Full Year 2020 Xenon Pharmaceuticals Inc Earnings Call

Good morning, ladies and gentlemen, and welcome to the quarter four two and that's why do you send in the Pharmaceuticals incorporated earnings Conference call. At this time all participants are in a listen only mode. Later, we will conduct the question and answer session and instructions will follow at that time.

If anyone should require assistance during the conference. Please press Star then zero on your Touchtone telephone.

Josie Raitt: 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. Our results may differ materially from those projected on today's call. We undertake no obligation to publicly update any forward-looking statement.

As a reminder of just conference being recorded I would now like to turn the conference over to your host today Ms. Jill Hewitt Ma'am. Please go ahead.

Thank you good afternoon, everyone and thanks for joining us on our call and webcast to discuss our financial and operating results for the year ended December 31, and 2020, joining me on today's call are Dr. Simon and Tim Stone seen on the Chief Executive Officer, Ian Mortimer of Xenon, as President and Chief Financial Officer, and Sherry Olin scene, and the Vice President Finance and the.

Josie Raitt: Today's press release summarizing the results of Xenon's 2020 year-end financial results and the accompanying annual report on Form 10-K will be made available under the investor section of our website at www.xenon-pharma.com and filed with the SEC and on CDAR. Now, I would like to turn the call over to Simon. Thank you, Jody, and good afternoon, everyone, and thank you all for joining us today. I hope everyone is staying safe and well.

Announced in January of this coming June at the time of the company's annual meeting of shareholders. So I am and will be transitioning to his new role as executive chair of the non sport at the same time and will be appointed president and CEO, while share he will be appointed Chief Financial Officer on today's call you will hear from both Simon and Ian as they provide of corporate update.

Josie Raitt: I would also like to welcome Sherry to today's call. Over the coming months, leading up to her transition to CFO in June, you'll have an opportunity to hear her comments on our business and plans moving forward. For my part, as you know, I'm moving into the new role of Executive Chair of Xenon's Board. In this capacity, I'll continue to be very active in the company as Ian leads the day-to-day operations. I couldn't be more excited about making the transition at this time when Xenon is at the strongest point in our history with a talented and capable management team and a neurology pipeline that is one of the most robust in our industry, and meaningful clinical data readouts in the near term.

And overview of our clinical development programs Sherry will provide some high level of financial commentary and we will then open up your call for questions. Please be advised the during this call. We will make a number of statements that are forward looking including statements regarding the anticipated impact and timing of COVID-19 pandemic on our business research and clinical development plans and.

<unk> lines and results of operations and the timing of and results from clinical trials and preclinical development activities of <unk>.

Terry and partnered product candidates and the potential efficacy safety profile of the future development plans addressable market regulatory success and commercial potential of our proprietary and partnered product candidates the anticipated timing of IND or IND equivalent submissions and the initiation of future clinical trials for our proprietary products.

Josie Raitt: Ian and I have a shared strategic vision, and we are looking forward to the next stage of growth at Xenon. With two of our most advanced proprietary product candidates, XEN1101 and XEN496, currently in phase 2 and 3 clinical trials, respectively, and numerous earlier clinical and non-clinical assets in development, I'm excited to provide a progress update today. I'd like to begin with some corporate and partner updates, followed by an overview of our clinical development programs.

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

Josie Raitt: I will then ask Ian to spend some time focusing on XEN 1101, including a summary of the new XEN 1101 preclinical data that was presented recently at the ESSENCE 2021 virtual meeting and how we are thinking about next steps for this program. Before diving in to our program updates, I'd like to take a moment to thank Dr. Ernesto Arcadi, our Chief Medical Officer, who will be moving on at the end of April to lead global development for a pharmaceutical company. Ernesto joined us at a time when we began concentrating our clinical efforts on neurological disorders with a particular focus on epilepsy.

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 and our S E.

<unk> filings our results may differ materially from those projected on today's call. We undertake no obligation to publicly update any forward looking statement today's press release summarizing the results of xenon in 'twenty and 'twenty year and financial results and the accompanying annual report on form 10-K will be made available under the investors section of our Webster.

Simon N. Pimstone: Perhaps his most impactful legacy will be his work building up our clinical development organization with an experienced team capable of supporting multiple mid- to late-stage clinical trials, and we are grateful for his contributions. With the XEN 1101 Phase IIb ePTOL study on track for top-line data readout in the third quarter of this year, and with the XEN 496 Phase III EPIC study now underway, we are looking forward to a very smooth transition.

And at Www Dot seen on Dash pharma Dot com and filed with the SEC and on SEDAR now I would like to turn the call over to Simon and Thank you Jody and good afternoon, everyone and thank you all for joining US today I hope everyone is staying safe and well.

I would also like to welcome Sherry to today's call.

And for the coming months, leading up to her transition to CFO and June good of an opportunity to share her comments on our business and plans moving forward.

Simon N. Pimstone: I'm also delighted to announce that Dr. Kenneth Somerville will serve as our Interim Chief Medical Officer. A board-certified neurologist, Ken is one of the most experienced epilepsy drug developers in the pharmaceutical industry today, with over 20 years of experience at companies including Abbott, GW, Pfizer, King, UCB, and Schwarzpharma. He has led Phase II and Phase III epilepsy trials in the U.S. and made major contributions to multiple successful NDA submissions. In addition to leading the development of Epidiolex to a successful NDA submission for GW Pharmaceuticals, Ken was highly involved in the clinical development of sodium valproate, Thiagabine, and Leucosamide.

For my part as you know on moving into the new role of executive Chair of Xenon as board and this capacity all continue to be very active and the company and leads the day to day operations.

And I couldnt be more excited and making the transition at this time with xenon is at the strongest point and our history with the talented and capable management team and neurology pipeline that is one of the most robust and our industry.

And meaningful clinical data readouts in the near term.

And I have a shared strategic vision and we are looking forward to the next stage of growth of gene on.

With two of our most advanced proprietary product candidates Ixia and 11 of one of next year and 49 six currently in phase two and three clinical trials, respectively, and numerous earlier clinical and non clinical assets and development.

Simon N. Pimstone: Ken's leadership and development experience will be a tremendous asset as we move our clinical development programs forward, especially at a time when we are anticipating important data readouts from the EXTOL study and the continued advancement of our Phase III EPIC study. Turning briefly to the latest guidance from our partnered programs, Neurocrine Biosciences anticipates initiating a Phase II clinical trial for NBI-921352 in adolescent patients aged 12 years and older who have SCN8A developmental and epileptic encephalopathy, otherwise known as SCN8A-DEE, in the third quarter of 2021, and the trial protocol will be amended to include younger pediatric patients aged 2 to 11 years with SCN8A-DEE as soon as the FDA has reviewed and approved additional non-clinical information.

I'm excited to provide a progress update today I'd.

I'd like to begin with some corporate and partner updates followed by an overview of our clinical development programs and I will then ask Ian to spend some time focusing on ex U and 11 of one including a summary of the new XC and 11 of one preclinical data that was presented recently at the <unk> 'twenty 'twenty, one virtual meeting and how we are.

Thinking about next steps for this program.

Before diving into our program updates I'd like to take a moment to thank doctor of Nestor Ekati, Our Chief Medical Officer, who will be moving on at the end of April to lead global development for a pharmaceutical company and it's Joe joined US at a time when we began concentrating on clinical efforts on neurological disorders, where the.

Particular focus on epilepsy Pepsi is most impactful legacy will be his work building up our clinical development organization with an experienced team capable of supporting multiple mid to late stage clinical trials and we are grateful for his contributions.

Simon N. Pimstone: In parallel, Neurocrine Biosciences is advancing clinical plans to develop the molecule NBI-921352 for the treatment of adult focal epilepsy and expects to initiate a Phase II clinical trial this year. We look forward to keeping you updated on NBI-921352 and its progress. Flexion Therapeutics is developing FX301, which consists of XEN402, a Xenon Nav1.7 inhibitor formulated for extended release from a thermosensitive hydrogel to support administration as a peripheral nerve block for the control of postoperative pain.

With the <unk> and 11 on one phase to be ex told study on track for topline data readout and the third quarter of this year and with <unk> and four nine and six phase III Epic study now underway, we're looking forward to a very smooth transition.

I'm also delighted to announce the doctor Kenneth some of them will serve as our interim Chief Medical Officer. The Board certified neurologist. Ken is one of the most experienced epilepsy drug developers and the pharmaceutical industry today with over 20 years of experience of companies, including Abbott GW Faiza King.

UCB and Schwartz pharma.

He has led phase II and phase III epilepsy trials and the U S and made major contributions to multiple successful NDA submissions in.

Simon N. Pimstone: Recently, the FDA cleared an IND for FX-301, resulting in a milestone payment due to Xenon. Flexion has guided that it anticipates initiating a Phase 1b proof-of-concept clinical trial of popliteal fossibloc with FX301 in patients undergoing bunionectomy in the first half of 2021, with top-line results potentially available later this year. Moving to our proprietary programs, XEN007 is a CNS-acting CAV2.1 and T-type calcium channel modulator that is being studied in treatment-resistant childhood absence epilepsy (CAE) in a physician-led Phase II proof-of-concept study.

In addition to leading the development of MP dialects two of successful NDA submission for GW Pharmaceuticals, Ken was highly involved and the clinical development of sodium valproate tiger being and low <unk>.

Ken's leadership and development experience will be a tremendous asset as we move our clinical development programs forward, especially at the time when we are anticipating important data readouts from the ex stalled study and the continued advancement of our phase three epic study.

Turning briefly to the latest guidance from our partnered programs Neurocrine Biosciences anticipates initiating the phase two clinical trial for N B, I and 90, 21352, and adolescent patients aged 12 years and older who have the S C and H, a developmental and epileptic encephalopathy, otherwise known as <unk>.

Simon N. Pimstone: At AES 2020, we presented promising interim data from a small number of patients, with all three CAE subjects having completed their maintenance phase of dosing and exhibiting a significant reduction in seizures as measured by seizure diary and confirmed by EEG. In response to COVID-19's impact on recruitment in the study, which is ongoing, we are working with our study collaborator to include additional sites, and we have adjusted guidance to expect results from a larger data set in the second half of 2021.

S G and H a D E and the third quarter of 2021, and the trial protocol will be amended to include younger pediatric patients aged two to 11 years with S. C and H a D E. As soon as the FDA has reviewed and approved additional non clinical information.

In parallel Neurocrine Biosciences is advancing clinical plans to develop the molecule N B I and 90 21352 for the treatment of adult focal epilepsy and expects to initiate a phase II clinical trial of this year. We look forward to keeping you updated on N B I and 90 21352 and its progress.

Simon N. Pimstone: While the AES 2020 presentation represents a small dataset, we believe we are seeing drug activity and seizure reduction and on EEG that is supportive of a broader development plan for XEN007 and we expect to make a decision this year regarding XEN007 in CAE. XEN-496, a proprietary pediatric formulation of the active ingredient isogavine, is being developed for the treatment of KCNQ2 developmental and epileptic To provide the regulatory backdrop for this program, Xenon has received Fast-Track Designation and Orphan Drug Designation for XEN496 for the treatment of seizures associated with KCNQ2-DEE from the U.S. FDA, as well as Orphan Medicinal Product Designation from the European Commission.

Flexion Therapeutics is developing FX three of one which consists of XC and and four O two of xenon and NAV one seven inhibitor formulated for extended release from of Thermo sensitive hydrogel to support the administration as a peripheral nerve block for control of postoperative pain.

Recently, the FDA cleared and indeed for the FX 301, resulting in a milestone payment due to xenon.

Collection has guided that it anticipates initiating the phase one be proof of concept clinical trial of popliteal Foster block with the FX 301 in patients undergoing bunionectomy and the first half of 'twenty 'twenty, one with top line results potentially available later this year.

Moving to on proprietary programs and 007 as the CNS acting Caf 2.1, and T type calcium channel modulator that is being studied and treatment resistant childhood absence, epilepsy or CAE and the physician led phase II proof of concept study at.

Simon N. Pimstone: We recently initiated a Phase III randomized double-blind placebo-controlled multi-center clinical trial called the EPIC study evaluating the efficacy, safety, and tolerability of XEN496 administered as adjunctive treatment in approximately 40 pediatric patients aged one month to less than six years with KCNQ2-DEE. We believe XEN496 may be efficacious and address a significant unmet need in this rare, severe pediatric neurodevelopmental disorder, based both on its KV7 mechanism of action, as well as published case reports from physicians who used Vizagabine to treat infants and young children with KCNQ2DEE.

And at Aes 2020, we presented promising interim data from a small number of patients with all three CAE subjects, having completed the maintenance phase of dosing and exhibiting a significant reduction in seizures as measured by seizure diary and confirmed by E. G.

In response to COVID-19 impacts on recruitment and the study which is ongoing we are working with our study collaborate on to include additional sites and we have adjusted guidance do you expect results from a larger dataset and the second half of 2021 well.

While the a F 'twenty and 'twenty presentation represents a small datasets. We believe we are seeing drug activity and seizure reduction and on the E. G that is supportive of abroad of development plan for Etsy, and 007, and we expect to make a decision this year regarding ex Ian Zero-zero, seven and C E.

Simon N. Pimstone: Advancing this program into Phase 3 is such an important milestone for Xenon, and we believe it is also significant for the physicians, caregivers, families, and patients with KCNQ2-DEE. We look forward to keeping you updated on the progress of this epic study. Before I turn the call over to Ian, I'll provide a few comments on Exe and 1101. We know that the KV mechanism is important in the CNS, and there have been supportive data for a wide variety of therapeutic approaches, including seizure disorders, pain, motor neuron disease, depressive disorders, and tinnitus. This is very common,

And she and four nine and six of the proprietary pediatric formulation of the active ingredient is zagha beans is being developed for the treatment of KC and Q2 developmental and epileptic encephalopathy, Okc and Q2 D E.

To provide the regulatory backdrop for this program Xenon has received fast track designation and orphan drug designation for Etsy and for 96 for the treatment of seizures associated with KC and Q2 D E from the U S FDA as well.

Simon N. Pimstone: Many CNS drugs work in a variety of neurological conditions. Within the KV mechanism, we have also seen strong clinical validation with the approval of flupertine in pain and ezogabine in adult focal epilepsy. And in the near term, there will be published randomized clinical data in the high-impact American Journal of Psychiatry related to the use of Isogabine in major depressive disorder and anhedonia. There is tremendous validation of the KV mechanism, but to date, a drug with the right pharmaceutical properties has not been developed.

And as orphan medicinal product designation from the European Commission.

We recently initiated a phase III randomized double blind placebo controlled multicenter clinical trial called the epic study evaluating the efficacy safety and Tolerability of <unk> and 496 administered as adjunctive treatment and approximately 40 pediatric patients aged one months to list and six years.

With KC and Q2 D E.

We believe ixia and 496 may be efficacious and address a significant unmet need and this raise severe pediatric neurodevelopmental disorder based both on its <unk> seven mechanism of action as well as published case reports from physicians, who use these all going to treat infants and young children with KC and Q2 D E.

Simon N. Pimstone: We believe that XEN11-01, with this drug, we have an opportunity to be the only in-class drug in adult focal epilepsy with the potential to broaden the opportunity into other neurological disorders given XEN11-01's attributes following the strong KV scientific and mechanistic rationale and Izogabin's clinical validation. This is an extremely exciting time for the profile of the KV mechanism and for XEN1101. And Ian will provide more details on our approach and future plans. Ian?

Advancing this program into phase III is such an important milestone for xenon and we believe it is also significant for the physicians caregivers and families and patients with KC and Q2 D E and we look forward to keeping you updated on the progress of the epic study.

Before I turn the call over to Ian I'll provide a few comments on the axion 11 of one.

We know that the cave mechanism is important and the CNS and there has been supportive data and a wide variety of therapeutic approaches, including seizure disorders pain and motor neuron disease depressive disorders and tinnitus.

Ian C. Mortimer: Ian Mortimer Thanks, Simon, and good afternoon, everyone. XEN1101 is Xenon's proprietary, differentiated KV7 potassium channel modulator being developed for the treatment of epilepsy and potentially other neurological disorders. Although we are interested in the potential broad applicability of the KV mechanism, our near-term focus is on our XTOL study, a Phase IIb randomized, double-blind, placebo-controlled, multi-center clinical trial that is currently underway to evaluate the efficacy, safety, and tolerability of XCN1101 administered as adjunctive treatment in approximately 300 adult patients with focal epilepsy.

Very common many CNS drugs work and a variety of neurological conditions.

Within the kv mechanism. We have also seen strong clinical validation with the approval of flip of teen and pain and it's all good bean and adult focal epilepsy and.

And in the near term it will be published randomized clinical data in the high impact the American journal of psychiatry related to the use of the zagha being and major depressive disorder and anhedonia.

And there is tremendous validation of the cave mechanism, but to date of drugs with the right pharmaceutical properties has not been developed.

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. This is a well-powered study with approximately 90% power. We remain highly confident in the conduct of the study and in the integrity of the data as captured by the Electronic Diary.

We believe that Etsy, and 11 O one with the strike we have an opportunity to be the only in class drug and adult focal epilepsy with the potential to broaden the opportunity and to other neurological disorders, given the ixia and 11 of one's attributes and following the strong kv scientific and mechanistic rationale and it's all gonna beans clinical valve.

Ian C. Mortimer: To date, dropout rates remain lower than modeled, and we continue to see excellent continuation into the open-label portion of the study. We are on track to complete patient screening and randomization in the first half of 2021, with top-line results anticipated in the third quarter of this year. This data readout represents an important inflection point for Xenon and an opportunity to drive XCN 1101 forward into a pivotal program.

<unk>.

This is an extremely exciting time for the profile of the cave mechanism and for Etsy, and 11 O one and Ian will provide more details on our approach and future plans and.

Thanks, Simon and good afternoon, everyone ex.

<unk> 11 O. One is the non is proprietary and differentiated <unk> potassium channel modulator being developed for the treatment of epilepsy and potentially other neurological disorders.

Although we are interested and the potential broad applicability of the cave mechanism. Our near term focus is on our X Tole study of phase <unk> randomized double blind placebo controlled multicenter clinical trial that is currently underway to evaluate the efficacy safety and tolerability of vaccine on 11 and one administered.

Ian C. Mortimer: Last week, Xenon hosted four presentations related to XCN 1101 at Ascent 2021, the virtual meeting of the American Society for Experimental Neurotherapeutics. When outlining XEN 1101's clinical development today, we highlighted a number of its unique properties and potential advantages. XEN11-01 is based on a proven anti-seizure KV mechanism of action and, if successful, will be the only drug in this class available commercially. XEN11-01 has been well tolerated in Phase I clinical studies, and we have reported a low dropout rate and high conversion to open label extension in the ongoing Phase IIb clinical trial to date.

The adjunctive treatment and approximately 300 adult patients with focal epilepsy the.

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

This is a well powered study with approximately 90% power.

We remain highly confident and the conduct of the study and and the integrity of the data is captured by electronic diary to date dropout rates remain lower the model and we continue to see excellent continuation into the open label portion of the study.

Ian C. Mortimer: We observed a strong PK-PD relationship in the Phase 1b transcranial magnetic stimulation, or TMS, study, with TMS results informing dose selection in our Phase 2b trial. And in our ongoing Phase IIb study, XEN 11-01 is administered as a once-daily and a low-daily dose in the evening with no dose titration. In addition, we presented new compelling data from preclinical studies examining XEN11-L1 in combination with other anti-seizure drugs, including lacosamide, levofotiracam, sinobamate, phenytoin, and valproic acid. We demonstrated that combining sub-effectivecious doses of 1101 and other ASMs provided robust efficacy in animal models and was well tolerated at the dose ranges explored.

We are on track to complete patient screening and randomization and the first half of 2021 with top line results anticipated in the third quarter of this year.

And this data readout represents an important inflection point for xenon and and opportunity to drive ex CN 11, and one forward into a pivotal program.

Last week xenon hosted four presentations related taxes and on 11 O. One out of sent 2021 of the virtual meeting of the American Society for experimental near of Therapeutics.

And outlining <unk> on 11 O one clinical development to date, we highlighted a number of its unique properties and potential advantages ex.

Ian C. Mortimer: This suggests that XEN11-01 may be well suited for use as monotherapy or applied in a rational polypharmacy setting to treat seizures. On the whole, taking into account our conclusions from pre-clinical studies and clinical results to date, along with market research exploring the current gaps in the adult focal epilepsy space, we believe XCN1101 has key ease-of-use attributes that could meaningfully differentiate it from other anti-seizu We have also been exploring the use of XEN11-01 in other non-epilepsy indications and presented scientific rationale, preclinical data, and clinical work to date supporting the use of KV modulators for the treatment of depression and anhedonia. Results from the Forced Swim Test and Progressive Ratio Test animal models support a potential benefit of XEN11-01 in mood disorders.

<unk> and 11 O. One is based on our proven anti seizure kv and mechanism of action and if successful we'll be the only drug and this class available commercially.

<unk> hundred 11, and one has been well tolerated and phase one clinical studies and we have reported of low dropout rate and high conversion to open label extension and the ongoing phase <unk> clinical trial to date.

We observed a strong PK PD relationship and the phase one b transcranial magnetic stimulation of our Tms study with Tms results and farming dose selection and our phase two b trial.

And in our ongoing phase <unk> study ex CN 11 O. One is administered as a once daily and our low daily dose and the evening with no dose titration.

In addition, we presented new compelling data from preclinical studies examining ex and 11 O. One in combination with other anti seizure drugs, including what cost of mine a lot of trough of the town Sonoma mate phenytoin and valproic acid with.

We demonstrated the combining some of the efficacious doses of 11 O one and other ASM provided robust efficacy in animal models and was well tolerated and the dose range of explored.

Ian C. Mortimer: Of note, the efficacious doses and plasma concentrations from the preclinical depression, anhedonia, and seizure studies overlap and occur at plasma levels achieved during the multi-ascending dose cohorts of our Phase I clinical trial, suggesting the current doses being used in the ongoing XCN 1101 Phase IIb clinical trial to treat epilepsy may have a beneficial impact on depressed moods. Supported by our analysis and these promising preclinical data, we expect our academic collaborators at the Icahn School of Medicine at Mount Sinai to initiate a Phase II proof-of-concept clinical trial this year examining XTN-1101 in major depressive disorder, or MDD. We look forward to updating you with further details in the coming months. Before I provide a brief conclusion of our upcoming milestones, I'll ask Sherry to recap our financial position. Sherry?

This suggests that X gene and 11 O one may be well suited for use as monotherapy or applied and irrational polypharmacy setting to treat seizures.

On the whole taking into account our conclusions from preclinical studies and clinical results to date, along with market research exploring the current gaps and the adult focal epilepsy space. We believe ex CN 11 O. One has key ease of use of attributes that could meaningfully differentiate <unk> and 11 O one from other anti seizure.

<unk>.

We have also been exploring the use of vaccine and 11 O one and other non epilepsy indications and presented the scientific rationale preclinical data and clinical work to date supporting the use of kv modulators for the treatment of depression and and Indonesia.

<unk> from the forced swim test and progressive ratio ratio test animal models support the potential benefit of Etsy on 11 O one and mood disorders.

Sherry Aulin: Thanks, Ian. And good afternoon, everyone. I'm excited to take on the role of CFO later this year, and I look forward to keeping Xenon shareholders and analysts updated on our continued progress. As Ian noted on the last quarterly call, we are in a sound financial position today and well situated to support Xenon's business objectives and the advancement of our clinical development program. Cash and Cash Equivalents and Marketable Securities as of December 31, 2020 were $177 million, compared to $141.4 million as of December 31, 2019.

Of note the efficacious doses and plasma concentrations from the preclinical depression, and Indonesia, and seizure studies overlap and of current plasma levels achieved during the multi ascending dose cohorts of our phase one clinical trial, suggesting the current doses being used and the ongoing <unk> 11 and <unk>.

On phase two b clinical trial to treat epilepsy may have beneficial impact on depressed mood.

Supported by our analysis and these promising preclinical data we expect our academic collaborators at the Icahn School of Medicine, and Mount Sinai to initiate the phase II proof of concept of clinical trials. This year examining ex general 11, O one and major depressive disorder or M. D D well.

We look forward to updating you with further details in the coming months before I provide a brief conclusion of our upcoming milestones all of Sherry to recap our financial position share. Thanks, Dan and good afternoon, everyone I'm excited to take on the role of CFO later, this year and I look forward to keeping the non shareholders and analysts updated on.

Sherry Aulin: Based on current assumptions, which include fully supporting the planned clinical development of XEN 11-01, XEN 4-9-6, and XEN 0-0-7, Xenon anticipates having sufficient cash to fund operations into 2023, excluding any revenue generated from existing partnerships or potential new partnerships. Therefore, we continue to have a lot of flexibility as we manage our business and continue to advance our product candidates. As of December 31, 2020, there were approximately 35 million common shares outstanding and approximately 1 million Series 1 preferred shares outstanding, which are convertible into common shares on a one-for-one basis at the option of the holder, subject to certain limitations.

On your progress.

And Ian noted on the last quarterly call. We are in a sound financial position today, and well situated to support xenon business objective and the advancement of our clinical development programs.

Cash and cash equivalents and marketable securities as of December 31, 'twenty, and 'twenty or 177 million compared to $141 4 million as of December 31, 2019 based on current assumptions, which include fully supporting the plan and clinical development of <unk> and 11 O. One.

Ex CN for nine six and ex the engineers Euro seven.

Seven xenon and anticipate having sufficient cash to fund operations into 2023, excluding any revenue generated from existing partnerships or potential new partner on the arrangements.

Ian C. Mortimer: I would refer you to today's press release and our 10K filing for other specific details from this year's financial statement. At this point, I'll turn the call back to Ian, who will summarize the key milestone events we're anticipating this year.

Therefore, we continue to have a lot of flexibility as we manage our business and continue to advance our product candidates.

Ian C. Mortimer: Thanks, Sherry. Looking ahead, our key corporate objectives include the continued advancement of our EPIC Phase III clinical trial in patients with KCNQ2-DEE. Top line results from a larger data set within the physician-led XEN007 proof-of-concept study and a decision around future development of XEN007 in CAE anticipated in the second half of the year; continued support of our partner program with Neurocrine Bioscience, including the anticipated initiation of two phase two clinical trials with MBI 921352 in 2021.

And as of December 31, 2020, there were approximately 35 million common shares outstanding and approximately 1 million series, one preferred shares outstanding which are convertible into common shares on a one for one basis at the option of the holder subject to certain limitations and.

We'd refer you to today's press release, and our 10-K filing for other specific details from this year's financial statements at this point I'll turn the call back to Ian who will summarize the key milestone events, we're anticipating this year.

Thanks, Gerry looking ahead, our key corporate objectives include the continued advancement of our epic phase III clinical trial and patients with Casey on the Q2 D. E. Top line results from the larger data set within the physician led <unk> 007 proof of concept study and a decision around fuel.

Ian C. Mortimer: The anticipated Phase 1B trial initiation by our partner, Flexion Therapeutics, with results potentially available in late 2021. In coordination with academic collaborators at the Icahn School of Medicine at Mount Sinai, the initiation of a Phase II proof-of-concept clinical trial examining XCN1101 in major depressive disorder and anhedonia.

The development of <unk>, 007, and CAE and anticipated in the second half of the year.

Operator: And importantly, within our XCN1101 Phase IIb extral clinical trial, we expect patient randomization to be completed in the first half of 2021, with top-line data anticipated in the third quarter of 2021. Adding this all up, we could potentially have up to seven clinical trials ongoing with five different molecules led by us, our corporate partners, and academic collaborators in 2021. In summary, to echo Simon's earlier comments, we believe Xenon has one of the most promising neurology pipelines currently in development, and we have the resources and talent in place to support the continued advancement of these promising therapeutics.

Continued support of our partnered program with Neurocrine biosciences, including the anticipated initiation of two phase II clinical trials with MDI 90, 21352, and 2021, the anticipated phase one b trial initiation by our partner flexion therapeutics with the results potentially available in late 2021.

One and coordination with academic collaborators at the Icahn School of Medicine, and Mount Sinai initiation of a phase II proof of concept clinical trial examining <unk> and 11 O one and major depressive disorder, and Antonio and importantly, within our ex CN 11, and one phase <unk> clinical trial, we expect patient random.

<unk> and have been completed and the first half of 'twenty and 'twenty, one with top line data anticipated in the third quarter of 2021.

Operator: On behalf of the Xenon team, we look forward to updating you on our progress over the coming months. At this point, we can open the call up for questions. I'll hand it back to the operator. Thank you. Ladies and gentlemen, if you have a question at this time, please press the star and then the number one key on your touch-tone telephone. If your question has been answered or you wish to remove yourself from the queue, please press the hash key.

Adding this all up we could potentially of up to seven clinical trials ongoing with five different molecules led by us our corporate partners and academic collaborators and 2021 in summary, the Echo Simon's earlier comments, we believe xenon has one of the most promising neurology pipeline is currently in development and we have the resources and talent and play.

To support the continued advancement of these promising therapeutics on the.

Paul Andrew Matteis: The first question comes from the line of Paul Matteis from CFO. Your line is now open. You may ask your question. Hey, thanks so much for taking the time to answer the questions. I wanted to ask you a couple quick ones on the 1101 depression program and some of this recent Azogavine data and then one question on 07. Regarding 1101 in depression, can you just tell us any more about this investigator study that's going to start and, you know, based on the Azogavine trial that was run at Sinai, how long do you think that study will take to complete?

Behalf of the xenon team, we look forward to updating you on our progress over the coming months at this point, we can open the call up for questions and I'll hand, it back to the operator.

Thank you ladies and gentlemen, if you had the question at this time. Please press the Star and then the number one key on your Touchtone telephone.

Austin has been answered or you wish to meet the staff of the peers and this question of Husky.

Our next question comes on the line of Paul <unk> from Stifel. Your line is now open and they asked the question.

Hey, thanks, so much for taking the questions I wanted to ask you a couple of quick ones on the 11 of one depression program and some of this recent exogamy and data and then one question on <unk> seven on 11 O one in depression.

Paul Andrew Matteis: And then second, on 1101 in depression, just curious, I don't know if you have a sense of this, but from looking at the population you've enrolled in the focal seizure study, what percent of patients do you think may have comorbid depression in this trial? And is there anything we could kind of glean from that subset in this study? And then I have one follow-up on 07, but I'll save it. Sure, Paul, Simon here.

Can you just tell us anymore about this investigator study of its going to start and you know based on the Zagha being trial that was run at Sinai. How long do you think that study will take the complete and then second on 11 don't want and depression, just curious I don't know if you have a sense of this but from looking at the population you've enrolled in the.

The focal seizure study what percent of patients do you think may have comorbid depression, and this trial and is there anything we can kind of glean from that subset of the study and then I have one follow up on all of us, but I'll save it. Thanks.

Simon N. Pimstone: Let me start with your second question, which is comorbid depression and extol. Of course, we didn't randomize subjects with that in mind, so comorbid depression will be, you know, not an endpoint per se, primary or secondary. We do have a 31-point questionnaire survey, which is a Quality of Life in Epilepsy, or QOLIE31 survey, which is delivered to the subject in the study at baseline and at the end of the study. I think it's just two time points, baseline and then at the end of the study. That is not a MADRS or SHAPS group.

Sure Paul Simon Here, let me start with your second question, which is co morbid depression and ex toll of.

Of course, we Didnt randomize subjects with that in mind, So co morbid depression will be.

It's not in the endpoint per se primary and secondary.

We do have a.

We do have a a city one point questionnaire survey.

Simon N. Pimstone: It's not a sort of specific depression score, but it is a good list of questions to give us a sense of the emotional well-being of patients in the study. So that will, of course, be interesting. We'll have that data at, whether it's at the top line or beyond, I can't say today, but certainly we'll have that data this year. Again, not strictly an MDD endpoint or an anhedonia endpoint, but we certainly will get a sense of patients' quality of life and emotional well-being, and you can look that up. It's a well-recognized scoring system.

Which is a quality of life and epilepsy of quality Q O L. I E 31.

Survey, which is delivered to the subject and the study at baseline and at the end of study I think it's just too two time points baseline and then study and.

And that that is not of a.

Madras or chaps, it's not a sort of specific depression.

And school, but it is a it is a good.

Simon N. Pimstone: In terms of the depression study, what I would say is that when the study comes out, as Ian referenced, we probably are weeks away from a publication, or at least our collaborators are weeks away from a publication. Our investigator-led study with Sinai will look very similar in design, so not to preempt the publication, which is an assurance we've given them. Stay tuned, we'll have that publication soon, and I think you could expect a very similar design. In terms of time to complete, it's tough to know at this point.

Questionnaire and lists to give us the sense of.

The emotional well being of patients in the study so that will of course the interesting we'll have that data at the whether it's a top line or beyond the icon say today, but Sydney will have that date of this year.

And again, not strictly and M D. The endpoint tornado and near end point, but we certainly will get a sense of a patients quality of life and emotional well being and you can look up that.

It's a well recognized of scoring system and in terms of the depression study what I would say is that.

Simon N. Pimstone: We're not guiding on that. I think we'd like to see how things go in the near term. It's not 2021, but we certainly hope it could be a 2022 timeframe, but we'll see.

When the study comes out as Ian referenced we probably of weeks away from of publication or at least our collaborate is weeks away from the publication.

Simon N. Pimstone: Okay, and then maybe one question on 07, Simon, that was really helpful. On the data coming later this year, I guess, what's kind of the hurdle for you moving forward? Is it consistent with the first three patients? How are you thinking about that? And then if you do decide to move forward, you know, because flunarazine was, I guess, ex-U.S., largely an adult drug, is there additional preclinical work you need to do to get the FDA comfortable for you to move, I guess, right into mid-stage trials? Yeah, I can take that.

All of investigator led study with cyanide will look very similar in design and so.

Not to preempt the publication, which is and assurance we've given them.

The state stay stay tuned, we'll we'll have that publication soon and the and I think you could expect a very similar design in terms of time to complete tough to know at this point, we're not guiding on that so I think we'd like to see how things go in the near term.

It's not it's not 2021 but.

Ian C. Mortimer: Thanks, Paul. So, you know, we think we're seeing a real signal right now in a small number of patients, and with the caveat that it's open label and it's a small number of patients, but given the seizure reduction and given the confirmation on EEG and that these were highly refractory patients with a high seizure burden and had had the disease for quite some time, we feel that we're getting I mean, some of these, a couple of these patients had quite material reductions, kind of in the 80 to 90% range.

But we certainly hope it could be of 'twenty 'twenty, two time frame, but we'll see.

Okay, and then just maybe one question on Oh, seven and Simon that was really helpful. On the data coming later this year I guess, what's kind of the hurdle for you moving forward something.

It's definitely the first three patients and how are you thinking about that and then if you do decide to move forward.

Cause the linearity was I guess, the ex U S largely and adult drug.

Is there additional preclinical work and you need to do to get the FDA comfortable for you to move I guess right into the mid stage trials and pediatrics.

Ian C. Mortimer: I don't think we have to see that to feel comfortable about moving forward, but I think we do have to get above where we would just be concerned that it's noise. So it's probably, you know, if we were anything kind of in the 50% range or greater, I think we would feel comfortable. If there was a situation where we had to produce some additional data before getting into a study in the U.S., the other option here, given the widespread use of the drug, is we could always start a study outside the U.S. and then bring it into the U.S.

And yes, I can take on it.

Thanks, Paul.

So we think we're seeing a real signal right now and a small number of patients and with the caveat. It's open label and it is a small and.

But given the seizure reduction and given the confirmation on the EG.

And the these were highly refractory patients with high seizure burden and that had the disease for quite some time, we feel that we're getting a signal.

I mean, some of the couple of these patients had had quite material reductions kind of and the 80% to 90% range. I don't think we have to see that feel comfortable about moving forward, but I think we do have to get above where we would just be concern that it's noise. So it's probably if we're anything kind of and the 50% range or.

Ian C. Mortimer: So I think we have some flexibility in the development plan, but we need that regulatory interaction to give us precise feedback. And just one additional comment is just a reminder; we do have a license to data that could support a submission using data that has been generated outside the US. The one caveat is that some of that data is old and so hard to know which of that is up to required ICH standards.

I think we would feel comfortable but we're really parallel processing. This we have less control over the current 007 study, but what we do have control over is our own development planning and also having some regulatory interaction. So we can't answer your question today on on if we need more preclinical data there is a lot and known and.

Simon N. Pimstone: But that review is well underway, and as Ian said, we expect an engagement with the FDA this year. There are other alternatives, as Ian said, so at least get the study going. Got it. Thank you guys. Appreciate it. Not at all.

About this drug in pediatrics, we expect to have regulatory interaction with the FDA. Later this year. Once we have our development plan and started and get that feedback. If there was a situation where we had to produce some additional data before getting into a study and the U S. The other option here is given the widespread use of the drug as we.

Operator: Thank you. The next question comes from the line of Andrew Chai from Jeff Swish. Your line is now open.

Andrew Chai: You may ask a question. Thanks, and congratulations, Simon, Ian, and Sherry, on your new roles. The first question is really just about the market opportunity for 1101. I mean, based on my conversations, investors seem to be doing a lot more work on the market potential for focal epilepsy. So can you help us understand why, I guess, some of these approved drugs out there are doing, for example, over $1 billion in sales? What would be some of their more favorable attributes?

Could always start of study ex U S and and then bring it to the U S. So I think we have some flexibility on the development plan, but we need that regulatory interaction to give us precise feedback.

And just one additional comment as just a reminder, we do have a license to data that could support the submission.

Using data that is being generated ex U S. The one caveat being some of that data is old and so hard to know which of that is up two required ICA ICH standards, but that review is well underway and as Ian said, we expect and engagement with the FDA. This year there are other alternatives as Ian said.

Ian C. Mortimer: And, you know, would 1101 have similar or even better attributes? Thanks, and I'll have a follow-up. Yeah, thanks, Andrew. Yeah, I mean, we've talked about for some time that we believe that the commercial opportunity for 1101 is sizable. You know, there are 3 million epilepsy patients in the U.S., and the majority of the phenotype is adult focal epilepsy.

And so at.

And it needs to get the study going.

Got it. Thank you guys appreciate it.

No.

Thank you. Your next question comes from the line of and it ties from Jefferies. Your line is now open you may ask your question.

Simon N. Pimstone: And then you still have a large proportion that aren't currently well-controlled. And so, you know, in the U.S., we have hundreds and hundreds of thousands of patients that currently aren't well-controlled and have a need for new drugs and new mechanisms. You know, some of the drugs that you've been referring to; we agree, I think these kind of ease of use attributes or the totality of the package of a drug are really important.

Thanks, and congratulations Simon and Ian and Cherry on your new roles.

First question is really just about the market opportunity for 11 on one.

Based on my conversations of investors seem to be doing a lot more on work about the market potential and focal epilepsy. So can you help us understand why I guess some of these approved drugs out there are doing for example over $1 billion and sales.

Simon N. Pimstone: You know, the two drugs that have done extremely well, Kepra and Vimpat. Kepra was a novel mechanism and the first SV2A drug that was launched, and now Kepra, even as a branded generic, there are over 2 million patients globally that are on Kepra. And Vimpat was a drug that, even as a BID drug, was very well tolerated and has, you know, the peak sales were guided by UCB, I think, are approaching closer to two billion than one.

And what would be some of their more favorable attributes and.

The 11, and one have similar or even better attributes.

And Oh, yes, thanks, Andrew.

We've talked about for some time that we believe that the commercial opportunity for 11 O one of the sizable theirs.

3 million epilepsy patients and the U S. The majority of the of the phenotype of adult focal epilepsy and.

And then you've got <unk>.

Still a large proportion that arent currently well controlled and so and the U S, where and hundreds and hundreds of thousands of patients that currently arent well controlled and and have a need.

Ian C. Mortimer: So yeah, there's a large commercial opportunity, and where we think 1101, and this is some of the data that we've confirmed both through market research as well as what we presented at the Ascent meeting recently, is that we think 1101 would fit really nicely in terms of it being an only-in-class drug, it will be adding a new mechanism for physicians to use, and then, as we've talked about in terms of QD at evening do We think the low risk of DDI from what we've seen to date really gives it a good opportunity to be a successful drug and a really important drug for patients.

And for new drugs and new mechanisms.

Some of the drugs that you have been referring to we agree I think these kind of ease of use the attributes or the the really totality of of the package of the drug is really important.

The two drugs that have done extremely well capra and vimpat.

<unk> was a novel mechanism.

And the first SP to a drug that was launched and now cap rate, even if the branded generic theres over 2 million patients globally that are on camera.

Ian C. Mortimer: Yeah, I'll just add to that, Andrew. I don't think, as we look at this, there are very few properties of the drug that we could consider changing in terms of ease of use. It's as easy as it gets in terms of what we're seeing today.

And vimpat with the drugs that even as of the drug was very well tolerated.

And and has the peak sales of the guided by UCB. I think is is approaching closer to 2 billion and one.

Simon N. Pimstone: Once a day, no titration, no DDI, no QT prolongation. Whether we're able to show, for example, benefits in depression will be a massive differentiator in addition. So, as Ian says, we're very bullish on this. We think there are huge opportunities still, and we think this drug can be very, very favorably positioned within the market.

So yes, there is a large commercial opportunity and where we think of 11 and won and this is some of the data that we've confirmed both through market research as well as we presented at the ascent media recently is that we think of 11 of one would fit really nicely in terms of it will be and only and class drug and it will be adding a new mechanism.

Our physicians to use and that and as we've talked about in terms of QD of evening dosing. So far no titration, we think low risk of DDI and from what we've seen to date really gives it a good opportunity to be successful drug and a really important drug for patients.

Andrew Chai: And my second question is, I'm actually curious, how are you guys thinking about sharing the open label data for extal, the open label extension? I mean, should we expect you to share it at the one-year mark or when patients have been treated for six months? Or could you actually potentially share the OLE data at the time of the top line readout in Q3, just a segment of it?

I'll just add to that Andrew.

I don't think as we look at this the there are very few properties of the drug that we could consider changing.

Changing.

In terms of ease of use.

Easy as it gets in terms of what we're seeing today once a day and no titration, no DDI and no Qt prolongation.

And whether we able to show for example benefits and depression.

We will be of massive differentiator in addition.

So.

And since we are very bullish on this.

Ian C. Mortimer: Thanks. Thanks, Andrew. Yeah, so for the top-line results in Q3, obviously, the focus is going to be on the double-blind portion, and we'll obviously provide top-line data on primary and secondary endpoints. We'll have commentary on safety and tolerability. The open-label extension, we may be able to give kind of some qualitative directional information. It is being used. It's not via an electronic diary.

We think there's huge opportunity still and we think this drug can be very very favorably positioned within the market.

Great. Thank you and second question is on.

And I'm actually curious how are you guys thinking about sharing the open label data for it extra on the open label extension and then should we expect you to share it at the one year mark or when patients have been treated at six months or could you actually potentially share of the the O L. E data at the time of the top line readout in Q3 just the.

Ian C. Mortimer: We use a paper diary for the open label extension, and so I think collecting and cleaning that data as efficiently as we can in the double-blind portion isn't really our goal. I mean, we have patients that have hit the 12-month mark already, and our guidance remains that we've had extremely high rollover to open label extension from the double-blind portion, but I would really focus the top-line results in Q3 on the double-blind portion and probably less information at that time on open label extension, and then that'll probably come out over time, as you say, as we have kind of a critical mass of patients going through Thank you. Operator, any other questions?

And.

A segment of it thanks.

Thanks, Andrew Yes, so for the.

Top line results and Q3.

The focus is going to be on the double blind portion and.

And we'll obviously provide top line data and primary and secondary endpoints will have commentary on safety and Tolerability.

The open label extension, we may be able to give kind of some qualitative.

The directional information.

It is being used it's not via an electronic diary and we'd use of paper diary for the open label extension and so I think to collect and clean that data as of <unk>.

Additionally, as we can and then within the double blind portion and Thats really not our goal I mean, we have patients that have hit the 12 month Mark already.

Operator: Yes, we do have a question from Mark Goodman from FBB Lyrics. Your line is now open, and you may ask your question. Hey guys, can you just tell us why you've decided to wait until later in the year to kind of give us the data? Just tell us again. Is that because you're trying to increase the number of sites and you're just trying to make it more robust? I mean, what was the rationale there? And secondly, on 007, are you considering additional indications to look at besides absence, epilepsy, any other type of epi I guess that's first. I'll wait a second.

And our guidance remains that we have had extremely high rollover to open label extension from the double blind portion, but I would really focus the top line results in Q3 on the double blind portion and probably less information at that time on open label extension and then that will probably come out over time as you as you say as we have.

Kind of of critical mass of patients going through certain time points like six months of 12 months.

Thank you.

Marc Harold Goodman: Sure. I'll talk about the indications, and Ian can talk about guidance. You know, there are a number of potential indications, Mark. We've talked about those previously, alternating hemiplegia, hemiplegic migraine, where the drug is used, both of which are indications where the drug is used widely off-label.

Operator any other questions.

Yes, we do have a question from Mark Goodman from SBB Leerink. Your line is now open you may ask a question.

Simon N. Pimstone: Just as a reminder. You know, at this point, we'd be relying primarily on exclusivity. And so while the drug has been approved for larger indications, outside the U.S., such as migraine and vertigo, I think the focus will be, at least initially, on orphan exclusivity. I think CAE is, to date, the standout opportunity. That doesn't mean there won't be others, but that's really where the bulk of our focus is and primarily because I think it, firstly, fits in very well with our epilepsy basket, but secondly, we do see an important need.

Yes, the guys.

And you just tell us.

Oh, seven you've decided to wait until later in the year to kind of give us the data just tell us again is that because youre trying to increase the number of sites and just trying to make it more robust I mean, what was the rationale of there.

And secondly on O seven and are you considering.

The additional indications to look at besides the absence epilepsy any other type of epilepsy.

I guess, that's first right of way.

The second sure I'll talk about the indications and Ian can talk about guidance.

Simon N. Pimstone: These are patients that are generally adolescents, so from a toxicology and non-clinical perspective, probably a bit easier than a very early infant population, which may be alternating hemiplegia, for example, and they're a good number, 40,000 to 50,000 CAE patients in the U.S., of which 30% to 40% are either refractory or intolerant of existing agents, so that's really what I think are some of the key.

The the there are a number of potential indications mark we've talked about those previously alternating hemiplegia of MEP, Jake migraine, where the drug is used both of which are.

Indications of the drug is used widely off label just as a reminder.

At this point.

We'd be relying primarily on.

Ofer and exclusivity and so while the drug has been approved for larger indications ex U S. Such as migraine and voted go I think the focus will be.

Ian C. Mortimer: Plus, I would just say that, again, if our larger cohort provides similar comfort to what we've seen in the first few subjects, I think strong validation for that indication. Yeah, so, I mean, the simple answer to your question, the answer is yes, Mark. We're, you know, this started as a single center locally, and that's where the first amount of data was generated from, and to accelerate and get some more patients in the study, we are going to expand to at least a couple additional sites, at www.thevenusproject.com And then, as we mentioned in parallel, we'll be working on our own regulatory strategy to get some feedback on moving this into a company-sponsored, And then just on 1101, the enrollment, I think your comment was pretty positive, the enrollment, we haven't really missed a beat on COVID in the past, you know, two, three months, it's gotten okay and no urinary issues are popping up.

Just initially.

On the on orphan exclusivity.

I think CAE has to date is the standout opportunity doesn't mean, there won't be others, but that's really where the bulk of our focuses and primarily because I think the first the fits and very well into the epilepsy basket, but secondly, we do see a and important need these of patients that are generally adolescence. So from.

The toxicology and non clinical perspective, probably a bit easier than the very early infant population, which may be alternating hemiplegia of for example.

And the good number 40 to 50000, and CAE patients and the U S of which 30% to 40% are either refractory or intolerant of existing agents. So that's really what what I think is of some of the key plus I would just say that again, if all of the larger cohorts provides similar comfort too.

What we've seen and the first few subjects.

On the strong strong validation for that indication and just on timing.

Ian C. Mortimer: So, yeah, I'll tackle the first one, and obviously, we have blinded data, so all we can say overall is that, you know, tolerability has been good, and kind of at that macro level, dropout rates have been lower than we modeled, and we've had very high rollover to open label extension. Yeah, you know, I think many people know the history here.

Yes, I mean, the simple answer to your question the.

The answer is yes, Mark were the started as a single center.

The locally and.

And that's where the first amount of data was generated from.

And to accelerate and get some more patients and the study we are going to expand to at least a couple of additional sites to increase enrollment and.

Simon N. Pimstone: This was a challenging study during the first wave of COVID, when a lot of clinical sites were completely shut down, and we did a number of things. Mark, in terms of the urinary issues, I mean, all we can say is, and Ian and I don't have visibility into every A in every patient, but we've not had any reports of issues of concern, any drug-related issues of concern, so we're not seeing any signals that we're aware of as of today.

And get some kind of a larger data set that we can share we will need to coordinate with the investigator at her study is the Pi and.

In terms of how we release that data so we'll be working closely with her and order to be able to release that.

Simon N. Pimstone: Again, blinded, unscrubbed data, just as a caution and caveat. So you know, again, knock on wood, the study, as we've reported on a few times now, appears to be going very well. We're very much on track, and you know, to Ian's point, we now, I think, finally do have visibility where we've had a few months of very, very consistent screening and randomization, and it's looking very good. Thank you. And as a reminder, to ask a question, you will need to press star 1 on your telephone keypad.

And obviously as you'd like to really set the likelihood and upcoming medical meeting.

And then as we mentioned in parallel and we'll be working on our own regulatory strategy to get some feedback on moving this into the company sponsored study.

And then just on 11 of one of the enrollment I think your comment was pretty positive because the enrollment we haven't really missed the beat on COVID-19 and the past two or three months its gotten okay and and no urinary.

Our profit up.

Operator: We will limit each participant to ask one question to give other participants on the queue time to ask their question respectively. You may also re-enter the queue for a follow-up question. The next question comes from the line of Laura Chico from Red Rush.

So.

And I will tackle the first one.

And obviously, we are blinded data. So all we can say overall is that.

The Tolerability has been good and kind of of that macro level dropout rates of being lower than we modeled and we've had very high rollover at the open label extension.

Kenneth: Your line is now open. You may ask your question. Hi, this is Kenneth on behalf of Laura Chico.

Ian C. Mortimer: Thanks for taking our question. So on 11-01, realizing it's still a little premature here, but it's still a study on track to report, top line 3Q21, we're just wondering if you could revisit here, what would be necessary to demonstrate the reductions in seizures? Also on the safety and tolerability profile, and I have a follow-up. Sorry, is the question, what would we consider successful, or what is the study modeled on? What is necessary to demonstrate on reduction in C2H4?

Yes.

I think many people know the history here. This was the challenging study during the first wave of Covid.

And and where a lot of clinical sites were completely shut and and and we did a number of things. We obviously worked to ensure that we could get drug to subjects that we could with the electronic diary and we can capture all of the data make adjustments in terms of telehealth and.

And even having caregivers go to homes and order to collect samples so we.

Ian C. Mortimer: Okay. So I'm going to answer that question. Kenneth, I think as we've talked about before, but just to remind everyone, we have close to 90% power to test the null hypothesis that there's no change between, remember this was a forearm study; we have placebo and then three active doses. And then the alternative hypothesis is that there is a dose response trend, and so it's a linear, what we call a linear trend test is the primary endpoint, and it'll be positive if at least one dose is better than placebo. The real power of the study is being driven by the high dose 25 MIG arm because that's where we have 100 subjects.

And we've done everything we can to.

For the study and we feel very positive in terms of the integrity of the data.

Enrollment has started to pick up again last fall and yes, I think your comments and.

<unk> is correct, we feel very confident and where we sit today that we've had consistent enrollment over the last number of months and we're on track to finish screening and randomization first half of this year and on track for top line data in Q3.

Thanks, Mark in terms of the urinary issues and all we can say is and you know and identive visibility on every area and every patient, but we've not had any reports of issues of concern any drug related issues of concern.

Ian C. Mortimer: We have 100 subjects in the placebo group and then 50 subjects in the two lower doses, 20 milligrams. And then the assumptions in terms of the model and the simulations we run for our power calculations, and obviously these will change, but just to give you an idea that we've spoken about in the past, are that the placebo rate would be around a 20% reduction, and then there would be a dose response with 10 milligrams at a 25% reduction, 20 milligrams at 30, and 25 milligrams at a 35% reduction.

And so we're not seeing any signals that we were aware of as of today again blinded on the scrub data just as of caution and caveats. So again knock on wood the.

As we've reported on a few times now appears to be going very well, we're very much on track and.

And at the end point, we now I think finally and do have visibility.

And we've had a few months of very very consistent screening and randomization and it's looking very good.

Thanks.

Thank you and as a reminder to ask a question you have the depressed part of one on the telephone keypad and you build.

Ian C. Mortimer: So that's the way that the study is designed from a powering perspective. And then in terms of safety and tolerability, I mean, obviously, you know, we're gonna have to wait and see. I think what is gonna be important is how this stacks up in comparison with other anti-seizure medicines and knowing that all of these patients are on ConMeds, so obviously, we're gonna need to take into consideration what that looks like when we're looking at an active. Okay, thank you, and then a follow-up. Please press star 1 again.

And its participants to ask one question to give the other participants on the queue to ask your question. The spot you may also be added to the Q4 of follow up question net.

Next question comes from the line of Laura Chico from Wedbush. Your line is now open you may ask a question.

Hi, This is kind of what's on for Laura Chico and thanks for taking our question so on.

11 of the one realizing it's still a little premature here, but the.

The study on track and report top line.

The 21 or just wondering if you could the resistant here and what would be necessary to demonstrate on the reductions in cedar and so on.

And so on the safety and Tolerability profile and the hypothalamus.

Sort of is the question and what what what would we consider successful of what is the study modeled on just can you.

Ian C. Mortimer: Thank you for the follow-up question. Again, we will limit each participant to asking one question to give other participants on the queue time to ask their question respectively. You may also re-enter the queue for a follow-up question. And you simply press star 1 on your telephone keypad.

And what is necessary to demonstrate.

Teachers.

Okay.

So.

Kenneth and I think as we've talked about before but just to remind everyone. We have close to 90% of power.

Operator: The next question comes from the line of Yatin Sinoha from Guggenheim. Your line is now open. You may ask a question. Hey guys, this is Eddie from Forgotten. Thanks for taking my questions. Are you there, Eddie?

To the the null hypothesis is that there is no change between and remember this is a four arm study with placebo and then three active doses and then the alternative hypothesis that there is a dose response trend and so its the linear what we call of linear trend and test as the primary endpoint and it will be positive.

Eddie: We just got disconnected from the queue; kindly press star 1 again to queue in again. Operator, I think we can just do the next one in the queue. All right, next question from the queue comes from the line. Oh, we have the line from Yatim Suneha from Guggenheim. Your line is now open, you may ask a question. Hey, can you hear me?

If at least one dose is better than placebo the real power of the study is being driven by the high dose of 25, Meg arm, because that's where we are of 100 subjects. We have 100 subjects on placebo and then 50 subjects and the two lower doses 20 milligrams and 10 milligrams and and then the the.

The assumptions in terms of the.

Operator: Yeah, that's good, Eddie. Thanks. Great. Thanks. So, yeah.

And the model and the simulations, we run for our power calculations is.

Eddie: So, given that you've opened some additional European sites for the 1101 study to speed up enrollment, are there any sort of major differences we should think about in terms of baseline criteria or background medications that are sort of more prevalent in Europe? And then just, like, if you could sort of let us know for the 496 study if you're going to give enrollment guidance at all or, as the study progresses, let us know when we should think about top-line data there. Thanks.

And then obviously these will change, but just to give you an idea that we've spoken about it and the past as of the placebo rate would be around a 20% reduction and then there'll be a dose response with 10 milligrams at a 25% reduction 20 milligrams at 30.

And 25 milligrams that of 35% reduction so that's the way that the study is designed from a powering perspective.

Ian C. Mortimer: So on 1101 Eddie, so yeah, about half of the clinical sites are in the U.S., and about half are in Europe, and we've seen so far in patient screening randomization, it's actually been almost even between the two jurisdictions. So in terms of, you know, most anti-seizure medicines that are approved in the U.S. or approved in Europe, we don't expect much imbalance or concerns in terms of background meds, depending on the jurisdiction. You know, we sometimes get questions about Sinovamate that was recently approved, but I think there'll probably be a small number of patients in this study, given the timing that would have had Sinovamate exposure coming into But we don't expect any concerns coming into the study or as we move through it.

And then in terms of safety and Tolerability of.

Obviously.

We're going to have to wait and see.

What is going to be important is how does the stack up and in comparison with other anti seizure of medicines and knowing the and all of these patients are on con meds, and so obviously, we're going to need to take into consideration what that looks like when we were looking at and active group versus placebo.

Okay. Thank you.

And then the follow up.

And just gets disconnected from the queue kinds of price.

Once again.

What sort of follow up question again, we will limit each participant to ask one question.

Participants on the queue to ask your question respectively.

And they also re enter to the queue for a follow up question.

Simply press Star one on the telephone Keypad next question comes from the line of Fiat. The instead of all have from Guggenheim. Your line is now open you may ask the question.

Oh, Hey, guys. This is eddie on for the yacht and thanks for taking my questions. So firstly.

Ian C. Mortimer: In terms of 496 enrollment, you're right, we haven't yet given guidance on enrollment or when we would see top-line data. You know, we'd like to get the studies up and running initially in the U.S., but it will be in other jurisdictions as well. We're looking later this year when we get a critical mass of sites up and running, and we can start to see what those enrollment curves look like.

Are you there already.

He just got disconnected from the two kinds of press Star One again two key win for a question.

Operator, I think we can just added to the next one and the kidney.

Ian C. Mortimer: This is obviously a rare condition, and so hopefully later this year we'll be able to provide some guidance on where we are. You know, normally we don't give specific enrollment guidance, but at some point, we'd like to give guidance in terms of when we would expect to see top-line data. Thank you. The next question comes from the line of Serge Belanger from Needham and Company. Your line is now open. You may ask a question. Hey, good afternoon.

Alright.

Next question from the queue comes from the line.

Hum.

The line from the us into Manhattan from that didn't have your line is now open you may ask your question.

Hey can you hear me, yes, that's good thanks, great. So yeah, so given that you've up and some additional European sites for the 11 on one study the speed up enrollment is there any sort of major differences. We should think about in terms of baseline criteria of our background medications that are sort of more prevalent.

In Europe, there and then just like if you could sort of let us know for the 496 study if youre going to get the enrollment guidance guidance at all or sort of as the study proceed let us know when we should we should think about top line data there. Thanks.

Serge D. Belanger: First one on 1101. So I mean, I think in your prepared comments, you mentioned that the KV channel had some data supporting its potential and additional non-epilepsy indications. I think you mentioned pain and tinnitus.

So on.

On 11 on one.

And so about half of the clinical sites are in the U S and about half of our in Europe and and.

Simon N. Pimstone: Should we expect to see depression as the first of other non-epilepsy indications for 1101? Yeah, right now, the focus is on MDD. I think, as we've said, that's an investigator-led study we're looking at now, which should initiate soon. We're certainly looking at other indications, but we don't have a budget allocated for other indication studies at this point, and we haven't made any decisions on any new indications at this point. That being said, as you've correctly pointed out, there are lots of interesting areas for KB7. We like MDD as an option among all of those for two reasons.

And we've seen so far and patient screening and randomization.

It's actually been almost even between between the two jurisdictions so.

In terms of most of the when we look at the anti seizure medicines the drugs that are approved and in.

And the U S are approved in Europe, we don't expect.

Much of balance or concerns in terms of background meds, depending on the jurisdiction.

So no we got sometimes questions about <unk> that was recently approved but I think there'll be probably a small number of patients in this study given the timing the would've had sonoco made exposure coming into and to the 11 on one study. So we don't have of concern that theres going to be some type of imbalanced based on geography, but obviously when we get into the.

Simon N. Pimstone: Well, three, validation, obviously, of the target, and you'll see more of that in an academic publication in the near term. But two, massive commercial opportunity, and number three, a very, very important comorbidity with epilepsy, and so I think taking those three into consideration. I think this is where you should expect to see the company focus most of its efforts and resources going forward in non-epilepsy indications for the KB7. Thank you. The next question comes from the line of Tim Lugo from William Blair. Your line is now open.

The detailed statistical analysis, we're always looking at any of those things.

But we don't expect any any concerns coming into the into the study or as we've moved through it in terms of 496 enrollment so you're right, we haven't yet given guidance on enrollment and ore.

When we would see top line data, we'd like to get the study is up and running initially and the U S. It will be and other jurisdictions as well.

We're looking later this year when we get a critical mass of sites up and running and we can start to see what those enrollment curves look like this is obviously of rare condition and so hopefully later this year, we'll be able to provide some guidance on where we are.

Timothy Francis Lugo: You may ask your question. Thanks for the question. For following up on depression, I know you don't want to go into too many details, but broadly, are you looking at randomized placebo-controlled studies for this next proof of concept study? And 1101 obviously combines well with anti-seizure medications, but do you have data where it combines well with any kind of depression therapy, or are you thinking of it as a monotherapy in this indication?

Normally we don't give specific enrollment guidance, but at some point, we'd like to give guidance in terms of when we would expect to see top line data.

Thank you. Your next question comes from the line of Sage Bon Jour from Needham and company. Your line is now open you may ask the question.

Hey, good afternoon.

The first one on one one on one.

And I think in your prepared comments you mentioned that.

Timothy Francis Lugo: Yeah, I mean, right now, we're thinking of it as monotherapy, and certainly, we'll be looking at combination work as time moves on. But in terms of the high-level study design elements, yeah, I think what we can say is we'd expect to see a randomized controlled study with an active and placebo arm and with typical blinding.

The kv channel had some.

Data supporting its potential and additional non epilepsy indications I think you've mentioned pain and Tonight is should we expect to see depression as the first of them.

Other non and epilepsy indications for a one on one.

Yeah right now of the focus is on the M. D. D. I think as we've said that's a.

Simon N. Pimstone: So you know, expect to see that, and then more details around endpoints, size, number of sites, etc. will be made available as the study kicks off. I'll just remind you, as I said to Paul earlier, Tim, when the publication comes out, I think there'll be... There are very similar elements in the study that we'll be launching as a next study to what is published in the upcoming manuscript that you should see over the next few days.

Investigator led study we're looking at now.

It should initiate soon.

We're certainly looking at other indications, but we don't have budget allocated for other indications studies at this point and we haven't made any decisions on any new indications at this point and that being said as you've correctly pointed out lots of interesting areas for <unk> seven.

Simon N. Pimstone: Thank you. There is time remaining for one more question, and we have a question from the line of Antonia Barovina from Bloomburton. Your line is now open.

We like M D D.

As an option of all of those for two reasons of three validation, obviously of the targets and Youll see more of that and the academic publication near term number two massive commercial opportunity and number three of very very important comorbidity with epilepsy, and so I think taking those three and.

Antonia Barovina: You may ask your question. Hi Simon and Ian, thank you for taking my question. I'm just wondering, have you compared Azogabine to 1101 preclinically in terms of mood and depression symptoms? And can you rule out that the other subtypes like 7.4 and 7.5 play any role in mood symptoms? That's a good question, Antonio. We don't think the other subtypes do.

The consideration I think this is where you should expect to see the company focus most of its efforts and resources going forward and non epilepsy indications for the <unk> seven mechanism.

Thank you and next question comes from the line of Tim Lugo from William Blair. Your line is now open you may ask your question.

Thanks for the question for following up on Depression, I know you don't want to go into too. Many details. The broadly are you looking at randomized placebo controlled studies for the next proof of concept study.

Simon N. Pimstone: We, you know, if you go to the literature, in fact, collaborators at Mount Sinai have published quite widely on the non-clinical chronic social defeat model, et cetera, where really KV73 stands out as the primary KV channel in this anhedonic and nor-depressive phenotype. We're pretty, we feel pretty confident that it is KV73 primarily and 723 heterotetramer, which is Of course, 1101 being more active on the target compared to Isogabine, so we really don't think it's a distinct KV7 mechanism. But a very good question.

And the 11, and one and obviously combines well with anti seizure medications, but do you have data where it combines well with kind of the depression therapies or.

Or are you thinking of all of the monotherapy isn't the case.

Yeah, I mean, right now we're thinking of it as monotherapy and certainly we'll be looking at combination work is as time moves on.

But in terms of.

The the high level of study design elements, Yeah, I think what we can say is we would expect to see a randomized controlled study.

With the active and placebo arm and.

And it was with typical blinding so expect to see that and then more details around the endpoints size number of sites etcetera. It will be made available.

Simon N. Pimstone: We haven't yet done the head-to-head work, but that's something we would like to do, and we'll plan on doing it. You know, similarly, we expect to start the study with 1101 in humans soon, which we're committed to. So, you know, we think it's the right mechanism. We think there's a good amount of non-clinical, genetic, and pharmacological mechanism for this in animals, and we think it's KB7-3 predominantly.

And as the study kicks off.

I'll just remind you as I said to Paul earlier, Tim when the publication comes out and so I think there'll be.

So very some of the elements in the study that we'll be launching as of next study to what are what is published and the upcoming.

Menu script that you should see over the next few weeks.

Operator: Okay, thank you. Thank you. I am showing no further questions at this time. I would now like to turn the conference back to Ms. Jodi Wright.

Thank you there is one of those time remaining for one more question.

And the other question from the line of Tony of Gogo Vena from Bloomberg. Your line is now open you may ask your question.

Jodi Wright: Ma'am, please go ahead. Thank you everyone for joining us today. Operator, we will now end the call. Thank you, ladies and gentlemen. This concludes today's conference. Thank you for your participation and have a wonderful day. You may all disconnect.

Hi, Simon and me and thank you for taking my question I'm. Just wondering have you compared the OCA being 211 and no one pre clinically in terms of the mood and depression symptoms and can.

Can you rule out that the other subtypes of like seven four and 7.5.

Play any role and and maybe.

And Doug.

That's a good question Antonio.

We don't think the other subtypes dude.

And we if you go to the literature and fact.

Collaborators at Mount Sinai.

Published quite widely on the non clinical and <unk>.

Conic social defeat model et cetera.

And we really cave seven three.

Stands out as the primary kv channel.

And this and had done Inc, and no depressive phenotype.

We're pretty we feel pretty confident that it is the cave seven three primarily and 72 three <unk>.

Which is acted upon by both of US all good bean and 11 O. One of course 11 of one being more active on the target compared to it's all good. So we really don't think it's a.

A distinct kv seven mechanism.

But a very good question.

We haven't yet done the head to head work, that's something we would like to do and we'll plan on doing but.

Similarly, we expect to start the study with 11 of one inhuman soon.

Which obviously we've committed to so.

We think it's the right mechanism, we think there's a good amount of non clinical.

Genetic and pharmacological mechanism for this in animals and.

And we think it's <unk> III predominantly.

Okay. Thank you.

Thank you and I'm showing no further question at this time I would now like to turn the conference about the MS. Jodi rights Ma'am. Please go ahead.

Thanks, everyone for joining us today, operator, we will now end the call.

Thank you ladies and gentlemen. This concludes today's conference. Thank you for participation and have a wonderful day you may all disconnect.

Uh huh.

[music].

And.

Okay.

And.

And.

[music].