered. So they're going to be significantly larger than the X-Nova in terms of the number of patients per arm. You know, the real reason to do three studies is that we all know the subjectivity and variability that you can see in depression studies.

Speaker Change: Thanks, Alex.

Speaker Change: Chris I can start you can you can add in.

Ian C. Mortimer: So we haven't given Alex we haven't given sample size numbers for the phase III program, yet that's to come but I think when you. When we do have those numbers out youll see that we believe each of these phase III studies as well powered so theyre going to be significantly larger.

Ian C. Mortimer: Then then the ex Nova in terms of number of patients per arm.

Ian C. Mortimer: Real reason to do three studies I think we are.

Ian C. Mortimer: No.

Ian C. Mortimer: The subjectivity and variability that you can see in depression studies and so we believe this is the right thing to do from a risk mitigation point of view to run three studies.

Ian C. Mortimer: And so we believe this is the right thing to do from a risk mitigation point of view to run three studies. They'll be, yes, they'll be very similar, I think, as we get into the more granular details, if there are any real differences or nuances, we can communicate at that time. But, yeah, essentially, you can think about them as similar studies, three ongoing, with the first one to start later this year. And as Chris mentioned in his remarks, we've kind of mapped out already for you the primary endpoint, the trial design, and some of the other details, including sample size to come over the next number of months as we just finalize the protocol.

Ian C. Mortimer: They'll they'll be yes, there'll be very similar.

Ian C. Mortimer: I think as we get into the more granular details.

Ian C. Mortimer: If there is any any any real differences or nuances, we can communicate at that time, but yes, essentially you can think about them as similar studies three ongoing first one to start later this year and as Chris mentioned in his remarks, we've kind of mapped out already for you the primary endpoint the trial design.

Ian C. Mortimer: And some of the other details including sample size to come over the next number of months as we just finalize the protocol, obviously, we need to submit it to the IMD and then and then get ready to get sites initiated and patients enrolled I'm Chris.

Ian C. Mortimer: Obviously, we need to submit it to the I&D and then get ready to get ready to get sites initiated and patients enrolled. Chris, anything else to add in terms of some details there? Sure, you know what I mean.

Speaker Change: Chris anything else to add in terms of some details there.

Ian C. Mortimer: Sure, you know, I mean, obviously, the question about how many studies we should do is something that we've intensely thought about over the past several months, really, over the past years. And it wasn't like we were weighing two scenarios, like, oh, let's partially power three studies versus really powering two studies. We went into it with the mindset that every study we conduct will be meticulously conducted to the extent that we can control variables.

Ian C. Mortimer: Sure.

Ian C. Mortimer: I mean, obviously the the question about how many studies, we should do is something that we intensely thought about.

Ian C. Mortimer: Over the past several months really over the past few years and it wasn't like we were weighing two scenarios like Oh, let's slips partially pilot studies versus really power. Two studies, we were going into it with a mindset that every study we conduct will be meticulously conduct it to the extent that we can control variables.

Ian C. Mortimer: And then it's just a question of, okay, we're going to do that. And so, as Ian's already said, I think when you see the size of these studies coming out, I think you'll see that we're not taking any shortcuts here. Thanks.

Ian C. Mortimer: And then it's just a question of Okay, we're going to do that how many times and so as <unk> already said.

Ian C. Mortimer: I think when you see the size of these studies coming out.

Ian C. Mortimer: You're going to see that we're not we're not taking any shortcuts here. Thanks.

Speaker Change: Great. Thanks, so much.

Speaker Change: Thank you.

Ian C. Mortimer: Thank you and your next question comes from the line of my Goodman from Leerink.

Christopher John Kenney: Thank you. And your next question comes from the line of Mark Goodman from Learing.

Marc Harold Goodman: Hi, Hi, good afternoon. This is <unk> on for Mike can you remind us again of the food effect of <unk> and what kind of food what is it like fatty food or any just any type of food.

Operator: Hi, hi, good afternoon. This is Basma on 4Mark. Can you remind us again of the food effect of Zine 11-01 and what kind of food it is? Like, is it fatty food or any, just any type of food?

Marc Harold Goodman: Also, we have another question. So even though Zine 11-01 is being developed as monotherapy for MDT, there's a high likelihood that it's gonna be used in combination with other antidepressants in later lines if the drug is successful in the indication. So are you planning to run any DTI studies just to confirm the safety of the combination of Zine 11-01 with other antidepressants? Thank you. That's it for us.

Speaker Change: Also we have another question so.

Marc Harold Goodman: <unk> hundred one is being developed this monotherapy for MTBE, there's high likelihood that it's going to be used in combination with other anti depressants.

Marc Harold Goodman: And later lines if the drug is successful and the indication. So are you planning to run any DDI studies just.

Marc Harold Goodman: Just to confirm the safety of the combination.

Marc Harold Goodman: Other anti depressants. Thank you asked that question.

Ian C. Mortimer: Thank you. I'll do the first one, Chris, on maybe a little bit of that background on food effects and what we're doing in all of the efficacy studies. And then, if you want to comment just on some comments on DDI and monotherapy versus adjunctive and MDD. So, we know from our Phase I work that Exantiocalonur has a marked food effect. And so all of our efficacy studies have been completed in the presence of food.

Speaker Change: Thank you.

Speaker Change: I can I'll do the first one and Chris on maybe a little bit of that background on food effect and what we're doing in all of the efficacy studies.

Chris: And then if you want to comment just on on some comments on DDI and monotherapy versus adjunctive and M D.

Ian C. Mortimer: So we know from our phase one work the axion alone or is that too calendar has as a mark food effect.

Chris: And so all of our efficacy studies have been completed and the presence of food and so.

Ian C. Mortimer: And so the drug is taken with the evening meal. That's important because we usually see a maximal concentration of the drug. We do obviously have patient to patient variability, but we see the maximal concentration of the drug during sleeping hours in the middle of the night. There isn't, so the protocols talk about it being administered or taking the drug with the evening meal. We don't have to specify what type of food the drug is taken with, so hopefully that addresses the food question. Chris, do you want to talk about our thinking around DDI and adjunctive therapy?

Ian C. Mortimer: The drug is taken with the evening meal.

Chris: That's important because we usually see maximal concentration of the drug we do have obviously patient to patient variability, but we see the maximal concentration of the drug.

Chris: During sleeping hours in the middle of the night.

Chris: There isn't so the protocol is talk about.

Chris: Being administered or taking the drug with the evening meal.

Chris: We don't have to specify on what type of food.

Chris: The drug is taken with so hopefully that addresses the food question Christy I want to talk about our thinking around DDI and injunctive.

Ian C. Mortimer: Sure.

Christopher John Kenney: Sure. So, in terms of DDIs, I mean, things have evolved over the past couple of decades or so, I think, from the standpoint where even if you didn't predict a specific DDI, you would sometimes do a drug-drug interaction study with one drug and another drug, say an anti-seizure medication or antidepressant that's used quite a bit. The field has kind of gone away from that because we've gotten pretty good at predicting drug-drug interactions.

Chris: So in terms of DDI is I mean things have evolved over the past couple of decades or so.

Christopher John Kenney: From the standpoint, where even if you didn't predict specific DDI you would sometimes do a drug drug interaction study with a drug and another drug say, an anti seizure medication or anti depressant that fits us quite a bit the field has kind of gone away from that because we've gotten pretty good at predicting drug drug interactions and so as it brings.

Christopher John Kenney: And so, as it pertains specifically to antidepressants, we don't foresee any major issues whatsoever in terms of drug-drug interactions with any of the antidepressants used. Thus, we don't see any need to do those additional NDA-enabling studies, and we haven't had any regulatory feedback to suggest that there was disagreement.

Christopher John Kenney: <unk>, specifically to anti depressant.

Christopher John Kenney: I don't foresee any major issues whatsoever in terms of drug drug interactions with any of the anti depressants used.

Christopher John Kenney: So the current so we don't see any need to do those additional NDA, enabling studies and we.

Christopher John Kenney: We haven't had any regulatory feedback to suggest that there was disagreement.

Speaker Change: Thank you.

Operator: Thank you. That was very useful. And your next question comes from a line to Andrew Chai from Jeff.

Christopher John Kenney: Okay.

Andrew Chai: Thanks, Chris.

Operator: Okay.

Operator: And your next question comes from Elaine of Andrew Chai from Jeff.

Andrew Chai: And your next question comes Chimerine, Angie Chang from Jefferies.

Andrew Chai: Hey, Thanks. Good afternoon. Thanks for taking my question can you just remind us how long it took ex nova to start up and generate the topline data and whether you think the phase III should also have a similar timing. Thank you.

Elaine: Thanks, Andrew Sherri do you want to go through the <unk> over time.

Andrew Chai: Thanks, Andrew. Sherry, do you want to go through the ex-NOVA timing? Yeah, absolutely.

Sherry Aulin: Yeah, absolutely so.

Sherry Aulin: Yeah, absolutely. So, just as a reminder, Ex Nova took us about 18 months, I would say, from start to finish. As a reminder, we randomized just over 160 patients in that study. As Ian mentioned earlier, these Phase 3 trials are going to be powered well for phase 3, so we're going to see multiples of the number of patients that we saw per arm in a one-to-one randomization. So think about a study size that's 2 to 3x the size of Ex Nova. These studies do take, I would say, generally less time to enroll than epilepsy. There are just more patients out there that meet the enrollment criteria.

Sherry Aulin: Yes, just as a reminder, X now that took us about 18 months I would say from start to finish.

Sherry Aulin: As a reminder, we randomized just over 160 patients in that study and as Ian mentioned earlier. These phase III trials are going to be powered well for phase III. So we're going to see multiples.

Sherry Aulin: At the number of patients that we saw per arm.

Sherry Aulin: And I went to one randomization, so think about a study size thats two to three X the size of the next Nevada.

Sherry Aulin: On a btu studies do take I would say generally last time to enrollment epilepsy, there's just more patients out there that meet the enrollment criteria. So we do expect that the timing will be.

Sherry Aulin: So we do expect that the timing will be not too dissimilar to Ex Nova, so probably somewhere kind of in the 2-year range, I would say. Andrew, if you think about start to finish for each of the Phase 3 studies, we're not going to start them all practically. These studies are typically staggered a little bit. So, as we've said, the first study will start later this year. Practically, though, there will be a little bit of a stagger, you know, a number of months for the second study and then again, a number of months for the third study.

Sherry Aulin: Not too dissimilar tax now that so probably some somewhere kind of in the two year range.

Sherry Aulin: Range I would say Andrew if you think about start to finish for the each of the phase III studies, and we're not going to start them. All practically these studies are typically staggered a little bit.

Operator: Hopefully, that helps. Very helpful. Thank you. And your next question comes from the line of Peyton Bonsack from TD Co.

Sherry Aulin: So as we said the first study will initiate later this year practically that there will be a little bit of a stagger.

Peyton Bonsack: Number of months to the second study and then again a number of months to the third study hopefully that helps.

Peyton Bonsack: Very helpful. Thank you.

Peyton Bonsack: And your next question comes from the line of Stephen Banteng from TD colleagues.

Operator: And your next question comes from the line of Peyton Bonsack from TD Cohen.

Peyton Bonsack: Hi, good afternoon, and thank you for taking our questions. Just a quick one for one from US can you remind us on what youre doing to control placebo rates in the <unk> program in.

Peyton Bonsack: In the phase III trials and highlight any changes that may have come from the learnings from the <unk> trial and the interactions with the FDA. Thank you.

Peyton Bonsack: Great. Thank you Ben Chris do you want to walk through.

Peyton Bonsack: Great. Thank you, Peyton. Chris, do you want to walk through both what we did and maybe focus more on what we expect to do to continue to keep an eye on the placebo rate in the Phase 3 MDD program?

Peyton Bonsack: Both are well.

Chris: What we had done and we are.

Peyton Bonsack: Maybe I focus more on what we expect to do to continue to keep an eye on placebo rate in the phase III <unk> program.

Chris: Yes, absolutely.

Christopher John Kenney: Yeah, absolutely. So I mean, you know, Ex Novo. We're quite pleased with the results that we saw with the Ex Novo study. And so in terms of trying to, you know, control the placebo effect to the extent that we could, we really focused on choosing a CRO that was highly experienced in major depressive disorder. We used the SAFER criteria to make sure that appropriate patients were getting into the study. So that's an external group that has no skin in the game in terms of whether a patient is enrolled or not.

Christopher John Kenney: So ex Nova we are quite pleased with the results that we saw with the ex Nova study and so in terms of trying to control placebo effect to the extent that we could we really focused on choosing a zero that was highly experienced major depressive disorder, we use the safer criteria to make sure that.

Christopher John Kenney: Patients were getting into the study so that is an external group that has no skin in the game in terms of whether a patient is enrolled or not.

Christopher John Kenney: We also obviously chose really high quality sites with lots of experience in NDD, made sure that the training on the scales was done appropriately. And then there's a bunch of ways that you can keep an eye on data in real time to make sure that you're not seeing anything unusual, either in a patient or at a site level, or, of course, at the study level. Obviously, you keep an eye on the baseline demographics and make sure that you're putting together a population that you expect.

Christopher John Kenney: We also obviously chose really high quality sites with lots of experience in MTBE made sure that the training on the skills was done appropriately. So and then there's a bunch of ways that you can keep an eye on.

Christopher John Kenney: On data in real time to make sure that youre not seeing anything.

Christopher John Kenney: Unusual either in a patient or a site level or of course at a steady level. Obviously, you keep an eye on the baseline demographics and make sure that you're putting together a population that you expect and then going forward.

Christopher John Kenney: And then going forward, you know, one thing that's absolutely clear from these studies is that a handful of patients can really have an untoward effect on all of the results. And one of the things that we've seen as a common theme in successful MDD studies is a real focus on making sure that patients with milder forms on the milder end of the spectrum don't get into the study. And so, as we share these design elements, you'll see that we're using a slightly higher cutoff on the EMD.

Christopher John Kenney: One thing that's absolutely clear.

Christopher John Kenney: In these studies is that a handful of patients can really have an untoward effect on the on all of the results and one of the things that we've seen is a common theme in successful Mgd studies is a real focus on making sure that patients with mild on the milder end of the spectrum don't get into the study and so as we shared these.

Christopher John Kenney: Design elements, you'll see that.

Christopher John Kenney: And a slightly higher cutoff on the AMD. That's one thing and then we're doing some other things too that we'll share publicly when the time is right. So we're really focused on trying to minimize the placebo effect to to the extent that we can and the only other thing I will say is that compliance is a major issue and so that were in the psychiatric.

Christopher John Kenney: That's one thing. And then we're doing some other things too, that we'll share publicly when the time is right. So we're really focused on trying to minimize the placebo effect to the extent that we can. And the only other thing I will say is that compliance is a major issue. And so we're in the psychiatric population. And so we're going to be doing as much or more as we transition to phase three to ensure compliance to the extent that you can. Thanks, Chris. And the only other one...

Christopher John Kenney: Population and so we're going to be doing as much or more as we transition to phase III to ensure compliance to the extent that you can.

Speaker Change: Thanks, Chris and the only other one that I would add to chris's unless that we've talked about publicly is in the phase III program. We had two active arms versus placebo and then phase III is we've talked about will go to a one to one randomization and so.

Christopher John Kenney: Thanks, Chris. And the only other one that I would add to Chris's list that we've talked about publicly is that in phase two, we had two active arms versus placebo. And in phase three, as we've talked about, we'll go to a one to one randomization. And so the literature teaches us that that should have an impact on the placebo rate by lowering the placebo rate in terms of expectation bias.

Christopher John Kenney: The literature teaches us that should have an impact on the placebo rate by lowering the placebo rate in terms of expectation bias.

Speaker Change: Great makes a lot of sense, thanks for taking our questions.

Speaker Change: Thank you.

Christopher John Kenney: Yes.

Operator: Your next question comes from the line of Tim Lugo from William Baer.

Christopher John Kenney: Our next question comes from the line of Tim Lugo from William Blair.

Operator: And for again for <unk> I know, there's been a lot of questions around MTBE, but you mentioned the higher cut off of the handy to try and manage the placebo effect.

Timothy Francis Lugo: And again, for MDD, I know there are a lot of questions here about MDD, but you mentioned the higher cutoff of the HAMD to try and manage the placebo effect. But also, given the anhedonia effect and the differentiation versus the existing modalities, did the FDA kind of give you any guidance during the meeting on how heavily pre-trained the population should be or how many, therapies may be failed or cycled through prior to enrollment?

Timothy Francis Lugo: But also given the danya.

Timothy Francis Lugo: And the differentiation versus the existing modalities does the FDA kind of give you any guidance during the meeting on how heavily pretreated population should be or how many.

Timothy Francis Lugo: Therapies, maybe failed or cycled through prior to enrollment.

Christopher John Kenney: Thanks, Tim. Chris?

Speaker Change: Thanks, Tim Chris.

Chris: Yes, I mean, the feedback that they provided wasn't so much in terms of medications failed or anything like that the resistance of the population per se. They did provide some cutoff excuse me. Some some feedback on cut offs that can be used to optimize the patient population and of course, we're going.

Christopher John Kenney: Yeah, I mean, the feedback that they provided wasn't so much in terms of medications failing or anything like that, the resistance of the population per se. But they did provide some cutoffs, excuse me, some feedback on cutoffs that can be used to optimize the patient population. And of course, we're going to implement those recommendations. I promise you'll hear more, you'll hear the specifics on all of that before too long.

Christopher John Kenney: <unk> two to implement those recommendations.

Christopher John Kenney: Promise Youll hear more specifics on all of that before too long.

Speaker Change: Okay. Thank you so it hasn't actually one last question. So when should we expect the Mount Sinai to result is that something thats still expected this year.

Operator: Okay, thank you so much. Actually, one last question. When should we expect the Mount Sinai K2 results? Is that something that's still expected this year?

Operator: Yeah, we.

Ian C. Mortimer: Yeah, just as a reminder, there is an ongoing IST for zetutaliner in an MDD study being run by Mount Sinai and Baylor. This is looking at 20 milligrams of the drug versus placebo.

Operator: Just as a reminder, there is.

Ian C. Mortimer: There is an ISP ongoing for that two calendar.

Ian C. Mortimer: And in Mds study being run by Mount Sinai and Baylor that says looking at 20 milligrams of the drug versus placebo. The primary endpoint of that as a functional endpoint. It's a functional MRI endpoint, but then there are secondary endpoints in clinical scales of depression and anhedonia.

Ian C. Mortimer: The primary endpoint of that is a functional endpoint. It's a functional MRI endpoint, but then there are secondary endpoints on clinical scales of depression and anhedonia. Tim, we don't have specific guidance on that. We do know, based on, obviously, we have a close relationship with the physicians running that study. We fully expect that patient enrollment will complete this year, and then it'll be a conversation with the physicians in terms of where those data may be presented. So, as we don't, we just don't have that information yet. As soon as that information's available, we'll be able to communicate it to you.

Operator: All right, thank you. Yep.

Operator: We don't have specific guidance on that we do know based on obviously, we have a close relationship with the physicians running running that study we fully expect that the patient enrollment will complete this year and then it'll be a conversation with the physicians in terms of where those data may be presented so has.

Operator: We just don't have that information yet has that information is available then we'll be able to communicate it to you.

Speaker Change: Alright, thank you.

Operator: Yes.

Operator: Your next question comes from the line of Mohit.

Operator: Your next question comes from the line of Mohit Bansal from Wells Fargo.

Mohit Bansal: <unk> from Wells Fargo.

Mohit Bansal: Great. Thank you very much for taking my question. I just wanted to ask you to think about your thought process on the depression market in general. There is a lot of development in the mid to late stage. Recently, we have seen the Kappa opioid receptor, and we have seen AMPA potentiator, interesting data on the depression scale, but there could be some effect on anhedonia as well. I just wanted to see how you compare and contrast with ZNL1101 and these other mechanisms, which also look really safe. So how do you think about the market evolving?

Mohit Bansal: Please go ahead, thank you Amy.

Speaker Change: Great. Thank you very much for taking my question.

Speaker Change: Just wanted to ask Uh huh.

Mohit Bansal: Take a think about the and your thought process on the on the depression market in general the days, there's a lot of development.

Mohit Bansal: Mid to late stage.

Mohit Bansal: Recently, we have seen Kappa opioid receptor of you have seen that about potentiate.

Mohit Bansal: Addressing data on depression scale, but I mean, there could be some effect on 900 <unk>. So just wanted to see like how do you compare and contrast with senior level 11, one.

Mohit Bansal: And.

Mohit Bansal: These other mechanisms also look really safe. So how do you think about the market evolving with these multiple drugs out there.

Speaker Change: Thanks Mohit.

Operator: Thanks Mohit. Yeah, excellent question that we think about a lot. Chris von Seggern, do you want to walk through how we just think about the overall medical need and where Zetucaliner would fit in, especially considering that there are other drugs that are in development? Yeah, absolutely. I think people

Speaker Change: Excellent question that we think about a lot Chris one figure and do you want to walk through how we just think about the overall medical need and where is that two calendar would fit and especially considering that there are other drugs that are in development.

Christopher E. Von Seggern: Yeah, absolutely. I think first and foremost, if you take a step back and think about the major depressive market, we're talking about an addressable population that is measured in the multi-multi-millions. And as we all know, the mainstay of therapy in this space is SSRIs and SNRIs, of which there are many, and patients typically cycle through a couple of those options before they transition into what we consider the more branded market.

Speaker Change: Yes, absolutely I think first and foremost if you if you take a step back and you think about the major depressive market.

Christopher E. Von Seggern: We're talking about an addressable population that is measured in the multi multi millions.

Christopher E. Von Seggern: And as we all know the mainstay of therapy in those spaces.

Christopher E. Von Seggern: The rise in asset Mris of which there are many patients typically cycled through a couple of those options before they transition into what we consider the more of the branded market.

Christopher E. Von Seggern: We think there's ample opportunity for a number of products to fill a void in the need for patients who don't have an adequate response to an SSRI or SNRI or, importantly, have greater need as it pertains to an adverse event associated with either weight gain or sexual dysfunction. So, we do appreciate that the competitive landscape in this space is quite a bit different from what we see in the focal onset seizure arena.

Christopher E. Von Seggern: We think there is ample opportunity for a number of products to fill a void in the need for patients who don't have an adequate response to an SSRI or SNRI or importantly have greater need as it pertains to a an adverse event associated with either gain or sexual dysfunction.

Christopher E. Von Seggern: But from a profile as it pertains to the ZETU calendar, clinicians are really excited and continue to express enthusiasm about that profile. The AB7 potentiation has a really strong link to the depressive state. The efficacy and safety profile that we've seen coming out of the Ex Nova study has really resonated with clinicians reaching for a novel mechanism of action. And then, importantly, other attributes such as rapidity of onset and the potential to address anhedonia are things that clinicians are really hungry for.

Christopher E. Von Seggern: We do appreciate that the competitive landscape in this space is quite a bit more than what we see in the focal onset seizure arena.

Christopher E. Von Seggern: But from a profile as it pertains to your calendar clinicians are really excited and have continued to express enthusiasm about that profile KD seven potentiation has really strong linked to the depressed state.

Christopher E. Von Seggern: Efficacy and safety profile that we've seen coming out of the <unk> study.

Christopher E. Von Seggern: He has really resonated with clinicians reaching for a novel mechanism of action and then importantly other attributes.

Christopher E. Von Seggern: Rapidity of onset and the potential to address.

Christopher E. Von Seggern: And Magellan here things that clinicians are really hungry for so the emergence of competition around us and we will further further bolster some of those attributes.

Christopher E. Von Seggern: So, the emergence of competition around us will further bolster some of those attributes, but there's still plenty of opportunity for multiple successful products from a branded standpoint, given the residual unmet need that is so substantial in the major depressive market.

Christopher E. Von Seggern: But there's still plenty of opportunity for multiple successful products from a branded standpoint, given the residual unmet need is so substantial in the major depressive market.

Speaker Change: Super helpful. Thank you.

Christopher E. Von Seggern: Thank you and your final question comes from the line of David Wong from Citigroup.

Operator: Thank you. And your final question comes from the line of David Wong from Citigroup.

David Wong: Hi, there thanks for taking me in.

Operator: Hi there. Thanks for taking my question and fitting me in.

David Wong: Thanks for taking my question and fitting me in.

David Wong: Just wanted to ask about your I guess latest thoughts on.

David Wong: Given everything we know about 11, new ones clinical profile, which now obviously includes a mood benefit.

David Wong: Does that impact how you think about the peak sales opportunity for the product in epilepsy, and MTBE and are there any I guess analogs out there historically in the market that we could think about as potential comps for level, one I know.

David Wong: I just wanted to ask about your, I guess, latest thoughts on, given everything we know about 1101's clinical profile, which now obviously includes a mood benefit, does that impact how you think about the peak sales opportunity for the product in epilepsy and MDD? And are there any, I guess, analogs out there in the market that we could think about as potential comps for 1101? I know products such as Vimpad have come up in discussions before, but just wanted to get a sense of what your current and latest thinking was on that.

David Wong: Next such as Vimpat have been have come up in discussions before but just wanted to get a sense of what youre correct and what your thinking was on that.

Ian C. Mortimer: Thanks, David. Yeah, you know, I'll pass the call to Chris von Seggern, because we've done a lot of work now on really understanding the mood benefits of his ettu calendar in epilepsy, and we've done even more market research just over the last few months. So Chris talked about that a little bit in his prepared remarks, but I think he can go into a little bit more detail now in terms of that as a differentiator and as an opportunity from a commercial perspective. Yeah, happy to do so. So

Speaker Change: Thanks, David Yes.

Speaker Change: I'll pass the call to Chris one segment, because we've done.

Speaker Change: A lot of work now on really understanding.

Speaker Change: Having a mood benefit or is that through calendar and epilepsy and we've done even more market research just over the last few months, so Chris talked about that a little bit in his prepared remarks, but I think you can go into a little bit more detail now in terms of that as a differentiator and as an opportunity from a commercial perspective.

Ian C. Mortimer: Okay.

Speaker Change: Yeah happy to so.

Christopher E. Von Seggern: Yeah, happy to, Ian. So, prior to the Ex Novo results, we felt very strongly, based on the research that had been conducted to date, that the Zetsu calendar product profile, should the product be approved, is really a market-leading profile. So, again, the attributes we've historically discussed—novel mechanism, vaccine, rapidity of onset, and ease of use—are really, really, really compelling when you think about the dozens of alternatives that exist in the focal onset seizure market. And you're right.

Christopher E. Von Seggern: Prior to the X Nova results, we felt very strongly based on the research that have been conducted to date that these etsy calendar of product profile I should the product be approved as really a market leading profile. So again the attributes. We've historically discussed novel mechanism of action rapidity of onset and ease of use attributes are.

Christopher E. Von Seggern: Really really really compelling when you think about the dozens of alternatives that exist in the focal onset seizure market.

Christopher E. Von Seggern: Historically, we've talked about Vimpath, the most recent blockbuster in our category, as being a product that we tend to think about as having—really occupying that first branded opportunity where we feel a Zetsu calendar is positioned well, should it come to market. I think what we've learned with the recent market research and the backbone of the Ex Novo data is that it really changes the profile of this product, and clinicians are even more enthusiastic when you think about the potential benefit in depression.

Christopher E. Von Seggern: And you're right historically, we've talked about the impact the most recent blockbuster in our category as being a product that we.

Christopher E. Von Seggern: We tend to think about as having really occupying that first branded opportunity where we feel is that two calendar is positioned well should.

Christopher E. Von Seggern: Come to market.

Christopher E. Von Seggern: I think what we've learned with the market with our recent market research in the back bone of the ex Nova data is that it really changes the profile of this product and clinicians are even more enthusiastic.

Christopher E. Von Seggern: When you think about the potential benefit.

Christopher E. Von Seggern: Depression, and Thats driven by a couple of factors the first of which is the mainstay of treatment in our category leveraged <unk> Tam is known to exacerbate mood related conditions.

Christopher E. Von Seggern: And that's driven by a couple of factors, the first of which is the mainstay of treatment in our category, levofotriacetam, is known to exacerbate mood-related conditions. And we often see clinicians choosing their anti-seizure medication based on the existence or emergence of mood-related disorders. The other component is that there is great evidence in the literature that suggests that as patients progress through lines of therapy, the rate of depression increases, and the outcomes for those patients who experience depression get worse, or compliance and poor seizure management and control.

Christopher E. Von Seggern: And.

Christopher E. Von Seggern: We often see clinicians choosing their anti seizure medication based on the existence or emergence of blood related disorders. The other component is there is great evidence in the literature that suggests that as patients progress through lines of therapy.

Christopher E. Von Seggern: Rate of depression increases and the outcomes for those patients who experienced depression get worse or compliance and poor seizure management and control that unmet medical need is amplified in these patients who have co morbid depression, and when presented with a profile of its at the calendar that includes a potential benefit in the mood really.

Christopher E. Von Seggern: That unmet medical need is amplified in these patients who have comorbid depression. And when presented with a profile of a Zetsu calendar that includes a potential benefit in the mood-related category, clinicians are just going to express really significant enthusiasm. This sort of moves the thinking from a product like Zympat, which was exceptionally successful in this market, to a product like Lamotrigine, which, from a category standpoint, is the second most used product in our category.

Christopher E. Von Seggern: Category clinicians are just express really significant enthusiasm and when.

Christopher E. Von Seggern: When we think about the market.

Christopher E. Von Seggern: This sort of moves the thinking from a product like <unk>, which was exceptionally successful in this market to a product like lamotrigine, which from a category standpoint is the second most utilized product in our category and clinicians often point to limit what your genes beyond seizure benefit derived from our perception.

Christopher E. Von Seggern: And clinicians often point to Lamotrigine beyond seizure benefit derived from a perception of mood benefit in the epilepsy population. So from the recent research and our continued evolution of thinking here, the data emerging from Ex Novo really do change the nature of the opportunity for Zetucalendar in the focal onset market.

Christopher E. Von Seggern: Of mood.

Christopher E. Von Seggern: The benefit in the epilepsy population.

Christopher E. Von Seggern: So from the.

Christopher E. Von Seggern: Research and our continued evolution of thinking here that the data emerging from X number really do change the nature of the opportunity for us actually calendar in the Oklahoma market.

Speaker Change: Thank you.

Sherry Aulin: Thank you. That concludes our question and answer session. I will now turn the call back over to Sherry Aulin for closing remarks.

Christopher E. Von Seggern: And that completes our question and answer session I will now turn the call back over to Ali for closing remarks.

Sherry Aulin: Thank you all very much for joining us on our Q1 2024 call today. Operator, you may now end the call.

Sherry Aulin: Thank you all very much for joining us on our Q1 2020 for our call today and operator, you may now on the call.

Speaker Change: Ladies and gentlemen that concludes today's call. Thank you all for joining you may now disconnect.

Operator: Ladies and gentlemen, that concludes today's call. Thank you all for joining us. You may now disconnect.

Operator: [music].

Operator: Okay.

Operator: [music].