Q2 2022 Xenon Pharmaceuticals Inc Earnings Call

Operator: Good afternoon, and welcome to the Xenon Pharmaceuticals Report's second quarter results conference call.

Good afternoon, and welcome to the Xenon Pharmaceuticals reports second quarter results Conference call.

Operator: All lines have been placed on mute to prevent any background noise.

All lines have been placed on mute to prevent any background noise. After.

Operator: After the speaker's remarks, there will be a question and answer session.

After the Speakers' remarks, there will be a question and answer session.

Operator: If you would like to ask a question during this time, simply press star followed by the number one on your telephone keypad.

If you would like to ask a question. During this time simply press star followed by the number one on your telephone keypad. If you would like to withdraw your question again press to Starwood. Thank you.

Operator: If you would like to withdraw your question, again, press the star one.

Sure Allen Chief Financial Officer, you May begin your conference.

Operator: Thank you.

Thank you good afternoon, everyone and thank you for joining us on our call and webcast to discuss the second quarter 2022 financial and operating results. Joining me are even more tomorrow.

President and Chief Executive Officer, Dr. Chris Kenny you know him as Chief Medical Officer and Dr. Chris One figure and you know I'm the Chief commercial officer. Please be advised that during this call. We will make a number of statements that are forward looking including statements regarding our and our collaborators development plan anticipated regulatory interactions and submit.

And anticipated results and related timelines, the potential efficacy safety profile addressable market and commercial potential of our proprietary and partnered product candidates the efficacy of our clinical trial designs and anticipated enrollment the potential receipt of milestone payments and royalties from our collaborators are expert.

Patient of having sufficient cash to fund operations into 2026, and the timing of potential release of future clinical data.

We're 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 today's press release summarizing.

You know in the second quarter 2022 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 xenon batch form of Dot com and filed with the SEC and on SEDAR.

Operator: Sherry Aulin, Chief Financial Officer, you may begin your conference.

I turn the call over to Ed.

Sherry Aulin: Thank you.

Thanks, Jerry good afternoon, everyone and thanks for joining our call we'll start today's call with a high level summary of our recent progress.

I'll turn the call over to Chris Kenny who will provide additional color around our <unk> 11 on one end of phase two meeting with the FDA and our next steps within our phase III program, including our expansion into the additional epilepsy indication of primary generalized tonic clonic seizures or PGA Tcs, Chris will also provide his perspective on the additional external data, which we recently released.

Ms Christina.

Chris One second and we'll then share some market research insights shaping our clinical plans in <unk>.

Commercial opportunity for developing exon 11 O one within this indication where there remains a significant unmet medical need.

Gary will conclude our call by briefly summarizing our partner programs.

Results in it.

Events.

We look forward to taking your questions during the Q&A session at the end of the call.

Sherry Aulin: Good afternoon, everyone.

I am pleased to report several important achievements within our <unk> one program. This past quarter, along with continued progress across the rest of our pipeline.

Sherry Aulin: Thank you for joining us on our call and webcast to discuss Xenon's second quarter 2022 financial and operating results.

With the next Gen 1100, one clinical data generated to date, along with feedback from Kols and primary research market market research findings support our belief that actually on 11 O. One could play a particularly important role in treating epilepsy with a differentiated profile and desirable attributes such as an only in class potassium channel mechanism and the dosing regimen.

One pill once a day with no titration, providing meaningful seizure reduction after only one week of dosing.

In addition to its robust efficacy and focal onset seizures. The <unk> hundred one AE profile is in line with other anti seizure medications.

In a positive end of phase two meeting with the FDA. We're excited to advance <unk> hundred one phase III program, starting with the initiation of <unk> two in the second half of this year, adding.

Additionally, we had strong scientific rationale supporting the use of <unk> 11 O. One to address primary generalized tonic clonic seizures, and we're looking forward to initiating our phase III exact clinical trial in PG Tcs ultimately our goal is to deliver deliver a new differentiated therapeutic option for.

A broad population about biloxi patients.

Sherry Aulin: Joining me are Ian Mortimer, Xenon's President and Chief Executive Officer, Dr. Chris Kenney, Xenon's Chief Medical Officer, and Dr. Chris von Seggern, Xenon's Chief Commercial Officer.

Our team recently completed additional analysis of efficacy data from our phase <unk> trial and these further support our phase III development plans for <unk>, including the time course of efficacy analysis, demonstrating that all doses of <unk> hundred one rapidly reduce the frequency of focal onset seizures within one week compared to.

Sherry Aulin: Please be advised that during this call, we will make a number of statements that are forward looking, including statements regarding our and our collaborators' development plans, anticipated regulatory interactions and submissions, anticipated results and related timelines, the potential efficacy, safety profile, addressable market, and commercial potential of our proprietary and partnered product candidates, the efficacy of our clinical trial designs and anticipated enrollment, the potential receipt of milestone payments and royalties from our collaborators, our expectation of having sufficient cash to fund operations into 2026, and the timing of potential release 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.

Placebo, Chris Kenny will provide some more details on these data as well as our first cut of open label extension efficacy data for Mexico, and our phase III plans.

In addition, our phase II <unk> study is underway examining <unk> hundred one in major depressive disorder or mbd in parallel with an investigator led phase II <unk> study being conducted by our collaborators at Mount Sinai.

Our decision to examine next Gen <unk> and MTGE was based in part on promising clinical results with the geography dose 300 milligrams tid as a treatment for MD DNS, Indonesia, as well as encouraging preclinical data with <unk> hundred one.

It is also important to note. The depression is one of the most common comorbidities within the epilepsy patient population.

Results from the ex Nova study are anticipated in 2023.

Turning to another program within our proprietary pipeline, we continue to support our ongoing <unk> 496 phase III epic pediatric clinical trial evaluating next Gen 496 in patients aged one months to less than six years with Casey on Q2 D. There is significant interest from caregivers and physicians to provide a precision medicine.

To address this important unmet medical need which has the potential to positively impact the lives of these young patients.

Clinical development plans are supported by published physician case studies with <unk> and <unk> <unk> seven mechanism of action.

We expect completion of epic in 2023. So overall, we continue to make meaningful progress across the pipeline and we're excited to move <unk> into a broad phase III program in the near term.

Sherry Aulin: Our results may differ materially from those projected on today's call.

I'll pause here and ask Chris <unk> to provide some more detailed comments on our end of phase two meeting with FDA, our phase III clinical trial designs as well as some additional supporting data from <unk> and the X Tole, OLED, which continues to support our high level of confidence and conviction in our <unk> hundred one program Chris over to you.

Sherry Aulin: We undertake no obligation to publicly update any forward-looking statement.

Sherry Aulin: Today's press release summarizing Xenon's second quarter 2022 financial results and the accompanying quarterly report on Form 10-Q will be made available under the investor section of our website at www.xenon-pharma.com and filed with the SEC and on CDAR.

Okay. Thanks, Ian.

Sherry Aulin: Now I'd like to turn the call over to Ian.

We're pleased with our end of phase II meeting with the FDA. This past quarter. This meeting was supported by non clinical and clinical data, including results from our previously completed phase one trials and the positive phase two B X tole clinical trial evaluating <unk> 11 O one in adult patients with focal.

Ian Mortimer: Thanks, Sherry.

Ian Mortimer: Good afternoon, everyone, and thanks for joining our call.

Onset seizures.

As a reminder, the X tole topline efficacy data demonstrated that the primary and secondary seizure reduction endpoints were statistically significant across all three dose groups.

With P values of less than.

001 for the 20, and 25 milligram groups and Seattle Webinar, one was generally well tolerated.

Ian Mortimer: I'll start today's call with a high-level summary of our recent progress.

We align with the FDA on key elements of the phase III program to support a new drug application or NDA submission, we plan to submit an NDA upon completion of the first exon 11 O. One phase III clinical trial ex told two if successful.

Ian Mortimer: I'll then turn the call over to Chris Kenney, who will provide additional color around our Xenon 1101 end of Phase 2 meeting with the FDA and our next steps within our Phase 3 program, including our expansion into the Additional Epilepsy Indication of Primary Generalized Tonic-Clonic Seizures, or PGTCS.

Yeah.

Ian Mortimer: Chris will also provide his perspective on the additional ex-pool data, which we recently released.

Chris We just lost you on our side are you still there.

Ian Mortimer: Chris von Sagern will then share some market research insights shaping our clinical plans in PGTCS and the commercial opportunity for developing Xenon 1101 within this indication where there remains a significant unmet medical need.

Okay I'll carry on with Christmas section I know for those on the line.

There was a storm going through where Chris Kenny was based and so he may have lost lost connection or loss power. So as Chris was mentioning we've aligned with the FDA on key elements of the phase III program to support our NDA submission and we plan to submit the NDA upon completion of the first <unk> 1100, one phase III clinical trial <unk> two.

If successful and we will use the existing data package from the phase two B X tole clinical trial, along with additional safety data from other clinical trials to meet regulatory requirements.

We've also had alignment with FDA was obtained on key elements of a single phase III clinical trial to pursue the epilepsy indication of primary generalized tonic clonic seizures.

So, we'll give a little bit more background and outlined for the designs of the planned <unk> hundred one phase III clinical trials. So design closely after the phase <unk> study, we plan to initiate two identical phase III clinical trials codecs told to an ex told three each study will enroll approximately 360 patients who will be <unk>.

<unk> one to one to one for once daily dosing of either 15, or 25 milligrams of <unk> or placebo.

Our dose selection for the Phase III studies was informed by the safety and efficacy data in <unk> as well as by additional PK PD modeling that we completed earlier this year.

The primary efficacy endpoint is the median percent change our MPC and monthly seizure frequency from an eight week baseline through a 12 week double blind period was <unk> hundred $11, one compared to placebo and we have greater than 90% power for the primary endpoint at both doses using modeling from our external data.

On completion of the double blind period in both ex told to an <unk> eligible patients may enter an open label extension study for up to three years extra week. Two is expected to be initiated in the second half of the year followed by the initiation of <unk> III. So both studies will run in parallel.

Following the initiation of X tole too. We also plan to initiate a single phase III clinical trial called exact to support a regulatory submission in PG. Tcs is successful exact will enroll approximately 160 subjects will be randomized one to one for once daily dosing of either 25 milligrams of <unk> hundred one or placebo.

Hi.

The primary efficacy endpoint is the MPC and monthly PGA Tcs frequency from an eight week baseline through a 12 week double blind period of vaccine and $11 one compared to placebo.

And on the completion of the double blind period, an exact eligible patients may also enter an open label extension study for up to three years.

Our plans for pursuing this additional epilepsy indication of PG Tcs within our phase III program are supported by a strong rationale specifically <unk> hundred 11, <unk> hundred one shows anti seizure activity in two preclinical models, both the mes and PTC in preclinical models, both of which are known to predict efficacy for primary.

Unrealized seizures further other <unk>, such as <unk>, valproic acid and Lamotrigine suppressed photo sensitivity in generalized epilepsy patients, thereby predicting efficacy in PG Tcs and another TV potassium channel opener previously in development was also shown to suppressed.

Total sensitivity in patients with generalized epilepsy, and a clinical study.

Additionally, in our phase <unk> clinical trial, <unk> demonstrated broad impact across all focal seizure subtypes, including focal seizures that progress to generalized seizures.

As I noted earlier, we have recently generated additional efficacy data from subgroup analyses from our phase <unk> clinical trial and these further support our phase III development plans for <unk> hundred 11 in Hawaii, and they suggest that <unk> may offer a compelling and differentiated option for patients seeking to quickly reduce seizure frequency.

In June we issued a news release summarizing these results and more recently, we presented the time course to efficacy data at the 14th European Epilepsy Congress in Geneva.

Our analyses show that all doses of <unk> hundred 11, and rapidly reduce the frequency of focal onset seizures within one week compared to placebo at week. One the median percent change percent reduction in monthly focal seizure frequency was 55, 4% in the 25 milligram.

Milligram group. This was a P value of lessons or zero 141, 5% in the 20 milligram group P value of 0.039 and.

39, 1% in the 10 milligram group for a P value of 0.002, and this compares to 22% in the placebo group.

So based on these strong phase II efficacy data, we are including a secondary endpoint of week, one median percent change in seizure frequency within the statistical hierarchy of the phase III focal onset seizures studies to build upon this differentiated profile of <unk> hundred 11 <unk>.

Additionally, within our analysis of the open label extension population, we're seeing seizure frequency continuing to improve after the double blind period, along with increased periods of seizure freedom subjects remaining in the <unk> for at least three months and 12 months experience are greater than 70% and 80%.

Reduction respectively in median monthly seizure frequency when compared to baseline and of the 275 patients who entered OLED 19, 6% and nine 5% experienced six and 12 months of seizure freedom respectively.

This is significant considering how difficult these patients were to treat given the number of previous ASM as they had failed the number of con ASM mats that they were on at baseline as well as their seizure baseline seizure burden. So based on these data and at the request of study investigators and based on the potential to continue.

To provide significant benefit to patients we're extending the open label extension from the X Tole study from three to five years.

The ongoing <unk> continues to generate important long term safety data for <unk> hundred one nsls.

Can we expect to present additional long term <unk> data at the American Epilepsy Society meeting later this year in December .

So in summary, the clinical team is committed and focused on executing our <unk> hundred one phase III plans, where further driven by our belief that there is a significant medical need for new therapeutics to treat epilepsy, and <unk> 11 O. One has the potential to significantly improve the lives of these patients I will now turn the call over to Chris <unk>, who will share.

Some market research insights shaping our plans for <unk> hundred 11 O one in PG Tcs Chris.

Thanks Ian.

<unk> background teachers are generally described in two major groups generalized onset seizures in focal onset seizures or fos primary generalized seizures initiate in both hemispheres of the brands simultaneously and are comprised of tonic clonic phases are the second most common type of seizure experienced by people with epilepsy.

<unk> also known as Grand Mal seizures, or convulsions or the most severe form of seizures and are generally considered more dangerous and focal onset seizures.

Tcs can be life, threatening due to seizure injury, resulting from falls or accidents in the chronic phase.

From suite App sudden unexpected death in epilepsy.

Approximately 30% of patients with epilepsy of generalized seizures, which results in a total adult generalized seizure patient population of approximately 900000 patients in the U S of which approximately 700000 patients experienced primary generalized tonic clonic seizures.

Despite the March severe seizure phenotype furious Ams are currently approved to treat PGE tcs compared to fos and approximately 30% of PT Tcs patients are considered inadequately managed with initial lines of therapy launching additional treatment options.

And our primary research and our Kols discussions physicians have indicated the need for new treatments with alternative mechanisms of action for patients inadequately managed with current anti seizure medications and.

An opportunity remains for a broad spectrum agent with activity across seizure types for these reasons, we believe that <unk> 11, O one with potentially broad seizure coverage and a unique <unk> mechanism of action may offer a compelling clinical alternative for these epilepsy patients.

In addition to its novel mechanism of action and potential broad seizure coverage, we believe the Nexsan <unk> once daily dosing with no need for titration, our differentiated differentiating attributes given the importance of compliance and the need for rapid seizure control in this patient population. Our hope is that exiting on 11, one may provide an effective treatment for these patients.

And we are excited to pursue PGE Tcs alongside our clinical trials in <unk>.

Ian Mortimer: Sherry will conclude our call by briefly summarizing our partner programs, financial results, and events ahead.

I would now like to turn the call over to Sherri, who will summarize our partnered programs financial position and upcoming milestones.

Okay.

Ian Mortimer: We look forward to taking your questions during the Q&A session at the end of the call.

Thanks, Chris before I make a few comments on our Q2 financials I'd like to turn the call briefly to our partnered programs. Neurocrine. Currently has two separate phase III clinical trials underway. One study is evaluating MDI 91, three <unk> in adult patients with focal onset seizures with data expected in 2023 and another study.

Examining its use in pediatric patients with <unk> related epilepsy.

Our other collaborator <unk> Biosciences is conducting a phase <unk> proof of concept trial that is evaluating the safety and Tolerability of <unk> 301 administered as a single dose in patients undergoing bunionectomy. We look forward to keeping you updated as these partnered programs reach important milestones.

Ian Mortimer: I am pleased to report several important achievements within our Xenon 1101 program this past quarter, along with continued progress across the rest of our pipeline. Within Xenon 1101, the clinical data generated to date, along with feedback from KOLs and primary market research findings, support our belief that Xenon 1101 could play a particularly important role in treating epilepsy. In addition to its robust efficacy in focal onset seizures, the XEN 11-01 AE profile is in line with other anti-seizure medications.

Next I will focus on some highlights from this quarters financial statements and I would refer you to our news release and 10-Q report for further details.

Ian Mortimer: Following a positive end of Phase 2 meeting with the FDA, we're excited to advance our XEN 11-01 Phase 3 program, starting with the initiation of X-Pool 2 in the second half of this year.

Cash and cash equivalents in marketable securities were $788 2 million as of June 32022.

Third to $551 8 million as of December 31, 2021. This increase as a result of the additional proceeds raised in our public offering in June totaling approximately $287 5 million before underwriting discounts and commissions and other offering expenses.

Ian Mortimer: Additionally, we have strong scientific rationale supporting the use of XEN 11-01 to address primary generalized tonic-clonic seizures, and we're looking forward to initiating our Phase 3 exact clinical trial in PGPCS.

Based on current assumptions, which include fully supporting our <unk> hundred 1100, one clinical development program, which includes the completion of our planned phase III epilepsy studies.

<unk> and preclinical and discovery programs, we anticipate having sufficient cash to fund operations into 2026, excluding any revenue generated from existing partnerships or potential new partnering arrangements.

Looking ahead, we have several key milestone opportunities, including we expect to.

To initiate ex told two our first phase III clinical trial in <unk> in the second half of this year, followed by the initiation of <unk> III and the exact clinical trial and PG Tcs.

Our ex Nova trial, and MD is ongoing and we expect to have top line results in 2023, while in parallel we are supporting the Mount Sinai ISP and MTBE.

And we continue to advance our FX phase III clinical trial in pediatric patients with Casey on Q2, ETE with study completion anticipated in 2023.

Ian Mortimer: Ultimately, our goal is to deliver a new, differentiated therapeutic option for a broad population of epilepsy patients. Our team recently completed additional analyses of efficacy data from our Phase 2 B-XTOL trial, and these further support our Phase 3 development plans for XEN 11-01, including a time course to efficacy analysis, demonstrating that all doses of XEN 11-01 rapidly reduced the frequency of focal onset seizures within one week compared to placebo.

In summary, this is an incredibly exciting time at <unk> with a number of late stage clinical trials in our pipeline, we intend to continue to build upon our positive momentum and execute on our clinical development plans with a strong balance sheet and prudent management of capital. We believe xenon is well positioned to support our business objectives across our proprietary programs.

Ian Mortimer: Chris Kenny will provide some more details on these data, as well as our first cut of open-label extension efficacy data from XTOL and our Phase 3 plans.

Ian Mortimer: In addition, our Phase 2 XNOVA study is underway examining XEN 11-01 in major depressive disorder, or MDD, in parallel with an investigator-led Phase 2 MDD study being conducted by our collaborators at Mount Sinai. Our decision to examine XEN 11-01 in MDD was based in part on promising clinical results with azogavine dose 300 mg TID as a treatment for MDD and anhedonia, as well as encouraging preclinical data with XEN 11-01.

Ian Mortimer: It is also important to note that depression is one of the most common comorbidities within the epilepsy patient population.

On behalf of the entire team we look forward to keeping you posted on our progress in the quarters ahead I'll now ask the operator to open the line for any questions operator.

Ian Mortimer: Top-line results from the XNOVA study are anticipated in 2023.

Thank you.

Ian Mortimer: Turning to another program within our proprietary pipeline, we continue to support our ongoing XEN 496 Phase 3 EPIC pediatric clinical trial evaluating XEN 496 in patients aged 1 month to less than 6 years with KCNQ2-DEE. There is significant interest from caregivers and physicians to provide a precision medicine to address this important unmet medical need, which has the potential to positively impact the lives of these young patients.

As a reminder, if you would.

To ask a question press Star then the number one on your telephone keypad.

Ian Mortimer: Our clinical development plans are supported by published physician case studies with azogavine and XEN 496's KB7 mechanism of action.

We asked today that you limit yourself to one question and one follow up.

Ian Mortimer: We expect completion of EPIC in 2023.

Ian Mortimer: So, overall, we continue to make meaningful progress across the pipeline, and we're excited to move XEN 11-01 into a broad Phase 3 program in the near term.

Thank you.

Your first question comes from the line of Paul <unk> with Stifel. Your line is now open.

Hi, This is James on for Paul Thanks for taking our question.

Maybe just a quick one on MDT could.

Could you remind us the dosing there.

This study in your trial.

And then Tim is there and is there any reason to believe that the extrapolation of exogamy into 1100, one an MTBE would be different than it would be higher than it was in epilepsy.

Just wondering.

How youre thinking about that thanks.

Okay.

Ian Mortimer: So, I'll pause here and ask Chris Kenney to provide some more detailed comments on our end-of-Phase 2 meeting with FDA, our Phase 3 clinical trial designs, as well as some additional supporting data from EXTOL and the EXTOL OLE, which continues to support our high level of confidence and conviction in our XEN 11-01 program.

Thanks, James Chris Kenny you, Jeff can you maybe just come off mute just to make sure that youre back on and we can hear you again.

Ian Mortimer: Chris, over to you.

Chris Kenney: Okay.

Can you hear me.

Chris Kenney: Thanks, Ian.

Okay perfect, Yes, just for Q&A, it's great that I know you got cut off there, but I'd say youre back on.

Chris Kenney: We're pleased with our end-of-Phase 2 meeting with FDA this past quarter. This meeting was supported by non-clinical and clinical data, including results from our previously completed Phase 1 trials and a positive Phase 2b EXTOL clinical trial, evaluating XEN 11-01 in adult patients with focal onset seizures. As a reminder, the XTOL top-line efficacy data demonstrated that the primary and secondary, seizure reduction endpoints were statistically significant across all three dose groups, with p-values of less than 0.001 for the 20 and 25 mg groups, and XEN11-01 was generally well-tolerated.

I can.

Chris Kenney: We aligned with the FDA on key elements of the Phase III program to support a new drug, application or NDA submission.

Chris Kenney: We plan to submit an NDA upon completion of the first XEN11-01 Phase III clinical trial, XTOL-2, if successful, and we will continue to work with the FDA to develop a new NDA application.

I can address this for for James.

Operator: Chris, we just lost you on our side.

So just as a reminder, we there's two MDT studies ongoing one with which is an ISP that we're supplying drug for that's true Mount Sinai and they have a second site at Baylor and then we have our company sponsored B the Mount Sinai study, they're looking one active dose which was 20 milligrams.

Operator: Are you still there?

Ian Mortimer: Okay.

Ian Mortimer: I'll carry on with Chris's section. I know for those on the line, there was a storm going through where Chris Kenny was, based, and so he may have lost connection or lost power.

And placebo and ours is a three arm study, it's a little bit larger so we have a bit more power.

Ian Mortimer: So, as Chris was mentioning, we've aligned with the FDA on key elements of the Phase, III program to support our NDA submission, and we plan to submit the NDA upon completion of the first XEN11-01 Phase III clinical trial, XTOL-2, if successful, and we'll use the existing data package from the Phase IIb XTOL clinical trial, along with additional safety data from other clinical trials to meet regulatory requirements.

And we're looking at two active doses and placebo 10 milligrams 20 milligrams and placebo and then your follow up question just on the extrapolation of the <unk> data.

Ian Mortimer: We've also had alignment with FDA was obtained on key elements of a single Phase III clinical, trial to pursue the epilepsy indication of primary generalized tonic-clonic seizures. So, we'll give a little bit more background and outline for the designs of the planned, XEN11-01 Phase III clinical trials.

Zagha being the randomized study.

They ran through the same collaborators, but we're working with the Mount Sinai and that data was published.

Last year, they used what we consider their their mid dose and epilepsy, which is 900 milligrams a day or 300 milligrams tid.

And when we look at their efficacy data in epilepsy, obviously, we've seen superior efficacy in our X Tole study.

Ian Mortimer: So, designed closely after the Phase IIb XTOL study, we plan to initiate two identical, Phase III clinical trials called XTOL-2 and XTOL-3. Each study will enroll approximately 360 patients who will be randomized one-to-one-to-one for, once daily dosing of either 15 or 25 milligrams of XEN11-01 or placebo. Our dose selection for the Phase III studies was informed by the safety and efficacy data, in XTOL, as well as by additional PK-PD modeling that we completed earlier this year.

Ian Mortimer: The primary efficacy endpoint is the median percent change, or MPC, in monthly seizure, frequency from an eight-week baseline through a 12-week double-blind period with XEN11-01 compared to placebo.

Ian Mortimer: And we have greater than 90 percent power for the primary endpoint at both doses using, modeling from our XTOL data.

So theres nothing Theres nothing that we would believe that we're going in with a dose that would be it would be less active than.

Ian Mortimer: Upon completion of the double-blind period in both XTOL-2 and XTOL-3, eligible patients, may enter an open-label extension study for up to three years. XTOL-2 is expected to be initiated in the second half of the year, followed by the initiation, of XTOL-3, so both studies will run in parallel.

Then the Zagha beam dose, obviously, we're doing cross trial comparisons here, but we feel very comfortable in terms of the dose range and the <unk> studies.

Great. Thanks, so much.

Your next question comes from the line of Brian Abrams with RBC capital markets. Your line is now open.

Hi, good afternoon, and thanks for taking my questions.

Ian Mortimer: Following the initiation of XTOL-2, we also plan to initiate a single Phase III clinical, trial called XACT to support a regulatory submission in PGTCS, if successful. XACT will enroll approximately 160 subjects who will be randomized one-to-one for once-daily, dosing of either 25 milligrams of XEN11-01 or placebo. The primary efficacy endpoint is the MPC in monthly PGTCS frequency from an eight-week, baseline through a 12-week double-blind period of XEN11-01 compared to placebo. And on the completion of the double-blind period in EXACT, eligible patients may also enter an open-label extension study for up to three years.

PG Tcs.

Ian Mortimer: Our plans for pursuing this additional epilepsy indication of PGTCS within our Phase III program are supported by a strong rationale. Specifically, XEN11-01 shows anti-seizure activity in two preclinical models, both the MES and PTZ preclinical models, both of which are known to predict efficacy for primary generalized seizures.

Mentioned that you've run several different preclinical models that are supportive of activity.

I'm curious based on the magnitude of benefit that youre observing in these models and their predictability.

Can you give us a sense of how you might benchmark potential efficacy.

The 25 Meg go forward dose in the generalized setting I guess relative to other drugs that are out there and then relative to what you've observed.

Focal onset setting and then I guess as a corollary to that is on the.

Epidemiological side.

What would your expectation be based on.

The preclinical data as well as some of your market research as to.

Where within that 30% of patients who failed two anti seizure medications would you expect this to be used with the Gulf Beach for this to be used as the.

First agent in that.

In that refractory population is there a potential for combinability.

<unk> to be used in that and that that one third of patients.

Great. Thanks, Brian I think Super comprehensive questions.

We can tackle.

And so maybe Chris Kenny you can go first and then Chris on <unk> on the on the FTE and kind of maybe the treatment algorithm and how these patients.

Moves through different therapies, but Christianity, probably good just to talk a little bit about the efficacy.

The drugs that work in so called the types of efficacy they see and primary generalize as well as those placebo rates and not all maybe kind of help answer Brian's question just around the extrapolation from.

From focal primary generalized.

Ian Mortimer: Further, other ASMs, such as levotriacetam, belproic acid, and lamotrigine, suppress photosensitivity in generalized epilepsy patients, thereby predicting efficacy in PGTCS.

Yes. The question was largely focused on the pre clinical signal with <unk> hundred one which is incredibly robust and to my knowledge. There wasn't a single preclinical experiment using an epilepsy model that wasn't that didn't show a benefit but I'm actually and that's great. That's compelling, but it's really the clinical data that I think is more.

More compelling and you have you have the compound <unk> one of the eicher Gen compounds that has the same mechanism of action.

That was used in a clinical trial with patients who have generalized epilepsy and it was shown to suppress photo sensitivity and that model has been incredibly predictive of drugs that work in primary generalized like the ones, we mentioned <unk> acid.

Ian Mortimer: And another KV potassium channel opener previously in development was also shown to suppress photosensitivity in patients with generalized epilepsy in a clinical study.

And also it doesn't show any significant suppression with drugs that don't work and primary generalized carbon as a team. So I think thats compelling and then of course, the fact that we're looking at our own clinical data.

Ian Mortimer: Additionally, in our Phase IIb expo clinical trial, XEN11-01 demonstrated broad impact across all focal seizure subtypes, including focal seizures that progress to generalized seizures. As I noted earlier, we have recently generated additional efficacy data from subgroup analyses from our Phase IIb expo clinical trial, and these further support our Phase III development plans for XEN11-01. And they suggest that XEN11-01 may offer a compelling and differentiated option for patients seeking to quickly reduce seizure frequency.

Ian Mortimer: In June, we issued a news release summarizing these results, and more recently, we presented the time course to efficacy data at the 14th European Epilepsy Congress in Geneva. Our analyses show that all doses of XEN11-01 rapidly reduced the frequency of focal onset seizures within one week compared to placebo. At week one, the median percent change, percent reduction in monthly focal seizure frequency was 55.4% in the 25 milligram group.

Ian Mortimer: This is a p-value of less than 001, 41.5% in the 20 milligram group, p-value of .039, and 39.1% in the 10 milligram group for a p-value of .002.

Ian Mortimer: And this compares to 20.2% in the placebo group. So based on these strong Phase IIb efficacy data, we are including a secondary endpoint of week one median percent change in seizure frequency within the statistical hierarchy of the Phase III focal onset seizure studies to build upon this differentiated profile of XEN11-01.

Ian Mortimer: Additionally, within our analysis of the open-label extension population, we are seeing seizure frequency continuing to improve after the double-blind period, along with increased periods of seizure freedom. Subjects remaining in the X-toll OLE for at least three months and 12 months experience a greater than 70% and 80% reduction, respectively, in median monthly seizure frequency when compared to baseline.

Ian Mortimer: This is significant considering how difficult these patients were to treat, given the number of previous ASMs they had failed, the number of con-ASM meds that they were on at baseline, as well as their baseline seizure burden.

Ian Mortimer: And of the 275 patients who entered OLE, 19.6% and 9.5% experienced six and 12 months of seizure freedom, respectively.

Seeing that there is fairly significant greater than 80% reduction in tight for seizures seizures that start focal and <unk>.

<unk> after that I think those kind of.

Clinical data set is actually more compelling in my mind and the preclinical data set that you.

You're asking the question and then as far as dose response.

We've seen with other anti seizure medications is that the dose response that occurs in focal onset seizures is very similar to what happens in primary generalized tonic clonic seizures, so using multiple precedents from the epilepsy world.

And then taking a look at our X tole data and focal onset seizures, where the 25 milligram dose clearly showed the best benefit we've decided to bring that as a primary dose forward into primary generalized tonic clonic seizures. So.

All of that makes us feel about as confident as we can in that study.

And to be seen what happens.

Okay.

And on the treatment paradigm side, what we see it in PG Tcs is actually quite similar to what we see in <unk> patients are typically initiated on <unk>.

Individual agent <unk> Tam is frequently use given its broad spectrum nature and then they progressed through multiple lines of therapy without if they don't achieve a sufficient benefit where we expect ex CN 11, I wanted to play is early in the branded lines of treatment and Thats with the expectation that we're offering an inline efficacy.

Similar to what we've seen on the Fos side, an important distinction and Chris is that the carbamazepine category just quite frequently use glass is not used in this disease space, which creates an even greater opportunity for a novel mechanism of action that offers a really potent benefit and what we've seen from our research is real.

Excitement around that opportunity.

<unk> mechanism all of the other ease of use attributes key opinion leaders are very very interested in seeing the benefit we can potentially provide to that patient population.

Super helpful. Thanks.

Your next question comes from the line of Tessa Romero with Jpmorgan. Your line is now open.

Hey, guys. Thanks, so much for taking the question.

I think in the past you've talked about presenting to my question.

Ill open label data from App store.

The American Epilepsy Society meeting later this year in December .

Can you please talk about the size and scope of the data we will see at the contract are there any additional analyses we should have an eye on and what would be considered a win.

Much.

Yeah.

Thanks Tessa.

I can address that yes, if you looked at so the open label extension as you know is ongoing and so every day, we're getting more mature data we did cut the data earlier this year those as part of our preparation for end of phase two meeting with FDA to share with some longer term safety data with them.

Ian Mortimer: So based on these data, and at the request of study investigators, and based on the potential to continue to provide significant benefit to patients, we're extending the open-label extension from the X-toll study from three to five years.

And then we also had shown some of the efficacy data and more recently in June of this year. So we have submitted abstracts for aes, including two follow up as you say on the on more mature open label extension data. So in August of this year. So this month.

Ian Mortimer: The ongoing Excel OLE continues to generate important long-term safety data for Xeon 1101 and FOS, and we expect to present additional long-term OLE data at the American Epilepsy Society meeting later this year in December.

Ian Mortimer: So, in summary, the clinical team is committed and focused on executing our Xeon 1101 Phase 3 plans. We are further driven by our belief that there is a significant medical need for new therapeutics to treat epilepsy, and Xeon 1101 has the potential to significantly improve the lives of these patients.

All of the patients will have gone through 12 months. So we'll now at least have a data set where every patient in an open label extension will have been.

Ian Mortimer: I'll now turn the call over to Chris von Seggern, who will share some market research insights shaping our plans for Xeon 1101 in PGTCS.

All of those remaining will have been on drug for at least 12 months. We will choose later this fall kind of where that cutoff point is in terms of <unk>.

Analyzing the data and getting ready for Aes, but will likely have a data point that is more mature than the 12 month data that we showed in June of this year. So it will just be more mature follow up where we will show both the MPC over time as well as looking at these intervals of seizure freedom for the <unk>.

<unk>, which are which are obviously really important so it will be similar data that you've seen in the past from us it'll be just a more mature data set as we move forward.

Chris von Seggern: Chris?

And maybe I'll just add a couple of things if you don't mind and so in addition to that the first patient will reach three years. This fall and so you're starting to get some patients who've been exposed for for quite a while.

Chris von Seggern: Thanks, Ian.

Chris von Seggern: By way of background, seizures are generally described in two major groups, generalized onset seizures and focal onset seizures, or FOS. Primary generalized seizures initiate in both hemispheres of the brain simultaneously and are comprised of tonic and chronic phases, are the second most common type of seizure experienced by people with epilepsy. PGTCS, also known as grand mal seizures or convulsions, are the most severe form of seizures and are generally considered more dangerous than focal onset seizures. PGTCS can be life-threatening due to seizure injury resulting from falls or accidents in the chronic phase or from SUDEP, sudden unexpected death in epilepsy.

Chris von Seggern: Approximately 30% of patients with epilepsy have generalized seizures, which results in a total adult generalized seizure patient population of approximately 900,000 patients in the U.S, of which approximately 700,000 patients experience primary generalized tonic-clonic seizures. Despite the more severe seizure phenotype, fewer ASMs are currently approved to treat PGTCS compared to FOS, and approximately 30% of PGTCS patients are considered inadequately managed with initial lines of therapy, warranting additional treatment options.

Chris von Seggern: In our primary research and our KOL discussions, physicians have indicated the need for new treatments with alternative mechanisms of action for patients inadequately managed with current anti-seizure medications.

Chris von Seggern: An opportunity remains for a broad-spectrum agent with activity across seizure types. For these reasons, we believe that XEN-1101, with potentially broad seizure coverage and a unique KV7 mechanism of action, may offer a compelling clinical alternative for these epilepsy patients. In addition to its novel mechanism of action and potential broad seizure coverage, we believe that XEN-1101's once-daily dosing with no need for titration are differentiating attributes, given the importance of compliance and the need for rapid seizure control in this patient population.

Chris von Seggern: Our hope is that XEN-1101 may provide an effective treatment for these patients, and we are excited to pursue PGTCS alongside our clinical trials in FOS and MDD.

Sherry Aulin: I would now like to turn the call over to Sheri, who will summarize our partner programs, financial position, and upcoming milestones.

Sherry Aulin: Thanks, Chris.

Sherry Aulin: Before I make a few comments on our Q2 financials, I'd like to turn the call briefly to our partner programs.

And then as far as like defining a win I mean, we what we've seen so far is that <unk> 101 is well tolerated and so we want to see that persists, we haven't had any.

Sherry Aulin: NeuroCRIN currently has two separate Phase 2 clinical trials underway. One study is evaluating NBI-921352 in adult patients with vocal onset seizures with data expected in 2023.

Sherry Aulin: And another study is examining its use in pediatric patients with SDNA-to-A-related epilepsy.

Sherry Aulin: Our other collaborator, Pacira Biosciences, is conducting a Phase 1b proof-of-concept trial that is evaluating the safety and tolerability of PCRX301 administered as a single dose in patients undergoing bunionectomy.

Sherry Aulin: We look forward to keeping you updated as these partnered programs reach important milestones.

Idiosyncratic toxic reactions like we've seen with other anti seizure medications. So we hope that that remains the same and then we've seen a beautiful maintenance of effect and over a prolonged period of time and so we'd like to see that continue and then see if that has any other impact on other skills like quality of life.

Great. Thanks, so much for taking our question.

Sherry Aulin: Next, I will focus on some highlights from this quarter's financial statements, and I would refer you to our news release and 10Q report for further details.

Your next question comes from the line of Marc Goodman with SBB. Your line is now open.

Sherry Aulin: Cash and cash equivalents and marketable securities were $788.2 million as of June 30, 2022, compared to $551.8 million as of December 31, 2021. This increase is a result of the additional proceeds raised in our public offering in June, totaling approximately $287.5 million before underwriting discounts and commissions and other offering expenses.

Sherry Aulin: Based on current assumptions, which include fully supporting our XEN 1101 clinical development program, which includes the completion of our planned Phase 3 epilepsy studies, XEN 496, and preclinical and discovery programs, we anticipate having sufficient cash to fund operations into 2026, excluding any revenue generated from existing partnerships or potential new partnering arrangements.

Sherry Aulin: Looking ahead, we have several key milestone opportunities, including we expect to initiate XTOL 2, our first Phase 3 clinical trial in FOS in the second half of this year, followed by the initiation of XTOL 3 and the exact clinical trial in PGTCS.

Yes, Hi, I was wondering if you could.

Give us a flavor for how you're thinking <unk> is doing out there in the marketplace and if theres been any.

The major dynamic changes in the epilepsy kind of commercial space. Thanks.

Yeah, Yeah, Chris do.

Do you want to go first or John why don't you go ahead and I'm happy to add any other comments from my side also.

Absolutely so.

We track Exco pre uptake in the U S quite quite carefully as it's the most recently launched product in the category and what we hear from both our research and just tracking the scripts and the data ex corporate is off to a nice launch it does have.

Uptake.

And lines of therapy, and what we hear from our at least our market research is.

That patients do experience a good benefit late in lines of therapy, So patients who are trending towards surgery <unk> represents a great opportunity.

What we have heard though from our researches that not all of the patients get all the way to the maximum dose that was used in the clinical trial and as a result, the efficacy might not translate the same way as what we've seen from our clinical experience at least in the controlled clinical setting.

That being said it's off to a good start trending ahead of what we've seen for a number of other products at least on a script basis over time and it does represent a bit of a shift in dynamic creating another key player that can hopefully help bolster all commercial products in there.

Space is this category Hasnt had really a giant players since the capra days impact as everyone knows recently lost exclusivity. So there is room for both that product and others to come in and replenish the commercial sales potential in this category.

Yes.

Thanks, Chris Yeah, I've got nothing nothing else to add.

Mark do you have a follow up.

Thanks, Karen.

Okay. Thanks, Mark operator, we can move to the next question.

Your next question comes from the line of Yadkin sooner and Jay with Guggenheim. Your line is now open.

Sherry Aulin: Our XNOVA trial in MDD is ongoing, and we expect to have top-line results in 2023, while in parallel, we are supporting the Mount Sinai IST in MDD.

Sherry Aulin: And we continue to advance our EPIC Phase 3 clinical trial in pediatric patients with KCNQ2-DEE, with study completion anticipated in 2023.

This is David muscle Yadkin. Thanks for taking a last question. So I have a quick one on the Mds study.

Sherry Aulin: In summary, this is an incredibly exciting time at Xenon with a number of late-stage clinical trials in our pipeline.

Sherry Aulin: We intend to continue to build upon our positive momentum and execute on our clinical development plans. With a strong balance sheet and prudent management of capital, we believe Xenon is well-positioned to support our business objectives across our proprietary programs.

Sherry Aulin: On behalf of the entire team, we look forward to keeping you posted on our progress in the quarters ahead.

And what type of profile you would like to see and is that a subset of patients that you would like to thank the to respond better to 11, one thank you.

Okay.

Chris do you want to talk about the profile and MDT.

Yes, I mean, so so as far as the profile. It goes I mean, the peace study designs for these MDT parks are fairly consistent with one another.

One of the differences that Youll see is that some include treatment resistant depression, and others don't ours doesn't and so we expect a profile that would be quite similar to those studies.

<unk> designed in that manner.

So if you're familiar with the Zagha being proof of concept trial, we expect population that will be somewhat consistent with that.

As far as subsets of patients.

I mean the road the data.

Was fairly robust and these all getting trial across the board and so and I don't remember that publication talking about subgroups, where there was a better response or a less favorable response. So I think we'll just have to kind of go into it with open eyes.

Okay.

Yes, the only thing I would add to Chris the only thing I would add to Chris' comment as we've talked about we're looking at a primary endpoint in our study we're looking at Madras.

Clinical scale of depression. We also these patients will have on Indonesia.

And so we are looking at that.

A key secondary endpoint is the is the shop scale, which will measure changes in amazonia.

Okay perfect.

Thank you.

Operator: I'll now ask the operator to open the line for any questions.

Your next question comes from the line of Andrew Tsai with Jefferies. Your line is now open.

Operator: Operator?

Okay very good thank you and congratulations on all the progress recently so.

Operator: Thank you.

Operator: As a reminder, if you would like to ask a question, press star, then the number 1 on your telephone keypad.

Operator: We ask today that you limit yourselves to one question and one follow-up.

Maybe I guess one on MDT for since we just spoke on it.

Operator: Thank you.

Just curious did you happen to design ex Nova such that if it were a positive study that it would be perhaps large enough to be considered by the FDA as a.

Potentially pivotal study or should we view this more as an exploratory study and if positive you would need two more placebo controlled studies thereafter.

Operator: Your first question comes from the line of Paul Matias with Stiefel.

Operator: Your line is now open.

James: Hi, this is James on for Paul.

Yeah.

James: Thanks for taking our question.

Thanks, Andrew.

James: Maybe just a quick one on MDD.

We've really been thinking about.

The <unk> study as a proof of concept. So it's designed as a proof of concept we're looking at two different doses.

James: Could you remind us the dosing there for this study in your trial?

We made an adjustment in the trial design post tax tool to include a lower dose based on the efficacy Nx tool.

10 milligrams, but yes, we're really viewing this as a proof of concept study to start generating some.

Some data in depression, and I think it will really be driven by those data in terms of next steps for 1100, one in that population.

James: And then, too, is there any reason to believe that the extrapolation of exogabine to 1101 in MDD would be different than it would be or than it was in epilepsy?

And then just a couple of things on that if you don't mind. So the zagha being trial the proof of concept had about half the number of patients for.

For treatment group and so it had demonstrated an effect size of <unk> 75, which is fairly high. Our study is powered for 0.5 and as Ian said, we've chosen a dose that was similar to the equivalent dose for <unk> and also we've seen efficacy in focal onset seizures at a dose that was also.

We've seen with that that's similar dose equivalent and.

Onset seizures for saga.

No.

Yeah.

Just to reiterate what Ian said, even though it's about this study has about twice as many patients per treatment group I don't think that this has a good chance of being considered pivotal.

Thanks makes sense and then as a follow up then shifting gears I actually was just a focal epilepsy program as you start independent all three.

James: Just wondering, you know, how you're thinking about that.

<unk> studies.

Maybe a high level question is just how are you thinking about.

James: Thanks.

<unk> success are there any like findings our learnings from the phase two that you had.

Ian Mortimer: Thanks, James.

Fly in phase III.

Chris Kenney: Chris, can you maybe just come off mute and just make sure that you're back on and we can hear you again?

Yes. Thanks.

Yeah.

Our.

Go ahead.

Chris Kenney: I'm here.

Let's see I'll start and then you jump in Greg.

Chris Kenney: Can you hear me?

Given the success of extra wall.

Really not changing much for <unk> III.

Chris Kenney: Okay, perfect.

Sorry, <unk>, two and <unk> three of the phase III trials, obviously, the studies are a little bit larger than the next door. So we do have more power than we did in the X Tole study, but in terms of inclusion exclusion criteria.

Ian Mortimer: Yeah, just for a Q&A, it's great that I know you got cut off there, but it's that you're back on.

Ian Mortimer: I can, address this for James.

Ian Mortimer: So just as a reminder, there's two MDD studies ongoing, one which is an ISP that we're supplying drug for.

It's going to be the same as the <unk> study. So we are really trying to replicate the X tole study and a little bit of a larger study.

Ian Mortimer: That's through Mount Sinai, and they have a second site at Baylor, and then we have our company sponsored.

Ian Mortimer: The Mount Sinai study, they're looking at one active dose, which is 20 milligrams, and placebo, and ours is a three-arm study.

With a 12 week endpoint and we know as <unk> seen from the open label data.

Ian Mortimer: It's a little bit larger, so we have a bit more power, and we're looking at two active doses and placebo, 10 milligrams, 20 milligrams, and placebo, and then your follow-up question just on the extrapolation of the Azogabine data.

We have very good signal at 12 weeks.

Ian Mortimer: So Azogabine, the randomized study that they ran through the same collaborators that we're working with at Mount Sinai, that data was published, last year.

Like the signal may be a little bit stronger than over eight weeks and external but really we're trying to keep as much the same as possible, including leveraging a lot of the same sites that we used to great success in the external study.

Ian Mortimer: They use what we consider their mid-dose in epilepsy, which is 900 milligrams a day, or 300 milligrams TID, and when we look at their efficacy data in epilepsy, obviously, we've seen superior efficacy in our X-Tool study.

Ian Mortimer: So there's nothing for, you know, there's nothing that we would believe that we're going in, with a dose that would be less active than the Azogabine dose.

Ian Mortimer: Obviously, we're doing cross-trial comparisons here, but we feel very comfortable in terms of the dose range in the MDD studies.

James: Great.

Chris anything else David.

Jeremy to complement those comments, we're going to try to avoid regions.

There are known to have a high placebo effect.

We're going to make sure that we're getting good quality patients by having them.

Reviewed by a couple of colleges before before they're randomized.

And comment as our guiding principle, which is X tole worked really well so let's not deviate much from that plan.

As many same sites as we can et cetera.

Alright, Thank you guys.

Operator: Thanks so much.

Thanks.

Yes.

Your next question comes from the line of David Hong with S. NBC. Your line is now open.

Operator: Your next question comes from the line of Brian Abrams with RBC Capital Markets.

Hey, Thanks for taking the questions. So my first one I had one on.

Operator: Your line is now open.

Brian Abrams: Hi, good afternoon, and thanks for taking my questions.

Brian Abrams: On PGTCS, you've mentioned that you've run several different preclinical models that are supportive of activity.

Brian Abrams: I'm curious, based on the magnitude of benefit that you're observing, you know, in these models and their predictability, can you give us a sense of how you might benchmark potential efficacy with the 25 mg go-forward dose in the generalized setting, I guess, relative to other drugs that are out there, and then relative to what you've observed, in the focal onset setting?

Generalized generalized epilepsy NPG Tcs. So could you just tell us a little bit about what are the major branded products that are branded <unk> being used for DG Tcs now and is there any off label usage of of drugs that do not have to generalize label.

Yes.

Yes, I can take that so what we've heard from our research is.

Brian Abrams: And then, I guess, as a corollary to that, as on the epidemiological side, what would your expectation be based on, I guess, the preclinical data as well as some of your market research as to, where within that 30% of patients who've failed to anti-seizure medications, would you expect this to be used?

That products that are known to be broad spectrum are used typically in advance of products.

Brian Abrams: Would the goal be for this to be used sort of as the first agent in that refractory population?

Brian Abrams: Is there a potential for combinability?

The labeled indication and I bring that up because.

Vimpat didn't get the PGE Tcs indication until very late in its lifecycle and we didn't see a material increase in net sales at that time in part probably because it was being used in advance of the indication.

Brian Abrams: How do you expect it to be used in that one-third of patients?

From our research we've heard both <unk> and <unk> being used in PG Tcs, despite neither yet having the label although both products are off our broad spectrum are known to be broad spectrum and therefore.

Brian Abrams: Thanks.

Opinion leaders have been extrapolating into that setting.

Other branded products that remain in this space.

Have two distinct stories sulfide copper is used in convulsive seizures. When we do see we hear that from our research <unk> being in the carbamazepine category. It doesn't have the indication and is not used here. So it's the same branded set minus <unk> today.

With reasonable use for those products that don't yet have the indication but are expected to do.

Got it that's really helpful.

And then just just a follow up I'm looking at some of the slides you had posted related to <unk> and.

It shows there is a population it looks like of about 300000 or so patients in this market sizing figure that out.

Undefined or combination epilepsy, and so if you have both local and generalized labels would you be able to access that population.

Yeah practically speaking the answer is probably yes, but that patient population from a coding standpoint, and we've looked into this actually quite in detail and in fact remains coded as an unknown cause of epilepsy. So.

They're having both focal and generalized seizures in all likelihood it and what we've what we've heard is that they are traditionally treated like APG tcs patients.

So clinicians could imagine using the product in that in that space, but from a strict coding standpoint, they don't have a definitive diagnosis and that could create an impediment from a payer.

Payers, who have very strict prior authorization criteria for select plans in the U S.

Okay, great. Thanks for taking the questions.

Your next question comes from the line of Lachlan Hanbury with William Blair. Your line is now open.

Ian Mortimer: Great, thanks, Brian.

Chris Kenney: I think super comprehensive questions that we can tackle.

Hey, guys. This is welcome.

Thanks for taking the question. So I was wondering you obviously have a we'll have a lot of long term data from the X Tole clinical label extension by the time you file but.

That's going to be at the 20, Meg dose and a high dose you'll be testing 25 make so did you sort of talk to the agency about.

What kind of long term data you will need at the 25 dose can.

Can you just discuss what the plans off of that is that all going to come from the installed two and three open label extension.

Chris von Seggern: And so maybe Chris Kenny can go first, and then Chris von Sagern on the, epi and kind of maybe the treatment algorithm and how these patients move through different therapies.

Chris Kenny do you want to join in chocolate.

Chris Kenney: But Chris, can you probably get just to talk a little bit about the efficacy that the drugs that work in focal, the type of efficacy they see in primary generalized as well as those placebo rates, and that'll maybe kind of help answer Brian's question just around the extrapolation from focal to primary generalization.

Chris Kenney: Yeah, I mean, the question was largely focused on the preclinical signal with XCN 1101, which, is incredibly robust.

Yeah sure Yeah, So you're right the X Tole open label study the target dose was 20 milligrams dose was chosen in advance of the data that we have right now so we're going to have an enormous amount of data on 20 milligrams, but also keep in mind that we have we're going to have three phase III studies going with like the 25 milligram dose along with <unk>.

Open label extension at 25, and so you know we're going to have an enormous amount of data for that dose as well and so when we interacted with the agency we broke it all down we show them exactly what we expected each dose and we made we tried to make the case that we think that the drug should be approved at multiple different doses.

And you know it will be a review issue but.

But.

They were you know.

Reading between the tea leaves they seem to be very open to the plan.

And last one if you look at the ICA ICH guidelines those kind of exposure unique exposures required in the long term.

Exposures of six and 12 months, we feel really comfortable as Chris has mentioned.

Just on the totality of the.

The safety data database that will provide to FDA and other regulators in the long term dosing wheelhouse as Chris mentioned, because we're doing the open label extension for all of the studies and the phase III, we're going to have a lot of data both 2020 one.

Okay got it thanks, and if I could.

Hello.

Yes, placebo responses in MD&A has typically been an issue and I know you guys.

You did pretty well in controlling that mean ex told.

Is there anything you can sort of transfer at M. D day or is there anything there.

I guess can you maybe just discuss what you are doing to try to minimize placebo responses in the MBT trial.

Yeah.

Yes sure sure yeah, So we recovered that.

So this will be a largely a repeat of the last quarterly call, but happy to go through that again. So first of all I mean, we've chosen the best sites that we can two to minimize the chance of a large placebo effect theyre all U S sites.

We've also.

Using to mass General group to train.

The sites and then also to make sure that we're getting patients who truly have a major depression into the trial. So we're doing absolutely everything we can to mitigate the risk of a placebo effect in.

In that trial.

Yes.

Do you want to add anything.

No no.

As Chris mentioned, there is a lot of similarities right, we kind of use the quality of the sites that you chose the investigators and kind of some more oversight.

Both in epilepsy.

It was epilepsy and depression, we can kind of have this third party kind of adjudication that can kind of set over top of the studies.

And help out to make sure that we're getting we're getting the right patients.

Chris Kenney: And to my knowledge, there wasn't a single preclinical experiment using an epilepsy model that wasn't, that didn't show benefit.

Alright. Thanks.

Chris Kenney: But I'm actually, and that's great, that's compelling.

Yeah.

Your next question comes from the line of.

Rohit basin with Needham Your line is now open.

Hi, this is broken on for Serge. Thanks for taking our questions can you share any feedback you've received from providers with the expansions of PG Tcs.

And then when can we expect an update from the partner 301 program with this year. Thanks.

Chris Kenney: But it's really the clinical data that I think is more compelling. And you know, you have, you have a compound, one of the icogen compounds that has the same mechanism of action that was used in a clinical trial with patients who have generalized epilepsy, and it was shown to suppress photosensitivity.

Chris One segment and do you want to talk about some of the feedback we've had on primary generalized and I'm sure you can address that.

Partnering milestones.

Yes, absolutely so the research we conducted.

Specifically thinking about the opportunity in PT Tcf.

Average the profile that emerged from.

<unk> with respect to safety and then we've.

Put forward estimates around what an inline product could be from an efficacy standpoint, and what we saw in that research was actually significant enthusiasm based on the safety and Tolerability profile in the space as well as the ease of use attributes and in primary generalized tonic clonic seizures, you can make the argument.

Chris Kenney: And that model has been incredibly predictive of drugs that work in primary generalized, like the ones we mentioned, levotriazetam, valproic acid, and also doesn't show any significant suppression with drugs that don't work in primary generalized, like carbamazepine.

That some of our either ease of use attributes are even more important than they are in Pos and that hinges on the importance of the lack of titration and the ability to achieve efficacy very rapidly remember these seizures tend to cluster and they are considered more dangerous than <unk>.

<unk> seizure with a greater likelihood of suite app as well as depth, resulting from accidents.

So the ease of use attributes were really encouraging in the eyes of the clinicians with which we spoke spoke and any other components.

To potentially Miss a dose a novel mechanism of action to be used in combination all of those components resonate really well with <unk>.

From the market research that we've seen and as a result.

Chris Kenney: So I think that's compelling.

We think this is going to be a very compelling offering for patients in this category.

Great and then on the Sierra side, So we really look to our collaborators.

With respect to updating the market at this time, we don't have this year.

That hasnt updated their guidance and in Q2, but we do expect to get more information in the coming months.

And we will take the lead from them and update accordingly.

Great. Thank you.

Seeing no other questions in the queue I will turn the call back over to Sherri Allen.

Chris Kenney: And then, and of course, you know, the fact that we're looking at our own clinical data, and seeing that there's a fairly significant, greater than 80% reduction in type 4 seizures, those seizures that start focal and then generalize after that.

Chris Kenney: I think those, that clinical data set is actually more compelling in my mind than the preclinical data set that you, you know, that you asked in the question.

Great well, thanks, everyone for joining us today on our Q2 call operator, we will now end the call.

Chris Kenney: And then as far as dose response, you know, what we've seen with other anti-seizure medications is that the dose response that occurs in focal onset seizures is very similar to what happens in primary generalized tonic-clonic seizures.

Chris Kenney: So using multiple precedents from the epilepsy world, and then taking a look at our ex-toll, data in focal onset seizures, where the 25 milligram dose clearly showed the best benefit, we've decided to bring that as our primary dose forward into primary generalized tonic-clonic seizures.

Chris Kenney: So all of that makes us feel about as confident as we can, you know, in that study, but it will remain to be seen what happens.

Operator: Operator, we will now end the call.

Chris Kenney: And on the treatment paradigm side, what we see in PGTCS is actually quite similar to, what we see in FOS. Patients are typically initiated on an individual agent. Levitiracetam is frequently used given its broad spectrum nature.

Chris von Seggern: And then they progress through multiple lines of therapy without, if they don't achieve a sufficient benefit.

Operator: This concludes today's call.

Chris von Seggern: Where we expect XEN-1101 to play is early in the branded lines of treatment, and that's with the expectation that we're offering an in-line efficacy profile similar to what we've seen on the FOS side.

This concludes today's call. Thank you for attending you may now disconnect.

Operator: Thank you for attending.

Chris von Seggern: An important distinction in CRISPR in this is that the carbamazepine category, which is quite frequently used in FOS, is not used in this disease space, which creates an even greater opportunity for a novel mechanism of action that offers a really potent benefit.

Operator: You may now disconnect.

Chris von Seggern: And what we've seen from our research is real excitement around that opportunity.

Chris von Seggern: KB7 mechanism, all of the other ease-of-use attributes, key opinion leaders are very, very interested in seeing the benefit we can potentially provide to that patient population.

Brian Abrams: This is super helpful.

Operator: Thanks.

Yes.

Operator: Your next question comes from the line of Tessa Romero with J.P. Morgan.

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Operator: Your line is

Operator: now open.

Tessa Romero: Hey, guys.

Tessa Romero: Thanks so much for taking the question here.

Tessa Romero: I think in the past, you've talked about presenting some additional open-label data from ECTL at the American Heart Association.

Tessa Romero: Can you please talk about the size and scope of data we will see at the conference and, are there are there any additional analyses we should have an eye on and what would be a win there?

Tessa Romero: Thanks so much.

Ian Mortimer: I can address assess.

Ian Mortimer: If you look at ...

Ian Mortimer: The open-label extension, as you know, is ongoing and every day we are, providing more mature data.

Ian Mortimer: We did cut the data earlier this year, both as part of our preparation for end-of-phase-two, meeting with FDA to share with some longer-term safety data with them and then we also had shown some of the efficacy data more recently in June of this year.

Okay.

Ian Mortimer: So we have submitted abstracts for AES, including to follow up, as you say, on more mature open-label, extension data.

Ian Mortimer: So in August of this year, so this month, all of the patients will have gone through, 12 months.

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Ian Mortimer: So we'll now at least have a data set where every patient in open-label extension will, have been ... All those remaining will have been on drugs for at least 12 months.

Ian Mortimer: We'll choose later this fall kind of where that cutoff point is in terms of analysing, the data and getting ready for AES, but we'll likely have a data point that's more mature than the 12-month data that we showed in June of this year.

Ian Mortimer: So it'll just be more mature follow-up where we will show both the MPC over time, as well, as looking at these intervals of seizure freedom for the patients, which are obviously really important.

Ian Mortimer: So it'll be similar data that you've seen in the past from us, it'll be just a more, mature data set as we move forward.

Chris Kenney: Yeah, maybe I'll just add a couple things, if you don't mind, Ian.

Chris Kenney: So in addition to that, the first patient will reach three years this fall, and so you're, starting to get some patients who've been exposed for quite a while.

Chris Kenney: And then as far as defining a when, I mean, what we've seen so far is that Xeon 1101 is, well-tolerated, and so we want to see that persist.

Chris Kenney: We haven't had any idiosyncratic toxic reactions like we've seen with other anti-seizure medications, so we hope that that remains the same.

Yeah.

Chris Kenney: And then we've seen a beautiful maintenance of effect over a prolonged period of time, and so we'd like to see that continue and then see if that has any other impact on other skills like quality of life.

Tessa Romero: Great.

Yes.

Operator: Thanks so much for taking our question.

Yes.

Operator: Your next question comes from the line of Mark Goodman with SVP.

Operator: Your line is now open.

Okay.

Mark Goodman: Yes, hi.

Mark Goodman: I was wondering if you could give us a flavor for how you think Inoxcopre is doing out there, in the marketplace and if there's been any major dynamic changes in the epilepsy kind of commercial space.

Chris von Seggern: Thanks.

Chris von Seggern: Yeah, Chris, do you want to go first, or do you want to – yeah, why don't you go ahead, and I'm happy to add any other comments from my side also.

Chris von Seggern: Yeah, absolutely.

Chris von Seggern: So as you – we track Xcopre uptake in the U.S. quite carefully, as it's the most recently, launched product in the category, and what we hear from both our research and just tracking the scripts and the data, Xcopre's off to a nice launch.

Chris von Seggern: It does have uptake later in lines of therapy, and what we hear from at least our market, research is that patients do experience a good benefit late in lines of therapy.

Chris von Seggern: So patients who are trending towards surgery, Xcopre represents a great opportunity.

Chris von Seggern: What we have heard, though, from our research is that not all the patients get all the way, to the maximum dose that was used in the clinical trial, and as a result, the efficacy might not translate in the same way as what we've seen from a clinical experience, at least in the controlled clinical setting.

Chris von Seggern: That being said, it's off to a good start, trending ahead of what we've seen for a number, of other products, at least on a scripts basis over time, and it does represent a bit of a shift in dynamic, creating another key player that can hopefully help bolster all commercial products in this space, as this category hasn't had really a giant player since the, Kepper days, and Vimpad, as everyone knows, recently lost exclusivity. So there is room for both that product and others to come in and replenish the commercial, sales potential in this category.

Chris von Seggern: Thanks Chris.

Ian Mortimer: Yeah, I've got nothing else to add.

Mark Goodman: Mark, do you have a follow-up?

Mark Goodman: No, thanks Chris.

Operator: Okay, thanks Mark.

Operator: Operator, we can move to the next question.

Operator: Your next question comes from the line of Yatin Sunenja with Guggenheim.

Operator: Your line is now open.

Delma: Hi, this is Delma for Yatin.

Delma: Thanks for taking our question.

Delma: So I have a quick one on the MDB study.

Delma: We would like to know what type of profile you would like to see and if there are subsets of patients that you would expect to respond better to 1101.

Chris Kenney: Thank you.

Chris Kenney: Chris, do you want to talk about the profile in MDD? Yeah, so as far as the profile goes, these study designs for these MDD POCs are fairly consistent with one another.

Chris Kenney: One of the differences that you'll see is that some include treatment-resistant depression and others don't.

Chris Kenney: Ours doesn't.

Chris Kenney: So we expect a profile that would be quite similar to those studies designed in that manner.

Chris Kenney: So if you're familiar with the azogabine proof-of-concept trial, we expect a population that will be somewhat consistent with that.

Chris Kenney: As far as subsets of patients, I mean the data was fairly robust in the azogabine trial across the board.

Chris Kenney: And I don't remember that publication talking about subgroups where there was a better response or a less favorable response.

Chris Kenney: So I think we'll just have to kind of go into it with open eyes.

Chris Kenney: The only thing I would add to Chris's comment is we've talked about we're looking to a primary endpoint in our study.

Chris Kenney: We're looking at Madras clinical scale of depression. And also these patients will have anhedonia.

Chris Kenney: And so we are looking at the key secondary endpoint is the SHOP scale, which will measure changes in anhedonia.

Chris Kenney: Okay, perfect.

Delma: Thank you.

Operator: Your next question comes from the line of Andrew Tai with Jeffries.

Operator: Your line is now open.

Operator: Very good.

Andrew Tai: Thank you and congratulations on all the progress recently.

Andrew Tai: So maybe I guess one on MDD first since we just spoke on it.

Andrew Tai: Just curious, did you happen to design Ex Nova such that if it were a positive study that it would be perhaps large enough to be considered by the FDA as a potentially pivotal study?

Andrew Tai: Or should we view this more as an exploratory study?

Andrew Tai: And, you know, if it were positive, you would need two more placebo-controlled studies thereafter.

Andrew Tai: Thanks.

Ian Mortimer: Thanks, Andrew.

Ian Mortimer: Yeah, I mean, we've really been thinking about this MDD study as a proof of concept.

Ian Mortimer: So it's designed as a proof of concept.

Ian Mortimer: We're looking at two different doses.

Ian Mortimer: We actually made an adjustment in the trial design post-Ex tool to include a lower dose based on the efficacy in Ex tool at 10 milligrams.

Ian Mortimer: But, yeah, we're really viewing this as a proof of concept study to start generating some data in depression.

Ian Mortimer: And I think we'll really be driven by those data in terms of next steps for 1101 in that population.

Chris Kenney: And then just a couple things on that, if you don't mind.

Chris Kenney: So the Azogabine trial, the proof of concept, had about half the number of patients per treatment, group, and so it demonstrated an effect size of about 0.75, which is fairly high.

Chris Kenney: Our studies powered for 0.5, and as Ian said, we've chosen a dose that was similar to the, equivalent dose for Azogabine.

Chris Kenney: And also, we've seen efficacy in focal onset seizures at a dose that was also seen, you, know, with that similar dose equivalent in focal onset seizures for Azogabine.

Chris Kenney: So yeah, but just to reiterate what Ian has said, even though the study has about twice, as many patients per treatment group, I don't think that this has a good chance of being considered pivotal.

Andrew Tai: Thanks.

Andrew Tai: Makes sense.

Andrew Tai: And then as a follow-up then, shifting gears to actually just the focal epilepsy program, you know, as you start the pivotal Phase 3 studies, maybe a high-level question is just how are you thinking about, you know, maximizing the success?

Andrew Tai: Are there any, like, findings or learnings from the Phase 2 that you would apply in Phase, 3?

Andrew Tai: Yeah.

Andrew Tai: Thanks.

Andrew Tai: Yeah, the guiding… You know, our… Go ahead.

Chris Kenney: Okay.

Chris Kenney: So yeah, I'll start, and then you jump in, Chris.

Ian Mortimer: You know, given the success of extol, we're really not changing much for extol 3.

Ian Mortimer: Obviously, or sorry, extol 2 and extol 3, the Phase 3 trials, obviously, the studies, are a little bit larger than extol, so we do have more power than we did in the extol study.

Ian Mortimer: In terms of inclusion-exclusion criteria, it's going to be the same as the extol study, so we're really trying to replicate the extol study in a little bit of a larger study with a 12-week endpoint, and we know, as you've seen from the open-label data, we have very good signal at 12 weeks.

Ian Mortimer: It looks like the signal may be a little bit stronger than over 8 weeks in extol, but really, we're trying to keep as much the same as possible, including leveraging a lot of the same sites that we used to great success in the extol study.

Chris Kenney: Chris, anything else to add?

Chris Kenney: Yeah, I mean, to complement those comments, we're going to try to avoid regions that, have…that are known to have a high placebo effect.

Chris Kenney: We're going to make sure that we're getting good-quality patients by having them, you, know, reviewed by epileptologists before they're randomized, and then, you know, Ian's comment is our guiding principle, which is extol worked really well, so let's not deviate much from that plan.

Chris Kenney: Use as many same sites as we can, et cetera.

Andrew Tai: Right.

Andrew Tai: Thank you, guys.

Operator: Thanks.

Operator: Your next question comes from the line of David Hong with SMBC.

Operator: Your line is now open.

David Hong: Hey.

David Hong: Thanks for taking the questions.

David Hong: So, my first one, I had one on generalized epilepsy and PGTCS, so could you just tell, us a little bit about what are the major branded products that are, you know, the branded AEDs that are being used for PGTCS now, and is there any off-label usage of drugs that do not have the generalized… B-C-G-H labeled.

David Hong: I can take that.

Chris von Seggern: What we've heard from our research is that products that are known to be broad spectrum, are used typically in advance of products being labeled indication.

Chris von Seggern: I bring that up because Vimpat didn't get the PGTCS indication until very late in its, We didn't see a material increase in its sales at that time, in part probably because it was being used in advance of the indication.

Chris von Seggern: From our research, we've heard both Briviact and ExcoPri being used in PGTCS despite neither, yet having a label, although both products are known to be broad spectrum and therefore opinion leaders have been extrapolating into that setting.

Chris von Seggern: Other branded products that remain in this space have two distinct stories.

Chris von Seggern: Phycompa is used in convulsant seizures, and we hear that from our research.

Chris von Seggern: Aptium, being in the carbamazepine category, doesn't have the indication and is not used, here.

Chris von Seggern: It's the same branded set minus Aptium today with reasonable use for those products that, don't yet have the indication but are expected to.

David Hong: Got it.

David Hong: That's really helpful.

David Hong: Just a follow-up, I'm looking at some of the slides you had posted related to PGTCS, and, it shows there is a population, it looks like, of about 300,000 or so patients in this market-sizing figure that have, I guess, undefined or combination epilepsy.

David Hong: If you have both focal and generalized labels, would you be able to access that population?

Chris von Seggern: Yeah, practically speaking, the answer is probably yes, but that patient population, from a coding standpoint, we've looked into this actually quite in detail, in fact remains coded as an unknown cause of epilepsy.

Chris von Seggern: They're having both focal and generalized seizures in all likelihood, and what we've, heard is that they are traditionally treated like a PGTCS patient.

Chris von Seggern: So clinicians could imagine using the product in that space, but from a strict coding standpoint, they don't have a definitive diagnosis, and that could create an impediment from payers who have very strict prior authorization criteria for select plans in the U.S.

Chris von Seggern: Okay.

David Hong: Great.

Operator: Thanks for taking the questions.

Operator: Your next question comes from the line of Lachlan Hanbury with William Blair.

Operator: Your line is now open.

Lachlan Hanbury: Hey, guys.

Lachlan Hanbury: This is Lachlan.

Lachlan Hanbury: I'm for Tim.

Lachlan Hanbury: Thanks for taking the question.

Lachlan Hanbury: So I was wondering, you obviously have, or will have, a lot of long-term data from the, ex-toll open label extension by the time you file, but that's going to be at the 20 MIG dose, and the higher dose you'll be testing is 25 MIG.

Lachlan Hanbury: So did you sort of talk to the agency about what kind of long-term data you'll need at, the 25 MIG dose, and can you just discuss what the plans are for that?

Lachlan Hanbury: Is that all going to come from the ex-toll two and three open label extension?

Chris Kenney: Chris Kenny, do you want to tackle that?

Chris Kenney: Yeah, sure.

Chris Kenney: Yeah, so you're right.

Chris Kenney: The ex-toll open label study, the target dose was 20 milligrams. That dose was chosen in advance of the data that we have.

Chris Kenney: Unknown Attendee, Dr. David Hoang, Unknown Attendee, Unknown Attendee, Unknown Attendee, Dr. David Hoang, Unknown Attendee, Unknown Attendee, Unknown Attendee, Unknown Attendee, I know, no, as Chris mentioned, there's a lot of similarities, right?

Chris Kenney: We kind of use, you know, the quality of the sites that you choose the investigators and kind of some more oversight where both in epilepsy and with epilepsy and depression, we can kind of have this third party kind of adjudication that can kind of sit over top of the studies and and help out to make sure that we're getting we're getting the right patients.

Chris Kenney: Hello, thanks.

Operator: Your next question comes from the line of Rohit Basin with Needham.

Operator: Your line is now open.

Operator: Hi, this is Rohit on First Search.

Rohit Basin: Thanks for taking our questions.

Rohit Basin: Can you share any feedback you received from providers with the expansion to PGTCS?

Rohit Basin: And then when can we expect an update from the partnered FX301 program with Basir?

Rohit Basin: Thanks.

Chris von Seggern: Chris, one second.

Sherry Aulin: Do you want to talk about some of the feedback we've had on primary generalized and then Sherry can address the partner in Boston?

Chris von Seggern: Yeah, absolutely.

Chris von Seggern: So the research we conducted specifically thinking about the opportunity in PGTCS leveraged the profile that emerged from XTOL with respect to safety.

Chris von Seggern: And then we've put forward estimates around what an inline product could be from an efficacy standpoint.

Chris von Seggern: And what we saw in that research was actually significant enthusiasm based on the safety and tolerability profile in the space as well as the ease of use attributes.

Chris von Seggern: And in primary generalized tonic-clonic seizures, you can make the argument that some of our ease of use attributes are even more important than they are in FOS. And that hinges on the importance of the lack of titration, the ability to achieve efficacy very rapidly. Remember, these seizures tend to cluster and they are considered more dangerous than an FOS seizure with a greater likelihood of SUDEP as well as death resulting from accidents. So the ease of use attributes were really encouraging in the eyes of the clinicians with which we spoke.

Chris von Seggern: And the other components, ability to potentially miss a dose, a novel mechanism of action to be used in combination, all of those components resonate really well from the marker research that we've seen.

Chris von Seggern: And as a result, we think this is going to be a very compelling offering for patients in this category.

Sherry Aulin: Great, and then on the Pacira side, so we really look to our collaborators with respect, to updating the market.

Sherry Aulin: So at this time, we don't have, Pacira hasn't updated their guidance in Q2, but we do expect, to get more information in the coming months, and we'll take the lead from them and update accordingly.

Rohit Basin: Great.

Operator: Thank you.

Sherry Aulin: Seeing no other questions in the queue, I will turn the call back over to Sherry Aulin.

Sherry Aulin: Great.

Sherry Aulin: Well, thanks, everyone, for joining us today on our Q2 call.