Greetings and welcome to the Alkermes conference call. My name is Rob, and I'll be your operator for today's call. All participants will be placed on mute to prevent background noise. If you should require operator assistance during the call, please press star zero on your telephone keypad. Please note that this conference is being recorded. I'll now turn the call over to Sandy Coombs, Senior Vice President of Investor Relations and Corporate Affairs. Sandy, you may now begin.
Good morning. Welcome to the Alkermes 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 investor 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 two 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. Today we're very pleased to announce a 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 key top-line measures. The open-label extension phase of the study remains ongoing, and there'll be more data to discuss over time. While we're still in the early stages of the data analysis, today's top-line results directly address the study's key objectives. They were first, efficacy.
The study successfully met the dual primary endpoints, MWT and ESS, demonstrating clear and statistically significant improvements in wakefulness 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 plans at NT2, but also as we pursue indications outside of narcolepsy across our orexin portfolio. 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 provide a strong foundation to advance into phase III and provide proprietary insights that we believe will support a successful registration program in NT2. We now have a new degree of confidence in the potential of alixorexton in the treatment of NT2. 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 objectives across 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. 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 eight-week double-blind period in the NT2 patient population, which is a group of patients with a variable degree of underlying orexin tone.
This is the first large phase II study to evaluate multiple doses of an orexin agonist in this patient population and clearly 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 shows 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 clear efficacy signal across the primary assessments, the maintenance of wakefulness test or MWT, and on the Epworth Sleepiness 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 this 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 of 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 eight-week double-blind placebo-controlled parallel design study evaluated three doses of alixorexton versus placebo and incorporated feedback from the FDA. After washing out of their current narcolepsy medications for two weeks, patients were randomized to one of three 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 eight-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 six minutes, with about half of the study subjects having a mean sleep latency of less than five minutes at baseline. The mean ESS scores at baseline was approximately 17.5, reflecting severe daytime sleepiness. Study retention was strong, with approximately 95% of patients completing the double-blind period and rolling into the optional five-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 1B data was that in comparison to NT1, NT2 patients are generally less sensitive to orexin agonists, requiring higher doses to drive improvements in efficacy parameters and correspondingly tolerating higher doses with respect to adverse events. This is exactly what we observed. Over eight 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, micturition 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 signs, 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, these 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 eight different situations.
Scores range from zero to 24, with higher scores indicating greater sleepiness and scores of over 15, severe sleepiness. We collected ESS data at weeks two, four, six, and eight, with the primary analysis conducted at week eight. Across all doses tested, alixorexton demonstrated clinically meaningful improvements from baseline in excessive daytime sleepiness compared to placebo on ESS at week eight. This can be seen in the graph at the left, which shows the mean scores for each dose arm over the eight-week double-blind period. Reductions in ESS were observed with alixorexton across all doses starting as early as week two, the first time point measured. Over the eight-week period, at the 14 and 18 milligram doses, mean ESS scores generally remained at 10 or below, which is the recognized threshold for normalization.
Based on the pre-specified analysis outlined in the table on the right, at week eight, the 18 mg 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, it is conducted on the final day of the double-blind period, with sleep latencies measured in four separate 40-minute tests conducted every two hours of an eight-hour period. The result is expressed as the average time a person stays awake over the four test periods. The primary analysis compares the change in MWT from baseline to week eight for each dose versus placebo. The MWT data from Vibrance-2 in 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 eight at all doses tested. Based on pre-specified 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. Unadjusted for multiplicity, 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 eight, observed mean sleep latency ranged from approximately 14 minutes-16 minutes across the alixorexton treatment arms. Considering the baseline severity, these observed values are quite meaningful.
That said, over the course of the eight-hour test at all doses tested, we observed strong, consistent responses at the first two time points measured, two hours and four hours post-dose, with more variability in mean wakefulness at the six and eight-hour time points. This did not correlate with the PK profile, indicating that the effect was not driven by reduced plasma exposure. We hypothesize 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 two endpoints, 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 condition. We are 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 in 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.
Thank you, Craig. We are very confident in the profile of alixorexton in 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. 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 dose and regimen as we prepare to launch the phase II 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. We'd like to thank all the investigators and patients, along with their families, for participating in this study.
Over the coming weeks and months, we'll learn even more from the study, and we'll look forward to sharing those data with you in the future. 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.
Thanks, Sandy. We'll now be conducting a question-and-answer session. If you'd like to ask a question at this time, please press star one on your telephone keypad, and a confirmation tone will indicate your line is in the question queue. You may press star two if you'd like to withdraw your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the Star keys. Thank you. Our first question is from the line of Joon Lee with Truist Securities Please proceed with your question.
Hey, guys.
Congrats on the data, and thanks for taking our questions. For the split dosing strategy, how would you space them out, and how does the doses in consideration include the ones that are higher than the ones tested in phase II? Any modeling data to show how much of a clinical benefit you may be able to extract by splitting the dose? Thank you.
Yeah. At this point in time, we're not going to, for proprietary 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 end-of-phase meetings with the regulators and FDA, and we'll finalize that at that time point.
This is Richard.
The only thing I'll add is that I think this is one of the virtues of running a study of this design and this duration, is that the learnings that come from a range of doses across a fixed period of time provide insights that we wouldn't have actually anticipated at the outset. Thank you.
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 Richard. 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. There are only two companies right now that have data of this richness and complexity, and that's Takeda and ourselves.
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. Our original design intention, which was to go after all three of the principal diseases of hypersomnolence with a range of doses to address both patient variability as well as patient preferences, that's very much intact.
Great. Thanks. Congrats again. Thank you.
The next question comes from the line of Paul Matteis at Stifel. Please proceed with your question.
Hey there. Thanks so much for taking our questions, and congrats on the progress. This is Julie on for Paul. A few questions from us. I guess, can you just clarify again sort of how you did the stats here, [Ari], the dual primary?
Did the MWT and ESS each have to have a p-value of less than 0.025 to hit stat-sig? If you could just clarify that, that would be helpful. Also, just on the visual adverse events, it sounds like patients were less sensitive, perhaps, than in NT1, sort of confirming your hypothesis, as you stated. I guess, given the drug was generally well-tolerated, can you talk about your interest in exploring higher doses and how you're thinking about that initially? That's it for now. Thank you.
Yeah. Let me start off with your question on the hierarchical analysis. There was a hierarchical analysis implemented. Obviously, we have dual primary endpoints in the study. The alpha at the high dose was split between Epworth and MWT.
If we hit both of those endpoints adjusted for multiplicity, we step down then to the mid-dose, and then from the mid-dose to the lower dose. 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 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 end-of-phase meetings.
Thanks. 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 visual adverse events occurring around the beginning of treatment and then attenuating over time?
It'd be great if you could just comment on that too. Thank you.
Yeah. 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 the most common adverse events. And as you saw, we didn't see any visual adverse events in the most commonly reported AEs.
Thanks so much. Congrats again.
The next question is from the line of Lou Kerman with Robert Baird. Robert W. Baird, please proceed with your questions.
Hi, guys. Big congrats on the readout, and thanks for the questions. 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 types 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. 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, in the—
Dose adjustments in OLE?
Yeah. Dose adjustments in the OLE were similar to what we saw in Vibrance-1. All patients start at the mid-dose and then have a two-week period in which they can titrate up or down. All patients will come onto the OLE on the 14 and then either go up to 18 or down to 10.
Great. Just one more, if I could. Can you talk about how solidified the phase III design is at this point?
Beyond the split dosing regimen, other learnings you're looking to gain from the upcoming FDA meetings?
Yeah. I mean, 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.
Okay. Thank you.
The next question is from the line of David Amsellem with Piper Sandler. Please proceed with your questions.
Hey, thanks. I just have a 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 oxybates, solriamfetol, pitolisant, all of which are fairly widely used in NT2?
Understanding that there's a good bit more disease heterogeneity in NT2 and also IH, I'm just trying to better get a sense of—and I know the data's hot off the press—how are you thinking about differentiation on these two endpoints here relative to the current armamentarium? 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? Thank you.
Hey, David. It's Richard. I'll start with the second question. Yes, I can confirm that. The commercial dynamics are really interesting because when you look at the data set around NT2 populations for the drugs that are being used, the data in the labels is actually an amalgam of data from NT1 and NT2.
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. What Craig referred to earlier is based upon what we have learned in the phase II, we believe, looking at MWT in particular, that we can tune up those later two endpoints and change the absolute MWT numbers that you will see in phase III. We think we are in a really good position to really compete in the NT2 space. Craig, anything you want to add?
Yeah. The only thing I would add is we have been speaking to some of our investigators in terms of the top-line data, and there is a lot of excitement around these data.
I think in many respects, I see this study as groundbreaking because it's one of the first well-controlled phase II studies in the NT2 population. They're pretty impressed with the clinical outcomes from the study.
Thank you. The next question is from the line of Umer Raffat with Evercore ISI. Please proceed with your questions.
Hi guys. Thanks for taking my question, and 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 it 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 do not have to obsess on p-values. 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 WorldSleep? Third, on multiplicity-adjusted p-value, which is technically below 0.05 on both the mid and high dose on MWT, I would have thought that should not preclude a p-value assessment at 10 mg dose unless you were being pegged to a 0.025 p-value for statistical significance. If you could remind us on that. Finally, I think I might have missed it on visual disturbances. Did you guys only comment on the ophthalmic exam, or did you also comment on any self-reported visual blur, etc.? Thank you very much.
Okay.
Let me take those one by one. In terms of the signal we saw, yeah, our design hypothesis has always been that you need higher doses in a [orexin] normal population. I think that's exactly what we've seen in terms of the outcome of this 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. We also believe that split dosing is something that we want to consider for phase III. In terms of the statistical methodologies employed, yeah, it was the same as Vibrance-1. In terms of the multiplicity adjustments, as I said, it was a hierarchical procedure split between Epworth and MWT.
As we stepped down to the mid-dose, while we prevailed in terms of multiplicity adjustments on MWT, we failed to hit for multiplicity at the 14 milligram Epworth. That precluded that, and the lower dose Epworth precluded us from assessing the 10 milligram dose. As you have seen, clinically meaningful improvements at the 10 milligram dose with a p-value unadjusted of 0.0023. Lastly, in terms of 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.
Thank you very much.
Thank you. The next question comes from the line of Jason Gerberry with Bank of America. Please proceed with your questions.
Hey guys. Thanks for taking my question.
Firstly, for me, just wondering how you see this data and the competitive interplay with oxybate. I think it's a relevant question given your investment in the space. In the Takeda data, it seemed like the treatment effect worsened from the midpoint analysis to the final analysis. I believe that observation was on Epworth. When I look at your 14 milligram dose, it does look like it gets worse from week four to week eight. Just wondering if there's any waning of effect you see on MWT over time, any kind of time course commentary you can make here. Thanks.
Yeah. Jason, it's Rich. Maybe I'll start with the oxybates. I think, as we said around the announcement of the Avadel transaction, we see an ongoing role for the oxybates in the treatment of narcolepsy for those patients who are really focused on consolidating their sleep at night.
Now, we do not have all the PSG data from Vibrance-1 or Vibrance-2 analyzed, but I think it stands to reason that for the patients who really benefit, which are not most patients with narcolepsy, but for those who are on oxybates, they really see a real virtue to being on them. A once-a-night version in the form of Lumryz is attractive, and we think that will continue to be the case. I think the overall phenomenon is that care and the treatment standards for narcolepsy improve with the advent of the orexin antagonist. I think there is going to be a larger pool of patients that are going to be addressable with all these medicines. We do not see any worsening or diminution in the ESS or MWT signal across the time course. Craig, do you want to comment on that?
Yeah. I mean, I would agree.
Over the eight-week period, we see sustained improvements on Epworth all the way through. From the data that we've seen thus far in the open-label extension, that extends through to the open-label extension as well.
Thanks, guys.
The next question is from the line of Joseph Thome with TD Cowen. Please proceed with your questions.
Hi there. Good morning. Congrats on the data, and thank you for taking my questions. The KOLs that we talked to often point to similarities between the NT2 population and IH. Just curious, how much are you extrapolating this result today to maybe the IH situation? Given the potential for split dosing 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 reads out next year? Is that a possibility?
Sorry if I missed it, but the few patients that did not make it to the eight-week endpoint, why was that? Thank you.
Okay. I'll start off with your first question. In terms of split dosing, yes, we do see that there are similarities between the NT2 and IH population. Obviously, they're different populations, but with a more normal erection tone. Obviously, split dosing is something that we may want to consider for IH 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. The second question was— On discontinuation. Oh, the discontinuation. We had three discontinuations in the double-blind period. One was due to a treatment-related AE of insomnia, and there were two unrelated discontinuations in the double-blind period.
Great. Thank you.
The next question is from the line of Ash [Verma] with UBS. Please proceed with your questions.
Hi. This is Hoyeong for Ash. Thank you for taking our question. I guess, do you think there's any read across for the ongoing IH phase II trial with alixorexton from the NT2 trial? I guess you have said there were no clinically meaningful changes observed on ophthalmic exams. Could you please elaborate or further define what you think as not clinically meaningful changes? I guess one more is, did you see how was the MWT curves look like over time? I guess over weeks, did it get better or worse over time?
Okay. I think it's obviously premature for us to opine on what the readout of the IH study is going to be. As I've said, we do see that there are similarities between the two 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. 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 sleep latencies towards the end of the day.
The third question was on the ophthalmic exams.
Oh, ophthalmic exams, yeah. These were similar to the NT1 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.
Thank you. Sorry, when I meant the MWT curve over time, I meant over the weeks, for instance.
Was it also measured like you did for the ESS after two weeks, four weeks? Because in the slide, we only see the eight-week change.
Oh, okay. Good. Yeah, yeah. Sorry. So essentially, we looked at MWT at week four and at week eight, and we saw similar effects at week four and week eight. I see.
Thank you.
The next question is from the line of [Uyeer] with Mizuho Securities. Please proceed with your questions.
Hey, guys. Yeah, congrats on the data. Maybe just a couple of questions. First one, I do not know if you have mentioned it, but what is the common—what is your threshold for, I guess, common AEs? Is it less than 10% or higher than 10%? Just wanted to get a better sense.
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—I do not know. You took, I guess, there are four measurements in the day. At what measurement did you sort of start seeing significant diminutions of efficacy? Thanks.
The threshold that we use is a common threshold of 10% across the alixorexton treatment arms. That is what we use there. In terms of the MWT, as we said in our prepared remarks, we saw strong effects and consistent effects across doses at the two and four-hour time points with more variability at the six and eight-hour time points. This is why we believe that considering a split dose is a prudent thing for us to do in phase III.
Okay. Thanks.
The next questions are from the line of Ami Fadia with Needham & Company. Please proceed with your questions.
Hi. Good morning. Congrats on the data, and thanks for taking my question. Just to follow up on the split dosing that you mentioned, I think I heard you say that it was not related to the PK. If you could sort of elaborate on that. 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? Separately, overall, it seems that you did not 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 MWT closer to 20 minutes as you test higher doses? Thank you.
Let me address your question around split dosing and PK. Yes. In terms of the PK, we do not see any decrease in PK at the time points at which we are seeing more variability on MWT. As I said, we see more variability at the six and eight-hour time points and hence the decision to consider split dosing. In terms of insomnia, as you have seen from the safety profile already in the NT2 population, in otherwise normal populations, the shift with higher doses seems to shift in terms of a better tolerated safety 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. Obviously, these are things that we're in the process of finalizing and we'll be discussing with the agency at end-of-phase meetings. Now, for the question around the higher dose, as I said, given the acceptable safety and tolerability profile, we do believe that it gives us maximal optionality as we consider potentially going to higher doses and a split dose for phase III. Once again, something we'll discuss with the agency.
Thank you. The next question is from the line of Benjamin Burnett with Wells Fargo. Please proceed with your questions.
Hey, guys. This is Craig on for Ben. I appreciate the chance to ask you guys a question on here. I guess first one from us.
Based on kind of what you've learned from this study, how are you thinking about MWT or ESS as kind of the primary endpoint for the phase III? Do you envision a world where maybe you only take one of those two forward? What are the pros and cons between both given kind of your understanding of the data that we have so far? I guess one more, just in terms of the heterogeneity in NT2 patients, did you guys see any kind of changes or anything notable from responder analyses to patients who might have shown a greater degree of benefit on those later time points? Thank you.
In terms of the endpoints, we believe both endpoints are important.
Obviously, as we move forward with our phase III designs, this is something that we'll be discussing with both the regulator in the U.S. and EMA 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. We haven't actually performed responder analyses and all of the additional analysis at this point in time.
Thank you. The next question is from the line of Douglas Tsao with HC Wainwright. Please proceed with your questions.
Hi. Good morning. Thanks for taking the questions. Congrats on the data. I guess just in terms of sort of some of the heterogeneity that we've seen in responses, it seems like, and correct me 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 you'll anticipate having multiple dosing regimens? Obviously, we'll have different doses for the NT1s. The confidence or the sort of guidance you'll be able to provide clinicians in terms of starting the patient or getting the patient to the right dose? Thank you.
Yeah. I think we've learned 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.
Obviously, coming out of a phase III program, we'll have a clear perspective on which dosing regimens to take forward to filing. The first step is for us to have an interphase meeting with the agency.
Hey, Douglas, this is Rich. Let me just add. We've always believed, as we move from NT1 into NT2 and IH, that we would experience a much more heterogeneous patient population. Just first principle, it seemed to stand to reason that a range of doses and now a range of regimens gives you the ability to tune the pharmacology to the patient's particular needs. A range of doses has always been part of our strategy, and I think we believe that now more than ever.
I think what's 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.
Okay. Great. And congrats again on the data.
Thank you.
The next question is from the line of David Hong with Deutsche Bank. Please proceed with your question.
Hi there. Thanks for taking my questions. I want to ask on the currently available therapies which have weight-promoting effects. If I think about some of those botulinum and stimulants and other things out there, can you remind us, if you're aware, if we were to look at these products in terms of MWT, how much efficacy will we see there for MWT for those currently available products?
In terms of your dosing strategy, just to clarify, you would have some split doses and some single doses in phase 3, or you're intending to have just every dose would be some variation of a split dose? Thanks.
Yeah. Let me take your first question. 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 populations of patients. It is 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 Rich has 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 dose regimen into the mix as well. Once again, we've got a very clear perspective on what our phase III design looks like, and we'll be taking that to end-of-phase meetings with the regulators.
Thank you.
Our last question comes from the line of Akash Tewari with Jefferies. Please proceed with your questions. Akash, you may be muted.
Oh. Yeah. This is Manuel on for. Regards. Just one question. How do you view the lack of clear dose response in MWT? Did you observe any dose response at any point of time, like at four 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 orexin agonism, both in terms of efficacy and on-target AEs? Do you see that as a possibility here?
If so, how is that going to affect the IH trial?
Look, Manoj, we did not catch the second question, but Craig, do you want to comment on the MWT dose response?
Yeah. I mean, our belief is, as we look at the data holistically, we do actually see a dose response for efficacy, but we do not see a dose response, interestingly, across the safety profile.
Just to follow up on that, do you expect some kind of plateauing both in terms of efficacy and on-target AEs with orexin agonism as a mechanism so that you kind of just see this kind of ceiling effect there?
I think in a narcoleptic normal population, we always hypothesized that we could go to higher doses and that patients would tolerate those higher doses. I think that is exactly what we have seen from this well-controlled phase II study.
You did not see any dose response at any point of time for phase II?
We saw no dose response across the incidence or severity of the adverse events in the study.
Yep. Thank you so much. Bye.
Thank you. At this time, we have reached the end of our question-and-answer session. I will turn the floor back to management for closing comments.
All right. Thank you, everyone, for joining us on the call this morning. Please do not hesitate to reach out to us if you have any follow-up questions. 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 from your lines and have a wonderful day.