Xenon Pharmaceuticals Inc. (NASDAQ:XENE) Q2 2022 Earnings Conference Call August 9, 2022 4:30 PM ET
Company Participants
Sherry Aulin – Chief Financial Officer
Ian Mortimer – President and Chief Executive Officer
Chris Kenney – Chief Medical Officer
Chris Von Seggern – Chief Commercial Officer
Conference Call Participants
Brian Abrahams – RBC Capital Markets
Tessa Romero – JPMorgan
Marc Goodman – SVB
Andrew Tsai – Jefferies
David Hoang – SMBC
Lachlan Hanbury – William Blair
Operator
Good afternoon and welcome to the Xenon Pharmaceuticals Reports Second Quarter Results Conference Call. [Operator Instructions] Thank you. Sherry Aulin, Chief Financial Officer, you may begin your conference.
Sherry Aulin
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 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. Our results may differ materially from those projected on today’s call. We undertake no obligation to publicly update any forward-looking statement. Today’s press release summarizing Xenon’s 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 would like to turn the call over to Ian.
Ian Mortimer
Thanks, Sherry. Good afternoon, everyone and thanks for joining our call. I will start today’s call with a high level summary of our recent progress. I will then turn the call over to Chris Kenney who will provide additional color around our XEN1101 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. 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 am 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 today, 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 1 pill once a day with no titration, providing meaningful seizure reduction after only 1 week of dosing.
In addition to its robust efficacy and focal onset seizures, the XEN1101 AE profile is in line with other anti-seizure medications. Following a positive end-of-Phase 2 meeting with the FDA, we are excited to advance our XEN1101 Phase 3 program starting with the initiation of X-TOLE2 in the second half of this year. Additionally, we have strong scientific rationale, supporting the use of XEN1101 to address primary generalized tonic-clonic seizures and we are looking forward to initiating our Phase 3 X-ACKT 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 2b X-TOLE. These further support our Phase 3 development plans for XEN1101, including a time course to efficacy analysis demonstrating that all doses of XEN1101 rapidly reduced the frequency of focal onset seizures within 1 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 and our Phase 3 plan.
In addition, our Phase 2 X-NOVA study is underway examining XEN1101 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 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 3 EPIC pediatric clinical trial evaluating XEN496 in patients aged 1 month to less than 6 years with KCNQ2-DEE. There is significant interest from caregivers and the 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 EPIC in 2023.
So overall, we continue to make meaningful progress across the pipeline and we are excited to move XEN1101 into a broad Phase 3 program in the near-term. So I will 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 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.
Chris Kenney
Okay. Thanks, Ian. We are pleased with our end of Phase 2 meeting with the FDA this past quarter. This meeting was supported by non-clinical and clinical data, including results from our previously completed Phase 1 trials and the positive Phase 2b 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 three dose groups, with p values of less than 0.001 for the 20 and 25 milligram groups and XEN1101 was generally well tolerated.
Relying with the FDA on key elements of the Phase 3 program to support a new drug application or NDA submission, we plan to submit an NDA upon completion of the first XEN1101 Phase 3 clinical trial, X-TOLE2 if successful.
Ian Mortimer
Chris, we just lost you on our side. Are you still there? Okay, I will carry on with Chris’s 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 have aligned with the FDA on key elements of the Phase 3 program to support our NDA submission. And we plan to submit the NDA upon completion of the first XEN1101 Phase 3 clinical trial, X-TOLE2 if successful and we will use the existing data package from the Phase 2b X-TOLE clinical trial, along with additional safety data from other clinical trials to meet regulatory requirements. We have also had alignment with FDA was obtained on key elements of a single Phase 3 clinical trial to pursue the epilepsy indication of primary generalized tonic-clonic seizures.
So we will give a little bit more background and outline for the designs of the planned XEN1101 Phase 3 clinical trial. To design closely after the Phase 2b X-TOLE study, we plan to initiate two identical Phase 3 clinical trials called X-TOLE2 and X-TOLE3. 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 XEN1101 or placebo. Our dose selection for the Phase 3 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 created a 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 3 clinical trial called X-ACKT to support a regulatory submission in PGTCS as successful. X-ACKT will enroll approximately 160 subjects who will be randomized one-to-one 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 3 program are supported by a strong rationale. Specifically, XEN1101 shows anti-seizure activity in two preclinical models both the MES and PGT 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 2b X-TOLE clinical trial, XEN1101 demonstrated broad impact across all focal seizure subtypes, including focal seizures that progressed to generalized seizures. As I noted earlier, we have recently generated additional efficacy data from subgroup analyses from our Phase 2b X-TOLE clinical trial and these further support our Phase 3 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 14th European Epilepsy Congress in Geneva.
Our analyses show that all doses of XEN1101 rapidly reduced the frequency of focal onset seizures within 1 week compared to placebo. At Week 1, 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 0.029 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 2b efficacy data, we are including a secondary endpoint of Week 1 median percent change in seizure frequency within the statistical hierarchy of the Phase 3 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 experience a greater than 70% and 80% reduction respectively in median monthly seizure frequency when compared to baseline. And of the 275 patients who undergo 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 are 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 3 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 will now turn the call over to Chris Von Seggern, who will share some market research insights, shaping our plans for XEN1101 in PGTCS. Chris?
Chris Von Seggern
Thanks, Ian. 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-clonic 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 experienced 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, they offer compelling clinical alternative for these epilepsy patients.
In addition to its novel mechanism of action and potential broad seizure coverage, we believe that XEN1101’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. 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 partnered programs, financial position and upcoming milestones. Sherry?
Sherry Aulin
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 2 clinical trials underway. One study is evaluating NBI-921352 in adult patients with vocal 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 1b 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 partnered 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 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 operating expenses.
Based on current assumptions, which includes fully supporting our XEN1101 clinical development program, which includes the completion of our planned Phase 3 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 to our first Phase 3 clinical trial in FOS in the second half of this year, followed by the initiation of X-TOLE3 and the exact 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 Mount Sinai IFT in MDD and we continue to advance our EPIC Phase 3 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 will now ask the operator to open the line for any questions. Operator?
Question-and-Answer Session
Operator
Thank you. [Operator Instructions] Your first question comes from the line of Paul Matteis with Stifel. Your line is now open.
Unidentified Analyst
Hi, this is James on for Paul. Thanks for taking our question. Maybe just a quick one on MDD, could you remind us the dosing there for the study and your trial? And then two, is there any reason to believe that the extrapolation of Ezogabine to 1101 in MDD would be different than it would be or than it was in epilepsy? Just wondering, how you are thinking about that? Thanks.
Ian Mortimer
Thanks, James. Chris Kenney, can you maybe just come off mute and just make sure that you are back on and we can hear you again?
Chris Kenney
I am here. Can you hear me?
Ian Mortimer
Okay, perfect. Yes, just for Q&A. It’s great that I know you got cut off there. But I’d say you are back on. I can address this for James. So just as a reminder, there is two MDD studies ongoing, one which is an IST that we are 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 are 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 are looking at two 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 are 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 have seen superior efficacy in our X-TOLE study. So there is nothing for – there is nothing that we would believe that we are going in with a dose that would be – that 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.
Unidentified Analyst
Great. Thanks so much.
Operator
Your next question comes from the line of Brian Abrahams with RBC Capital Markets. Your line is now open.
Brian Abrahams
Hi, good afternoon and thanks for taking my questions. On PGTCS, you have mentioned that you have run several different preclinical models that are supportive of activity. I am curious based on the magnitude of benefit that you are 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 have observed in the focal onset setting? And then I guess as a corollary to that on the epidemiological side, what would your expectation be based on? I guess, the preclinical data as well as 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 goal for this to be used sort of as the first agent in that refractory population? Is there a potential for compatibility? How do you expect it to be used in that one-third of patients? Thanks.
Ian Mortimer
Great. Thanks, 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 FDA and kind of maybe the treatment algorithm and how these patients move through different therapies. But Chris Kenney probably get just to talk a little bit about the efficacy that the drugs that work and folk call 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?
Chris Kenney
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 am 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, 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 of course the fact that we are looking at our own clinical data and seeing that there is a fairly significant greater than 80% reduction in Type 4 seizures, the seizures that start focal and then generalized after that. I think those – that clinical dataset is actually more compelling in my mind than the preclinical dataset that you asked him the question. And then as far as dose response what we have 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 sing 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 have 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.
Chris Von Seggern
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 progressed or 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 are offering an inline efficacy profile similar to what we’ve seen on the FOS side. An important distinction and crispness is that the carbamazepine category does quite frequently use 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. And what we’ve seen from our research is real excitement around that opportunity. Kv7 mechanism, all 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 Abrahams
Super helpful. Thanks.
Operator
Your next question comes from the line of Tessa Romero with JPMorgan. Your line is now open.
Tessa Romero
Hey, guys. Thanks so much for taking the question here. I think in the past, you have 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? Thanks so much.
Ian Mortimer
Thanks, Tessa. I can address that. If you looked at – so the open label extension as you know is ongoing. And so everyday we are getting more mature data. We did cut the data earlier this year both as part of our preparation for end of Phase 2 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 [Technical Difficulty], including to follow-up, as you say on the – on more mature open label extension data. So I guess this year, so this month, all of the patients will have gone through 12 months. So we will now at least have a dataset where every patient and open label extension will have been all those remaining will have been on drugs for at least 12 months. We will choose later this fall kind of where that cutoff point is in terms of analyzing the data and getting ready for ADS, but we will 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 have seen in the past from us, it will be just a more mature dataset as we move forward.
Chris Kenney
And maybe I will just add a couple of things if you don’t mind Ian. So, in addition to that, the first addition [ph] will reach 3 years, this fall, and so you are starting to get some patients who have been exposed for quite a while. And then as far as like defining of when, I mean what we have 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 have seen with other anti-seizure medications. So, we hope that that remains the same. And then we have seen a beautiful maintenance of the fact over a prolonged period of time. And so we would like to see that continue, and then see if that has any other impact on other scales, like quality of life.
Tessa Romero
Great. Thanks so much for taking my question.
Operator
Your next question comes from the line of Marc Goodman with SVB. Your line is now open.
Marc Goodman
Yes. I was wondering if you could give us a flavor for how you think and Xcopri is doing out there in the marketplace? And if there has been any major dynamic changes in the epilepsy kind of commercial space? Thanks.
Ian Mortimer
Yes. Chris, do you want to go first, if you want to – yes, why don’t you go ahead. And I am happy to add any other comments from my side also?
Chris Kenney
Yes. Absolutely. So, we track Xcopri 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, 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 towards 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 have 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 have seen for a number of other products, at least on a script basis over time. 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 a couple of [ph] 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.
Ian Mortimer
Thanks Chris. Yes. I have got nothing else to add. Marc, do you have a follow-up?
Marc Goodman
No. Thanks.
Ian Mortimer
Okay. Thanks Marc. Operator, we can move to the next question.
Operator
Your next question comes from the line of Yatin Suneja with Guggenheim. Your line is now open.
Unidentified Analyst
Well, this is Diana [ph] for Yatin. Thanks for taking our questions. So, I have a quick one on the MDD study. And 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. Thank you.
Ian Mortimer
Chris, do you want to talk about the profile in MDD?
Chris Kenney
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 will see is that some include treatment resistant depression, and others don’t, ours doesn’t. And so we expect to profile they would be quite similar to those studies designed in that manner. So, if you are familiar with the Ezogabine being proof-of-concept trial, we expect population will be consistent with that. As far as subsets of patients, I mean wrote that 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 will just have to kind of go into it with open eyes.
Unidentified Analyst
Got it.
Ian Mortimer
Yes. And the only thing I would add to Chris’ comment is we have talked about, we are looking to a primary endpoint in our study. We are 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 sharp scale, which will measure changes in anhedonia
Unidentified Analyst
Okay. Perfect.
Ian Mortimer
Thank you.
Operator
Your next question comes from the line of Andrew Tsai with Jefferies. Your line is now open.
Andrew Tsai
Hi. Very good. Thank you and congratulations on all the progress recently. So, maybe I guess one on MDD first, since we just spoke on it. I am 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 will need two more placebo controlled studies there? Thanks.
Ian Mortimer
Thanks Andrew. Yes. I mean we have really been thinking about this MDD study as a proof-of-concept. So, it’s designed as a proof-of-concept. We are looking at two different doses. We actually made an adjustment in the trial design post X-TOLE to include a lower dose based on the efficacy in X-TOLE at 10 milligrams. But yes, we are 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.
Chris Kenney
And then just a couple things on that, if you don’t mind. So, the Ezogabine trialed, the proof-of-concept had about half the number of patients per treatment group. And so it demonstrated an effect size of 0.75, which is fairly high. Our studies powered for 0.5. And as Ian said, we have chosen a dose that was similar to the equivalent dose for Ezogabine. And also we have seen efficacy and focal onset seizures at a dose that was also seen with that similar dose equivalent in focal onset seizures for Ezogabine. So, yes, but just to reiterate what Ian has 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.
Andrew Tsai
Thanks. It makes sense. And then as a follow-up then, shifting gears to actually just the focal epilepsy program. As you start the pivotal Phase 3 studies, it may be a high-level question is just how are you thinking about maximizing the success? Are there any, like findings or learnings from the Phase 2 that you would apply in Phase 3? Yes. Thanks.
Ian Mortimer
Yes. So, yes, I will start and then you jump in Chris. Given the success of X-TOLE, we are really not changing much for X-TOLE3, obviously, sorry, X-TOLE2 and X-TOLE3, the Phase 3 trials. Obviously, the studies are a little bit larger than in X-TOLE. So, we do have more power than we did in the X-TOLE study. And in terms of inclusion-exclusion criteria, it’s going to be the same as the X-TOLE studies. We are really trying to replicate the X-TOLE study in a little bit of a larger study with a 12-week endpoint. And we now as you have 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 eight weeks in X-TOLE. But really, we are trying to keep as much the same as possible, including leveraging a lot of the same sites that we use to great success in the X-TOLE study. Chris, anything else to add?
Chris Kenney
To complement those comments, we are going to try to avoid regions that have – that are known to have a high placebo effect. We are going to make sure that we are getting good quality patients by having them reviewed by epileptologist before they are 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 this as many same sites as we can, etcetera.
Andrew Tsai
Right. Thank you, guys. Thanks.
Operator
Your next question comes from the line of David Hoang with SMBC. Your line is now open.
David Hoang
Hey. Thanks for taking the questions. 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 – the branded ADs [ph] are being used for PGTCS now. And is there any off label usage of drugs that do not have the generalized label?
Ian Mortimer
Yes. I can take that. So, what we have heard from our research is that products that are known to be broad spectrum are used, typically in advance of products being the labeled indication. And I bring that up because the impact didn’t get the PGTCS indication until very late in its lifecycle. And we didn’t see a material increase in sales at that time in part probably because it was being used in advance of the indication. From our research, we have heard both BRIVIACT and Xcopri being used in PGTCS, despite neither yet having the label, although both products are off our broad spectrum are known to be broad spectrum. And therefore, opinion leaders have been extrapolating into that setting. Other branded products that remain in this space have two distinct stories. So, FYCOMPA is used in convulsive 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 is 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.
David Hoang
Got it. That’s really helpful. And then just a follow-up, I am 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?
Ian Mortimer
Yes. Practically speaking, the answer is probably yes. But that patient population from a coding standpoint, we have looked into this actually quite in detail, in fact, remains coded as an unknown cause of epilepsy. So, they are having both focal and generalized seizures and all likelihood. And what we have heard is that they are traditionally treated like a PGTCS patient. So, clinicians could imagine using the product in that space, but from a strict coding standpoint, they don’t have definitive diagnosis and that could create an impediment from payers who have very strict prior authorization criteria for select plans in the U.S.
David Hoang
Okay. Great. Thanks for taking the questions.
Operator
Your next question comes from the line of Lachlan Hanbury with William Blair. Your line is now open.
Lachlan Hanbury
Hey, guys. This is Lachlan on for Tim. Thanks for taking the question. So, I was wondering you obviously have or will have a lot of long-term data from the X-TOLE label extension by the time you file. But that’s going to be at the 20 mg dose and the higher dose will be tested at 25 mg. So, did you sort of talk to agency about what kind of long-term data you will 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 3 of label extension?
Ian Mortimer
Kenny, do you want to join us?
Chris Kenney
Yes. Sure. Yes. So, you are 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 are going to have an enormous amount of data on 20 milligrams. But also keep in mind that we have – we are going to have three Phase 3 studies going with like that 25 milligram dose, along with an open label extension in 25 milligram. And so we are 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 tried 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.
Ian Mortimer
And Lachlan, if you look at the ICH guidelines of kind of unique exposures required in the long-term exposures of 6 months and 12 months, we feel really comfortable as Chris has mentioned just in the totality of the safety database that we will provide to FDA and other regulators and the long term dosing we will have. As Chris mentioned, because we are doing the open label extension for all of the studies in the Phase 3, we are going to have a lot of data both 20 milligrams, and 25 milligrams.
Lachlan Hanbury
Got it. Thanks. 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 at controlling them in X-TOLE. Is there anything you can sort of transfer 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?
Chris Kenney
Yes. Sure, yes. So, I mean we covered that. So, this will be a largely repeat of the last quarterly call, but happy to go through that again. So, first of all, I mean we have chosen the best sites that we can to minimize the chance of a large placebo effect. They are all U.S. sites. We have also – we are using the mass general group to train the sites, and then also to make sure that we are getting patients who truly have major depression into the trial. So, we are 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?
Ian Mortimer
No. As Chris mentioned, there is 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, 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 to make sure that we are getting the right patients.
Lachlan Hanbury
Thanks.
Operator
Your next question comes from the line of Rohit Bhasin with Needham. Your line is now open.
Unidentified Analyst
Hi, this is Robin on for Rohit [ph]. Thanks for taking our questions. Can you share any feedback you received from providers with the expansions of PGTCS? And then when can we expect an update from the partnered 301 program with Pacira? Thanks.
Ian Mortimer
Chris, one second. Do you want to talk about some of the feedback we have had on primary generalized and Sherry can address the partner milestone?
Chris Kenney
Yes. Absolutely. So, the research we conducted specifically thinking about the opportunity PGTCS, leverage the profile that emerged from X-TOLE with respect to safety and then we have 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 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 deaths resulting from accidents. So, the use of each attributes were really encouraging in the eyes of the clinicians with which we have spoken. 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 have seen. 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. 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 will take the read from them and update accordingly.
Unidentified Analyst
Great. Thank you.
Operator
Seeing no other questions in the queue, I will turn the call back over to Sherry Aulin.
Sherry Aulin
Great. Well, thanks everyone for joining us today on our Q2 call. Operator, we will now end the call.
Operator
This concludes today’s call. Thank you for attending. You may now disconnect.
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