Alkermes plc (ALKS) Earnings Call Transcript & Summary

Greetings and welcome to the Alkermes plc Conference Call. My name is Rob, and I'll be your operator for today's call. [Operator Instructions] Please note that this conference is being recorded. I'll now turn the call over to Sandra Coombs, Senior Vice President, Investor Relations and Corporate Affairs. Sandy, you may now begin.

Good morning. Welcome to the Alkermes plc conference call to discuss the top line results of the Vibrance-2 Phase II study of alixorexton in patients with narcolepsy type 2. With me today are Richard Pops, our CEO; and Dr. Craig Hopkinson, our Chief Medical Officer. A press release, along with the slide presentation that we'll discuss today are available on the Investors section of alkermes.com. Our discussions during this conference call will include forward-looking statements. Actual results could differ materially from these forward-looking statements. Please see Slide 2 of the accompanying presentation, our press release issued this morning and our most recent annual and quarterly reports filed with the SEC for important risk factors that could cause our actual results to differ materially from those expressed or implied in the forward-looking statements. We undertake no obligation to update or revise the information provided on this call or in the accompanying presentation as a result of new information or future results or developments. Our prepared remarks today will include data from the randomized double-blind treatment period of our Vibrance-2 Phase II clinical trial for alixorexton, formerly known as ALKS 2680. These data may not be indicative of future data from this trial or results of the other ongoing or future clinical trials. After our prepared remarks, we'll open the call for Q&A. And now I will turn the call over to Richard for some opening remarks.

Thank you, Sandy. Good morning, everyone. So today, we're very pleased to announce the positive outcome from the Vibrance-2 study in narcolepsy type 2. This is a major milestone for our company and for the broader field of sleep medicine. This is the first large randomized multi-dose Phase II study to demonstrate the potential utility of an orexin 2 receptor agonist in the treatment of patients with NT2. The press release issued this morning summarizes the positive top line results. On this call, with the accompanying slides, Craig will take you through the top line measures. The open-label extension phase of the study remains ongoing, and there'll be more data to discuss over time. So while we're still in the early stages of the data analysis, today's top line results directly address the study's key objectives, and they were first efficacy. The study successfully met the dual primary endpoints, MWT and ESS, demonstrating clear the statistically significant improvements in weight fullness and excessive daytime sleepiness compared to placebo. The two endpoints capture different information and both are important from a clinical and regulatory perspective. In this study, we gained critical new insights into their time course and correlation in this diverse patient population. Second, and just as important, our safety and tolerability. We confirmed our hypothesis regarding the shift in dose response in patients with NT2. Consistent with our modeling, alixorexton was generally safe and well tolerated at the doses tested in this study. Interestingly, visual AEs were not among the most commonly reported, and there was no increase in the rate or severity of AEs with increasing doses. This is encouraging information, of course, for our planned NT2, but also as we pursue indications outside of narcolepsy across our orexin portfolio. And third is our readiness for Phase III, the Vibrance-2 study design particularly its dose range, sample size and longer-term duration, generated new insights into orexin biology in patients with NT2. These are patients with variable degrees of baseline orexin tone. The data provides a strong foundation to advance into Phase III and provide proprietary insights that we believe will support a successful registrational program in NT2. So we now have a new degree of confidence in the potential of alixorexton in the treatment of NT2. And with that, I'll turn it over to Craig to walk you through the study in much more detail.

Thank you, Richard. Today's positive top line results represent an exciting milestone as we seek to advance a new therapeutic option for patients with narcolepsy type 2. The Vibrance-2 Phase II study met its primary objective all of the domains we focused on: safety, tolerability and efficacy. The data from this study provide a strong foundation to advance into Phase III. But beneath the top line are key insights some of which we'll review today and others that we will retain as proprietary for competitive reasons. In Vibrance-2, we tested a range of therapeutic doses of alixorexton over an 8-week double-blind period patient population, which is a group of patients with a variable degree of underlying orexim front. This is the first large Phase II study to evaluate multiple doses of an orexin agonist in this patient population and demonstrate a safety, tolerability and efficacy profile in patients with NT2 that supports advancement into Phase III. The study confirmed the dose response shift from the NT1 population that we had anticipated and chose the viability of this range of higher doses. We're very pleased with the safety and tolerability of alixorexton demonstrated in the study and believe it gives us significant flexibility as we move into registrational studies. We observed a key efficacy signal across primary assessments, the maintenance of Wakefulness test or MWT, and on the Epworth Sleep in the Scale or ESS, we achieved statistical and clinical significance. As you will see, we saw greater variability in response compared to NT1 and there are new learnings in the study that we plan to apply in Phase III. Narcolepsy type 2 is a chronic neurologic sleep disorder. It has many similarities to narcolepsy type 1 in terms of the clinical presentation of excessive daytime sleepiness. However, the underlying disease pathophysiology is much less clear. Unlike narcolepsy type 1, patients with narcolepsy type 2 do not have a known absence or deficiency orexin. The differential diagnosis of NT2 is more challenging and the patient population is considerably more variable in terms of disease severity response to treatment and baseline orexin tone. With that said, it is a population with significant unmet needs and a limited number of currently available efficacious and well-tolerated medicines. The Vibrance-2 Phase II study was designed to capture the significant patient-to-patient variability and provides a substantial data set evaluating a range of doses of alixorexton in a multi-week study with well-powered cohorts of patients with NT2. The 8-week, double-blind, placebo-controlled parallel design study evaluated 3 doses of alixorexton versus placebo and incorporated feedback from the FDA. After washing out of their current narcolepsy medications for 2 weeks, patients were randomized to 1 of 3 once-daily dose levels of alixorexton, 10, 14 or 18 or placebo. Following the double-blind treatment period, patients had the option to roll into an open-label extension. The dual primary endpoints of Vibrance-2 are the change from baseline in mean sleep latency on the MWT and the change from baseline on the ESS at the end of the 8-week randomized double-blind period. We enrolled a total of 93 patients across 47 sites in the United States, Europe and Australia. In terms of baseline characteristics, these NT2 patients were highly symptomatic with MWT and ESS scores consistent with severe disease. The mean sleep latency on MWT at baseline was approximately 6 minutes with about half of the study subjects having a mean sleep latency of less than 5 minutes at baseline. The mean ESS scores at baseline was approximately 17.5%, reflecting severe daytime plus. Study retention was strong with approximately 95% of patients completing the double-blind period and rolling into the optional 5-week open-label extension, which is currently ongoing. Those who have completed the open-label period had the option to enroll in a separate long-term extension study. The safety and tolerability results are among the most important findings from the study. Overall, alixorexton was generally well tolerated in the NT2 population. The data being shared today are as of the data cutoff for the double-blind period. Similar to Vibrance-1, we'll continue to collect safety data during the open-label extension period. Our pretest hypothesis based on our Phase Ib data was that in comparison to NT1, NT2 patients are generally less sensitive to orexin agonist, requiring higher doses to drive improvements in efficacy parameters and correspondingly tolerating higher doses with respect to adverse events, and this is exactly what we observed. Over 8 weeks, alixorexton was generally well tolerated at all doses tested. No treatment emergent serious adverse events were reported, and most TEAEs were mild to moderate in severity. The most commonly reported TEAEs in the randomized double-blind treatment period were polyuria, insomnia, micturation urgency, dizziness and headache. There was no dose response observed in terms of the frequency or severity of these events. Further and importantly, no safety signals were observed in hepatic or renal parameters, vital science or ECGs, and there were no treatment-related changes on visual exams in patients treated with alixorexton. We have not encountered any dose-limiting AEs in this NT2 patient population and believe these results provide significant flexibility for Phase III. Overall, the safety and tolerability data are encouraging and add to the growing body of evidence supporting the use of alixorexton in the treatment of narcolepsy and begin to establish the safety exposure requirements to support potential registration. Turning now to the dual primary endpoints as assessed by the Epworth Sleepiness Scale and maintenance of Wakefulness test. Starting with ESS. You'll recall that the ESS is a self-administered questionnaire that measures a person's general level of daytime sleepiness by rating their likelihood of dozing off in each different situations. Scores range from 0 to 24 with higher scores indicating greater sleepiness and scores of over 15 severe sleepiness. We collected ESS data at weeks 2, 4, 6 and 8 with the primary analysis conducted at week 8. Across all doses tested, alixorexton demonstrated clinically meaningful improvements from baseline in excessive daytime sleepiness compared to placebo on ESS at week 8. This can be seen in the graph at the left, which shows the mean scores for each dose arm of the 8-week double-blind period. Reductions in ESS were observed with alixorexton across all doses, starting as early as week 2, the first time point measured. Over the 8-week period at the 14 and 18-milligram doses, mean ESS scores generally remained at or below, which is the recognized threshold for normalization. Based on the prespecified analysis outlined a table on the right, at week 8, the 18-milligram dose achieved statistical significance with a p-value of less than 0.05 adjusted for multiplicity. At that dose, approximately 70% of subjects reported normalization. The MWT provides a quantitative assessment of daytime sleepiness. For the primary analysis is conducted on the final day of the double-blind period with sleep latencies measured in 4 separate 40-minute tests conducted every 2 hours of an 8-hour period. The result is expressed as the average time of person stays awake over the 4 test periods. The primary analysis compares the change in MWT from baseline to week 8 for each dose versus placebo. The MWT data from Vibrance-2 and NT2 reveal new learnings in comparison to what we observed in NT1 patients. Despite a high degree of variability, both in terms of baseline MWT and the response to treatment, we had a statistically significant outcome. Overall, on the MWT, alixorexton demonstrated clinically meaningful improvements from baseline in mean sleep latency compared to placebo at week 8 at all doses tested. Based on prespecified analysis, the 14- and 18-milligram doses achieved statistical significance with a p-value of less than 0.05 adjusted for multiplicity. The study employed a hierarchical analysis to control for multiplicity, which precluded the assessment of statistical significance of the MWT endpoints at the 10-milligram dose. And adjusted for multicity, the 10-milligram dose drove numerical and clinically meaningful improvements in mean sleep latency with a p-value of equal to 0.0023. At week 8, observed mean sleep latency ranged from approximately 14 to 16 minutes across the alixorexton treatment arms. Considering the baseline severity, these observed values are quite meaningful. That said, over the course of the 8-hour test that all doses tested, we observed strong consistent responses at the first 2 time points measured 2 hours and 4 hours post dose, with more variability in mean wakefulness at the 6- and 8-hour time points. This did not correlate with the PK profile, indicating that the effect was not driven by reduced plasma exposure. We have hypothesized that this phenomenon emerges over multiple weeks of dosing in patients with existing baseline orexin tone, reflecting an adaptive response to daily administration of an exogenous orexin agonist. We believe a split dosing regimen could increase mean sleep latencies at the later time points. Looking at the data holistically across the 2 end points, we saw a clear signal of efficacy with statistically significant and clinically meaningful findings in both patient reported and objective measures of wakefulness and excessive daytime sleepiness. Against the backdrop of a highly variable and heterogeneous patient population, the efficacy of alixorexton was clearly demonstrated, both in terms of statistical and clinical significance, which speaks to the robustness of the underlying pharmacology. We look forward to presenting these data as well as other important findings from the study as we complete the analysis, including data from the open-label extension as well as the patient reported outcomes related to fatigue and concession. We're still in the early stages of our analysis, but we can already draw some key conclusions. First, and most importantly, the study demonstrated that alixorexton can drive wakefulness in a highly variable population of narcolepsy patients without a known absence of orexin with a generally safe and well-tolerated profile. Second, there are key learnings from the data set that we will apply to our registrational program. We have always believed in the value of providing a range of doses to accommodate disease variability and patient preference. We are even more convinced of that now. The nuances and underlying trends of the data provide an opportunity to amplify the signal in Phase III. In Phase III, we plan to advance a range of doses including once-daily administration as well as split dosing regimens. With these data now in hand, our Phase II narcolepsy program is largely complete. We will initiate end of Phase II interactions with FDA and other health authorities. Alixorexton is in a strong position to provide a potential best-in-class profile and be first to market in NT2.

Well, done, thank you, Craig. We are very confident in the profile of alixorexton narcolepsy. This is based on data. Now with nearly 200 patients having received a range of doses of alixorexton for 13 weeks or longer across narcolepsy type 1 and type 2, we have a substantial data set supporting its efficacy, and we have a strong foundation of patient exposures supporting its generally safe and well-tolerated profile. We have a database now that captures the variability of these distinct patient populations, and we have a refined understanding of dosing regimen as we prepare to launch the Phase III program. Every patient that has participated in Vibrance-1 and Vibrance-2 advances our understanding of narcolepsy informs our Phase III dose selection and contributes to our understanding of this therapeutic category. I'd like to thank all the investigators and patients along with our families for participating in this study. Over the coming weeks and months, we'll learn even more from the study, and we look forward to sharing those data with you in the future. So with that, I'm going to turn the call back to Sandy to manage the Q&A.

All right. Thank you, Richard. We'll now open the call for Q&A.

[Operator Instructions] And our first question is from the line of Joon Lee with Truist Securities.

Congrats on the data. For the split dosing strategy, how would you state them out? And how -- and does the doses in consideration include the ones that are higher than the ones tested in Phase II? And any modeling data to show how much of a clinical benefit you may be able to extract from by splitting the dose?

Yes. At this point in time, we're not going to -- for provide the reasons, obviously disclose our dosing strategy. We've got a very clear concept as to what our Phase III design will look like. And we're going to be moving into interface meetings with the regulators and the FDA, and we'll finalize that at that point.

This is Richard. The only thing I'll add is I think this is one of the virtues of running a study of this design and this duration. The learnings that come from a range of doses across a fixed period of time to provide insights that we wouldn't have actually anticipated at the outset.

And I have a quick follow-up. Our base case is that there will be multiple orexin agonists in the market. How do you see the market being segmented the hypersomnia market being segmented by different orexin agonists?

This is Rich, I'll give you just a quick answer. And then I think the most important to realize is that these products are going to segregate based on data. And there are all 2 companies right now that have data of this richness and complexity and that's ticked and ourselves. And I think right now, it's clear that the first entrant is going to have a drug for NT1 and it looks like now that we're going to have a drug for NT2 and NT1, and we'll complete our RH study next year. So our original design intention, which was to go after all 3 of the principal diseases of hypersaline with a range of doses to address both patient variability as well as patient preferences that's very much intact.

The next question comes from the line of Paul Matteis, Stifel.

And congrats on the progress. This is Julian on for Paul. A few questions from us. So I guess, can you just clarify again sort of how you did the stats here are the dual primary and -- the MWT and ESS each have to have a p-value of less than 0.025 is that [indiscernible] if you could just clarify that, that would be helpful. And then also, just on the visual adverse events, it sounds like patients were less sensitive, perhaps than an NT1 sort of confirming your hypothesis as you stated. So I guess given the drug was generally well tolerated, can you just talk about your interest in exploring higher doses and how you're thinking about that initially? And that's it for now.

Yes. So let me start off with your question on the racial analysis. So there was a hierarchical analysis implemented. Obviously, we have dual primary end points in the study. So the alpha at the high dose was split between Epworth and MWT. If we hit both of those end points adjusted for multiplicity, we stepped down then to the mid dose and then from the mid-dose to the lower dose. Then for the question in terms of visual AEs, yes, I think we're excited about the safety profile that's emerged in the study with alixorexton being generally well tolerated. This, we believe, allows us to consider potentially going to higher doses, as I said in the first -- in the answer to the first question. We've got a very clear concept of what our Phase III design looks like, and we're going to be discussing that with regulators at the end of phase meetings.

And just one quick follow-up, if you don't mind. I guess, are you seeing a similar pattern as you saw in NT1 with respect to most of these digital adverse events occurring around the beginning of treatment and then attenuating over time? It would be great if you could just comment on that, too.

Yes, I think it's important to remember that the study is still ongoing. So we've got the open label extension, which is still ongoing. So what we've reported at this time is most common adverse events. And as you saw, we didn't see any visual adverse events in the most common reported AEs.

The next question is from the line of Luke Herrmann with Robert W. Baird.

Big congrats on the readout. Can you talk about whether there were any additional baseline characteristics that would have driven the outsized numerical MWT response at the 10-milligram dose? And then can you talk about the type of dosing adjustments you've seen in the OLE thus far?

I think at this point in time, we've obviously got our top line data in hand. There's a wealth of data that we still need to analyze. So we haven't actually looked at a large number of the subgroup analyses at this point in time. Obviously, that's something we will be looking at. Sorry, and the second...

Dose adjustments in OLE.

Yes. So those adjustments in the OLE were similar to what we saw in Vibrance-1. So all patients start at the mid dose and then have a 2-week period in which they can titrate up or down. So all patients will come on to the OLE on the 14 and then either go up to 18 or down to 10.

Great. And then just one more, if I could. Can you talk about how solidified the Phase III design at this point and beyond the split dosing regimen, other learnings you're looking to gain from the upcoming FDA meetings?

Yes. With the data in hand now, we've got a very clear concept of what our Phase III program will look like. Obviously, the next step is to request an end of phase meeting and to confirm that with the agency.

The next question is from the line of David Amsellem with Piper Sandler.

I just have the commercial dynamics question here. Just looking at the data, both on ESS and also on MWT, how would you think about the competitiveness of that data relative to the oxybate, soriampetol, pitolisant, all of which are fairly widely used in NTI. And understanding that there's a bit more disease heterogeneity in NT2 and also IH, I'm just trying to better get a sense of -- and I know the data is hot off the press. But how are you thinking about differentiation on these end point here relative to the current armamentarium. And then secondly, just coming back to visual AEs, can you confirm that the incidence rates that you saw in Vibrance-2 was lower than the 8-milligram dose tested in NT1 and Vibrance-1?

David, it's Rich. I'll start with the second question. Yes, I can confirm that. So the commercial dynamics are really interesting because when you look at the data set around NT2 population for the drugs that are being used, the data in the label is actually an amalgam of data from NT1 and NT2. So I think that the new mechanism with this safety and tolerability profile, showing such a profound and clear change on MWT on an average basis is really differentiating. And what Craig referred to earlier, based on what we've learned in the Phase II, we believe looking at MWT in particular, that we can tune up those later 2 endpoints and change the absolute PT number that you'll see in Phase III. So we think we're in a really good position to really compete in the NT2 space. Craig, anything want to add?

Yes. The other thing I would add is we've been speaking to some of our investigators in terms of the top line data, and there's a lot of excitement around these data. I think in many respects, I see this study is groundbreaking because it's one of the first well-controlled Phase II studies in the NT2 population. And they're pretty impressed with the clinical outcomes from the study.

The next question is from the line of Umer Raffat with Evercore ISI.

Congratulations. I have a few here, if I may. Perhaps, first, it was very interesting to see Takeda fail with the same dose in type 1 versus type 2. whereas you guys pushed at just a bit higher versus type 1 and you were able to see a signal even at your 10-milligram dose, even though PK and Cmax wasn't dramatically higher. I'm curious how you think about that observation, number one. Number two, on p-value on MWT, which is 0.0485. Obviously, this is not a registrational study, so we don't have to obsess on p-values. But I just wanted to confirm the multiple imputation method for the ANCOVA model, was it using the same interaction effects as you did in your Vibrance-1 study at World Sleep. Third, on multiplicity adjusted p-value, which is technically below 05 on both the mid and high dose on MWT. I would have thought that should not preclude a p-value assessment of 10 mg not unless you are being pegged to a 025 p-value for statistical significance. If you could remind us on that. And then finally, I think I might have missed it on visual disturbances. Did you guys only comment on the ophthalmic exam? Or did you also count on any self-reported visual blur, et cetera?

Okay. So let me take those one by one. In terms of the signal we saw, yes, design hypothesis has always been that you need higher doses in orexin normal population. And I think that's exactly what we've seen in terms of the outcome of the study. Obviously, as I've said, with an acceptable safety profile that gives us a lot of optionality in terms of where we go with this. And we also believe that a split dosing is something that we want to consider for Phase III. In terms of the statistical methodologies employed that at was the same as Vibrance-1. And then in terms of the multiplicity adjustments, as I said, it was a hierarchical procedure split between Epworth and MWT. And as we step down to the mid dose, while we prevailed in terms of multiplicity adjustment on MWT, we failed to hit for multiplicity at the 14-milligram Epworth. And that's precluded that and the lower dose Epworth precluded us from assessing the 10-milligram dose. But as you've seen clinically meaningful improvements of 10-milligram dose worth with a p-value unadjusted of 0.0023. And then lastly, in terms of ophthalmic. Ophthalmic exams, we saw no treatment emergent changes on ophthalmic exams what we reported in our prepared remarks were the most common adverse events reported in the study and visual AEs were not amongst those.

The next question comes from the line of Jason Gerberry with Bank of America.

Firstly for me, just wondering how you see this data in the competitive interplay with oxybate, I think it's a relevant question given your investment in the space. And then in the Takeda data, it seemed like the effect treatment effect worsened from like the midpoint analysis to the final analysis. I believe that observation was on Epworth. Your -- when I look at your 14-milligram dose, it does look like it gets worse from week 4 to week 8. So just wondering if there's any waning of effect you see on MWP over time? Any kind of time course commentary you can make here?

Jason, it's Rich. Maybe I'll start with the oxybate it. I think as we said around the announcement of the Avadel transaction, we'll -- we see an ongoing role for the oxybate in the treatment in narcolepsy for those patients who are really focused on consolidating their sleep at night. Now we don't have all of the PSG data from Vibrance-1 or Vibrance-2 analyze. But I think it stands to reason that for the patients who really benefit, which are not most patients on with narcolepsy. But for those who are on oxybate, we see a real virtue to being on them. And a once-a-night version in the form of Lumeris is attractive. We think that will continue to be the case. And I think the overall phenomenon as a care and the treatment standards for narcolepsy improve with the advent of the orexin agonist. I think there's going to be a larger pool of patients that are going to be addressable with all these medicines. So we don't see any worsening or emission in the ESS or MWT signal across the time course. Craig, do you want to comment on that?

Yes. I mean I would agree. Over the 8-week period, we see sustained improvements on Epworth all the way through. and from the data that we've seen thus far in the open-label extension that extends through to the open-label extension as well.

Next question from the line of Joseph Thome with TD Cowen.

The KOLs that we talk to often point distillery between the NT2 population and IH. And so just curious, how much are you extrapolating this result today to the IH situation and given the potential for split testing here? Are you anticipating maybe incorporating a split dose either in the ongoing Phase II to kind of see how that might look for IH before that readout next year? Is that a possibility? And then sorry, if I said, but the few patients that did not make it to the 8-week endpoint, why was that?

Okay. So I'll start off with your question. So in terms of split dosing, yes, we do see that there are similarities between the NT2 and IH population. Obviously, different populations, but with a more normal orexin tone. Obviously, split dosing is something that we may want to consider for as well. We think it's premature at this point in time as to our timing of when we actually implement the split dosing strategy, but it's something we're considering. And then the second question was on the discontinuation. So we had 3 discontinuations in the double on period. The one was due to a treatment-related AE of in some year, and there were 2 unrelated discontinuations in the double-blind period.

The next question is from the line of Ash Varma with UBS.

This is [indiscernible] on for Ash. I guess do you think there's any rate across for the ongoing IH Phase II trial with alixorexton from the NT2 trial? And I guess you have said there was no clinically meaningful changes observed on ophthalmic exams. Could you please elaborate further, like define what you think as clinical not clinically meaningful changes? And I guess one more is like did you see how has the MWT curves look like over time, I guess, over weeks, did it get better or worse over time?

Okay. So I think it's not premature for us to reply on what the out of the IH study is going to be. We -- as I've said, we do see that there are similarities between the 2 populations. We have the same dose range in both studies, and we'll wait on the data for that. In terms of the MWT time curve, as we said in our prepared remarks, we did see more variability at the later time points in the day, and we believe that moving to or considering a split dose will help us address that and give us better resolution and potentially further improve the steep latencies towards the end of the day. And the third question was...

The third question was on the ophthalmic exams.

Ophthalmic exams, yes, these were similar to the N1 population. These were performed at baseline as well as the end of the double blind treatment period. We saw no treatment-related changes in the conduct of those studies.

Sorry, when I meant the MWT curve over time. I meant over the weeks, for instance, like was it also a major like you did for ESS like after like 2 weeks, 4 weeks, because it looks like we 8 weeks changed.

Okay, good. Yes, yes. Sorry. So essentially, we looked at MWT at week 4 and at week 8, and we saw similar facts at week 4 and week 8.

The next question is from the line of Uy Ear with Mizuho Securities.

Congrats on the data. Maybe just a couple of questions. First one, I don't know if you've mentioned it, but what's the common? What's your threshold for, I guess, common AEs? Is it like less 10% or higher than 10%, just wanted to get a better sense. And secondly, can you maybe sort of just help us understand a little bit about the waning of the efficacy during the day, I guess, from the start and towards like I don't -- you took, I guess, there are 4 measurements in the day and when -- what measurement did you sort of start seeing significant diminution of efficacy?

So the threshold that we use is a common threshold of 10% across the alixorexton treatment arm. So that's what we use there. In terms of the MWT, as we said in our prepared remarks, we saw strong effects and consistent effect across doses at the 2- and 4-hour time points with more variability at the 6 and 8 hours time points, and this is why we believe that considering a split dose is a prudent thing for us to do in Phase III.

The next question is from the line of Ami Fabia with Needham & Company.

Congrats on the data. Just a follow-up on the split dosing that you mentioned, I think I heard you say that it was not related to the PK. So if you could sort of elaborate on that. And as you consider split dosing how would you think about managing impact on insomnia rate as patients take the second dose at a later time point? And then separately, overall, it seems that you didn't see the rate of AEs that you would have expected to see at these higher doses in NT2. Do you -- does that mean that you'd be able to test higher doses than what you tested here? And could we sort of expect you to see an increase in WTT closer to 20 minutes as you test higher doses?

So let me address your question around split dosing and PK. Yes, in terms of the PK, we don't see any decrease in at the time points at which we're seeing more variability on MWT. So as I said, obviously, more variability at the 6- and 8-hour time points and hence the decision to consider a split dosing. In terms of insomnia, as you've seen from the safety profile already in the NT2 population in the orexin normal populations, the shift is with higher doses seems to shift in terms of a better tolerated SECI profile as well. We believe that we can model in the split dose so as not to necessarily have an impact on the safety profile and events like insomnia. But obviously, these are things that we're in the process of finalizing, and we'll be discussing with the agency at into phase meetings. Now for the question around the higher dose, as I've said, given the acceptable safety and tolerability profile, we do believe that it gives us maximum optionality as we consider potentially going to higher doses and a split dose for Phase III. But once again, something we'll discuss with the agency.

The next question is from the line of Benjamin Burnett with Wells Fargo.

This is Craig on for Ben. I appreciate the chance to ask a question here. I guess first one from us, based on kind of what you've learned from the study, how are you thinking about MWT or ESS as kind of the primary endpoint for the Phase III you envision a world where maybe you only take 1 of those 2 forward? And kind of what are the pros and cons between both, given kind of like your understanding of the data that we have so far? And I guess one more, just in terms of the heterogeneity and NT2 patients. Did you guys see any kind of changes or anything notable from like responder analysis to patients who might have shown a greater degree of benefit on those later time points?

In terms of the endpoints, we believe both endpoints are important. And obviously, as we move forward with our Phase III designs are something that we'll be discussing with both the regulator in the U.S. and as we move forward. With regard to your question on heterogeneity, at this point in time, we have the top line data in hand. And obviously, a lot more analysis will be ongoing, but we haven't actually performed responder analysis and all of the additional analysis at this point in time.

The next question is from the line of Douglas Tsao with H.C. Wainwright.

Congrats on the data. I guess just in terms of sort of some of the heterogeneity that we've seen responses, it seems like it's in question if I'm wrong, that perhaps different patients in the NT2 population will need different dose levels I guess when you think about the Phase III design, as you move into split dosing as well as different dose levels, do you think that this will be a situation where ultimately sort of one dosing regimen will be approved or do you think they will interest having multiple dosing regimens obviously while doses for the NT1. The confidence or the sort of guidance you'll be able to provide clinicians in terms of starting the patient -- or getting the patients to the right dose.

Yes, I think we've learned -- we've learnt a lot from this well-controlled Phase II study. Obviously, there is a lot more heterogeneity in this patient population and certainly far more so than we saw in the NT1 responses. As such, we've got a very clear perspective on what effective dosing regimens would look like in our Phase III program. And obviously, coming out of a Phase III program, will have a cap perspective on which dosing regimens take forward to filing. But first step is for us to have an interface meeting with the agency.

Doug, this is Rich. I may just add. We've always believed as we move from NT1 into NT2 and IH, that we experienced a much more heterogeneous patient population. So just first principle, it seems to stand a reason that a range of doses and now a range of regimens gives you ability to tune the pharmacology to the patient's particular needs. So a range of doses has always been part of our strategy, and I think we believe that now more than ever. So I think what other striking about the study is notwithstanding all that variability, you still see the efficacy signal power through all that variability with statistically significant results in the heterogeneous population. I think that bodes very well for the Phase III.

The next question is from the line of David Hoang with Deutsche Bank.

So I want to ask on the currently available therapies, which have weight promoting effects. If I think about some of those, pitolisant and stimulants and other things out there, if -- can you remind us if you're aware if we were to look at these products on -- in terms of MWT, how much efficacy what will we see there for MWT for those currently available products? And then in terms of your dosing strategy, just to clarify, you would have some split doses and some single doses in Phase III? Or you're intending to have just every dose would be some variation of a split dose?

Yes. So let me take your first question. The -- it's interesting as you look at the programs that were conducted for the currently approved standard of care, these are invariably just combined NT1, NT2 population of patients. So it's very difficult to actually tease apart a signal for MWT in those populations. What's compelling about this study is it's the first well-controlled Phase II study in a dedicated population of NT2 patients. In terms of the split and single doses, as Richard just said, we see the value in a range of doses. We think we drove clinically meaningful results with once a day dosing. Obviously, we see the value of adding a split dust regimen into the mix as well. Once again, we've had a very clear perspective on what our Phase III design looks like, and we'll be taking that to end of phase meeting with the regulators.

Our last question comes from the line of Akash Tewari with Jefferies.

Akash, you may be muted.

Yes, this is Manoj on for Akash. Just one question. How do you view the lack of clear dose response in MWT? Did you observe any those response at any point of time like at 4 weeks or something? And how does this data inform you for the Phase III dosing? And just lastly, did you see any kind of response plateauing with products in agonist in terms of efficacy on target is? Do you see that as a possibility here? And if so, how is that going to affect the IH trial?

Look, Manoj, we didn't catch the second question. But Craig, do you want to comment on MWT [indiscernible].

Yes. So I mean our belief is as we look at the data holistically, we do actually see a dose response for efficacy, but we don't see a dose response interestingly across the safety profile.

So just to follow up on that. So do you expect like some kind of plateauing both in terms of efficacy and on target as with orexin agonism as a mechanism so that you kind of just see this kind of seeing effect there.

Well, I think in a direction normal population, we always have prophesized that we could go to higher doses and that patients would tolerate those higher doses. I think that's exactly what we're seeing from this well-controlled test study.

And you didn't see any dose response at any point of time for...

So across the incidence or severity of the adverse events in the study.

At this time, we've reached the end of our question-and-answer session. And I'll turn the floor back to management for closing comments.

All right. Thank you, everyone, for joining us on the call this morning. Please don't hesitate to reach out to us if you have any follow-up questions. And we hope you have a wonderful day. Thank you.

Ladies and gentlemen, thank you for your participation. This does conclude today's teleconference. You may now disconnect your lines, and have a wonderful day.