Xenon Pharmaceuticals Inc (XENE) 2022 Q2 法說會逐字稿

Good afternoon, and welcome to the Xenon Pharmaceuticals Reports Second Quarter Results Conference Call. (Operator Instructions) Sherry Aulin, Chief Financial Officer, you may begin your conference.

Thank you. Good afternoon, everyone. Thank you for joining us on our call and webcast to discuss Xenon's second quarter 2022 financial and operating results. 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.

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 real time lines; 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. Our results may differ materially from those projected on today's call. We undertake no obligation to publicly update any forward-looking statements. 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 Investors section of our website at www.xenon-pharma.com, and filed with the SEC and on SEDAR.

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

Thanks, Sherry. Good afternoon, everyone, and thanks for joining our call. I'll start today's call with a high level summary of our recent progress. I'll then turn the call over to Chris Kenney, who will provide additional color around our XEN1101 and the Phase II 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 PGTCS. Chris will also provide his perspective on the additional X-TOLE data, which we recently released. Chris Von Seggern will then share some market research insights, shaping our clinical plans in PGTCS and the commercial opportunity for developing XEN1101 within this indication, where there remains a significant unmet medical need.

Sherry will conclude our call by briefly summarizing our partner programs, financial results and events ahead. We look forward to taking your questions during the Q&A session at the end of the call. I'm pleased to report several important achievements within our XEN1101 program this past quarter, along with continued progress across the rest of our pipeline. Within XEN1101, the clinical data generated to-date, along with feedback from KOLs and primary research -- market research findings support our belief that XEN1101 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 a dosing regimen of one pill once a day with no titration, providing meaningful seizure reduction after only one week of dosing.

In addition to its robust efficacy in focal onset seizures, the XEN1101 AE profile is in line with other anti-seizure medications. Following a positive end of Phase II meeting with the FDA, we're excited to advance our XEN1101 Phase III program, starting with the initiation of X-TOLE2 in the second half of this year. Additionally, we have a strong scientific rationale supporting the use of XEN1101 to address primary generalized tonic-clonic seizures, and we're looking forward to initiating our Phase III X-ACKT's clinical trial in PGTCS. 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 IIb X-TOLE trial, and these further support our Phase III development plan for XEN1101, including a time course to efficacy analysis, demonstrating that all doses of XEN1101 rapidly reduce the frequency of focal onset seizures within one week compared to placebo. Chris Kenney will provide some more details on these data as well as our first cut of open-label extension efficacy data from X-TOLE in our Phase III plan.

In addition, our Phase II X-NOVA study is underway examining XEN1101 in major depressive disorder, or MDD, in parallel with an investigator-led Phase II MDD study being conducted by our collaborators at Mount Sinai. Our decision to examine XEN1101 in MDD was based in part on promising clinical results with ezogabine dosed 300 milligrams TID as a treatment for MDD and anhedonia, as well as encouraging preclinical data with XEN1101. It is also important to note that depression is one of the most common comorbidities within the epilepsy patient population. Top line results from the X-NOVA study are anticipated in 2023.

Turning to another program within our proprietary pipeline. We continue to support our ongoing XEN496 Phase III EPIK pediatric clinical trial evaluating XEN496 in patients aged one 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.

Our clinical development plans are supported by published physician case studies with ezogabine and XEN496's Kv7 mechanism of action. We expect completion of EPIK in 2023. So overall, we continue to make meaningful progress across the pipeline, and we're excited to move XEN1101 into a broad Phase III program in the near-term.

So I'll pause here and ask Chris Kenney to provide some more detailed comments on our end of Phase II meeting with FDA, our Phase III clinical trial designs, as well as some additional supporting data from X-TOLE and the X-TOLE OLE, which continues to support our high level of confidence and conviction in our XEN1101 program. Chris, over to you.

Okay. Thanks, 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 I trials and the positive Phase IIb X-TOLE clinical trial, evaluating XEN1101 in adult patients with focal onset seizures.

As a reminder, the X-TOLE top line efficacy data demonstrated that the primary and secondary seizure reduction endpoints were statistically significant across all 3 dose groups. With p values of less than 0.001 for the 20 and 25 milligram groups and XEN1101 was generally well tolerated. We aligned 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 XEN1101 Phase III clinical trial, X-TOLE2, if successful, (technical difficulty)

Chris, we just lost you on our side. Are you still there? Okay. I'll carry on with Chris' section. I know for those on the line, there was a storm going through where Chris Kenney was based, and so he may have lost connection or lost 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 XEN1101 Phase III clinical trial, X-TOLE2, if successful, and we'll use the existing data package from the Phase IIb X-TOLE2 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 outline for the designs of the planned XEN1101 Phase III clinical trial. So designed closely after the Phase IIb X-TOLE study, we plan to initiate 2 identical Phase III clinical trials called X-TOLE2 and X-TOLE3, each study will enroll approximately 360 patients who will be randomized 1:1:1 for once daily dosing of either 15 or 25 milligrams of XEN1101 or placebo.

Our dose selection for the Phase III studies was informed by the safety and efficacy data in X-TOLE as well as by additional PK/PD modeling that we completed earlier this year. The primary efficacy endpoint is the median percent change or MPC in monthly seizure frequency from an 8 week baseline through a 12 week double-blind period was XEN1101 compared to placebo. And we have greater than 90% power for the primary endpoint at both doses using modeling from our X-TOLE data.

On completion of the double-blind period in both X-TOLE2 and X-TOLE3, eligible patients may enter an open-label extension study for up to 3 years. X-TOLE2 is expected to be initiated in the second half of the year, followed by the initiation of X-TOLE3, so both studies will run in parallel. Following the initiation of X-TOLE2, we also plan to initiate a single Phase III clinical trial called X-ACKT to support a regulatory submission in PGTCS, if successful. X-ACKT will enroll approximately 160 subjects who will be randomized 1:1 for once daily dosing of either 25 milligrams of XEN1101 or placebo.

The primary efficacy endpoint is the MPC in monthly PGTCS frequency from an 8 week baseline through a 12 week double-blind period of XEN1101 compared to placebo. And on the completion of the double-blind period in X-ACKT, eligible patients may also enter an open-label extension study for up to 3 years. Our plans for pursuing this additional epilepsy indication of PGTCS within our Phase III program are supported by a strong rationale. Specifically, XEN1101 shows anti-seizure activity in 2 preclinical models, both the MES and PTZ in preclinical models, both of which are known to predict efficacy for primary generalized seizures.

Further, other ASMs such as levetiracetam, valproic acid and lamotrigine suppressed photosensitivity in generalized epilepsy patients, thereby predicting efficacy in PGTCS. And another Kv potassium channel opener previously in development was also shown to suppress photosensitivity in patients with generalized epilepsy in a clinical study. Additionally, in our Phase IIb X-TOLE clinical trial, XEN1101 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 X-TOLE clinical trial. And these further support our Phase III development plans for XEN1101. And they suggest that XEN1101 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 14 European epilepsy Congress in Geneva. Our analysis show that all doses of XEN1101 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 group, this is a p-value of less than 0.001, 41.5% 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 20.2% in the placebo group. So based on the 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 XEN1101.

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-TOLE OLE for at least 3 months and 12 months experienced a greater than 70% and 80% reduction, respectively, in median monthly seizure frequency when compared to baseline. And of the 275 patients who entered OLE, 19.6% and 9.5% experienced 6 and 12 months of seizure freedom, respectively. 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 a 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 3 to 5 years. The ongoing X-TOLE OLE continues to generate important long-term safety data for XEN1101 and FOS, and we expect to present additional long-term OLE 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 XEN1101 Phase III plans. We are further driven by our belief that there is a significant medical need for new therapeutics to treat epilepsy and XEN1101 has the potential to significantly improve the lives of these patients.

I'll now turn the call over to Chris Von Seggern, who will share some market research insights shaping our plans for XEN1101 in PGTCS. Chris?

Thanks, Ian. By way of background, seizures are generally described in 2 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. 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. 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. An opportunity remains for a broad spectrum agent with activity across seizure types.

For these reasons, we believe that XEN1101 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 in potential broad seizure coverage, we believe that XEN1101's once daily dosing with no need for titration or differentiating attributes given the importance of compliance and the need for rapid seizure control in this patient population. Our hope is that XEN1101 may provide an effective treatment for these patients, and we are excited to pursue PGTCS alongside our clinical trials in FOS and MDD.

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

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 2 separate Phase II clinical trials underway. One study is evaluating NBI-921352 in adult patients with focal onset seizures with data expected in 2023. And another study is examining its use in pediatric patients with SCN8A related epilepsy. Our other collaborator, Pacira BioSciences is conducting a Phase Ib proof-of-concept trial that is evaluating the safety and tolerability of PCRX301 administered as a single dose in patients undergoing bunionectomy. We look forward to keeping you updated as these partner programs reach important milestones.

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

Based on current assumptions, which include fully supporting our XEN1101 clinical development program, which includes the completion of our planned Phase III epilepsy studies, XEN496 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 initiate X-TOLE2, our first Phase III clinical trial in FOS in the second half of this year, followed by the initiation of X-TOLE3 and the X-ACKT clinical trial in PGTCS. Our X-NOVA 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 and MDD, and we continue to advance our EPIK Phase III clinical trial in pediatric patients with KCNQ2-DEE with study completion anticipated in 2023.

In summary, this is an incredibly exciting time at Xenon 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. 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?

(Operator Instructions) Your first question comes from the line of Paul Matteis with Stifel.

This is James on for Paul. Maybe just a quick one on MDD. Could you remind us the dosing there for the study in your trial? And then 2, is there any reason to believe that the extrapolation of ezogabine to 1101 and MDD would be different than it would be, than it was in epilepsy? Just wondering how you're thinking about that.

Thanks, James. Chris, can you maybe just come off and just make sure that you're back on, and we can hear you again.

I'm here. Can you hear me?

Okay. Perfect. Yes. Just for Q&A, it's great that I know you got cut off there, but you're back on. I can address this for James. So just as a reminder, there's 2 MDD studies ongoing, one which is an IST that we're supplying drug for, that's through Mount Sinai and they have a second site at Baylor. And then we have our company sponsored. The Mount Sinai study, they're looking at one active dose, which is 20 milligrams and placebo and ours is a 3 arm study, it's a little bit larger, so we have a bit more power, and we're looking at 2 active doses in placebo, 10 milligrams, 20 milligrams and placebo.

And then your follow-up question just on the extrapolation of the ezogabine data. So ezogabine the randomized study that they ran through the same collaborators that we're working with at Mount Sinai that data was published last year. They used 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-TOLE study. So there's nothing that we would believe that we're going in with a dose that would be -- it would be less active than the ezogabine dose. Obviously, we're doing cross-trial comparisons here, but we feel very comfortable in terms of the dose range in the MDD studies.

Your next question comes from the line of Brian Abrahams with RBC Capital Markets.

On PGTCS, you've mentioned that you've run several different preclinical models that are supportive of activity. I'm curious, based on the magnitude of benefit that you're observing 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?

And then I guess, as a corollary to that is 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 failed to anti-seizure medications? Would you expect this to be used with the gold beats for this to be used sort of as the first agent in that refractory population? Is there a potential for combinability? How do you expect it to be used in that one-third of patients?

Brian, I think super comprehensive questions that we can tackle. And so maybe, Chris Kenney can go first and then Chris Von Seggern on the epi and kind of maybe the treatment algorithm and how these patients move through different therapies. But Chris, can you probably get just to talk a little bit about the efficacy of the drugs that work in focal, the type of efficacy they see in primary generalized as well as those placebo rates, and that will maybe kind of help answer Brian's question just around the extrapolation from focal to primary generalized.

Yes. I mean the question was largely focused on the preclinical signal with XEN1101, 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 benefit. But I'm actually -- and that's great, that's compelling. But it's really the clinical data that I think is more compelling. And you have a compound in -- one of the Icagen 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.

And that model has been incredibly predictive of drugs that work in primary generalized, like the ones we mentioned, levetiracetam, valproic acid. And also it doesn't show any significant suppression with drugs that don't work in primary generalized, like carbamazepine. So I think that's compelling. And then -- and of course, the fact that we're looking at our own clinical data and seeing that there is fairly significant greater than 80% reduction in Type 4 seizures, those seizures that start focal and generalize after that. I think those -- that clinical data set is actually more compelling in my mind than the preclinical data set that you asked in the question.

And then as far as dose response, 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. So using multiple precedents from the epilepsy world and then taking a look at our X-TOLE 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. So all of that makes us feel about as confident as we can in that study, but it will remain to be seen what happens.

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, levetiracetam is frequently used given its broad spectrum nature. And then they progress through multiple lines of therapy without -- if they don't achieve a sufficient benefit. Where we expect XEN1101 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. An important distinction in (inaudible) is that the carbamazepine category just quite frequently (inaudible) is not used in this disease space, which creates an even greater opportunity for our novel mechanism of action that offers a really potent benefit.

And what we've seen from our research is real excitement around that opportunity, Kv7 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.

Your next question comes from the line of Tessa Romero with JPMorgan.

I think in the past, you've talked about presenting some additional open-label data from X-TOLE at the American Epilepsy Society Meeting later this year in December. Can you please talk about the size and the scope of the data we will see at the conference? And are there any additional analyses we should have an eye on? And what would be considered a win there?

I can address that. Yes, if you look 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, both as part of our preparation for end of Phase II 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. So we have submitted abstracts for AES, including to follow-up, as you say, on the -- on more mature open-label extension data.

So in August of this year, so this month, all of the patients will have gone through 12 months. 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 drug for at least 12 months. We'll choose later this fall kind of where that cutoff point is, in terms of analyzing 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. 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 patients, which are obviously really important. So it will be similar data that you've seen in the past from us. It will be just a more mature data set as we move forward.

Yes. Maybe I'll just add a couple of things, if you don't mind, Ian. So in addition to that, the first patient will reach 3 years this fall, and so you're starting to get some patients who've been exposed for quite a while. And then as far as like defining a win, I mean, we -- what we've seen so far is that XEN1101 is well tolerated. And so we want to see that persist. 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. 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.

Your next question comes from the line of Marc Goodman with SVB.

I was wondering if you could give us a flavor for how you're thinking Xcopri is doing out there in the marketplace? And if there's been any major dynamic changes in the epilepsy kind of commercial space.

Yes. Chris, do you want to go first? Or do you want to -- Yes, why don't you go ahead, and I'm happy to add any other comments from my side also.

Yes, absolutely. So as we track Xcopri uptake in the U.S. quite carefully, as it's the most recently launched product in the category. And we -- what we hear from both our research and just tracking the scripts and the data, Xcopri is off to a nice launch. 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. So patients who are trending toward surgery, Xcopri, represents a great opportunity.

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. 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 Keppra days and Vimpat 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.

Thanks, Chris. Yes, I've got nothing else to add. Marc, do you have a follow-up?

No.

Your next question comes from the line of Yatin Suneja with Guggenheim.

This is Delma for Yatin. So I have a quick one on the MDD study. 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 that to 1101.

Chris, do you want to talk about the profile in MDD?

Yes. I mean, so as far as the profile goes, I mean, these study designs for these MDD POCs are fairly consistent with one another. One of the differences that you'll see is that some include treatment-resistant depression and others don't, ours doesn't. And so we expect the profile that'll be quite similar to those studies designed in that manner. So if you're familiar with the ezogabine proof-of-concept trial, we expect a population that will be some inconsistent with that. As far as subsets of patients, I mean the data was fairly robust in the ezogabine 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.

Yes. And the only thing I would add to Chris' comment is, we've talked about -- we're looking to a primary endpoint in our study. We're looking at MADRS clinical scale of depression. We also -- these patients will have anhedonia. And so we are looking at the key secondary endpoint is the shop scale, which will measure changes in anhedonia.

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

Congratulations on all the progress recently. So maybe, I guess, one on MDD first since we just spoke on it. Just curious, did you happen to design X-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 they were positive, you would need 2 more placebo-controlled studies thereafter?

Yes, I mean, we've really been thinking about this MDD study as a proof-of-concept. So it's designed as a proof-of-concept to -- we're looking at 2 different doses. We actually made an adjustment in the trial design post X-TOLE to include a lower dose based on the efficacy on X-TOLE at 10 milligrams. But yes, we're really viewing this as a proof-of-concept study to start generating some data in depression, and I think will really be driven by those data in terms of next steps for 1101 in that population.

And then just a couple of things on that, if you don't mind. So the ezogabine trial, the proof-of-concept had about half the number of patients per treatment group. And so -- and it demonstrated an effect size of 0.75, 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 ezogabine. And also, we've seen efficacy in focal onset seizures at a dose that was also seen with that similar dose equivalent in focal onset seizures for ezogabine. So yes, but I -- 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.

Makes sense. And then as a follow-up then, shifting gears to actually just the focal epilepsy program. As you start the pivotal Phase III studies, maybe a high-level question is just, how are you thinking about maximizing the success? Are there any like findings or learnings from the Phase II that you would apply in Phase III?

Yes, the -- go ahead.

Yes, I'll start and then you jump in, Chris. Given the success of X-TOLE, we're really not changing much for X-TOLE3, obviously, sorry, X-TOLE2 and X-TOLE3 of the Phase III trials. Obviously, the studies are a little bit larger than the X-TOLE, so we do have more power than we did in the X-TOLE study. But in terms of inclusion/exclusion criteria, it's going to be the same as the X-TOLE study. So we're really trying to replicate the X-TOLE 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. It looks like the signal may be a little bit stronger than over 8 weeks in X-TOLE. But really, we're trying to keep as much the same as possible, including leveraging a lot of the same sites that we use to create success in the X-TOLE study. Chris, anything else to add?

Yes. I mean, to complement those comments, I mean, we're going to try to avoid regions that have -- that 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 epileptologists before they're randomized. And then Ian's comment is our guiding principle, which is X-TOLE worked really well. So let's not deviate much from that plan, use as many same sites as we can, et cetera.

Your next question comes from the line of David Hoang with SMBC.

So my first one, I had one on generalized epilepsy in PGTCS. So could you just tell us a little bit about what are the major branded products that are -- the branded AEDs are being used for PGTCS now? And is there any off-label usage of drugs that do not have the generalized label?

Chris, do you want to take that?

Yes, I can take that. So what we've heard from our research is that products that are known to be broad spectrum are used typically in advance of products in the labeled indication. And I bring that up because Vimpat didn't get the PGTCS indication until very late in its life cycle. And 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. From our research, we've heard both Briviact and Xcopri being used in PGTCS despite neither yet having a label, although both products are off -- are broad spectrum, are known to be a broad spectrum, and therefore, opinion leaders have been extrapolating into that setting.

Other branded products that remain in this space have 2 distinct stories. So Fycompa is used in convulsion seizures. I mean we do see -- and we hear that from our research, Aptiom being in the carbamazepine category, it doesn't have the indication and it's not used here. So it's the same branded set minus Aptiom today with reasonable use for those products that don't yet have the indication but are expected to.

Got it. That's really helpful. And then 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. And so if you have both focal and generalized labels, would you be able to access that population?

Yes. Practically speaking, the answer is probably yes. But that patient population from a coding standpoint, 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. And what we've heard is, they are traditionally treated like a PGTCS patients. 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.

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

This is Lachlan on for Tim. So I was wondering, you obviously have or will have a lot of long-term data from the X-TOLE open-label extension by the time you file, but that's going to be at the 20 mg dose, on the higher dose, you'll be testing 25 mg. So did you sort of talk to the agency about what kind of long-term data you'll need at the 25 mg dose? And can you just discuss what the plans are for that? Is that all going to come from the X-TOLE2 and X-TOLE3 open-label extension?

Chris Kenney, do you want to talk about it?

Yes, sure. Yes. So you're right. The X-TOLE open-label study, the target dose was 20 milligrams that 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 3 Phase III studies going with like that 25 milligram dose along with an open-label extension at 25. And so 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 showed them exactly what we expect at each dose, and we made -- we try to make a case that we think that the drug should be approved at multiple different doses. And it will be a review issue, but they were reading between the tea leaves, they seem to be very open to the plan.

And Lachlan, if you look at the ICH guidelines of kind of unique exposures required in the long-term exposures of 6 and 12 months, we feel really comfortable, as Chris has mentioned, just in the totality of the safety database that we'll provide to FDA and other regulators and the long-term dosing we'll have, as Chris mentioned, because we're doing the open-label extension for all of the studies in the Phase III, we're going to have a lot of data at both 20 and 25.

Got it. And if I could have a follow-up. Placebo responses in MDD have typically been an issue. And I know you guys sort of did pretty well in controlling them in X-TOLE. Is there anything you can sort of transfer to MDD? Or is there anything that -- I guess, can you maybe just discuss what you are doing to try to minimize placebo responses in the MDD trial?

Sure. Yes. So I mean, we covered that, yes, so this will be 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 to minimize the chance of a large placebo effect, they're all U.S. sites. We've also -- we're using the 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 that trial. Do you want to add anything to that, Ian?

No. As Chris mentioned, there's a lot of similarities, right? We kind of use 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 help out to make sure that we're getting the right patients.

Your next question comes from the line of Rohit Bhasin with Needham.

This is Rohit on for Serge. Can you share any feedback you received from providers with the expansion to PGTCS? And then when can we expect an update from the partnered FX301 program with Pacira?

Chris, one second, do you want to talk about some of the feedback we've had on primary generalized and then Sherry can address the partner milestone?

Yes, absolutely. So the research we conducted, specifically thinking about the opportunity in PGTCS, leverage the profile that emerged from X-TOLE with respect to safety. And then we've put forward estimates around what an in-line 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 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 in. 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 with -- from the market research that we've seen. And as a result, we think this is going to be a very compelling offering for patients in this category.

Great. And then on the Pacira side, so we really look to our collaborators with respect to updating the market. 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.

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

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

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