Q1 2021 Xenon Pharmaceuticals Inc Earnings Call

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Ladies and gentlemen, thank you for standing by and welcome to the first quarter 2020 one seen him Pharmaceuticals earnings conference call. At this time, all participants are in a listen only mode.

Operator: Thank you for standing by and welcome to the first quarter, 2021, Lina Pharmaceuticals earnings conference call. At this time, OPT disciplines are on a list-only mode.

Operator: After the speaker's presentation, there will be a question and answer session. To ask a question during this session, you will need to press the start and the one key on your touchstone telephone. Please be advised that today's conference is being recorded. If you recall upper assistance, please press star, then zero. I would like to hand the conference over to your speaker host, Jody Rex. Please go ahead.

And after the speaker's presentation, there will be a question and answer session. Just a question. During this session you will need to press the star and under one key on your touched on telephone. Please be advised that today's conference is being recorded.

If he would go on auto and assistance. Please press Star then zero I would now like to hand, the conference I'll, let you speak of House Jodi racks. Please go ahead.

Jody Rex: Thank you. Good afternoon.

Thank you. Good afternoon. Thank you for joining us on our call and webcast to discuss our first quarter 2020, one financial and operating results joining me on today's call our Doctor assigned and Tim Stone seen on as Chief Executive Officer, Ian Mortimer, Xenon, and <unk>, President and Chief Financial Officer, and sharing all and seen on Vice President.

Jody Rex: Thank you for joining us on our call and webcast to discuss our first quarter 2021 financial and operating results. Joining me on today's call are Dr. Simon Pimstone, Xenonon Chief Executive Officer, Ian Mortimer, Zeynon President and Chief Financial Officer, and Sherry Allen, Zan's Vice President of Finance. As a reminder, this coming June, at the time of the company's annual meeting of shareholders, Simon will be transitioning to his new role as Executive Chair of Zon's board. At the same time, Ian will be appointed President and Chief Executive Officer, while Sherry will be appointed Chief Financial Officer.

As a reminder, this coming June at the time and the company's annual meeting of shareholders Simon will be transitioning to his new role as executive chair and seen on for it at the same time and will be appointed President and Chief Executive Officer will share he will be appointed Chief financial Officer.

Jody Rex: Please be advised that during this call, we will make a number of statements that are forward-looking, including statements regarding the anticipated impact and timing of the COVID-19 pandemic on our business, research, and clinical development plans and timelines and results of operations, the timing of and results from clinical trials and pre-clinical development activities of our proprietary and partnered product candidates, the potential efficacy, safety profile, future development plans, addressable market, regulatory success The anticipated timing of IND or I&D equivalent submissions and the initiation of future clinical trials for our proprietary products and those related to other partnered candidates.

Please be advised that during this call we will make a number and statements that are forward looking including statements regarding the anticipated impact and timing of the COVID-19 pandemic on our business research and clinical development plans and timelines and results of operations and the timing of and results from clinical trials and preclinical development activities of our.

Terry and partnered product candidates and the potential efficacy safety profile future development plans addressable market regulatory success and commercial potential and our proprietary and partnered product candidates the anticipated timing of eye and D. R. I N D equivalents submissions and the initiation and future clinical trials for our proprietary.

Dairy products and those related to other partnered candidates the efficacy of our clinical trial designs and our ability to successfully develop our proprietary development programs, the timing and results and our and our collaborators interactions with regulators and the timing and anticipated enrollment and our clinical trials the potential.

Jody Rex: The efficacy of our clinical trial designs, our ability to successfully develop our proprietary development programs, the timing and results of our and our collaborators' interactions with regulators, the timing and anticipated enrollment in our clinical trials, the potential receipt of milestone payments and royalties from our collaborators, our expectation of having sufficient cash to fund operations into 2023, and the timing of potential publication or presentation of future clinical data. Forward-looking statements are subject to numerous risks and uncertainties, many of which are beyond our control, including the risks and uncertainties described from time to time in our SEC filings.

Receipt of milestone payments and royalties from our collaborators our expectation of having sufficient cash to fund operations into 2023, and the timing and potential publication or presentation of future and clinical data.

Forward looking statements are subject to numerous risks and uncertainties many of which are beyond our control, including the risks and uncertainties described from time to time and our SEC filings. Our results may differ materially from those projected on today's call. We undertake no obligation to publicly update any forward looking statements.

Jody Rex: Our results may differ materially from those projected on today's call. We undertake no obligation to publicly update any forward-looking statement. Today's press release, summarizing Xenon's first quarter financial results and the accompanying quarterly report on Form 10Q will be made available under the investor section of our website at www. Zenon-Farma. And I have filed them with the SEC and on CEDAR. Now, I would like to turn the call over to Ian. Thank you.

Today's press release summarizing seen on the first quarter financial results and the accompanying quarterly report on form 10-Q will be made available under the investors section of our website at Www Dot fine on Dash farm on Dot Com and filed with the SEC and on SEDAR now I would like to turn the call over to Ian.

Ian C. Mortimer: Thanks, Jody, and good afternoon. Thanks, everyone, for joining us.

Thanks, Jody and good afternoon, and thanks, everyone for joining us I hope everyone is healthy and while we have made significant progress over this past quarter and I'm excited to provide an update today as we enter a period of important clinical data readouts over the coming quarters on.

Ian C. Mortimer: I hope everyone is healthy and well. We have made significant progress this past quarter, and I'm excited to provide an update today as we enter a period of important clinical data readouts over the coming quarter. I'll focus on our two proprietary KV7 programs, XN11 and XN4901. Later in the call, Simon will update you on our XEN 007 CAE program, as well as partnered programs with academic and industry collaborators, followed by a financial update from Shari. We'll then open the call-up for your question.

I'll focus on our two proprietary kv seven programs actually on 11, and one and actually on for nine and sex later on the call Simon will update you on our <unk> seven and CAE program as well as partnered programs with academic and industry collaborators.

Followed by a financial update from Sherry will then open the call up for your questions. So I'll begin with axiom and 11 O and one which is a novel Nextgen <unk> seven modulator being developed for the treatment of epilepsy and potentially other neurological disorders. We are very encouraged about the compelling product profile that is emerging for actually on 11.

Ian C. Mortimer: So I'll begin with XN1101, which is a novel next-gen KV7 modulator being developed for the treatment of epilepsy and potentially other neurological disorders. We are very encouraged about the compelling product profile that is emerging for XN11. In addition to my comments on XN1101, Simon will provide some commentary on our work examining XN1101 in indications outside of epilepsy. In the near term, our focus is on the upcoming data readout from our Phase 2B XPulse study. As a reminder, XTol is designed as a Phase 2B, randomized, double-blind, placebo-controlled, multi-center clinical trial to evaluate the efficacy, safety, and tolerability of XN1101, administered as adjunctive treatment in approximately 300 adult patients with focal epilepsy.

And one.

In addition to my comments on X day on 11 O. One Simon will provide some commentary on our work and examining actually on 11 O one and indications outside of epilepsy in.

And the near term our focus is on the upcoming data readout from our phase two B X Tole study.

As a reminder, <unk> is designed as a phase <unk> randomized double blind placebo controlled multicenter clinical trial to evaluate the efficacy safety and Tolerability of <unk> on 11 O. One administered as adjunctive treatment and approximately 300 adult patients with focal epilepsy.

The primary endpoint is the median percent change and monthly focal seizure frequency from baseline compared to the treatment period of active versus placebo.

Ian C. Mortimer: The primary endpoint is the median percent change in monthly focal seizure frequency from baseline compared to the treatment period of active versus placebo. We believe that this is a well-powered and well-run study, which gives us confidence in the integrity of the key efficacy endpoints as captured by E. Diary. I am pleased to report that we have now completed patient screening, with the final patients now in the baseline phase of the study.

We believe that this is a well powered and well run and study, which gives us confidence and the integrity of the key efficacy endpoints as captured by your diary.

I am pleased to report that we have now completed patient screening with the final patients now and the baseline period of the study.

Patient randomization is expected to be complete and June with top line data anticipated by the end of the third quarter of this year.

Ian C. Mortimer: Patient randomization is expected to be complete in June, with top-line data anticipated by the end of the third quarter of this year. Given our current numbers already randomized and those last subjects and baseline, we expect we will randomize more than 300 subjects.

Given our current numbers already randomized and those last subjects and baseline we expect we will randomized more than 300 subjects.

This upcoming data readout represents a notable inflection point for xenon and and opportunity to drive <unk> and 11 in one and forward into a late stage pivotal program.

Given this important and I'd like to expand upon the unique properties and potential advantages associated with axiom and 11 on one.

Ian C. Mortimer: This upcoming data readout represents a notable inflection point for Xenon and an opportunity to drive XN1101 forward into a late stage pivotal program. Given this importance, I'd like to expand upon the unique properties and potential advantages associated with XN111. First, some comments on the potential efficacy of XAN11. X101 is based on a previously proven KV mechanism of action with broad anti-seizure activity. We reported strong target engagement in our Phase 1B Transcranial Magnetic Stimulation, Interestingly, from our interviews and research with KOLs and community health care providers, we understand that the efficacy of many anti-seizure medications is perceived to be roughly equivalent, and that the other ease of use and tolerability attributes are important in prescribing, Therefore, if we obtain efficacy measures that are statistically significant and within the range of other anti-seizure medications, there are a number of other positive attributes of XTN1101 that we believe could further differentiate it within the adult focal epilepsy market.

For some comments on the potential efficacy of vaccine on 11 on one.

Actually on 11, and one is based on our previously proven kv mechanism of action with broad anti seizure activity, we reported strong target engagement and our phase one b trans can't transcranial magnetic stimulation studying <unk>.

Interestingly from our interviews and research with Kols and community health care providers, we understand that the efficacy of many anti seizure medications is perceived to be roughly equivalent and that the other ease of use and tolerability attributes are important and prescribing decisions and therefore, if we obtain efficacy measure.

<unk> that are statistically significant and within the range of other anti seizure medications. There are a number of other positive attributes of extra and 11 and one that we believe could further differentiated within the adult focal epilepsy market.

We believe that actually on an 11 O. One has the potential to address some key ease of use considerations for physicians and <unk> and 11 O ones kv seven mechanism would represent the only drug and its class available on the market.

From our discussions we believe that this unique mechanism of action and currently apparent low DDI risk, maybe leverage and irrational polypharmacy approach, we believe <unk> and 11 O ones. One pill once daily dosing may be attractive to both physicians and patients with a forgiving PK profile.

Ian C. Mortimer: We believe that XN1101 has the potential to address some key ease of use considerations for physicians, and XN1101's KV7 mechanism would represent the only drug in its class available on the market. From our discussions, we believe that this unique mechanism of action, and currently apparent low DDI risk, may be leveraged in a rational polypharmacy approach. We believe XN1101's one pill, once daily dosing may be attractive to both physicians and patients with a forgiving PK profile that may provide coverage for missed doses. Additionally, no drug dose titration is envisaged, which compares favorably to the majority of other therapies used to treat adult focal seizures.

That may provide coverage for Miss doses. Additionally, no drug dose titration is envisaged which compares favorably to the majority of other therapies used to treat adult focal seizures.

Further given that <unk> are generally perceived as having non and differential efficacy safety and Tolerability profile is another key treatment driver and.

And 11 O one was reported as safe and well tolerated and a phase one clinical trial.

When taken as an evening dose the drug female taxes reached during sleeping hours and Thats patients may avoid some C. Max related CNS aes. Additionally.

Additionally, based on the lower than modeled dropout rates and high conversion to open label extension and external we have further reasons to believe that axiom on 11 O. One could have competitive safety tolerability and properties.

Ian C. Mortimer: Further, given that ASMs are generally perceived as having non-differential efficacy, the safety and tolerability profile is another key treatment driver. XN1101 was reported as safe and well tolerated in a phase one clinical process. When taken as an evening dose, the drug CMAX is reached during sleeping hours, and thus patients may avoid some CMAX related CNS-AE.

Digging in a little deeper into the potential move benefits of vaccine and 11 O. One.

We have strong scientific rationale to further explore and major depressive disorder or M. D. D based on preclinical data and clinical work to date that supports the use of <unk> seven modulators for the treatment of depression, and and Antonio <unk>.

Ian C. Mortimer: Additionally, based on the lower-than-model dropout rates and high conversion to open label extension and extol, we have further reasons to believe that XN1101 could have competitive safety tolerability. Digging a little deeper into the potential mood benefits of XN111, we have strong scientific rationale to further explore major depressive disorder or MDD based on preclinical data and clinical work to date that support the use of KV7 modulators for the treatment of depression and anadonia.

And if axion 11, and one could present, a mood benefits beyond its impact on seizures. This added positive effect would also be a key differentiator and.

And if actually on 11 O. One has a good safety and tolerability profile without psychiatric Aes this too could potentially encourage and views on the whole taking two on accounts our conclusions from preclinical studies and clinical results to date, along with the market research exploring the current gaps and the outflows on.

Blotchy space, We believe X gene and 11 O. One has a product profile that could be meaningfully differentiated from other anti seizure medications.

Ian C. Mortimer: If XN111 could present a mood benefit beyond its impact on seizures, this added positive effect would also be a key differentiating feature. And if XN1101 has a good safety and tolerability profile without psychiatric AEs, this too could potentially encourage it.

Turning now to <unk> for nine six which is a proprietary pediatric formulation of the active ingredient and saga being that we're developing for the treatment of Casey on Q2, developmental and epileptic encephalopathy, or Casey and Q2 D E. A rare severe pediatric neuro developmental disorder.

Ian C. Mortimer: On the whole, taking into account our conclusions from preclinical studies and clinical results to date, along with market research exploring the current gaps in the adult focal epilepsy space, we believe XN1101 has a product profile that could be meaningfully differentiated from other anti-seizure medications. Turning now to XEN 496, which is a proprietary pediatric formulation of the active ingredient isogabine that we're developing for the treatment of KCNQ2 developmental and epileptic encephalopathy or KCNQ2 DE, a rare severe pediatric neurodevelopmental disorder.

Under <unk>.

Now in Phase III development actually on for 96 represents our most advanced program and the clinic and we have received fast track fast track designation and orphan drug designation and the U S as well as orphan medicinal product designation from the European Commission.

Our phase III epic clinical trial is evaluating the efficacy safety and Tolerability of <unk> on for nine six administered as adjunctive treatment and approximately 40 pediatric patients aged one months to less than six years with Casey on Q2 D. He.

Designed as a randomized double blind placebo controlled parallel group multicenter clinical trial enrollment is underway. Our team continues to collaborate with kols and physicians and patient advocacy groups to identify potential patients. We recently hosted a webinar and partnership with the KC and Q2 share Alliance for.

Ian C. Mortimer: Now in phase three development, XN 496 represents our most advanced program, and we have received fast track designation and orphan drug designation in the U.S., as well as orphan medicinal product designation from the European Commission. Our Phase 3 epic clinical trial is evaluating the efficacy, safety, and tolerability of XN 496 administered as adjunctive treatment in approximately 40 pediatric patients aged one month to less than six years with KCNQ2 DE. Designed as a randomized, double-blind, placebo-controlled parallel group, multi-center clinical trial enrollment is underway. Our team continues to collaborate with key opinion leaders, physicians, and patient advocacy groups to identify potential patients.

Asia, which featured Dr. John Millichap, our principal investigator and the Epic study, who outlined study details and answer questions about the clinical trial from the families of the KC on Q2 day patient.

Based on its kv seven mechanism of action as well as published physician and case studies, we believe that axiom for nine six has the potential to address an important unmet medical need for these young patients and we look forward to keeping you updated on the progress of the epic study at this point on assignment to provide and update on our <unk>.

And with academic collaborators and industry partners, including the investigator led studies with both <unk> seven and <unk> 11 on one channel.

Thank you Yan.

Simon N. Pimstone: We recently hosted a webinar in partnership with the KCNQ2 Cure Alliance Foundation, which featured Dr. John Milichap, our principal investigator of the Epic Study, who outlined study details and answered questions about the clinical trial from the families of the KCNQ2 DEA patients. Based on its KV7 mechanism of action, as well as published physician case studies, we believe that XEN 496 has the potential to address an important unmet medical need for these young patients.

This is an exciting time for xenon and as our partnered and proprietary programs continue to make great progress and.

You had mentioned we're exploring other neurological indications for <unk> and 11 and one outside of adult focal epilepsy and wanted to highlight for you today. The recent cost for you at all article published and the American General of Psychiatry examining the use of its all going to being on the reward circuit activity and clinical symptoms of depression, and a randomized clinical trial is all good.

Been compared with placebo was associated with a significant improvement and depression as measured by the Montgomery aspect depression rating scale and associated with a significant improvement and hedonic capacity as measured by the snake Hamilton pleasure of chaps scale.

We believe these new data provide further validation of the great potential of the cave seven mechanism to differentiate from other anti seizure medicines and patients with epilepsy, and the comorbidity of depression or a standalone to treat M. D D.

Simon N. Pimstone: And we look forward to keeping you updated on the progress of the epic. At this point, I'll ask Simon to provide an update on our work with academic collaborators and industry partners, including the investigator-led studies with both XN 007 and XN 1101. Simon.

And we recently announced a collaboration with the Icahn School of Medicine at Mount Sinai, and New York, and we expect that and investigator sponsored phase II proof of concept randomized parallel arm placebo controlled clinical trial examining <unk> and 11 O one and as a treatment for M. D D and N idonia as measured by specific functional and <unk>.

Simon N. Pimstone: Thank you, Ian. This is an exciting time for Xenon, as our partnered and proprietary programs continue to make great progress. As Ian mentioned, we're exploring other neurological indications for XN111 outside of adult focal epilepsy. I wanted to highlight for you today the recent Kosti Adol article published in the American Journal of Psychiatry, examining the use of isogabine on the reward circuit activity and clinical symptoms of depression in a randomized clinical trial.

On nickel endpoints will be initiated in the coming months.

In parallel we're planning a company sponsored study and M. D D focusing on clinical endpoints. Most of these planned M. D day studies are supported by promising preclinical data with <unk> and 11 O one as well as clinical data generated from open label and randomized placebo controlled studies that explodes targeting the cave.

They have and mechanism using <unk> as a potential treatment for M. D. D. We're excited about this focus on the potential of the cave seven mechanism and the related promise for HCA and 11 and want to be the only and class drug and adult focal epilepsy with the potential for broader opportunities and other neurological disorders, given extra and 11 O ones.

Simon N. Pimstone: Izogabine, compared with placebo, was associated with a significant improvement in depression as measured by the Montgomery Asperg Depression Rating or Madras scale and associated with a significant improvement in hedonic capacity as measured by the Snaith Hamilton Pleasure or Schap scale.

Unique pharmaceutics attributes.

Turning now to <unk> 007, which is a CNS acting caf II and one and T type calcium channel modulator being studied and treatment resistant childhood absence, epilepsy, or CAE and a physician led phase II proof of concept study.

Simon N. Pimstone: We believe these new data provide further validation of the great potential of the KV7 mechanism to differentiate from other anti-seizure medicines in patients with epilepsy and the comorbidity of depression or as a standalone treatment for MDD. We recently announced a collaboration with the ICAN School of Medicine at Mount Sinai in New York, and we expect that an investigator-sponsored Phase 2 proof of concept randomized parallel-armed placebo-controlled clinical trial, examining XE and 1101 as a treatment for MDD and an adonia, as measured by specific functional and clinical endpoints, will be initiated in the coming months.

At the virtual E. F 2020 meeting, we presented promising interim data from a small number of patients that showed three CAE subjects exhibiting a significant reduction in seizures as measured by seizure diary and confirmed by E. G.

And while this is a small dataset. We believe we are seeing drug activity and seizure reduction that is supportive of a broader development plan for <unk> 007.

And as we've stated previously the COVID-19 pandemic has impacted recruitment in this investigator led study. However, we are adding other sites and we expect to be able to provide results from a larger data set and the second half of 2020 one.

I'm pleased that our industry partnered programs also continue to advance and progress our collaborator Neurocrine Biosciences continues to guide the initiation of two phase III clinical trials. This year to evaluate the use of N. B, I 921352, which used to be called <unk> and 901 and both PD.

Simon N. Pimstone: In parallel, we're planning a company-sponsored study in MDD, focusing on clinical endpoints. Both of these planned MDD studies are supported by promising pre-clinical data with XN111, as well as clinical data generated from open-label and randomized placebo-controlled studies that explored targeting the KV7 mechanism using Izogabine as a potential treatment for MDD. We're excited about this focus on the potential of the KV7 mechanism and the related promise for XN1101 to be the only in-class drug in adult focal epilepsy with the potential for broader opportunities in other neurological disorders given XN1101's unique pharmaceutical attributes.

Accurate and adult indications with planned studies and patients with SPN eight day, developmental and epileptic encephalopathy, or a C and H D E and and focal epilepsy, respectively.

In addition, we continue to make good progress on the advancement of earlier stage molecules and within our ongoing discovery based collaboration with Neurocrine.

We're also excited to report that our partner flexion Therapeutics recently announced treatment of the first patient and a phase <unk> proof of concept trial evaluating the safety and Tolerability of FX 301 administered as a single dose popliteal fossil block and patients undergoing bunionectomy and <unk>.

<unk> 301 consists of athene undeveloped molecule previously known as <unk> for O two which has been formulated for extended release from a semi sensitive hydrogel.

Simon N. Pimstone: Turning now to XEN 007, which is a CNS acting CAV 2.1 and T-type calcium channel modulator being studied in treatment-resistant childhood absence epilepsy or CAE in a physician-led phase 2 proof of concept study. At the virtual AES 2020 meeting, we presented promising interim data from a small number of patients that showed three CAE subjects exhibiting a significant reduction in seizures as measured by seizure diary and confirmed And while this is a small data set, we believe we are seeing drug activity and seizure reduction that is supportive of a broader development plan for XEN 007. As we have stated previously, the COVID-19 pandemic has impacted recruitment to this investigator-led study.

And as guided that it anticipates data from the phase one b trial of <unk> 301 in late 2021.

I'll now ask Sherry to recap our financial position Sherri.

Thanks, Simon we are and a solid financial position today and I believe we are well situated to support xenon and business objectives and the advancement of our clinical development program today I will focus on some highlights from this quarters financial statements and would prefer you to our news release and 10-Q report for further details following up on Simons com.

On the progress made by our partner selection this quarter, we recognized $3 million and milestone revenue and we are eligible to receive additional milestones and royalties and the future.

Past quarter, we also closed and oversubscribed 115 $15 million public offering with strong support from both existing and new high quality institutional investors.

Cash and cash equivalents in marketable securities as of March 31, 2021 were $274 7 million compared to 177 million as of December 31, 2020.

Simon N. Pimstone: However, we are adding other sites, and we expect to be able to provide results from a larger data set in the second half of 2021. I'm pleased that our industry-partnered programs also continue to advance and progress. Our collaborator Neurocron Biosciences continues to guide the initiation of two phase two clinical trials this year to evaluate the use of NBI 921352, which used to be called XEN 901, in both pediatric and adult indications, with planned studies in patients with SCN-8A, developmental and epileptic encephalopathy, or SCN-8-D-E, and focal epilepsy, respectively.

Based on current assumptions, which include fully supporting the planned clinical development of the <unk> and <unk>.

And no one X tole trial and M. D. D proof of concept study the <unk> on for 96 Epic study.

And here's your seven physician led proof of concept study as well as funding our preclinical and discovery activities, we anticipate having sufficient cash to fund operations into 2023, excluding any revenue generated from existing partnerships or potential new partnering arrangements.

We plan to revisit our cash runway guidance post X all day with increased visibility on our spend in 2022 and beyond with our strongest balance sheet to date, we continue to have a lot of flexibility as we manage our business and continue to advance our product candidates.

Simon N. Pimstone: In addition, we continue to make good progress on the advancement of earlier stage molecules within our ongoing discovery-based collaboration with neurocrimm. We're also excited to report that our partner Flection Therapeutics recently announced treatment of the first patient in a phase 1B proof of concept trial, evaluating the safety and tolerability of FX301, administered as a single-dose popliteal fossil block in patients undergoing bunionectomy. Flexions FX301 consists of a xenon-derived molecule, previously known as XEN 4202, which has been formulated for extended release from a thermosensitive hydrojole. Flection is guiding that it anticipates data from the phase 1B trial of FX301 in late 2021. I'll now ask Sherry to recap our financial position. Sherry?

As of March 31, and 2021.

And there were approximately 41 million common shares outstanding $1 1 million pre funded warrants and 1 million series, one preferred shares outstanding and we.

I'd refer you to today's press release, and our 10-Q filing for other specific details from this quarter's financial statements at this point I will turn the call back to Ian.

Summarized the key milestone events, we are anticipating for the remainder of this year.

Thanks Shari looking ahead, our key corporate objectives include the continued advancement of our epic phase III clinical trial and patients with Casey on Q2 D E.

And development decision and results from a larger dataset and the second half of the year from the physician led <unk> 007, and proof of concept study and CAE.

Support for our partner program with Neurocrine biosciences, including the anticipated initiation of two phase II clinical trials with MDI 90, 21352 and 2021.

Sherry Aulin: Thanks, Simon. We are in a solid financial position today, and I believe we are well situated to support Zinon's business objectives and the advancement of our clinical development programs. Today, I will focus on some highlights from this quarter's financial statements and would refer you to our news release and 10-Q report for further details. Following up on Simon's comments on the progress made by our partner reflection, this quarter we recognized $3 million in milestone revenue, and we are eligible to receive additional milestones. and royalties in the future.

Results from flexion FX 301 phase one b trial anticipated in late 2021.

Anticipated initiation of an investigator led phase II proof of concept study as well as the ongoing planning for a company sponsored clinical trial examining <unk> 11 on one and M. D D and importantly, within our <unk> 11, and one phase two B X tole clinical trial, we expect patient randomization to be complete and June.

And with top line data anticipated by the end of the third quarter this year.

In summary, we are incredibly proud of the breadth and depth of our neurology pipeline.

Sherry Aulin: This past quarter, we also closed an oversubscribed $150 million public offering with strong support from both existing and new high-quality institutional investors. Cash and cash equivalents, and marketable securities as of March 31, 2021 were $247 million compared to 177 million as of December 31, 2020. Based on current assumptions, which include fully supporting the planned clinical development of the XCN-1101 Exalt trial and MDD proof-of-concept study, the XN 496 EPIC study, the XN-007 physician-led proof-of-concept study, and the XN-007 physician-led proof-of-concept study.

There is an immense amount of momentum and both our proprietary and partner programs for the first time and xenon and history, we could have up to eight clinical trials underway with five different molecules led by us our corporate partners and academic collaborators in 2020 one.

Before we open the call up for your questions. Simon has a couple of concluding remarks and thank.

Thank you Ian.

So this is my last quarterly call and xenon and C E O S.

As you know I'm handing the baton over to Ian who has worked alongside me for the past seven years.

I'll leave this role with great anticipation and optimism.

In part driven by the strength of our current pipeline and part driven by the exciting data Readouts ahead of us and in part driven by the strong leadership and xenon and will continue to work tirelessly for you our shareholders as well as the patient communities we serve.

It's been a privilege to serve such a talented executive team and to work alongside such wonderful colleagues. This has been an incredible on AR and emission for me and Jenny I'll always treasure.

Sherry Aulin: As well as funding our pre-clinical and discovery activities, we anticipate having sufficient cash to fund operations into 2023, excluding any revenue generated from existing partnerships or potential new partner arrangements. We plan to revisit our cash runway guidance post-extual data, with increased visibility on our spend in 2022 and beyond. With our strongest balance sheet to date, we continue to have a lot of flexibility as we manage our business and continue to advance our product candidates.

As you know I'll be working and a different capacity as executive Board chair and.

And in that capacity and I look forward to continuing to support xenon and to interacting with all of you I wanted to thank you all for the faith that you have shown in me and the safety of Shine and xenon and I firmly believe that our best is yet to come and I'll now ask the operator to open the line for any questions.

Operator, thank you.

Ladies and gentlemen to ask a question you will need to press the start and the one key on your Touchtone telephone to withdraw your question press the pound key.

Fairness to all participants please limit yourself to one question and one follow up.

Now first question coming from the line of Paul My Taste with Stifel. Your line is now open.

Sherry Aulin: As of March 31, 2021, there were approximately 41 million common shares outstanding, 1.1 million pre-funded warrants, and 1 million Series 1 preferred shares outstanding. I would refer you to today's press release and our 10Q filing for other specific details from this quarter's financial statements. At this point, I will turn the call back to Ian, who will summarize the key milestone events we are anticipating for the remainder of this year. Thanks, Sherry.

Paul can you hear us.

Operator, perhaps we go to the next question just while Paul.

Tries to solve the technical issue.

Sure.

Operator.

And our next question coming from the line of.

Laura Chico with Wedbush Securities. Your line is open.

Yeah.

And our best wishes.

Graduations for Ian and share again.

I guess I have one question on 11 O one and so obviously exciting to hear that the X tole readout is coming up and the third quarter beyond the primary endpoint I'm wondering if you could talk about your communication strategy.

Ian C. Mortimer: Thanks, Sherry. Looking ahead, our key corporate objectives include: The continued advancement of our epic phase three clinical trial in patients with KCNQ2, DEE, and a development decision and results from a larger data set in the second half of the year from the physician-led XEM-007 proof of concept study in CAE. Continued support for our partner program with Neurferrand Biosil, including the anticipated initiation of two phase two clinical trials with MBI 921 352 in 2021.

Around some of the non seizure related stuff and its quality of life measures and then I just have one follow up for you.

Yeah.

Thanks, Yeah, Thanks, Laura maybe I'll I'll answer that by providing a little bit of background and color. So as we mentioned and we'll have topline data by the end of Q3 on.

That'll be by way of a press release.

We'll have key end points, we haven't mapped out everything that will be on that first press release.

It will come and go after we unblinded data just how much of the data analysis, we can do balancing and getting out that topline data.

And as quick and manner as we can key efficacy endpoints primary and secondary for sure as you know the primary we talked about on today's call key secondary endpoints focused on a lot of the responder analyses and we'll have some data on those will definitely comment on safety and Tolerability and and.

Ian C. Mortimer: Results from Flections, FX301, a Phase 1B trial, anticipated in late 2020, the anticipated initiation of an investigator-led phase two proof of concept study, as well as the ongoing planning for a company-sponsored clinical trial examining XN1101 in MDD. And importantly, within our XNN1101 phase 2B X stole clinical trial, we expect patient randomization to be complete in June with top line data anticipated by the end In summary, we are incredibly proud of the breadth and depth of our neurology. There is an immense amount of momentum in both our proprietary and partner programs.

Some other metrics within the study.

And as you mentioned, we do have some additional endpoints around quality of life, how much of that full data analysis will be completed and.

And ready for the topline data and we don't know right today.

So we will be ready to talk about that at the next quarter and advance of data and then.

The standard will have more detailed analyses upcoming at scientific meetings, we may be able to get just under the wire for a late breaker at Aes This year, which would be excellent and then obviously we have a on next spring our conferences that we're looking forward to presenting additional analysis.

That's great you and thank you and then maybe one follow up on the commercial market and the focal epilepsy setting it's been about a year or so.

Poultry has been on the market.

And obviously there'll be some additional studies to conduct with 11 and one of successful here, but I'm. Just curious if you could talk about any learnings or takeaways that you can take from current Albert made year on the market. Thanks very much.

Ian C. Mortimer: For the first time in Xenon's history, we could have up to eight clinical trials underway with five different molecules led by us, our corporate partners, and academic collaborators. Before we open the call to your questions, Simon has a couple of concluding remarks.

Yes, Simon and I'll make a comment on and other day in for some additional color. Yeah look I mean, just as conjecture I'm not going to give you a perspective.

From a detailed.

Analytical review, but.

Simon N. Pimstone: Thank you, Ian. So this is my last quarterly caller, Zenon CEO. As you know, I'm handing that baton over to Ian, who has worked alongside me for the past seven years. I leave this role with great anticipation and optimism, in part driven by the strength of our current pipeline, in part driven by the exciting data readouts ahead of us, and in part driven by the strong leadership at Xenon. It will continue to work tirelessly for you, our shareholders, as well as the patient communities we serve.

It looks and overnight Sydney has shown.

And it's and its final dose to have a good effect size.

And a proportion of patients with this condition. It is a significant titration required to get there three to four months of dose titration and.

And so I think what needs to still play out in terms of the real world usage of the drug is really how well that can be integrated into our refractory.

Focal epilepsy patient population. These are patients that are having regular seizures.

Simon N. Pimstone: It's been a privilege to serve such a talented executive team and to work alongside such wonderful colleagues. This has been an incredible honor and a mission for me, a journey I'll always treasure. As you know, I'll be working in a different capacity as Executive Board Chair, and in that capacity, I look forward to continuing to support Zinon and to interacting with all of you. I wanted to thank you all for the faith that you have shown in me and the faith you have shown in Zinon.

And having to wait this amount of time to get drug to <unk>.

And the concentration required for maximal effect I think we will have some limitations and it's one of the key differentiators, where they live and O. One we don't need to titrate, the drug and we appear to reach a maximal.

Steady state exposure and around plus or minus two to three weeks with no long term accumulation and so I think that's a really significant differentiation of course.

Simon N. Pimstone: I firmly believe that our best is yet to come. I'll now ask the operator to open the line for any questions. Operator? Thank you. Ladies and gentlemen, to ask a question, you will need to press the start button.

We've not seen any of the hyper eosinophilic syndrome that was observed and studies with higher dose.

Ex Capri.

And in all studies to date and we don't have any reason to believe we will but of course the dose titration differential I think he is going to be very very important Ian referred to the the the ease of use and once a day.

Operator: Operator? Thank you. Ladies and gentlemen, to ask a question, you will need to press the start and the one key on your touch phone telephone. To withdraw your question, press the pound key. In fairness to all participants, please limit yourself to one question and one follow-up. Now, the first question coming from the line of Paul Matisse with Steve Fulianna is open.

I think both of those are going to be very very important differentiator and concepts and I think you can look to a drug like Vimpat <unk>.

Which is far less effective in terms of median seizure frequency reduction 35 to two high 30% and median seizure versus plus or minus 50 with X Capri, yet is selling about one and a half to $2 billion a year largely because of its ease of use and.

Operator: Operator, perhaps we should go to the next question just while Paul tries to solve the technical issue.

Operator: And our next question comes from the line of Laura Shika with Wedbush Securities. Your line is open.

Ian C. Mortimer: Best wishes, Simon, and congratulations to Ian and Sherry again. I guess I have one question on 1101, so obviously exciting to hear that the X-Pull readout is coming up in the third quarter. Beyond the primary endpoint, I'm wondering if you could talk about the communication strategy around some of the perhaps non-st seizure-related assessments, quality of life measures, and then I just have one follow-up for you.

This indication so I think that's some of my own personal color in and.

Maybe just a couple of comments.

So we don't have perfect information on your specific question on how the launch has gone for for Capri, but our understanding and it's gone reasonably well and obviously this is.

A large market opportunity was still significant unmet need where.

And there's absolutely room for a number of branded drugs to do well.

Ian C. Mortimer: Yeah, thanks Laura. Maybe I'll answer that by providing a little bit of background in color. So, as we mentioned, we'll have top-line data by the end of Q3. That'll be by way of a press release. We'll have key endpoints. But we haven't mapped out everything that'll be in that first press release. It will come, you know, after we unblind the data, just how much of the data analysis we can do, balancing, getting out that top line data in as quick a manner as, you know, as we can.

I think Simon walked through a lot of the differentiating points. The other thing that I would mention that we didn't cover on this call, but we have presented recently is that we've generated some really nice preclinical data of 11 and one in combination with Sanofi I mean, obviously different mechanisms of action and.

And when you dose these drugs together, you can get quite significant efficacy and.

And the in vivo models that we've run so.

Ian C. Mortimer: Key efficacy endpoints, primary and secondary, for sure, as you know, the primary we talked about on today's call. Key secondary endpoints focus on a lot of the responder analyses, and we'll have some data on those. We'll definitely comment on safety and tolerability and some other metrics within the study. And, as you mentioned, we do have some additional endpoints around quality of life. How much of that full data analysis will be completed? and ready for the top line data? We don't know right now.

We look forward to having 11 on one.

As another drug available for for physicians and their patients.

Thanks, very much guys.

And our next question coming from the line of Paul Matteis with Stifel. Your line is open.

Hey, Thank you can you guys hear me, we can yet to be non cat and yet.

Yeah.

Alright awesome. Thank you sorry about that well first off congrats Simon and congrats again on your knee growth.

Always appreciate the dialogue we've had.

I wanted to ask a question on the M. D. D plans and then also on the <unk> plans on on NPD, What's your current thinking on when you're going to engage the FDA. What the next study could look like and.

Ian C. Mortimer: So we will be ready to talk about that at the next quarter in advance of data. And then, as a standard, we'll have more detailed analyses in the coming weeks at scientific meetings. We may be able to get just under the wire for a late breaker at AES this year, which would be excellent. And then, obviously, we have AAN next spring, our conferences that we're looking forward to presenting additional analysis.

How are you thinking about dosing and MTV is the same as epilepsy or might you try to go a little bit a little bit lower due to Tolerability dynamics and then for O. Seven I guess similar question just plans to engage the FDA would you do that after this initial investigator data or would you start before and how do you think about next steps. Thank you.

Sure.

I'll start and Paul and then Simon can add.

So on the <unk> side.

We don't believe we need any upfront engagement with the agency to move ahead with a company sponsored mdt's or we're not looking for any specific feedback obviously, we'd need to follow a protocol and get up and running but there's not specific feedback that we're looking for.

Simon N. Pimstone: That's right, Ian, thank you. And then maybe one follow-up on the commercial market in the focal epilepsy setting. It's been about a year since Copry has been on the market.

I think with the Zagha B and experience from Dr. Moreau and his group at Sinai.

Simon N. Pimstone: You know, obviously, there will be some additional studies to conduct with 11-1 if successful here, but I'm just curious if you could talk about any learnings or takeaways that you could take from Sonobamate's year on the market. Thanks very much. Yeah, Simon, I'll make a comment. I turn over to Ian for some additional color.

And and and other trials that are being run and M. D. D. We have a pretty good protocol synopsis already that we're working on.

We are looking to use we haven't finalized the dose, but we'd be looking to use a dose that we're currently using and the epilepsy study, where we just have a lot of experience that.

That said from just an order of events perspective before we start the M D day study and.

And the finite study will start before.

The final study will start and then we'll have the X tole data. So we will have some information on and unblinded and.

Simon N. Pimstone: Yeah, Simon, I'll make a comment. I'll hand over to the end for some additional color.

Total data of 11 O. One before we initiate the company sponsored <unk> study. So that is another data point that we can take into consideration as we refine our thinking.

Simon N. Pimstone: Yeah, look, I mean, just as conjecture, I'm not going to give you a perspective from a detailed analytical review. But, you know, look, Synobamed certainly has shown at its final dose to have a good effect size in a proportion of patients with this condition. It is a significant titration required to get there, three to four months of dose titration. And so, you know, I think what needs to still play out in terms of the real world usage of the drug is really how well that can be integrated into a refractory focal epilepsy patient population. These are patients that are having regular seizures and having to wait, you know, this amount of time to get the drug to a final concentration required for maximal effect. I think we'll have some limitations.

007, our plans are really in parallel. So this year is both to expand the dataset from for.

From those few number of patients where we saw some intriguing data at Aes last year. So that's the goal for the second half of the year and then in parallel we do expect to have some regulatory interaction to talk about next steps and the development.

And obviously our planning if if the if the data continues to support it.

And CAE is to run company sponsored development exactly what that looks like is really what we're doing in terms of our development planning right now and then we expect to have that regulatory interaction later this year.

Paul let Simon and the only thing I'd add is you know just going back to the M. D D.

Simon N. Pimstone: And that's one of the key differentiators with 1101. We don't need to titrate the drug, and we appear to reach a maximal steady state exposure at around plus or minus two to three weeks with no long-term accumulation. So I think that's a really significant differentiation. Of course, we haven't seen any of the hyperhearsinophilics.

Key distinctions I guess from the Zagha Bean study and also from the current study Dr. Melrose, We're on with 11 and one is.

And in those studies functional MRI was the primary endpoint with clinical secondaries.

More interested in and out sponsored study is a clinical primaries.

Simon N. Pimstone: That was observed in studies with higher dose excopri in our studies to date, and we don't have any reason to believe it will. But of course, the dose titration differential is going to be very, very important. Ian referred to the ease of use and once a day. I think both of those are going to be very, very important differentiating concepts. And I think you can look to a drug like Vimpat or Lachosamide, which is far less effective in terms of median seizure frequency reduction, 35 to high 30% in median seizure versus plus or minus 50 with ex-copry, yet is selling about one and a half to two So I think that's some of my own personal color, Ian. Yeah, maybe just a couple of comments.

The other unknown at this point, which will define still is going to be the.

And the interplay with anhedonia and now <unk>.

Sponsored study so as you know the saga being study was done and M. D D and <unk> patients and will similarly be tested with Dr. Tomorrow's 11 on one trial.

And we're currently sort of looking through that to decide whether we will have a purion M. D. D patient population meeting thresholds of severity in terms of inclusion I think that's the on the additional comment I'd make.

Great. Thank you Simon I appreciate it okay.

Okay.

Operator next question.

Our next question in queue coming from the line of.

Marc Goodman with SBB Leerink your line is open.

Yes, Hi, Simon and the past you kind of hinted at.

Work, that's going on behind the scenes you're talking about disclosing some of that work soon and I was just wondering are we getting closer and what's going on behind the scenes, maybe you could just give us a little hint.

Ian C. Mortimer: So we don't have perfect information on your specific question on how the launch has gone for ex-copry, but our understanding is that it's gone reasonably well. And obviously, this is a large market opportunity with still significant unmet needs where there's absolutely room for a number of branded drugs to do well. I think Simon walked through a lot of the differentiating points.

I mean, you're probably referring to what's out on non clinical programs Mark.

Yeah look we have some very exciting work underway some of which we've.

We've talked about in the past we do have.

Right.

<unk> seven program that obviously is looking at next generation molecules, which has made outstanding progress.

Ian C. Mortimer: The other thing that I would mention that we didn't cover on this call but that we have presented recently is that we've generated some really nice pre-clinical data for 1101 in combination with Sonobamate. Obviously, different mechanisms of action, and when you dose these drugs together, you can get quite significant efficacy in the in vivo models that we've run. So, you know, we look forward to having 1101 as another drug available for physicians and their patients.

We have a and <unk>.

1.1.

Program targeting <unk> and potentially other indications, which has also made some very exciting progress.

And then we have a few other programs in addition, which we aren't yet ready to talk about but Sydney of.

The coming months I expect it will be.

A bit more so you know.

This is this is really just.

A stage of the programs Mark will we will we will make disclosures when we think they really moved to and materials stage and up until then we will keep the keep the programs under wraps and those are just two of the programs we have referenced in the past day on others, but.

Operator: Now, next question coming from the line of Palmetis with Steeful: your line is open.

Operator: Hey, thank you. Can you guys hear me?

Operator: We can, yep. We now can, yeah. All right, awesome. Thank you. Sorry about that.

That's about what we'll cover for now.

And then just one quick follow up from a previous question or two about double of seven win.

Operator: Well, first off, congratulations Simon and congratulations Ian on your new roles. I always appreciate the dialogue we've had. I wanted to ask a question about the MDD plans and then also about the O7 plans. For MDD, what's your current thinking on when you're going to engage the FDA, what the next study could look like, and how are you thinking about dosing in MDD? Is it the same as epilepsy, or might you try to go a little bit lower due to just tolerability? dynamics.

I guess, how many patients do we have right now that's already been.

And then rolled and.

Comedy is the goal for this year.

Our markets and so we haven't just like any other clinical trial that we run we don't give update on kind of quarter to quarter on where we are and enrollment only when we had kind of key inflection points.

Our goal as we've always said debt.

The first three patients the data looked really intriguing and if we could get to you know kind of 10 plus patients and then continue to.

Enrolled patients and study in that population.

Ian C. Mortimer: And then for 07, I guess a similar question, just plans to engage the FDA. Would you do that after this initial investigator data? Would you start before? And how do you think about next steps? Thank you. Sure, I'll start Paul and then Simon can add.

As we get more and more subjects and that study it just gives us more confidence and and and that opportunity and that indication. So the goal was to increase for.

And the handful two into double digits, and then grow from there.

Okay. Thanks.

Our next question coming from the line of Tim Lugo with William Blair. Your line is open.

Ian C. Mortimer: So on the MDD side, we don't believe we need any upfront engagement with the agency to move ahead with a company-sponsored MDD, or we're not looking for any specific feedback. Obviously, we'd need to file a protocol and get up and running, but there's not any specific feedback that we're looking for. You know, I think with the Izogabian experience from Dr. Murrow and his group at Sinai and other trials that have been run in MDD, we have a pretty good protocol synopsis already that we're working on. We are looking to use, we haven't finalized the dose, but we'd be looking to use a dose that we're currently using in the epilepsy study where we just have a lot of experience.

Thanks for taking my question and congratulations to the team as well on their new roles.

For going back to 11 O one and M. D. D. I believe the Mount Sinai study is going to take relatively long to enroll given the NIH is roll on this study as well.

Can you just talk about maybe the company sponsored study and how that might I assume that should be faster to conduct.

Especially if you're using clinical end points versus Europe and Lora.

Yeah, that's right Tim I think the way, we think about it and.

And you're probably referring to the clinical trials dot Gov.

Post steam from Sinai that that study and May take it may take a few years.

I think unknown right now and hopefully as that study gets up and running.

Ian C. Mortimer: That said, from just an order of events perspective, before we start the MDD study, the Sinai study will start first, and then we'll have the XTOL data. So we will have some information on unblinded X-toll data of 1101 before we initiate the company-sponsored MDD study.

And get a little bit more granularity on when we may see top line data, but our expectation is that the Sinai study will start first.

Our study would follow but our study would likely readout first and really for the reasons that you talked about primarily.

Sinai is going to be at two centers, we would go to more than two and.

And with our control of the CRO that we would it would likely enroll more aggressively on the Mount Sinai study.

Ian C. Mortimer: So that is another data point that we can take into consideration as we refine our things. On 007, our plans are really in parallel. So this year, our goal is both to expand the data set from those few number of patients where we saw some intriguing data at AES last year. So that's the goal for the second half of the year.

Okay. Thanks for that and I guess, given the low DDR risks and help the let's see.

Have you explored.

Kind of adequate DDR information for some of the classrooms using M D D as well or was that all worked on.

Simon N. Pimstone: And then, in parallel, we do expect to have some regulatory interaction to talk about next steps in the development. And obviously, our planning, if the... if the data continues to support it in CAE, is to run a company-sponsored development. Exactly what that looks like is really what we're doing in terms of our development planning right now, and then we expect to have that regulatory interaction later. Paulette, Simon, the only thing I'd add is, you know, just going back to the MDD, key distinctions, I guess, from the Zogabine study and also from the current study Dr. Maras will run with 1101 are in those studies.

And of concurrently anti epilepsy DDI information.

So we've done.

Where we are in development for 11 O. One we havent completed all of the DDI work that would be required we've done.

Standard DDI work, regardless of therapeutic indication.

And so a lot of the in vitro work and other profiling that we believe overall, it's going to have.

Low DDI risk.

The Mount Sinai study.

This is dosed as a single agent we haven't made a final decision on our Mds study on whether there'll be con meds or not but.

But overall the profile of 11 O. One we believe it has low <unk>.

Simon N. Pimstone: Functional MRI was the primary endpoint with clinical secondaries. But you know, we're much more interested in our sponsored study as clinical primaries. I think the other unknown at this point, which we'll define still, is going to be the interplay with anhedonia in our sponsored study. So, as you know, the Zogabine study was done in MDD and anadonic patients and will similarly be tested with Dr. Murrow's 1101 trial. We're currently sort of looking through that to decide whether, you know, we'll have a purer MDD patient population meeting thresholds of severity in terms of inclusion.

And I risk, we're also initiating and more detailed peaky PK PD modeling.

With the initial data set being the clinical data that we've generated to date and phase one to start building that model.

And once the once we have all of the phase two <unk> data in hand.

And then our PK PD modeling can become more robust and and we can see if there's any differential.

Exposure from 11 on one or other con meds, depending on as you know all of the patients on <unk>.

Simon N. Pimstone: I think that's the only additional comment I'd make. Great. Thank you, Simon. I appreciate it.

<unk> will be on those background therapies, and so we will be able to have a better understanding of any DDI as we generate more data and do more modeling.

Operator: Operator. Next question. Our next question in Q comes from the lineup: Mark Goodman with SB Beler and Carolina Salpin.

Great. Thank you for the color.

Our next question coming from the line of Andrew Tsai with Jefferies. Your line is open.

Operator: Yes, hi Simon in the past, you gave me kind of a hint.

Operator: You kind of hinted at work that's going on behind the scenes. You're talking about disclosing some of that work soon. I was just wondering if we're getting closer.

Hi, guys. Thanks, and good afternoon day, congrats on the progress and as well for the X Tole study.

Very nice to see that it's wrapping up soon and so can you talk about what you would construe as positive safety data and then presumably all show a easing of topline, but will you for example, a share biomarker data or other measurements like eye exams chromatin area and south for can you just talk a little bit about that.

Simon N. Pimstone: What's going on behind the scenes? Maybe you could just give us a little hint. Thanks.

Simon N. Pimstone: I mean, you're probably referring to our non-clinical programs, Mark. Yeah, look, we have some very exciting work underway, some of which we've talked about in the past. We do have, you know, a KV7 program that is obviously looking at next-generation molecules, which has made outstanding progress. We also have an NAB 1.1 program targeting Drave and potentially other indications, which has also made some very exciting progress. And then we have a few other programs in addition, which we aren't yet ready to talk about, but certainly in the coming months, there will be a bit more.

Yes, because in as Ian said, Andrew we haven't.

And nailed exactly what's going to be disclosed in the top line yet.

So of course sort of high level safety Tolerability will be.

I think we need to think this through carefully we obviously recognize there on CIT.

CIT and safety and Tolerability datasets, which are going to be very very relevant and we understand that.

Some of that I think will.

Simon N. Pimstone: So, you know, this is really just a stage in the programs, Mark. We'll make disclosures when we think they've really moved to a material stage, and up until then, we'll keep the programs under wraps. Those are just two of the programs we have referenced in the past. There are others, but that's about what we'll cover for now. And then just one quick follow-up from a previous question or two, about 007. When... I guess how many patients do we have right now that have already been enrolled and how many is the goal for this year? Mark A.

B, particularly important over time.

And so I'm measurements are being done and obviously year and is being looked at.

Your and re hesitancy and all.

Retention of course is being captured if any as it could and so we will have that data.

I think Ian made the point earlier, which I think is always the the point and topline is balancing the speed to present with debt material information and hand with the amount of data and analysis, one needs to do and so typically we would do at.

Ian C. Mortimer: So we haven't, just like any other clinical trial that we run, we don't give updates kind of quarter to quarter on where we are in enrollment only when we hit kind of key inflection points. You know, our goal is we've always said that, you know, the first three patients, the data looked really intriguing, and if we could get to, you know, kind of 10 plus patients and then continue to enroll patients and study in that population as we get more. and more subjects in that study. It just gives us more confidence in that opportunity and that indication. So the goal was to increase from a handful to double digits and then grow.

These stage releases driven by at least having this topline material data and hand press release that as Ian said with a with a press release and then follow up for the number of what we know are important analytics, which will come between now and then and and.

And and Aes.

As you'll likely time point and so hard to pinpoint exactly at this point, what's going to be and that that first press release, Andrew but we will we will.

Come up with a plan as when Ian said I think before data after the second quarter will probably be and are positioned to upload and.

Operator: Our next question comes from the lineup: Tim Lugo with William Blair. Your line is open.

And trust that you download on what is exactly going to be presented.

Operator: Thanks for taking the question and congratulations to the team as well on their new roles. Going back to 1101 in MDD, I believe the Mount Sinai study is going to take relatively long to enroll, given the NIH's role in the study as well. Can you just talk about maybe the company-sponsored study and how that might, I assume that should be faster to conduct, especially if you're using clinical endpoints versus the FMR?

Sure.

That's very clear and my second question is actually back on offense.

Back at that same conference I believe one of your team members and affirm that.

On a handful of patients had completed the open label phase none of them had seen any safety issues.

That's true.

I'm wondering if there had been more patients have completed the open label phase and the safety profile still looks pretty pristine and asking and you had expected.

Ian C. Mortimer: Yeah, that's right, Tim. I think the way we think about it, and you're probably referring to the Clinical Trials.gov posting from Sinai that that study may take a few years. You know, I think it's unknown right now, and hopefully, as that study gets up and running, we can get a little bit more granular on when we may see top-line data. But our expectation is that the Sinai study will start first. Our study would follow, but our study would likely come out first.

Okay.

Yes.

And I won't make any specific comments on safety.

I will confirm so the way the study on the open label extension and the way. The study was designed initially as we know it's an eight week double blind.

With the opportunity for every subject regardless of dose group and it worked well see boat to go on to open label extension and we've said we've had a very high conversion rate into OLED Hello leaves that a single dose which is 20 milligrams.

And and that OLED was initially designed for 12 months, which is which was quite standard.

Ian C. Mortimer: And really, for the reasons that you talked about, primarily Sinai is going to be at two centers; we would go to more than two, and with our control with a CRO that we would, it would likely enroll more aggressively than the Mount Sinai study.

We had starting at the end of last year and into the early part of this year as patients were rolling off of 12 months, we had questions and <unk>.

<unk> from from physicians and steering Committee members.

Ian C. Mortimer: Okay, thanks for that. And I guess given a low DDI risk in epilepsy, have you explored kind of adequate DDI information for similar classes used in MDD as well, or was that all worked on kind of concurrently with the epilepsy DDI information?

For a continuation of the open label extension and and and.

And we did that and we extend it out to three years and.

And we've gone through a number of key regulatory filings to extend that and I think where that maybe.

Ian C. Mortimer: So we've done, you know, where we are in development for 1101, we haven't completed all of the DDI work that would be required. We've done, you know, standard DDI work regardless of therapeutic indication. So a lot of the in vitro work and other profiling that we believe overall is going to have a low DDI risk. The Mount Sinai study, this is dosed as a single agent. We haven't made a final decision on our MDD study whether there'll be con meds or not.

And to link back to your earlier question I think where some of that long term safety data is going to be important as your question around.

Some of those safety.

Events that showed up with his auger being after cumulative dosing over a longer period of time. So the more data that we can collect for.

For our patients going out with more than a year or multiple years, when we talk about pigmentation risk.

No.

Ian C. Mortimer: But overall, the profile 1101, we believe it has a low DDI risk. We're also initiating more detailed PKPD modeling with the initial data set being the clinical data that we've generated to date in phase one to start building that model. But once we have all of the phase two, XTal data in hand, then our PKPD modeling can become more robust, and we can see if there's any differential exposure from 1101 or other con meds, depending.

To be clear the possession from us at the company as we don't believe 11 on one has any pigmentation risk, but the more data that we can generate and release over time from open label extension is going to be important for.

For a number of our constituents.

Great. Thanks for the color.

And as a reminder, ladies and gentlemen to ask a question. Please press star one and please limit yourself to one question and one follow up.

And our next question coming from the lineup of Christopher <unk> with Needham Your line is open.

Ian C. Mortimer: As you know, all of the patients in extol will be on those background therapies, and so we'll be able to have a better understanding of any DDI as we generate more data and do more modeling. Great, thank you for the caller.

And good afternoon.

Couple of questions for me the first one on.

One one on one.

Operator: Our next question coming from the line of Andrews, I would say, Jeffreis, your line is open.

More specifically the MPT program.

Just wanted to clarify something you plan on initiating the company sponsored study before you get results from the physician.

Operator: Hi guys, thanks, and good afternoon. Big congratulations on the progress as well. For the XTOL study, very nice to see that it's wrapping up soon. So can you talk about what you would construe as positive safety data? I mean, presumably you'll show AEs on the top line, but will you, for example, share biomarker data or other measurements like eye exams, chromatria, and so forth? Can you just talk a little about that?

Study and at this point, maybe I missed this in your prepared comments, but.

This is gonna be open label or placebo controlled and and dose ranging.

And then secondly on the for 96 epic trial.

I think it's too early to give an enrollment update here, but maybe just give us an idea of how many sites are up and running and maybe.

You know with COVID-19 and restrictions.

And a serious impediment to enrollment and should we expect a and.

Simon N. Pimstone: Yeah, look, as Ian said, Andrew, we haven't nailed exactly what's going to be disclosed in the top line yet. So, of course, sort of high-level safety tolerability will be. You know, I think we need to think this through carefully. We obviously recognize there are certain safety tolerability data sets which are going to be very, very relevant. We understand that.

A significant improvement and once the restrictions are lifted.

Yes.

Thanks search and so on the on the <unk> question.

So for them in order of events, Yes, we expect the Sinai study is ready to be up that all of that study I'll start and the near term. So that one is ready to go and then yes. Our current plan is to initiate a company sponsored Mds study.

Simon N. Pimstone: Some of that, I think, will be particularly important. So eye measurements are being done, you know, obviously urine is being looked at, urinary hesitancy and or retention, of course, is being captured if any has occurred. So we will have that data. I think Ian made the point earlier, which I think is always the point in the top line: balancing the speed to present with that material information in hand with the amount of data analysis one needs to do.

In advance of that physician sponsored and Mount Sinai readout.

And and.

And the commentary, we made and Q&A is that our expectation.

Although we can't predict with certainty today, but our expectation is that we'd have a readout of our study likely before the Sinai readout would.

And would be would be the likely order of events.

You also had a question just on that trial design. We're still we have a protocol synopsis for still on the planning stages of that study, but we would expect it to be a randomized study with placebo control.

Simon N. Pimstone: And so, you know, typically, we would do these staged releases driven by at least having this top-line material data in hand, a press release that, as Ian said, with a press release, and then follow up with a number of what we know are important analytics, which will, you know, come between now and AES as your likely time point. So hard to pinpoint exactly at this point. to be in that first press release, Andrew.

And maybe not dose range, finding we wanted to answer a number of questions and the X tole study around around dose dose response minimum effective dose where is likely on a proof of concept study and M. D D.

I would choose a dose and a.

And a placebo controlled study.

Moving to epic.

Simon N. Pimstone: But, you know, we'll come up with a plan. As Ian said, I think before the data, after the second quarter, we'll probably be in a position to upload and, should I say, download on what is exactly going to be presented.

And the study is up and running so this is actually on for 96 for Phase III program and.

We have kind of what we've said in the past and we don't get granular on specific site numbers, but we expected it starting in the U S debt.

Really for the first.

Simon N. Pimstone: That's very clear. And my second question is, actually, back at Ascent, at the Ascent Conference, I believe one of your team members affirmed that a handful of patients had completed the open-label phase. None of them had seen any safety issues. If that's true, I'm wondering if there have been more patients who've completed the open-label phase, and the safety profile still looks pretty pristine, as you had expected. Thanks.

Few quarters of this year is when we were looking to get a number of sites up and running and the U S. And then other jurisdictions outside of the U S would come on line.

As the year progresses, so we're still on track for that.

I would say, there's probably been some COVID-19 impact.

We do hear from sites that some of them have been and that's probably lessening over time.

But they have been focused on either COVID-19 clinical trials or sites that have just been busy day.

Simon N. Pimstone: Yeah, I mean, we, I won't make any specific comments on safety. Okay, I will confirm.

And with the with the pandemic and dealing with COVID-19 patients. So it's likely had some impact its always difficult to know exactly how much but that's some of the feedback we've received.

Simon N. Pimstone: So the way the study on the open label extension, the way the study was designed initially, as we know, it's an eight-week double blind with the opportunity for every subject, regardless of dose group or placebo, to go on to the open label extension, and we've said we've had a very high conversion rate into OLE. OLE is at a single dose, which is 20 milligrams. And that OLE was initially designed to be 12 months, which is quite standard.

And then we've also mentioned as we get a couple of quarters and for enrollment that's when we'll be in a position, where we would feel comfortable trying to give some top line guidance on when we should see data from that study.

And our next question coming from the line of <unk>.

And so now with Guggenheim Your line is open.

Simon N. Pimstone: We had starting at the end of last year and into the early part of this year, as patients were rolling off of 12 months, we had questions and asked from physicians and steering committee members for a continuation of the open label extension. And we did that, and we extended OLE out to three years. And we've gone through a number of key regulatory filings to extend that. And I think where that maybe to link back to your earlier question, I think where some of that long-term safety data is going to be important is your question around some of those safety events that showed up with Zagabine after cumulative dosing over a longer period of time.

Hey, guys. Thanks. This is Eddie on for you out and so just a high level question on 11 to one.

How should we think about the potential efficacy coming next quarter and comparisons to the old is arguably and data do you need to show and enhanced efficacy profile over those those older data or is it really just a story about safety and dosing regimens for those and how should we think about those top on data.

Yeah, So Eddie and that's a good question. It's a question, we often get and.

And we did.

Design, the statistical analysis plan and the powering for the study taking into consideration and the <unk> data, we know as AGA being same mechanism.

The data.

That is all get being generated over a decade ago and adult focal epilepsy was statistically significant and was.

Simon N. Pimstone: So the more data that we can collect for patients going out more than a year or multiple years when we talk about pigmentation risk, you know, to be clear, the position from us at the company is we don't believe 1101 has any pigmentation risk, but the more data that we can generate and release over time from open label extension is going to be important for a number of our constituents. Thanks for the correction.

Was impressive and so that was data that we've looked at and thought about as we've put in on.

Our assumptions into the modeling and the powering calculations, we've taken that into consideration that said.

And as AGA being or <unk> is no longer commercially available it's on on the market this isn't and active comparator.

R and the treatment and the drugs that are available for these patients are different today than when his auger being was trialed and so overall.

Operator: Great, thanks for the caller.

Operator: And as a reminder, ladies and gentlemen, to ask a question, please press Star 1, and please limit yourself to one question and one follow-up. Our next question comes from the line of Trich Palentja with Meetham. Your line is open.

Although I think that that's a backdrop that we think about.

Don't think we need to necessarily compare to the <unk> data, we want to compare to where 11 and one is going to fit currently in the anti seizure market. Both from an efficacy point of view, but importantly, as we've talked about a lot on today's call and we've done a significant amount of market research is on the safety and Tolerability profile.

Operator: Good afternoon. A couple questions for me.

Operator: The first one on the 101, more specifically the MDD program. Just wanted to clarify something. You plan on initiating the company-sponsored study before you get results from the physician study. And at this point, maybe I miss this and your prepared comments, but

And the ease of use attributes.

Got you. Thanks, and then just really quickly on the AE profile and the.

Operator: Is this going to be open-label or placebo-controlled at dose ranging?

Phase one you did show some mild cognitive effects and I'm just wondering if that's something that you think could be exacerbated and a larger study, but we could potentially be concerned about thanks.

Operator: And then secondly, on the 496 epic trial, I think it's too early if you give an enrollment update here, but

I'll take that Simon and Eddie.

Yeah look.

Operator: I think it's too early to give an enrollment update here, but maybe just give us an idea of how many sites are up and running and, maybe..., you know, with COVID restrictions, has that been a serious impediment to enrollment? And should we expect a significant improvement once restrictions are lifted? Thanks, search.

Any phase one study with a CNS acting drug in volunteers.

Is likely to exaggerate the tolerability of the drug when you go to a.

And community base.

<unk> and patients on the outpatient based study.

It is generally very very different these are patients that are used to taking on more used to taking anti seizure meds and remember these individuals and I'll try that.

Ian C. Mortimer: So on the MDD question, so from an order of events, yes, we expect the Sinai study to be ready to go, you know, that study will start in the near term, so that one's ready to go. And then, yes, our current plan is to initiate a company-sponsored MDD study in advance of that physician-sponsored Mount Sinai readout. is that our expectation, although we can't predict with certainty today, but our expectation is that we'd have a readout of our study likely before the Sinai readout would be the likely order of events.

Many but are on 1% to three additional mids at the time of inclusion.

And so they're quite used to the Tolerability and we have also as you probably recall designed the study such that with dosing and the evening, which was different from our phase, one setting, which where the dosing was in the morning, but dosing and the evening and this trial.

Ian mentioned in his notes earlier, we should see C. Max during sleeping hours and that was specifically designed given the PK of the drug to allow for any of the most significant CNS tolerability issues to hopefully be slipped through and so.

Ian C. Mortimer: You also had a question just on that trial design. We're still, we have a protocol synopsis. We're still in the planning stages of that study, but we would expect it to be a randomized study with placebo control, maybe not a dose range finding. You know, we wanted to answer a number of questions in the X-10 study around dose, dose response, and minimum effective dose, whereas, likely, in a proof-of-concept study in MDD, we would choose a dose in a placebo-controlled study. Moving to Epic.

We don't expect the AE.

And all to be the same as phase one and I will just say and reiterate that actually the phase one safety.

It was relative to other drugs actually good and relative to its all going been was excellent I mean, we have on.

Most all were mild and were reversible and clearly a dose dependency with the aggregation of Aes at the 25 make dose.

Ian C. Mortimer: So the study is up and running, so this is XN 496 the Phase 3 program, and we have kind of what we've said in the past, and we don't get kind of granular on specific site numbers, but we expected it to start in the U.S., and really, for the first few quarters of this year, is when we were looking to get a number of sites up and running in the U.S., and You know, I would say there's probably been some COVID impact.

And remember our.

But this study has dosed at night and and in a patient.

And population so ill population is quite distinct and we expect to see.

Much improved Tolerability I think Ian mentioned earlier, the very low dropout rates and the very high conversion to OLED would suggest would suggest that at least the patients.

Tolerating a drug to a degree where they stay in the study and moving to the open label with a and the investigators know they're getting the active drug.

Got you. Thank you and then just one final one is there is there any possibility and at this phase two could be potentially pivotal and that being considered and then if it's successful like do you have a baseline assumption on how many other trials you'd need to get approval.

Ian C. Mortimer: You know, we do hear from sites that some of them have been, and that's probably lessening over time, but they have been focused on either COVID clinical trials or sites that have just been busy dealing with the pandemic and dealing with COVID patients. So it's likely had some impact. It's always difficult to know exactly how much, but that's some of the feedback we've received. And then we've also mentioned, as we get a couple of quarters in enrollment, that's when we'll be in a position. We'll feel comfortable trying to give some top-line guidance on when we are. You should see data from that step.

Yes, it's a good question, we don't know because it's going to require and FDA discussion, but certainly if the study is very.

Significant remember, it's a one sided phase II trials, so we'd have to essentially double the effect size in the terms of the P value.

For this to potentially be deemed significant debt, a two sided which will be a requirement for this to be deemed registration.

Operator: Now, next question coming from the lineup, Yatinseneha with Guggenheim, your line is open.

Assuming we were to see that so in other words, a P less than 0.0 to five.

Operator: Hey guys, thanks, this is Eddie on Friotton. So just a high-level question on 1101. You know, what should we think about the potential efficacy coming next quarter?

Rather than less than zero and zero five we would sit and engage the FDA on that discussion and then of course the obvious discussion is do we just require.

One additional for the U S at least one additional phase III trial for Europe.

Operator: in comparison to the old Azagabine data, do you need to show and

It's almost certain one would require two distinct studies 12 weeks dosing designed as two sided but for the U S.

Operator: deficiency profile over those older data, or is it really just the story about safety and dosing regimens? Or how should we think about those top line data?

It is possible that this could be deemed a registration or should we say one or two registration trials remember, we still have to have a certain number of subjects and a safety database and that number's around 1500, but they don't all have to come from efficacy trials. They can come from Clinton Pharm Studies open label study single.

Ian C. Mortimer: Yeah, so Eddie, it's a good question. It's a question we often get, and we did design the statistical analysis plan and the powering for the study taking into consideration the Azagabine data. We know Azagabine, same mechanism; the data that Azagabine generated over a decade ago in adult focal epilepsy was statistically significant and impressive, and so that was data that we've looked at and thought about, as we've put in our assumptions into the modeling and the powering calculations.

Dose studies et cetera, So we're going through that right now, but our goal would be to engage the FDA on that exact discussion if we see a highly statistically significant effect.

Thank you and congrats on.

Thank you.

Our next question coming from the line of Antonio Bardolino with Bloomberg and your line is open.

Ian C. Mortimer: We've taken that into consideration. That said, you know, Isagabine or Potiga is no longer commercially available. It's not on the market. This isn't an active comparator.

Hi, Thanks for taking that and.

I just have one.

Which was kind of related to a question asked earlier for maybe another way of asking net so I.

And I know that your actual trial.

Ian C. Mortimer: You know, and, you know, the treatment and the drugs that are available for these patients are different today than when Azagabin was trialed. And so overall, you know, although I think that's a drug that is available for these patients today are different than when Azagabin was trialed. that that's a backdrop that we think about. I don't think we necessarily need to compare to the Azogabine data. We want to compare where 1101 is going to fit currently in the anti-seizure market, both from an efficacy point of view, but importantly, as we talked about a lot on today's call, and we've done a significant amount of market research, is on the safety and tolerability profile and the ease of use attributes.

Power to show, a 15% delta between placebo and active so im just wondering if you just to reach cash flow can you believe that this competitive commercially from and advocacy perspective.

And when it goes on and I'll add.

Yeah Yeah.

A difficult question to answer because I think and all of these things any prescribing decision is based on totality right. It's not just based on a single.

Data point and it's interesting when you when you talk to a lot of the community based prescribers and I'm not sure that they can rattle off for clinical trial efficacy data like we can right. So they are really thinking about the experience they've had with a drug how they are individual patients have done on that drug what.

Operator: Gotcha, thanks. And then just really quickly on an AE profile, in phase one, you did show some...

Operator: In phase one, you did show some mild cognitive effects. I'm just wondering if that's something that you think could be exacerbated in a larger study that, you know, we could potentially be concerned about, right? I'll take that, Simon, Eddie.

And what the characteristic of that patient is in.

And the prescribing decision that they're making so I would never want to think about one single data point.

As being a driver of the ultimate commercial success for this for this.

Simon N. Pimstone: Yeah, look, any phase one study with a CNS-acting drug in volunteers is likely to exaggerate the tolerability of the drug. But when you go to a community-based study in patients or an outpatient-based study, it's generally very, very different. These are patients that are used to taking or more used to taking antiseasure meds. Remember, these individuals in our trial have been on many but are on one to three additional meds at the time of inclusion. So they're quite used to the tolerability.

For 11 on one I would also say yes.

The statistical and it's a well powered study from a statistical perspective to show, it's a linear trend try and test to show a dose response and separation and if you look at it you are correct it for placebo.

Versus the high dose of 25 milligrams for modeling as a 15% differential obviously that.

A bunch of other things go into that model at the end of the day in terms of the standard deviation.

Simon N. Pimstone: And we have also, as you probably recall, designed the study such that with dosing in the evening, which was different from our phase one setting, where the dosing was in the morning. But dosing in the evening in this trial, as Ian mentioned in his notes earlier, we should see CMAX during sleeping hours. And that was specifically designed, given the PK of the drug, to allow for any of the more significant CNS tolerability issues to hopefully be slept through. And so we don't expect the AE program.

And and other things.

Would would provide the P value at the end of the day so.

The way, we think about it is if we're in that range of.

30% to 40% median reduction we need to be statistically significant and then we believe we're absolutely.

Comparable to what the market is for efficacy and anti seizure medications and then when you start thinking about some of the other attributes which are really a massive driver of.

Simon N. Pimstone: to be the same as phase one, I will just say and reiterate that, relative to other drugs, the phase one safety was actually good and, relative to isogene, excellent. I mean, we have almost all were mild and that were reversible, and clearly a dose dependency with the aggregation of Aes at the 25 meg dose. Remember our, you know, but this study is done dosed at night and in a patient population population.

And how decisions are made.

Kevin O one as you line it up against the other drugs, both generic and branded drugs and adult focal epilepsy, that's where 11 O one lines up really well and I won't list those offering now, but we have gone through those and are prepared remarks, where we believe both on and ease of use and safety and Tolerability. So far 11 on one looks very strong.

Okay.

Our next question coming from the line of David <unk>. Your line is open.

Simon N. Pimstone: So our population is quite distinct, and we expect to see much improved tolerability. As Ian mentioned earlier, the very low dropout rates and the very high conversion to OLE would suggest that at least the patients are tolerating a drug to a degree where they stay in the study and move into the open label where they and the investigators know they're getting the active drug.

Alright, thanks for the update it taking my questions and so I just had a couple of quick ones.

And no one I know the inclusion criteria for the phase <unk> study allows one to three comp.

Concomitant and her background.

So I was just wondering if you had a sense of how many patients are actually on only one background therapy and in.

Operator: Gotcha, thank you. And then just one final one. Is there any possibility that this phase two could be potentially pivotal? Is that being considered? And then if it's successful, like, do you have a baseline assumption on how many others there might be?

And the real World setting do you think that you'd be able to pick up some patients in second line usage or would it mostly be third line plus debt that you'd expect.

Thanks, David.

Good questions.

We don't have neither assignment and nor I are in the details of exactly what the patient demographics looks like and the current study.

Operator: assumption on how many other trials you'd need to get approval. It's a good question.

Simon N. Pimstone: We don't know because it's going to require an FDA discussion, but certainly if the study is very significant, remember it's a one-sided phase two trial, so we'd have to essentially double the effect size in terms of the P value for this to potentially be deemed significant at two-sided, which will be a requirement for this to be deemed registration. But assuming we were to see that, so in other words, a P less than 0.025, rather than less than 0.05, we would certainly engage the FDA in that discussion.

And we purposely kind of stay away from that so I don't know the answer today of your question on how many are on one two or three background meds and the study obviously, we will be able to.

Disclose that data once the trials complete when.

When we think about prescribing decisions I mean, why don't we why don't we just spend a quick minute walking through them because we've done a lot of this work recently.

So generally yes at first line many of these.

So first line, meaning newly diagnosed patients they are going to be on a generic drug.

Simon N. Pimstone: And then, of course, the obvious discussion is, do we just require one additional, for the U.S. at least, one additional phase three trial? For Europe, it's almost certain that one would require two distinct studies, 12 weeks of dosing, designed as two-sided. But for the U.S., it is possible that this could be deemed a registration, or should we say one-aids, of two registration trials. Remember, we still have to have a certain number of subjects in a safety database, and that number is around 1,500, but they don't all have to come from efficacy trials.

And second line Youre going to you often see branded Capra show up and again not every.

Patient is the same and not every physician prescribing habits are the same but you often see branded camera show up or other generics and at that point still what we see.

On a percentage of patients often it's quoted and the 30% to 40% range that are still not well controlled and thats. When physicians are starting to think about rational polypharmacy.

And that's where Vimpat often shows up has the first branded agent and I think we believe that's where 11 and one based on its attributes also has the opportunity to play a role based on its going to be the only and class drug at launch with a caveat mechanisms so it'll be a non.

Simon N. Pimstone: They can come from Clint Farm studies, open label studies, single dose studies, et cetera. So we're going through that, Eddie, right now, but our goal would be to engage the FDA in that exact discussion if we see a highly statistically significant benefit. Thank you.

Operator: Our next question coming from the lineup is Antonio Paravina with Bloomberg. Yelan is open. Hi, thanks for taking my question. I just have one, which was kind of related to a question asked earlier, but maybe another way of asking it. So I know that your ex-trial trial is power to show a 15% delta between placebo and active. So I'm just wondering if you just reach this threshold, do you believe this is competitive commercially from an F2 perspective?

<unk> mechanism and some of the other ease of use attributes and we've seen and obviously once we have the safety and Tolerability and efficacy data in hand, but that's generally as we think about the progression of a patient and potentially where 11 and one could fit in there or as has additional agents are added to treat these patients.

Got it thanks for providing color and Thats really helpful and.

Ian C. Mortimer: Ian, you want to go? Yeah, I mean, that's a difficult question to answer because I think in all of these things, any prescribing decision is based on the totality, right? It's not just based on a single data point, and it's interesting when you talk to a lot of community-based prescribers. I'm not sure that they can rattle off the clinical trial efficacy data like we can, right? So they're really thinking about the experience they've had with a drug, how their individual patients have done on that drug, and what its characteristics are.

And then just final question was on the below seven and I know the active ingredient is now regime and theres been some experience.

Commercially with that molecule. So it's just trying to get a better sense of what has the experience historically been with Oh seven.

And in terms of safety, Tolerability and efficacy and such.

Yes. Thanks, So it's approved on label outside of the U S and a number of countries European and South American and.

Ian C. Mortimer: of that patient is and the prescribing decision that they're making. So I would never want to think about one single data point as being a driver of the ultimate commercial success of this, for this, for 1101.

And others.

For chronic migraine prevention and Vertigo.

CNS acting.

Primarily calcium channel modulator, but it has some other effects and <unk>.

One of the actual very interesting features of the drug which was compelling for us is not only.

Ian C. Mortimer: I would also say, yes, you know, the statistical, it's a well-powered study from a statistical perspective to show, it's a linear trend test to show a dose response and separation, and if you look at, you're correct, at the placebo versus the high dose of 25 milligrams, the modeling is a 15% differential. Obviously, a bunch of other things go into that model at the end of the day in terms of the standard deviation and other things that would provide the P value at the end of the day.

Has there been some non clinical data supportive of the use and CAE.

But actually the tolerability of the drug, particularly in the pediatric population is actually very very good.

So there are some side effects and one with scenario Z and particularly in an elderly population.

Depression.

And pyramidal extra pyramidal features can be observed again at low frequency, but in the elderly.

I'd say the only outside of that population that would need to consider as some weight gain and it's not that significant but it is there and some subjects, but interestingly in the pediatric population and this drug is very very well tolerated, which is actually very important because often drugs used and kids for the.

Ian C. Mortimer: So, you know, the way we think about it is if we're in that range of, um, you know, of that 30 to 40% median reduction, we need to be statistically significant, then we believe we're absolutely comparable to what the market is for efficacy and anti-seizure medications. And then when you start thinking about some of the other attributes, which are really a massive driver of how decisions are made, 1101, as you line it up against the other drugs, both generic and branded drugs in adult focal epilepsy, That's where 1101 lines up really well, and I won't list those off right now, but we have gone through those in our prepared remarks, where we believe both on an ease of use and safety intolerability, so far 1101 looks very strong.

Seizure control independent of type of seizure. This could be focal this could be generalized this could be absence.

And is often these orphan drugs that impair the scholastic scholastic ability of these kids that have cognitive impairment and Pittsfield Sleepy and and so this is a drug which appears to be mostly devoid of the Sydney relative to the gold standard drugs in this indication being valproate and <unk> this would be.

Very good alternative from a CNS perspective, so it's actually one of the reasons.

David We wanted to move this product forward in this population.

It was because of the predicted excellent safety and Tolerability Thats now being shown in tens and tens and tens of thousands of users of scenarios in and around the world.

Operator: Now, next question coming from the line of David Foward, SMBC. Your line is open.

Okay.

Operator: Hi, thanks for the update and for spending time answering my questions. So I just had a couple quick ones.

Okay.

Yes.

Said another way if the drug and if the drug fails and I don't think it's for safety and Tolerability that would be my guess and this population I think we don't obviously, we don't know the final efficacy, albeit it looks very good and a small subset, but safety tolerability is well understood.

Ian C. Mortimer: With 1101 patients, I know the inclusion criteria for the Phase 2B study allow one to three, you know, concomitant or background ADDs. So I was just wondering if you had a sense of how many patients are actually on only one background therapy. And in a real world setting, do you think that you'd be able to pick up some patients in second line usage, or would it mostly be third line? plus that you know, that you know, that you expect. Thanks, David, and good questions. We don't have, nor are Simon nor I aware of the details of exactly what the patient demographics look like in the current study. We purposely kind of stay away from that.

Okay, and I'm not showing any further questions at this time I would now like to turn the conference back over to Jodi <unk> for any closing remarks.

Thank you on behalf of Athene on leadership team and look forward to updating you on our progress over the coming months, operator, we will now and the cost.

Ladies and gentlemen that does go conference for today. Thank you for your participation you may now disconnect.

Ian C. Mortimer: So I don't know the answer today to your question about how many are on one, two, or three background meds in the study. Obviously, we'll be able to disclose that data once the trial's complete. When we think about prescribing decisions, I mean, why don't we just spend a quick minute walking through them because we've done a lot of this work recently? So generally, yes, at first line, many of these, first line meaning newly diagnosed patients, they are going to be on a generic drug. At the second line you're going to, you often see branded KEPRA show up.

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Ian C. Mortimer: And again, not every patient is the same, and not every physician is the same, and prescribing habits are the same, but you often see branded KEPRA show up or other generics. And at that point, still, we see a percentage of patients, you know, often it's quoted in the 30 to 40% range that are still not well controlled. And that's when physicians are starting to think about rational polypharmacy. That's where VIMPAT often shows up as the first branded agent.

Ian C. Mortimer: And I think, you know, we believe that 1101 also has the opportunity to play a role based on it being the only in-class drug at launch with a KV mechanism, so it'll be a novel mechanism, and some of the other ease of use attributes that we've seen, and obviously once we have the safety and tolerability and efficacy data in hand. But that's generally speaking, as we think about the progression of a patient and potentially where 1101 could fit in there, or as a disability. Agents are added to treat these patients. I got it. Thanks for providing the color.

Operator: That's really helpful. And then just my question was on 007. I know the active ingredient is lunarasine, and there's been some experience, you know, commercially with that molecule. So it's just trying to get a better sense of, you know, what the experience historically has been with 07, you know, or flu narazine in terms of safety, tolerability, and, you know, efficacy. Yeah, thanks. So it's approved on label outside of the US in a number of countries, Europe, South America, and others, for chronic migraine prevention and vertigo.

And.

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Operator: It's a CNS acting... primarily calcium channel modulator, but it has some other effects. One of the really interesting features of the drug, which was compelling for us, is not only that there had been some non-clinical data supportive of the use in CAE, but actually the tolerability of the drug, particularly in the pediatric population, is actually very, very good. So there are some side effects known with Flanarazine, particularly in an elderly population. Depression and pyramidal or extra-paramidal features can be observed, again, at a low frequency, but in the elderly. I'd say the only AEA.E.

Simon N. Pimstone: Outside of that population, one thing that one would need to consider is some weight gain. It's not that significant, but it is there in some subjects. But interestingly, in the pediatric population, this drug is very, very well tolerated, which is actually very important because often drugs used in kids for their seizure control, independent of the type of seizure, this could be focal, this could be generalized, this could be absence, are often drugs that impair the scholastic performance of these kids. They have cognitive impairment, and kids feel sleepy.

Simon N. Pimstone: And so this is a drug which appears to be mostly devoid of those side effects, certainly relative to the gold standard drugs in this indication, being valproate and ethosaxamide. This would be a very good alternative from a CNS perspective. So it's actually one of the reasons, David, we wanted to move this product forward in this population because of the predicted excellent safety tolerability that's now been shown in tens and tens and tens of thousands of users of Lunarisin around the world.

Simon N. Pimstone: Okay. Yeah. You said another way, if the drug fails, I don't think it's because of safety tolerability. That would be my guess in this population. I think we don't, obviously, we don't know the final efficacy, albeit it looks very good in a small subset, but safety tolerability is well understood.

Operator: Okay. I'm not showing any further questions at this time. I would like to turn the conference back over to Jody Ritz for any closing remarks.

Jody Rex: Thank you. On behalf of the Xenon Leadership Team, we look forward to updating you on our progress over the coming weeks.

Operator: you on our progress over the coming months. Operator, we will now end the call.

Operator: Ladies and gentlemen, the task for our conference for today is over. Thank you for your participation. You may now disconnect.

Operator: Bhopal, Bhopal, and the United States, and so on the way, and so much, you know, and so much, and I'm I'm going to be able to be. I'm going to be able to be. And so on the and, and so on the end up.

Operator: Thank you. Thank you. Thank you. Thank you. Thank you, and so on. The President, I don't know.