Supernus Pharmaceuticals, Inc. (SUPN) Earnings Call Transcript & Summary

Good afternoon, and welcome to Supernus Pharmaceuticals' conference call to discuss the planned interim analysis of the exploratory open-label Phase IIa study of SPN-817 for treatment-resistant seizures. [Operator Instructions] As a reminder, this conference is being recorded. I would now like to turn the conference over to Peter Vozzo of ICR Westwicke, Investor Relations representative for Supernus Pharmaceuticals. You may begin.

Thank you, Lisa. Good afternoon, everyone, and thank you for joining us today for Supernus Pharmaceuticals' conference call to discuss the planned interim analysis of the exploratory open-label Phase IIa clinical study of SPN-817 for treatment resistant epilepsy. Today, after the close of the market, the company issued a press release announcing these interim results. On the call with me today are Jack Khattar, Supernus' Chief Executive Officer; and Jonathan Rubin, Senior Vice President, Research and Development, and Chief Medical Officer. Today's call is being made available via the Investor Relations section of the company's website at ir.supernus.com. During the course of this call, management may make certain forward-looking statements regarding future events and the company's future performance. These forward-looking statements reflect Supernus' current perspective on existing trends and information, including the company's reporting on preliminary and partial interim data from the exploratory open-label clinical study of SPN-817. Any such forward-looking statements are not guarantees of future performance and involve risks and uncertainties, including those noted in the Risk Factors section of the company's latest SEC filings. Actual results may differ materially from these -- from those projected in these forward-looking statements. For the benefit of those of you who may be listening to the replay, this call is being held and recorded on May 23, 2024. Since then, the company may have made additional announcements related to the topics discussed. Please reference the company's most recent press releases and company filings with the SEC. Supernus declines any obligation to update these forward-looking statements except as required by applicable securities laws. I will now turn the call over to Jack.

Thank you, Peter, and good afternoon, everyone, and thanks so much for joining us on this call. I would like to start first following the slide sequence by Slide 4 with an introduction and agenda covering an executive summary as to what the data [ briefly ] sees and mentions, SPN-817 overview, and then I will transition over to Dr. Rubin to walk you through the study design for the Phase IIa study and the interim results, and then I'll come back and talk about the conclusions of the day. So starting with Slide 5 on the executive summary. The emerging profile of SPN-817 suggests that we have a highly differentiated antiseizure product candidate for focal seizures. Briefly, when it comes to efficacy, the product seems to exhibit strong efficacy across several measures, as you will see in the next few minutes as we present the data across so many different metrics. In addition to that, the product seems to have high responder rates and the higher efficacy in more severe patients. So consistently across several measures, the efficacy story seems to be evolving and emerging as a potent, effective antiseizure product. In addition to all that, in an area which is very important in epilepsy, cognitive improvement, the product seems to also show a potential for cognitive improvement. Regarding safety, the product is safe, and it has a competitive and acceptable tolerability profile. And finally, the product also represents a novel and unique mechanism of action for epilepsy, an area which we covered briefly at our R&D Day back in October of 2023. So as a quick reminder on Slide 6, you'll see that, that mechanism of action is fairly unique as far as we are aware, this is the only acetylcholinesterase inhibitor that is in development for focal seizures currently. Huperzine A, which is the drug in SPN-817 is a potent and selective acetylcholinesterase inhibitor. It is an enzyme that metabolizes acetylcholine and by inhibiting this enzyme, you can basically increase the extracellular levels of acetylcholine. Higher levels of acetylcholine activate the cholinergic pathways in different cell types in the brain and that we believe ends up restoring the excitatory and inhibitory balance, which is important for seizure control. In addition to that, we have also shared with you at one point back in October 2023 that we have significant data on this molecule showing the antiseizure effect in different seizure models and genetic models of epilepsy. With that now, I will transfer it over to Dr. Rubin to take you through the Phase IIa study.

Thanks, Jack. So I'd like to start talking about the Phase IIa study design. This is an ongoing study for Phase IIa open-label, flexible dose, safety and tolerability exploratory study. The study enrolled 41 adult subjects with treatment resistant seizures. And in terms of the inclusion criteria, we included subjects who had at least 4 motor seizures during screening. This was assessed during the screening period with a 42-day baseline seizure diary that was normalized to a 28-day period, which is standard with clinical trials of seizures. When we did this, we saw that the median baseline seizure frequency was 11.3. In addition, we included subjects who took at least 1 concomitant antiseizure medication or ASM. This was an adjunctive trial. There was no upper limit on the amount of antiseizure medications that they could take. And the average number of concomitant antiseizure medications was 3.4 with a range of 1-6. It's important to note that other clinical trials of seizures typically will set an upper maximum of either 3 or 4 antiseizure medications. And we -- with these 2 inclusion criteria, we included patients who had intractable seizures, whose seizures were not well controlled and were more severe. As I mentioned, the study is ongoing and is being conducted in 8 sites in Australia. SPN-817 is being given orally and twice daily during the study, starting out at 0.25 milligrams BID or twice daily and can be titrated up to 4.0 milligrams twice a day. In terms of the conduct of the study, there was a screening period of 8 weeks during which the baseline seizure diary was included. And then onto a dose titration and optimization period of roughly 8 weeks and then to a maintenance period of 12 weeks. And for those who got through the maintenance period, they had an optional open-label extension period of up to 52 weeks or they could be tapered off the drug over a 4-week period. I'm now going to go to Slide 8. So in this study, the primary assessment was safety. It's an open-label study. We looked at adverse events, and specifically, we looked at adverse events leading to discontinuation. We also looked at efficacy, a variety of efficacy measures and the key secondary or primary efficacy analysis was the percent change from baseline and the quantifiable motor seizure frequency for 28 days through maintenance and also during the open-label extension period. This analysis is standard for seizure studies. We also looked at treatment response at 30%, 50% and 75% reduction in median seizure frequency, and we looked at the Clinical Global Impression of Severity or CGI-S scores as well as EpiTrack. EpiTrack is a cognitive screening tool that was designed for patients with epilepsy to look at the cognitive effects of antiseizure medication. I'm now going to go to Slide 9. So in terms of the current disposition, we -- this is the data cutoff as of May 1. And again, I want to remind the audience that this is an ongoing study. 41 subjects were enrolled into the safety population, they received at least 1 dose of 817. 9 subjects discontinued during the titration period or 22% and 2 subjects discontinued because of lack of efficacy, and 2 subjects discontinued related to just withdrawal, they didn't want to be in the study anymore. During the maintenance period, 1 subject discontinued related to an adverse event and 1 subject discontinued related to the lack of efficacy. Now I'm going to go to Slide 10. In terms of the overall summary of safety and tolerability, during the titration period, 95% or more subjects had at least 1 treatment-related adverse event, TEAE and 1 subject had a treatment-related serious AE, the details of that event are in the footnote at the bottom, dizziness and nausea that occurred early during the study [ were resolved ]. In terms of the severity of the TEAE, there were 18 subjects had a mild AE or 43%, and 21 subjects had a moderate AE during titration or about half. There were no severe AEs during titration or maintenance during the study, and there were no deaths. We can see just globally, if we compare the titration column and the maintenance column that the -- looking at severity, the severity dropped off when we got to the maintenance period. This was related to 2 aspects, which will be evident in the next slide as well. One is that people dropped because of adverse events. So there's a selection component to that. But in addition to that, and consistent with acetylcholinesterase inhibitors, people who stay on the drug, even if they had AEs became tolerant to the effects of the drug. Now on Slide 11. So if we look at the individual adverse events that occurred during the study so far. Again, we see 95% of subjects had at least 1 TEAE during titration. The most common side effect, almost half had nausea. And we also saw diarrhea, headache, dizziness, decreased appetite and there were 5 subjects who had vomiting during titration. Again, the numbers and the percents decreased during the maintenance period. Now the protocol allows for the concomitant use of antiemetics during the study to treat both -- to treat and prevent both nausea and vomiting. And actually, during the study, we sent out an administrative memo to the investigators, hey, you need to use this as needed to help manage nausea and vomiting. But despite this being included in the protocol and reminding the investigators, only 7 subjects were given an antiemetics during the study. This has important consequences, which we'll get to later. Now I'm going to Slide 12. So in terms of efficacy, looking at subjects of all seizure types across all doses. This is the full analysis set, subjects who had at least 1 measurement of a seizure reduction, 14 days post baseline. We see that in terms of the median improvement or median reduction in seizures, we look at the maintenance group, n equals 19 in that group. There was a 54% overall median reduction, which is quite good. It dropped a little bit during the open-label extension to 37%. Now going to Slide 13. Now we're just going to focus on the focal seizure population. And the focal seizure population is the population that we will be taking forward in our planned Phase IIb study. You can see that there were 3 subjects who had generalized tonic-clonic seizures. So the sample size went from 19 to 16 here in maintenance and from 11 to 8 in the open-label extension. The median reduction in seizures slightly increased but roughly consistent, 58% in maintenance and 38% in the open-label extension. Going to Slide 14. If we look at the focal seizure population by the maximal dose, we see that in the 3-milligram to 4-milligram BID category, where there were 6 subjects in maintenance and 3 in open-label extension, we got to a 75% to an 86% reduction in the seizure frequency, which is quite striking. But even in the subjects who were at less than 3 milligrams BID, they still had a 52% reduction. So there are 2 things that we can take away from this slide. One is, even though this is a flexible dose study, which is not designed to evaluate those response, there's a suggestion here that if you can get to the 3- to 4-milligram BID dose, you're going to get a much stronger response. But in addition, we see that 10 subjects were not able to get to the 3- to 4-milligram BID category. And we believe that with more aggressive use of antiemetics to get to a higher tolerated dose, that perhaps we could get an even higher response for some of those 10 subjects. And looking at the response rate, again, in the focal seizure population. First, looking at the maintenance category. We saw that 13 of 16 or 81% had a relatively decent response greater than or equal to 30%. But if you look at a 50% response rate, we see 63% of the group had greater than or equal to 50% response. That is a competitive profile, both with an approved seizure drugs as well as drugs that are in the pipeline. 3 out of 16 or 19% had a greater than or equal to 75% in the maintenance phase. If we look at the open-label extension phase in the second row, we see the numbers are relatively similar, although slightly smaller for the greater than a 50% response. Now we did not specifically tabulate seizure freedom in the table. But if you see the call-out box in the right, the green box, there was 1 subject to achieved 91% seizure reduction during the overall open-label extension, and that subject has been seizure-free or having 0 seizures, 100% reduction for the most recent 7 weeks. Another subject has achieved 86% reduction in the open-label extension. So that subject is getting close. For the subject -- the 3 subjects who are in the maintenance phase, there's 1 subject who had a very high response in the maintenance phase who is just entering into the open-label extension. So we don't have information yet but we will share that later. I'm going to Slide 16. So now we can analyze the data in a variety of ways. One is we can look by baseline seizure frequency. As I mentioned at the outset, the median baseline seizure frequency was 11.3 seizures. So we can look at people who were above the median in terms of the baselines or below the median. And we see for the people who are above the median, people who had pretty significant baseline amount of seizures, a 74% reduction for the maintenance group and 86% for the open-label extension. For those who had lower than the median frequency of seizures, 50% reduction for the maintenance phase, slightly lower 23% for the open-label extension. Now I'm going to go to Slide 17. Analyzed a different way, looking at the amount of antiseizure medications at baseline. So just focusing on the group of subjects who had greater than equal to 3 antiseizure medications at baseline, an intractable population. We had a really nice response here, 70% during the maintenance phase with 11 subjects and 60% during the open-label extension with 5 subjects. And if we look at the response rate in the same group, so it's the group who had focal seizures who are on 3 or more antiseizure medications at baseline. We see all of them, 11 out of 11 during the maintenance phase had a greater than or equal to 30% response. This response continued in 5 out of 5 or all of them during the open-label extension, a pretty strong response in a group that has intractable seizures. And we see also in the greater than or equal to 50% response range, 9 out of 11 or 82% had a response and 3 out of 5 or 60% in the open-label extension had a response. And then going to the last column, greater than or equal to 75%, 3 out of 11 or 27% had a greater than or equal to 75% response. And in the open-label extension, 2 out of 5 or 40% had this level of response. Now looking at other secondary outcomes. So we looked at the CGI severity or CGI-S score. We had 16 subjects who had baseline and end of maintenance scores. Baseline was 3.4%, and the end of maintenance had a mean of 2.7%. This is a drop of minus 0.8%, and lowering the CGI severity is an area that's the direction of improvement. For an individual, a drop of 1.0 is considered significant, and for a group, a drop of minus 0.8 would be a good reduction in the CGI-S score. In addition to the CGI-S, we looked at the EpiTrack, which is an assessment of cognition. We had 12 subjects that had baseline measurement and end of maintenance measurement. The mean baseline score went from 28.7% to 30.9%, an improvement of 2.3%. Now in looking at the EpiTrack assessment and looking at improvement, 10 out of 12 or 83% of the subjects were improved or unchanged in terms of their assessment of cognition and 5 out of 12 or 42% were improved. And notably, 3 subjects improved from significantly impaired cognition at baseline, which is an EpiTrack score of less than or equal to 28 to average cognition, which is a score in the range of 32 to 38 at the end of maintenance. Now I'd like to pass it along to Jack.

Thank you, Jonathan. So to conclude, what the data really mean. We're going to Slide 20 of the conclusions. First, starting with the safety and tolerability as we just reported most of the treatment emerging AEs occurred as you can see during the titration. And as Jonathan mentioned, as expected, a lot of these cholinergic side effects, obviously, were expected with a class of drug like this and are the most common ones that we saw in the study so far. In the maintenance period, which was extremely important to note that once the patients were able to transition to the maintenance period, those who did, we had a fairly low discontinuation rate because of AEs, which was only 2.4%. So discontinuations during the titration are something that we will be focused on moving forward. And we believe we can manage that going forward with a much more structured and fixed or about a short period of antiemetic use, make sure that the investigators actually use the antiemetics as instructed during the titration period. Moving on to efficacy. To wrap it up, basically, the data, as you saw across several measures, seems to have a very consistent trend, and it's showing a very consistent direction. It's showing a drug that actually is potent where we saw strong efficacy and focal seizures with patients who were able to reach the dose of 3 to 4 milligrams, which we believe is the dose range where this drug can be very effective for a lot of patients given twice daily, 75% median seizure reduction in the maintenance period, and 86% median seizure reduction in the open-label extension. In addition to that, across all the doses, not just the 3 milligrams to 4 milligrams but even across all the doses, even the lower doses, you see very high responder rates. In the maintenance period, 81% of subjects had 30% response or more seizure reduction, 63% of subjects at the 50% or more, and then 19% of subjects had 75% or more focal seizure reduction. Moving on to Slide 21. Again, very consistent data. If you look at subjects that have 3 or more other concomitant antiepileptic medications, 70% reduction, which was the median focal seizure reduction in the maintenance period, and 60% in the open-label expansion. Again, looking at the responder rates, very strong striking data as far as the responder rates in subjects across all doses, not just with 3 [Technical Difficulty] antiseizure medications. 100% of the subjects had 30% or more seizure reduction, 82%, 50% or more and then 27% that had 75% or more focal seizure reduction. And of course, we also touched on the 2 patients who are in the open label. One of them is seizure-free and the other one is fairly close to seizure-free in the 86% seizure reduction. As far as the median focal seizure reduction in more severe patients using this time, looking at the 11.3% mean baseline number for patients who were higher than that. Again, consistent with the above data, 74% in the maintenance period and 86% in the open-label extension. And then finally, looking at all the subjects that had focal seizure, which is 16 subjects across all the doses, not just the 3 to 4 milligram, even the low doses, a fairly good level, strong level of 58% reduction in the maintenance period and 38% in the open-label extension. And then finally, on Slide 22. If you look at the cognitive improvement, as Jonathan mentioned, using the EpiTrack, which is a very standard screening tool, which is also validated and using in these situations. 83% of subjects basically equally split between improved or unchanged at the end of maintenance period. And one thing I would mention very briefly here, to be unchanged in this patient population from a cognitive perspective is also potentially a very positive thing because typically, these patients especially as who have this intractable or refractory patients, they tend to continue to have cognitive decline as time goes on and as they continue to take more and more medications. So to have unchanged and improved around 83%, we think, at this point, as early as this data is, is really very encouraging for us to see. So finally, as far as the plan forward, moving forward, we are looking at extending the open-label study that is still ongoing, as Jonathan mentioned, to assess approaches to mitigate the typical cholinergic AEs that we talked about, and we continue to expect the full results of the Phase IIa study, excluding, of course, the recent extension in the second half of this year. And finally, the initiation of the Phase IIb study continues to be on track by year-end of this year. With that, I'll turn it over back to the conference for Q&A.

[Operator Instructions] The first question that we have for today is coming from Andrew Tsai of Jefferies.

Jack and team, congrats. So the first question is, can you confirm if you have any data or if you've tabulated seizure freedom rates for all 16 focal epilepsy patients completing the maintenance across all doses? And do you have seizure freedom rates for the subset of patients who did make it to the 3- to 4-milligram dose?

Yes, Andrew. Yes, I mean, basically, if you look back on Slide 15, where we report the response rate in the box, which we talk about being 2 patients, right? So these are 2 patients out of 8 in the open label. So it looks like about 25%. Or the other way around also looking at it, it's 2 out of 16, right, who are in the maintenance. So 2 out of all the 16 subjects with focal seizures in the maintenance, 2 of them right now at this point. There could be later more or it could be less as fine goes on. So that will be 12.5%. So it's basically between 12.5% to 25% seizure freedom more or less. And I'll ask Jonathan if he has a different perspective but that's at least what the data seems to suggest at this point.

Yes. That's right. But I just want to mentioned a slight change in that, the seizure freedom was obtained during the open-label extension on the 1 subject. But you got it right.

Yes. But it's out of the total 16, to your question.

Right. Okay. And could it make sense to enroll more patients in this Phase IIa/b, just to make sure you have -- you've locked in the titration schedule or make sure the use of antiemetics will mitigate the AEs, and basically to confirm patients can get to the 3- to 4-milligram range? Or are you at this juncture definitely committed to starting up the Phase IIb?

Yes. It's yes to both. So we are definitely committed to, as I mentioned, extending the Phase IIa, the current Phase IIa to explore a couple of things, not just antiemetic use. We have other ideas that we would like to explore. Since we have the study open, we are going to enroll more patients, and it is in patients, which is also good in the set of healthy volunteers, and look at a couple of other concepts or ideas that we're looking at. And as we're doing that -- and we're going to do that as quickly as we can, of course, as we are doing that, we will continue to plan and continue to move forward with the plan to initiate the Phase IIb before year-end. Now as we do in parallel these 2 efforts, should anything great that we learned with the new extension of the Phase IIa, we can easily incorporate into the Phase IIb. Even if it had started, we can make amendments to the protocol, obviously, because also the Phase IIb study by nature is a dose-finding study. It's not a Phase III study, obviously. So we have that flexibility and that's what the plan is at this point.

Makes sense. And then my last question is just out of curiosity, based on this data set, efficacy safety profile, are there any approved epilepsy drugs you think 817 is more similar to in terms of the drug profile? Or are there any approved epilepsy drugs do you think 817 already has a drug profile?

Yes. I mean, as we all know and everybody, it's always very hard to compare drugs and trials. And obviously, everybody reports data differently, and they have different inclusion, exclusion criteria and so forth. So with that caveat, clearly, it's very important to watch when we're comparing data. Even just to give you an example, I mean, seizure freedom. We are defining seizure freedom as purely what it means, seizure freedom, meaning 0 seizures, right? Other people report seizure freedom where they may allow maybe 1 seizure or 2 seizures, or whatever in 6 months. There are so many different definitions of seizure freedom. So I would always caution people when they try to compare neck-to-neck. But I can tell you, I mean, we've been in this space for a long time. The levels we've seen here are pretty striking. Again, early data, not a huge sample size so far. But I mean, the levels of responder rate, I mean, to have a 100% response rate, 11 out of 11. So the end is not really too small, but it's still 11 out of 11 patients with 100% response with a seizure reduction of 30% up to 50%, that is pretty huge as far as the strength of this product or what it seems like, and the potency of the product and so forth, and the consistency of the data across different sub-analyses that we went through today. So that's really all I can say. I mean I'm sure different people have different things and they report on different things in the public domain, but I think 100% is 100%, right? So you can't get any better than that. But clearly, that's a very strong report. And even across the other [ metrics ] somewhere in the 74% to 86% or 84% to 85% -- 74% to 85%, I mean all of these are very strong levels of median seizure reduction, and what I believe are fairly competitive, very competitive versus what we've seen from other companies at this point.

And our next question will be coming from David Amsellem of Piper Sandler.

So just a couple from me. So you mentioned in the press release that you're focused on optimizing the synthesis process of the synthetic drug, and also developing a novel dosage form. So I'm wondering if you can elaborate on that and how that fits in to the advancement of the program. So that's number one. And then number two is, as you think about tolerability, can you talk about the extent to which these AEs attenuated over time as patients passed through the maintenance period? Were these mainly just short term issues with the titration and then they attenuated? Or were there other things to consider? And then the last question I have is, regarding the nausea and the use of antiemetics, can you talk about that, how that's going to play commercially? Does that render the product, perhaps commercially challenged if in practice, there is a need for significant antiemetic use upon the initiation of therapy? Just talk about how you think that's going to play commercially.

Yes. Sure. I'll take the first portion on the API synthesis and the formulation. This is actually an effort that we've had since we took the project over as far as making the synthesis process more -- instead of an extract, clearly a purely synthetic process, that's what we've developed over time since we made the acquisition, and we've optimized the process. It still needs some little work but we are getting there. So this is not like something we're just initiating right now, clearly. So that's been a work that has been ongoing. And similarly, with the formulation. So the formulation that is being tested in this study and will be tested initially in the Phase IIb study is also a new formulation that we developed with the extended release. And clearly, we will be looking if there is any other avenues from a formulation point of view that will also improve tolerability, you bet we can be looking at it. Clearly, that's an area of extreme strength and competency that we have as a company. As far as the use of an antiemetic and the commercial aspect of it, and then I'll let Jonathan talk about the tolerability and attenuation of AEs. I mean even if we don't use antiemetic, as Jonathan mentioned earlier, investigators really didn't use it diligently as we were hoping they should and would, and they didn't use it on too many subjects. So even without using, obviously, I know of a lot of products on the market that have 40% nausea and 40% -- is it ideal? Of course, not. Now clearly, when you get to this patient population, also a lot of these patients are taking so many other drugs. And a lot of these side effects end up being confounded as far as all these drugs contributing. They do tend to tolerate more, some of these issues and willing to stick with the drug because of their situation and condition, specifically if they are more severe patients clearly. And specifically, if they know that if they can tolerate it and get to the 3- to 4-milligram BID or whatever ends up being the actual dose -- daily dose and they can see somewhere in the 74% to 80% or even seizure freedom, they might be willing actually to do that, and put up with the titration, put up with the nausea, the vomiting, and so forth because clearly, the gold standard here is you really need to control these seizures. And unfortunately, as these seizures continue over time, progress over time, their condition worsens, and their ability, even their ability to achieve seizure freedom starts to go away over time. So even if we don't use antiemetic, what I'm saying, I guess, is -- there is a profile here that we see can be doable. It is -- we can live by it by just using more antiemetic or by just sticking to it. But we feel very good about our chances of improving the tolerability profile and we have some -- a couple of good ideas that we think we can pursue and will be pursuing. Jonathan?

Yes. So in answer to your second question, we've looked at adverse events over time and also by dose. And we looked at overall adverse events. We looked at cholinergic adverse events, and then we looked at emetic events with either nausea or vomiting as a category. And when we looked at that and we looked at it by an onset of the event, we saw that the onset of the event tends to occur early. It tends to occur within the first several weeks of titration. When we looked at it by dose, it tends to occur before getting to 2 milligrams. So the take home from that is we believe that using an antiemetic early in the titration phase will be able to prevent the onset of those events and get the person over the hump where they can let their natural tolerability to the cholinergic effects emerge. This, by the way, has been seen, as I mentioned earlier, the tolerability to the cholinergic events has been seen with other acetylcholinesterase inhibitors. And so we believe using the medication early on, maybe enable us to get to higher doses and also allow patients to stay on the drug.

That's helpful. If I may just sneak in a quick follow-up, just on the discontinuations. So you had 9 discontinued due to an AE, 2 lack of efficacy, 2 withdrawals by subjects, so that's 13. But you had -- you went from 41 to 19 patients in the maintenance phase. So were there other patients who were just lost to follow up? Is that what's happening here?

Not quite. So as I mentioned, this is an ongoing study. So in terms of the breakdown, we didn't present the data in this way, but just to help you get a sense. 41 subjects were enrolled in the safety population and got at least 1 dose of huperzine. And of those 41, 14 completed the maintenance, 15 discontinued and you saw the discontinuation data. And there are 12 who are ongoing who are still in the maintenance phase of the study.

And our next question will be coming from Stacy Ku of Cowen.

Congrats on the data. So just first, to be more specific, SK Biosciences XCOPRI, it has had success because it's a really good effective agent despite tolerability limitation. So can you just first talk about the clinician prescribing and practicing that you're seeing there as you think about 817 and their long-term opportunity? So that's the first question, just the big picture where you think 817 could go. And then for the patients that got to 3 to 4 milligrams, it seems like it's roughly 30%, kind of depends on how you kind of cut the data. But you talked about the antiemetics but how else can you go on to reduce discontinuations? So can you kind of go into more details around your key learnings? Is it also setting expectations as we think about the Phase IIb or even continuation of this study? And obviously, for the Phase IIb, will the longer titration schedule help? That's kind of a 2-part second question. And then just last, a bit of a clarification. So of the patients that -- the 6 patients that got the higher doses during maintenance, did they all take antiemetics? And then for the patients with improved cognition, have you -- did you -- maybe I missed this, what doses were they at to achieve improvements?