Greetings. Welcome to the Alkermes Conference Call. My name is Rob, and I'll be your operator for today's call. All participant lines will be placed on mute to prevent background noise. If you should require operator assistance during the call, please press star zero from your telephone keypad. Please note this conference is being recorded. I'll now turn the conference call over to Sandra Coombs, Senior Vice President of Investor Relations and Corporate Affairs. Sandy, you may now begin.
Welcome to the Alkermes plc Conference Call to discuss the results of the Vibrance-1 Phase II study of alixorexton in patients with narcolepsy type 1. With me today are Richard Pops, our CEO, Dr. Craig Hopkinson, our Chief Medical Officer, Dr. Marcus Yountz , Vice President, Clinical Development, and special guest Professor Giuseppe Plazzi, the Lead Investigator for Vibrance-1 . A press release, along with the slide presentation that we'll discuss today, is 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 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 statement.
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 development. Our prepared remarks today will include data from our Vibrance-1 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 other ongoing or future clinical trials. After our prepared remarks, we will open the call for Q&A. Now I'll turn the call over to Richard for some opening remarks.
Thank you, Sandy. We are glad to be joining you from the World Sleep Congress here in Singapore, where earlier today we shared data in three oral presentations from the Phase II Vibrance-1 study of alixorexton in patients with narcolepsy type 1 or NT1. This study provides an important new increment of data, some of it entirely new information, not only for alixorexton , but for the broader field of orexin 2 receptor agonists for the treatment of narcolepsy. I think we can say two things now with a new level of confidence. First, from a patient perspective, alixorexton has demonstrated compelling therapeutic benefits in patients with NT1, with a profound effect on excessive daytime sleepiness and significant improvements in fatigue and cognitive function, key drivers of patient quality of life and daily functioning.
Taken together, we believe alixorexton has the potential to transform the treatment of NT1. The second observation relates to competitive positioning. We see now that in a large randomized double-blind multi-week study, alixorexton administered once daily across a range of doses has demonstrated new potential best-in-class features, which may redefine what a leading agent in this category should deliver. With data from a rigorous Phase II study now in hand, we're confident in the profile of alixorexton in NT1, and we're moving rapidly to initiate the Phase III registrational program. The key objective of the overall Phase II program is to more fully elaborate the dose response curve of alixorexton across multiple safety, tolerability, and efficacy measures, broadening the understanding of the therapeutic benefit of targeting this pathway and informing dose selection for Phase III.
Vibrance-1 delivered on these goals and has revealed differentiating properties of alixorexton . Today, Dr. Craig Hopkinson and Dr. Marcus Yountz will review the detailed data from Vibrance-1 . Craig is our Chief Medical Officer, and he'll review the study design and the primary and key secondary endpoints. Markus is a neurologist and Vice President, Clinical Development here at Alkermes, and he's the clinical lead for the alixorexton program. He'll provide an overview of the exploratory patient-reported outcome measures and a detailed discussion of the safety and tolerability profile. We're also delighted to be joined by Professor Giuseppe Plazzi, the Lead Investigator for the Vibrance-1 study, to share his perspectives on the data and his experience with alixorexton in his patients. We've got a lot to cover, so I'll hand it over now to Craig to get us started.
Thank you, Richard. Today we will review a comprehensive data set from the Vibrance-1 study in terms of both efficacy and safety. The study had a clear positive outcome. The results demonstrated alixorexton 's significant effect on wakefulness and other important measures and a generally well-tolerated profile. One of the differentiating features of the Vibrance program is our intent to explore and broaden the definition of efficacy in patients with narcolepsy. This figure shows some of the many assessments included in the Vibrance-1 to evaluate how alixorexton may address the clinical needs of patients with NT1. In the study, we assessed standard narcolepsy endpoints, including the Maintenance of Wakefulness Test, Epworth Sleepiness Scale, and weekly cataplexy rates, along with safety and tolerability. We also collected additional data from a series of measures to further characterize the multiple dimensions of patients' response to treatment with alixorexton .
Today, important data were presented relating to a broad range of symptoms that patients experience, including fatigue and cognition, as well as disease severity as assessed by the patients themselves and by their clinicians. As the field begins to recognize the broader potential of targeting the orexin pathway, these patient and clinician-reported outcomes take on new importance. We believe the ultimate value of alixorexton will be driven by its potential to deliver symptomatic relief across a more comprehensive spectrum of disease symptoms and to redefine the expectations of what an effective medicine should achieve. Excessive daytime sleepiness is a central feature of narcolepsy and often the symptom most commonly associated with it. NT1 patients often endure a broad set of debilitating symptoms, including cognitive impairment and persistent fatigue. This is what makes the disease so devastating and what makes the complete data set from Vibrance-1 so compelling.
The Vibrance-1 Phase II study was designed to provide a substantial data set evaluating a range of doses of alixorexton in a multi-week study with well-powered cohorts of patients with NT1. This six-week double-blind placebo-controlled parallel design study evaluated three doses of alixorexton versus placebo, followed by an open-label extension. We enrolled a total of 92 patients across 45 sites in the U.S., Europe, and Australia. After washing out of their current narcolepsy medications for two weeks, patients were randomized to one of three once-daily dose levels of alixorexton : four, six, or eight, or placebo. The primary endpoint of Vibrance-1 is the change in mean sleep latency on the Maintenance of Wakefulness Test, or MWT, compared to placebo at the end of the six-week randomized double-blind period. Key secondary endpoints included the Epworth Sleepiness Scale and weekly cataplexy rates.
Following the double-blind period, patients had the opportunity to enter a seven-week open-label extension, which included the option to adjust their dose. This feature provided valuable information regarding patient preference and informs our dose selection for Phase III. Those who completed the open-label period had the option to enroll in a separate long-term extension study for up to two years, which is currently ongoing. In terms of baseline characteristics, these NT1 patients were highly symptomatic. The mean sleep latency on MWT at baseline was approximately three minutes, and the Epworth score was 18.5, reflecting severe excessive daytime sleepiness. With respect to cataplexy, on average, the study population reported 26 cataplectic events per week at baseline. As you can see, high variability was observed in patient-reported weekly cataplexy rates, which we will discuss further when we review the data.
On the Narcolepsy Severity Scale, patients reported a mean total score of 31.3 at baseline, which corresponds to severe narcolepsy symptoms, with a strong completion rate with 99% of subjects randomized completing the six-week double-blind period. Turning now to the efficacy results, starting with the primary endpoint, the MWT is a standardized quantitative measure of how long a patient can stay awake during a 40-minute test period in an environment that is conducive to sleep. The tests are conducted at two, four, six, and eight hours post-dose, and the mean score is calculated by averaging the results of the four tests. While the MWT is less frequently used in real-world clinical settings, it's an important objective endpoint commonly used for regulatory purposes. The table on the right shows the pre-specified analysis.
At week 6, alixorexton showed statistically significant and clinically meaningful improvement from baseline in mean sleep latency compared to placebo at all doses tested. The graph on the left shows observed mean sleep latency at baseline and at week 6 by treatment group. At baseline, participants fell asleep within approximately three minutes, consistent with the broader NT1 patient population. At week 6, the placebo group did not demonstrate any benefit, while the alixorexton treatment groups, the data demonstrated a dose-dependent improvement in wakefulness. On an observed basis, the 4, 6, and 8 mg dose groups were associated with a mean sleep latency of approximately 24, 26, and 28 minutes, respectively, well above the 20-minute threshold considered normative wakefulness. These data represent mean values across each of the alixorexton dose cohort. However, individual patients have differing responses, so it's instructive to look deeper beyond the average values.
At week 6, a significant majority, approximately 75%- 80% of subjects, achieved normative wakefulness. Some patients across each alixorexton dose group achieved the maximum 40 minutes on MWT across the full eight-hour assessment period. In the 8 mg group, the majority of subjects achieved an observed mean sleep latency of 30 minutes or greater. These findings underscore a central principle: patients differ in their physiologic response. This is the logic underpinning our strategy to develop multiple effective doses. Turning to the key secondary endpoints, first, the Epworth Sleepiness Scale, or ESS. ESS is a patient-reported symptom questionnaire. Unlike the MWT, this scale is widely used in the clinic as a diagnostic tool to assess excessive daytime sleepiness. ESS is useful in that the seven-day look-back period provides a holistic view of a patient's sleepiness beyond the eight-hour MWT test period.
Higher scores indicate a greater likelihood of falling asleep, with a score of 10 or below considered normal. The graph on the left shows the mean scores for each study arm across the six-week double-blind period. At baseline, patients in Vibrance-1 reported an ESS score of approximately 18.5, reflecting excessive daytime sleepiness. Reductions in ESS were observed with alixorexton across all doses, starting as early as week 2, the first time point measured. The mean ESS scores remain below 10, indicating normalization of daytime sleepiness during the six-week treatment period. The table on the right reflects the pre-specified analysis. All doses of alixorexton given once daily demonstrated statistically significant improvements from baseline in excessive daytime sleepiness compared to placebo.
The 6 and 8 mg doses showed the greatest reductions in sleepiness, with improvements of 11 -1 2 points compared to baseline, while placebo improved by 3 points during that window. At the time of the analysis of the top-line results of the double-blind period, 59 patients had completed the entire 13-week study, including the 7-week open-label extension. ESS was collected at weeks 8 and 13, as shown in the shaded area on the right-hand side of this graph. Recall that in the open-label extension, all patients started on 6 mg of alixorexton and could make dose adjustments between weeks 6 and 8. The dotted lines correspond with the dose that patients had received in the double-blind treatment period. Two key observations: first, the improvements with alixorexton in mean ESS scores reported during the initial 6-week period were sustained through week 13.
Second, patients who transitioned from placebo to active treatment in the open-label extension demonstrated improvements in ESS comparable to those randomized to alixorexton in the double-blind period, highlighting the drug's consistent profile. We will present the full data set from the open-label extension at a future medical meeting. Now let's look at cataplexy. In addition to excessive daytime sleepiness, NT1 patients can experience a sudden involuntary loss of muscle tone called cataplexy. Vibrance-1 evaluated mean weekly cataplexy rates as a key secondary endpoint. Baseline cataplexy rates varied widely across individuals, with some subjects reporting several hundred episodes per week. The graph on the left shows the median weekly cataplexy rates at baseline and week 6.
Median cataplexy rates numerically decreased from baseline across all groups, including placebo, with the alixorexton treatment groups reporting median rates as low as 1 cataplexy event per week in the 6 mg arm. The table on the right shows the pre-specified analysis, the incidence-rate ratios for each group at week 6 compared to placebo. Here, alixorexton demonstrated numerical and clinically meaningful improvements across all doses tested. On the pre-specified analysis, the 6 mg dose met the threshold of statistical significance and demonstrated a nearly 70% reduction in event rate compared to placebo. Given the numerical changes on the left, it may be surprising that statistical significance was only achieved at one dose. This was primarily driven by significant variability in this patient-reported outcome and a small number of outliers.
Another way to interpret the cataplexy data is by examining the proportion of patients who experienced no cataplectic events during the assessment period. On this analysis, 24% of patients in the 4 mg group and more than 40% of patients in both the 6 and 8 mg groups achieved a 100% reduction in cataplexy events during week 6 of the study. This compared to only 5% of patients in the placebo arm. We are confident in alixorexton 's effects on controlling cataplexy. Collectively, these data show a clinically meaningful improvement on cataplexy across all doses tested. We learned a great deal in Phase II relating to the implementation of this assay, and we will apply these key learnings in our Phase III program.
Having reviewed the primary and key secondary endpoints relating to efficacy, I'll now hand the call over to Markus for a review of the exploratory patient-reported outcome measures across disease severity, fatigue, and cognition, as well as a review of the safety and tolerability profile. Markus?
Thank you, Craig. While excessive daytime sleepiness is the hallmark symptom of narcolepsy, many patients also experience other symptoms, such as fatigue and cognitive dysfunction. These can result in significant morbidity, as well as impaired quality of life. The disease of narcolepsy type 1 (NT1) is caused by a deficiency of orexin. What is so exciting about alixorexton is its potential to address the underlying cause of the disease by effectively replacing the deficient neuropeptide to deliver a broad spectrum of potential therapeutic benefits. These effects derive not only from increased wakefulness, but from downstream engagement of brain circuitry related to mood, fatigue, and cognition. The assessments I'll discuss today were exploratory, and as such, p-values reflected in the slides are nominal. Let's start with measures of overall disease severity from the patient's own perspective.
The Narcolepsy Severity Scale, or NSS, is a validated instrument that was specifically developed to assess the frequency and impact on daily life over the past seven days of five key narcolepsy symptoms: excessive daytime sleepiness, cataplexy, nighttime sleep disturbance, hallucinations, and sleep paralysis to determine disease severity ranging from mild to very severe. At baseline, patients enrolled in the Vibrance-1 study were highly symptomatic, reporting average NSS scores of approximately 31 points across the study population, which corresponds to severe disease. Looking at the chart on the left, at week 6, patients in the 6 and 8 mg dose groups achieved average scores in the mild disease range, the lowest severity category of the NSS, indicating clinically meaningful reductions in narcolepsy symptom severity.
In the table at the right, we see that the improvements from baseline at week 6 were statistically significant compared with placebo for all doses of alixorexton . Now let's take a closer look at the reported shifts in severity over the six weeks. On the left, you see each treatment group at baseline, at which point many patients reported moderate or severe disease, as you can see in light blue and yellow. Moving to the right, at week 6, most patients across all doses of alixorexton reported mild disease severity, indicated by dark blue. You'll see similar representations for the other patient-reported outcomes, so please keep in mind that on these charts, bluer always means better. The study also provided entirely new and exciting findings related to fatigue and cognition.
These are among the most debilitating symptoms patients with narcolepsy experience, and they are distinct from excessive daytime sleepiness. Let's look at findings related to fatigue. Fatigue is reported by the majority of patients with narcolepsy. While fatigue and sleepiness may be related, patients do distinguish between them, with fatigue often being described as a feeling of mental and physical exhaustion that is not improved with sleep alone. PROMIS- Fatigue is a comprehensive instrument that has been broadly used across several disease states. Scores less than 55 signify normal levels of fatigue, while higher scores signify progressively more severe fatigue. This graph shows the PROMIS- Fatigue scores at each time point measured. At baseline, patients enrolled in Vibrance-1 had scores consistent with moderate fatigue.
At the first time point measured, mean scores for all alixorexton dose groups fell below 55 into the normal range, and these were sustained through week 6. The improvements in fatigue scores were statistically significant compared to placebo for all alixorexton dose groups. Now let's turn to cognition. In speaking with narcolepsy patients, brain fog and cognitive complaints are among the most commonly mentioned challenges they face. In the study, we used an established patient-reported measure, the British Columbia Cognitive Complaints Inventory, or BC-CCI, to assess patients' perception of the severity of their cognitive impairment. The BC-CCI is multidimensional and evaluates several areas of cognition that may be impaired, such as memory, attention, and word finding, among others. Scores range from 0- 18, with higher numbers representing greater severity and with scores below 4 indicating minimal or no cognitive complaints.
Alixorexton significantly reduced the severity of cognitive impairment across all doses tested. Mean cognitive impairment scores fell within the none or minimal impairment category across all time points and at all doses, effectively achieving normalization for most patients. Improvements were observed at the first time point measured and were sustained through week 6. In addition to being clinically meaningful, the improvements from baseline at week 6 were highly statistically significant compared to placebo. Another way of looking at this data is by the proportion of patients falling into the different severity categories of the BC-CCI . On this slide, baseline is shown on the left. Again here, blue colors represent more mild symptoms. At week 6, shown on the right, most patients treated with alixorexton across all doses reported none or minimal cognitive impairment.
We also looked at the expanded version of the BC-CCI , which includes additional questions related to the perceived impact of cognitive impairment on work, relationships, and daily activities. Similar to the severity items, improvements were observed at the first time point measured and were sustained through the six-week period. At week 6, the improvements were statistically significant for all alixorexton doses tested. Taken together, these results suggest that patients who received alixorexton experienced statistically significant and clinically meaningful improvements in cognitive functioning. Vibrance-1 also included a collection of clinician and patient global impression assessments, commonly referred to as CGI and PGI. Data from these assessments were similarly striking and were presented as part of today's oral presentations. These presentations are available on our website for reference.
From a clinical perspective, the results of these patient-reported outcomes are compelling due to the robustness and particularly the consistency of effect and durability across all doses of alixorexton , as well as across the various assays that were used in the study. This is the first time that we've seen data from the orexin class on these fatigue and cognition scales. We believe this differentiates alixorexton from other development programs and builds upon the evidence base that orexin 2 receptor agonists with appropriate pharmaceutical properties could have broad potential utility across a range of neurological or neuropsychiatric disorders where the orexin system may be implicated. Now turning to safety and tolerability, Vibrance-1 was our first opportunity to assess safety and tolerability over multiple weeks of repeat dosing in a randomized double-blind study, as well as to start building the long-term safety database for alixorexton .
In this study, alixorexton was generally well tolerated at all doses tested. As Craig mentioned, study retention was strong, with 99% of patients completing the double-blind period. One patient randomized to the 8 mg dose discontinued after reporting treatment-emergent adverse events, or TEAEs, within the first few days of treatment. No treatment-emergent serious adverse events were reported. Most TEAEs were mild to moderate in severity, and the most commonly reported TEAEs—pollakiuria or urinary frequency, insomnia, salivary hypersecretion, micturition urgency or urinary urgency, and blurred vision—were consistent with on-target effects of orexin 2 receptor agonists and were largely associated with treatment initiation and resolved without medical intervention. Understanding the temporal nature of these events is an important element of the profile, so let's take a closer look at the onset and duration of some of these. First, let's discuss urinary events, including frequency and urgency.
These events were primarily mild and generally more persistent during the 6-week double-blind period. Importantly, none led to discontinuation of study drug. Next is insomnia. The vast majority of insomnia events occurred and resolved within the first week of treatment. This was consistent with our expectation and what has been observed in other multi-week studies of orexin II receptor agonists. Events of blurred vision were dose-dependent and occurred primarily at the 8 mg dose, with infrequent events at the 4 and 6 mg doses, as well as in placebo-treated patients. Events were mostly mild and intermittent and largely occurred and resolved within the first 3 days of treatment. This also held true for the events that were reported beyond week 1, mostly mild and intermittent in nature, in other words, not necessarily occurring on a daily basis and episodic as opposed to continuous.
As previously disclosed, all patients were subject to thorough ophthalmic assessments at baseline and at the end of the double-blind period. No clinically meaningful treatment-emergent changes were observed on these exams in the alixorexton treatment groups. Further and importantly, no clinically meaningful changes in patients treated with alixorexton were reported across hepatic or renal parameters, vital signs, or ECGs. Overall, these safety and tolerability data are encouraging and add to the growing body of evidence supporting the use of orexin II receptor agonists in the treatment of NT1. Taken together with the strong efficacy demonstrated in Vibrance-1 , the emerging benefit-risk profile for alixorexton is clear and compelling. With that, I'll turn the call back to Craig.
Thank you, Markus. As a testament to the generally well-tolerated profile and robust efficacy observed in the six-week double-blind period, more than 95% of study subjects chose to enroll into the open-label extension. We will present a full analysis of the open-label extension period at a future medical conference, but today we will share a few initial observations. First, the design of the open-label extension and the data it yields about patient preference are some of the most interesting and important findings from the study. After completing the six-week double-blind period, all subjects started the open-label extension at the 6 mg dose and then, in consultation with investigators, had the option to remain at 6 mg , move down to 4 mg , or move up to 8 mg . The results provide us with new insights into patient dose preference and the safety and tolerability profile.
Let's start with the dose adjustment trends. Starting with the placebo cohort, upon initiating active treatment in the open-label extension at the 6 mg dose, the majority of these subjects elected to remain at that dose throughout the open-label period. Now let's look at those patients treated with alixorexton in the double-blind period. Of subjects that had been randomized to the 4 mg dose, approximately 2/3 chose to move up to the 8 mg during the flexible dosing period. Of subjects that had been randomized to 6 mg , approximately 2/3 chose to remain at that dose in the open-label extension, and approximately 1/3 escalated to 8 mg .
Of the subjects that had been randomized to 8 mg after stepping down to 6 mg at the start of the open-label extension, approximately 2/3 chose to return to the 8 mg dose, and about 1/3 elected to remain at the 6 mg dose. Overall, five subjects of 90 elected to move down to the 4 mg dose in the open-label extension. The remaining 85 subjects chose the 6 and 8 mg doses at approximately equal rates. This result reinforces the hypothesis that patients will have varying preferences and underscores the importance of providing a range of doses to accommodate individual patient needs. Turning to the initial safety and tolerability findings from the open-label extension, overall, the incidence of TEAEs was lower in the open-label extension than in the double-blind treatment period. Consistent with the findings from the six-week double-blind period, alixorexton continued to be generally well tolerated.
Treatment-emergent adverse events were mostly mild to moderate, and no serious treatment-emergent adverse events were reported. Among the TEAEs that were most commonly reported in the double-blind period that Markus discussed in the open-label extension, onset of new events was primarily associated with treatment initiation. In other words, events occurred primarily in patients that had been randomized to placebo in the double-blind period who started alixorexton at the 6 mg dose for the first time in the extension. In the open-label extension, we also learned that for patients with prior exposure to alixorexton , new onset of these TEAEs was low.
For example, looking at the 46 patients that elected to move to the 8 mg dose in the extension, while on the 8 mg dose, new onset of TEAEs most commonly reported in the double-blind period was minimal, with no new events of pollakiuria, insomnia, salivary hypersecretion, or blurred vision reported. These data build on the findings from the double-blind period and demonstrate a strong safety and tolerability profile. They are invaluable as we finalize our Phase III dose strategy. On behalf of Alkermes plc, I'd like to thank all of the investigators and patients along with their families for participating in this groundbreaking study. These data represent a substantial new contribution to narcolepsy research.
And now, I'd like to welcome Professor Giuseppe Plazzi, the lead investigator in the Vibrance-1 study. Dr. Plazzi, thank you for being here to share your clinical insights on the clinical relevance of the Vibrance-1 data.
Thank you, Craig. The data presented at World Sleep today represent a significant milestone in the treatment of narcolepsy. The orexin 2 receptor agonist class has the potential to transform how patients with NT1 are treated, and the alixorexton data presented today reinforce and further define this potential. The detailed Vibrance-1 dataset highlights the robust efficacy of once-daily alixorexton in improving wakefulness and reducing excessive daytime sleepiness in patients with narcolepsy type 1, along with a generally well-tolerated safety profile. What you begin to see in this dataset are additional nuanced aspects in the NT1 patient experience. Narcolepsy is a debilitating disease that goes far beyond the cardinal symptoms of excessive daytime sleepiness and cataplexy. Patients often take multiple medications and suffer from debilitating cognitive dysfunction and fatigue, which interferes with their daily activities. In Vibrance-1 , untreated baseline, patients were highly symptomatic and reported severe disease.
The rapid and profound effect that alixorexton demonstrated in this study is truly exciting. With this class of medicines, I often say that patients are awakening, but this encompasses much more than just wakefulness. As a physician, it's particularly satisfying to see how patients are transformed with effective treatment. I'll offer a few clinical perspectives on the data reported today, and I will be happy to take questions during the Q&A. In terms of wakefulness, it is encouraging to see the magnitude and consistency of effect across MWT and Epworth. First, on MWT, I am very pleased with the results. A lixorexton treatment groups achieved a normative wakefulness on the MWT. As a clinician, this is the goal. While MWT is a helpful assay in the clinical trial setting, maximizing MWT is not a key objective when treating a patient, and pushing too high may result in adverse events.
We should look at MWT in the context of other endpoints. Epworth and NSS scores provide an important additional dimension to the patient experience. As the data presented today demonstrated, patients treated with alixorexton achieved normal wakefulness on the ESS and symptoms in the lower severity category on the NSS. This reinforced the MWT data. In terms of cataplexy, this is an important clinical symptom, but it is nuanced, and even many physicians may not recognize it. The clinical assay itself is subjective and variable in that the way patients identify and count events can vary. For example, reporting multiple separate events, which are actually part of the same cataplexy episodes. When I look at the overall data from the Vibrance-1 study and from my own experience, alixorexton has a clear effect on cataplexy. I think that it can be more clearly elaborated in the Phase III.
In patients with NT1, when orexin 2 is reactivated, you can see a number of effects. Wakefulness and cataplexy are only two elements. NT1 patients often experience fatigue and cognitive dysfunction that impair their daily functioning. From a clinical perspective, the cognition and fatigue data captured in Vibrance-1 are compelling and aim to provide a more complete picture of alixorexton 's potential therapeutic benefit to patients. Patients often forgo many opportunities for education and professional development due to their symptoms, and this could have a real impact on patients and further opportunities this may enable them to pursue. The complete safety and tolerability profile observed in Vibrance-1 is encouraging and was consistent with what I observed with my patients in the study, with adverse events that were mostly mild to moderate and largely associated with treatment initiation. This is a very manageable profile.
I am pleased with the outcome of the study. This data underscores alixorexton 's potential to be an important new treatment option for NT1 and to reduce the broader disease burden for this complex neurological disorder.
Thank you very much, Professor Plazzi. It has been an exciting day here at World Sleep in Singapore. We've had the privilege of presenting our Phase II data for alixorexton in NT1 and engaging directly with leading sleep medicine experts. Now, based on our Vibrance-1 data and a clear understanding of the competitive landscape, we believe alixorexton has a differentiated and potential best-in-class profile that could redefine the standard of care in narcolepsy type 1. NT1 is just the beginning. In narcolepsy type 2, where we expect to be first in class, our Phase II Vibrance-2 study will generate the largest dataset to date for an orexin 2 receptor agonist in NT2. We recently completed enrollment in that study and plan to have top-line data later in the fall. Data from Vibrance-3 , which is our Phase II study in idiopathic hypersomnia, will follow next year.
In parallel to these Phase II studies, preparations for Phase III are underway, and we're working to initiate the Phase III program in narcolepsy as quickly as possible. Alkermes plc is well positioned as a leader in the development in this exciting new therapeutic category in sleep disorders and beyond. With that, I'll turn the call back to Sandy to manage the Q&A.
Thank you, Richard. We'll now open the call for Q&A.
At this time, we'll be conducting a question and answer session. If you'd like to ask a question at this time, you may press star one from 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 remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. You may address questions to as many as possible. We ask you to please limit yourself to one question. One moment, please, for our first question. The first question comes from the line of Paul Matisse with Stifel. Please proceed with your question.
Hey there. This is Julian on for Paul. Thanks so much for taking our question and congrats on the data. Just wanted to ask a little bit more color around the visual adverse events. If you could provide some color on the duration and the frequency of these events for these patients, it would be helpful. I know you described it as not necessarily happening every day, but color around that would be great. Also, you know, what does this result or how does it inform your expectations for adverse event rates for the NT2 readout coming later this fall? Any color there would be really helpful. Thank you so much.
Markus, why don't you go ahead on that?
Sure. Thanks. Thanks for that question. I'll start with the first part as far as frequency and duration and maybe just sort of setting it up initially. Given that these were mostly mild events, we wouldn't normally characterize these events beyond the typical elements that we include in the collection of adverse events. That being said, because there's been a lot of focus on these from this stakeholder group in particular, we did make extra efforts to gather additional information from investigators about these events. What that means is we're not going to have detailed information about every one of these, but for the ones we do have information about, at least half of the patients that reported events noted events that lasted an hour or less. That's an important point. You asked about the question of us pointing out, you know, these are not necessarily every day.
Maybe I'll describe what I mean by that. We really mostly, again, saw these as mild events that were episodic. They weren't necessarily happening on a daily basis or on a continuous basis. Just to give you a sort of a hypothetical example of how we captured events in this trial, if a patient, let's say, had a blurred vision on day one and then perhaps, let's say, day seven and day 10, but nothing in between there, that would be captured as a 10-day adverse event, potentially listed as intermittent, but a 10-day adverse event. Again, that's not like the patient had the symptoms for 10 days straight. I just want to highlight when we say it's not necessarily every day for an adverse event of X number of days, that's what we mean.
Markus, the predictive value for NT2 ?
Yes. I think it's going to be hard to translate this to NT2, honestly. I think our theory is that all of this is sort of shifted to higher doses with NT2. In other words, we think you need higher doses for efficacy, and we think that the higher doses are not necessarily going to create additional adverse events differently from what we see in NT1. We think the NT1 population is different in how they're going to respond to Erexins than the NT2 population. We think, again, everything's essentially just going to shift over to the right in that population. That being said, we need to wait for the data, and we'll be seeing that hopefully not too long from now.
All right. Thanks, Julian.
The next question is from the line of Akash Tewari with Jefferies. Please proceed with your question.
Thank you so much. Is there any appetite to include BID dosing for idiopathic hypersomnia and narcolepsy type 2 in order to have better late afternoon coverage in those indications given the underlying variability? Also, maybe you can kind of thread the needle between AUC versus Cmax-related AEs. Maybe just on the visual disturbances, can you remind us what was the percentage of patients where basically there was complete resolution within three days of treatment? Thank you.
Thanks, Akash. I'll take your first question. I think our belief is that alixorexton performed in line with our design intent, so it delivered meaningful wakefulness during the daytime hours. Obviously, we want that profile to drop below that threshold for efficacy in the afternoon hours as patients would like to have normal nighttime sleep. Our belief is that this profile has, this is exactly what the profile has demonstrated in the Vibrance-1 study. Importantly also, if you look at the subjective measures, which I think are a better reflection of patient experience, we see Epworth Sleepiness Scales where you see profound effects as early as the first time point. Those effects are maintained across doses all the way through the double-blind period.
We've even followed up the 59 patients which, at the time of database lock, had completed the open-label extension, and those effects are maintained all the way through. Importantly, as you saw today, I think one of the new endpoints that we assessed was really on the cognition and fatigue. On both those endpoints across all doses, we demonstrated normalization. We think our profile is ideally suited to once-daily dosing. Do you want to add this?
Sure. Yes. I can take the question about the proportion of vision events. You'll be able to see on our slides, we showed really a list of each patient there, as you can see on the bar chart there. What you can see there is that 6 out of the 10 treated patients had events that lasted 3 days or resolved within 3 days. I just want to make the point that the ones that were longer, again, it doesn't mean they had, for instance, we have one that's the next one is 21 days. That doesn't mean they had 21 days of straight blurred vision. I just want to highlight that point. To make another interesting point, we have a placebo patient, in fact, that had blurred vision as well that lasted out to 42 days.
I just want to make the point that when we're looking at these single events later on, it's always challenging to draw out conclusions.
Any thoughts on Cmax versus AUC and the AEs?
In this trial, I don't, and that's because we collected just sparse PK in this trial. We don't have PK on enough of a frequency that we can easily make that conclusion. Because the events weren't happening that frequently, the combination of that plus the sparse PK makes it really challenging to draw any connection there.
Thanks, Akash.
The next question is from the line of Andrea Newkirk with Goldman Sachs. Please proceed with your question.
Good morning. Thanks so much for taking the question. Maybe a follow-up there just on the ESS score and the open-label extension data that you showed. Given the majority of patients in that 4 mg cohort did end up dose escalating either to 6 or to 8, are you surprised that there wasn't a deepening of response? Does this maybe suggest to you a potential plateauing of benefit on this particular measurement? Thanks so much.
No. I think what we saw was really sort of profound improvement early on in the study at the earliest time point across all three doses. That was maintained all the way through week 6. Bear in mind, all patients started open-label extension on the 6 mg dose. It is a blend of doses that you're really looking at there. In terms of the switch over from 6 mg from the placebo to 6 mg , you saw profound effects once again between week 6 and week 8, and those effects were maintained all the way through the 13 weeks. We believe that this is reflective of maintenance of effect all the way through.
Thanks, Andrea.
The next question is from the line of Jessica Fye with JPMorgan. Please proceed with your question.
Hey, guys. Thanks for taking my question. I appreciate all the comments on the importance of dose flexibility as evidenced by what patients did in the open-label extension. I'm curious, with the higher rate of blurred vision at the high dose here, just what your latest thoughts are for what you'd expect to see with the higher doses being tested in narcolepsy type 2 and idiopathic hypersomnia. Thank you.
Go ahead, Markus.
Sure. I think probably similar to my previous answer that we think that in this case, everything's going to shift over. We think that you're going to need higher doses for efficacy in the NT2 and IH populations. Likewise, we think that we don't necessarily expect to see additional adverse events in that population because it doesn't necessarily represent the same population from a sensitivity to orexin standpoint as the NT1 population.
All right. Thanks, Jess.
The next question is from the line of Ami Fadia with Needham & Company. Please proceed with your question.
Hi, good morning. Thanks for taking my question. Can you talk about how the MWT evolves during the course of the day, the four time points where it's measured? Maybe qualitatively, talk about how that sort of was experienced by the patients. In the open-label portion, how do you see the MWT evolving? You've commented on some of the other endpoints, but if you could give us some color in the open-label. Thank you.
Yeah. Obviously, for competitive reasons, we're not necessarily going to be disclosing the time course of the MWT. As I've said previously, alixorexton performed as we would have expected by design intent, delivering meaningful wakefulness during the daytime hours and dropping below that threshold to allow for normal sleep in the nighttime hours. What we can say is that across all of the doses tested, we saw patients maximize their MWTs at 40 across all time points. Equally, at the 8 mg dose, we saw that the majority of patients had MWTs of greater than 30. What this really reflects to us is the importance of an effective range of doses that can meet individual patient needs.
Ami, it's Rich. I'll just say that in the OLE, we didn't do the MWT test. The efficacy measure in the OLE was the Epworth, and those data were presented.
All right, Rob, we'll take the next question, please.
The next question is from the line of David Amsellem with Piper Sandler. Please proceed with your question.
Thanks. Can you just help us contextualize insomnia and the incidence of insomnia a little more? I'm just wondering, what is the extent to which insomnia was related to greater benefit in terms of MWT and Epworth? That's number one. On urinary urgency, pollakiuria, I think you mentioned in the slide it's persistent. I also wanted to contextualize that. How problematic do you see it being in practice? It's certainly a non-target effect, but wanted to get your thoughts on how to think about managing this particular AE in clinical practice.
Thank you.
Sorry, Markus. Perhaps just up your head, I'll be sure.
Yeah. I'll start with the first question on insomnia versus MWT versus Epworth. We haven't done specific correlation analyses there at this point. What we did see, again, is that the great majority of the insomnia that we did see was mild and really very early on in the treatment course. When people started on alixorexton , we would tend to see insomnia, and the majority of the insomnia was gone by the third day. It's something that does come on. We do think it's on target, but it doesn't seem to persist in the great majority of these patients. The question on pollakiuria and how problematic it's been, maybe I'll start, and then I'll ask Professor Giuseppe Plazzi if he has thoughts there. That did persist longer in the trial, as you pointed out, and is really thought to be an on-target effect here as well.
The point I'd make there is that, again, the great majority of those were mild, which by the definition in our trial meant it didn't impair daily functioning, it didn't impair patients' daily activities, didn't require any additional treatment. No one discontinued from the trial due to pollakiuria. I think those are all important points. In fact, as you heard from our earlier comments, 95% of the people rolled into the open-label extension despite pollakiuria persisting in some of those. We think that overall it's manageable by the patients. I'll ask Professor Giuseppe Plazzi if he has any other thoughts.
Thank you, Markus. Yes. From what I can add from the clinical point of view is only that pollakiuria was not really a clinical complaint for these patients and was very mild and did not require any medical treatment. Indeed, patients prefer to stay, decided to stay in the trial for sure. They are not disturbed by this increase in urgency.
All right. Thanks. We'll take the next question, please.
Thanks. The next question comes from the line of Mark Goodman with Leerink Partners.
Yeah. On this visual blur that you're describing, can you just describe to us, like, is there photophobia? Is it a visual? Like, how would you describe these? Are the patients complaining about different types of visual blurriness, or do they all seem to have the same type of complaint? Secondly, for Professor Giuseppe Plazzi, maybe you can discuss how you view the orexins relative to standard of care. You know, if these patients are all on Provigil and then they're going to switch from Provigil over to an orexin, do you view that as something that'll be very easy? The side effect profile from one to the other, is that an easy transition? Just talk about that a little. Thank you.
Sure. I can start with the blurred vision. I think it's going to be challenging to describe it further. We go based on essentially what's recorded by the investigators based on what the patients are telling them. Given that the majority of these were mild in the trial, we have less detailed information than we might need to answer some of the questions you're asking. Essentially, what we understand is that they were describing blurred vision. That's the furthest we can get with it. Really what we understand is it's majority mild, which in this trial meant not impacting daily functioning and coming episodically. It's something obviously that we can continue to watch. Past that, I don't have additional data on what they mean by that.
Maybe Markus, just to add that we performed visual exams at the beginning of the trial and then at the end of the double-blind period, and those visual exams were all normal. We didn't see any changes there as well.
Thank you. Concerning the positionment of the orexin agonist for narcolepsy type 1, for sure, I see a targeted therapy. The first choice for patients with narcolepsy type 1. We have to remember that more than 50% of patients with narcolepsy type 1 take multiple medications, and none of these four therapies reach an important, complete control of the symptoms. Having drugs that act on all the symptoms and completely control the symptomatology in over 50% of the cases, 40% of the cases is a huge opportunity.
Thanks, Marc.
Thanks. Our next question is from the line of Leonid Timashev with RBC Capital Markets. Please proceed with your question.
Hi, guys. It's Anish on for Leo. Congrats on the data, and thanks for taking our question. Just on the potential use of alixorexton in the real world, how are you thinking about the potential for polypharmacy? Would you need to run studies to test how an orexin 2 receptor agonist drug would fit into the treatment paradigm with other therapies on board? Thanks so much.
In terms of polypharmacy as it relates to alixorexton , obviously, in terms of the interaction studies we performed, we think it will work well. At this point in time, in terms of the efficacy, obviously, we've studied these agents as monotherapy in the trials that we've performed, and we really don't have any combination studies. Obviously, in the future, that may be something that we'll need to focus on as well.
Thanks, Leo.
Our next question is from the line of Uy Ear with Mizuho Securities. Please proceed with your question.
Hey, guys. Thanks for taking our question. On the blurred vision, just quickly, you mentioned the number of patients and that some patients may have these visions episodically over time. Maybe just give us, like, how many patients are there actually, you know, the number of patients, not the number of cases that have blurred visions in each of the doses? Secondly, can you remind us if there's any food effect? Thanks.
Sure. I can go back to the blurred vision. I think the answer is similar. I mean, they were mild events that we saw. They resolved relatively quickly within the trial. As far as answering your questions, we get back to those same numbers that we've been talking about.
In terms of the food effect, obviously, examining food effect as part of any development program, we're dosing alixorexton fasting at least an hour before breakfast. With a drug with a true once-daily profile, we think that that works really well and is easy for patients to manage.
Great. Rob, we'll take the next question, please.
The next question comes from the line of Jason Gerber with Bank of America. Please proceed with your question.
Hey, guys. Thanks for taking my question or questions. Just given the clustering of insomnia and the visual disturbance in that early couple of weeks, and the dose dependency that appears to be a dynamic there, wondering your latest thoughts just on managing that with titration in a future Phase III. The main reason I ask that is just given the competitive nature of the category, you know, in terms of positioning the drug optimally. Just to confirm, I think you've been saying most of the visual blurriness cases have been mild. Just wanted to confirm that none were severe. I know there were two severe adverse events reported in the eight mega arms, so just wanted to rule that out. Thanks.
Yeah, sure. I can answer that. To start, actually, I'll start with your second question around the visual events. We did see, as I mentioned, the great majority of those are mild. That's essentially what we saw in that case. Mild in this trial means not really interfering with daily activities, not requiring medical intervention, etc. Then the.
Craig, do you want to take the titration question?
Which was that again?
If there were considerations of titration in Phase III.
Yeah. Obviously, the alixorexton was well tolerated both in the double-blind period and, as you heard, in the open-label extension, we actually saw a lower incidence of adverse events in patients that were experienced on alixorexton . At this point in time, we're not going to be commenting on our dosing strategy. We obviously are well on the way with our Phase III planning based on the wealth of data that we've collected, but we won't be commenting on the dosing strategy at this point in time.
Okay. Thanks. Rob, we'll take the next question, please.
Yes. The next question is from the line of Luke Herrmann with Robert W. Baird. Please proceed with your question.
Hi, guys. Thanks for taking the question. On cataplexy, given what looks like maybe more consistent improvement across doses than what would have maybe been expected given the top-line statistics, given the high baseline severity, what is your level of confidence that you can achieve a static result with Phase III powering?
Yeah. Look, I think in terms of cataplexy, we saw numerical improvements across all doses, as well as clinically meaningful improvements across all doses. There was a high degree of variability in the study, which was driven primarily by outliers as well as the implementation of the assay. We'll be applying these key learnings in our Phase III program. We also looked at cataplexy through a more objective lens, which is 100% cataplexy control because that better controls for placebo. There, as you heard from the prepared remarks, we saw over 40% of patients at both the 6 and 8 mg doses with 100% cataplexy control versus only 5% on placebo.
Okay. Rob, we'll take the next question, please.
Yes. That would be coming from the line of Ash Verma with UBS. Please proceed with your question.
Hi. Thanks for taking our question. I just wanted to ask about efficacy. We're seeing quite a bit of degradation in terms of efficacy for the RxSync competitor going from Phase II to Phase III. Just curious to get your thoughts on that. As you think about the evolution of your own data, any reason why you believe that you wouldn't face the same challenge in Phase III? Thanks.
Yeah, thanks for the question. We specifically looked at tachyphylaxis in our data set. We specifically looked at four-week MWT as it relates to the six-week, and we saw no degradation of our signal there. We saw no sign of tachyphylaxis. In addition to that, just examining the more subjective Epworth Sleepiness Scale, we saw profound improvement, as I said, at week 4. That was maintained all the way through week 6. In those patients that had completed the 13 weeks, we saw maintenance of signal all the way through 13 weeks. Obviously, as you move to larger studies, there is some heterogeneity that may come in. Given that our MWT scores are in the mid to upper 20s and the 8 mg dose is approaching 30, we're pretty confident in our ability to design Phase III studies.
Thanks, Craig. All right. We'll take the next question, please.
This is a question from the line of David Hoang with Deutsche Bank. Please proceed with your question.
Hi. Congrats on the data, and thanks for taking my questions. Just to clarify, the discontinuation that was reported, what was that caused by? How do these data inform how many doses you might potentially take forward into Phase III in the commercial setting? Thank you.
Sure. I could start with the discontinuation. There was one patient who discontinued who had a number of concurrent adverse events. Those included self-assessed tachycardia, as well as increased blood pressure, and then self-reported blurred vision. All of those resolved upon cessation of study medication. Within measuring within the clinic, all of those parameters were normal. Visual blurring had resolved, and the patient's ophthalmologic exam was normal. I'll take the question on the number of doses we carry forward in Phase III. As I've said in some of my earlier remarks, I think one of the key design features and one of the key aspects that we've learned from the Vibrance-1 study is the value of having multiple effective doses. We know that individual patient responses vary. Ultimately, having multiple doses to address individual patient needs and preferences is going to be important.
As such, moving into Phase III, our planning scenario is to take multiple doses into Phase III. We won't comment now on what those doses are or how many doses we'll be taking into Phase III.
Thanks, Bob. We'll take our next question, please.
Thank you. Our next question is from the line of Benjamin Burnett with Wells Fargo. Please proceed with your question.
Thank you. I wanted to go back to some comments we made earlier just regarding the expectation for there being a step function and sensitivity to adverse events in type 2 patients. I guess, what informs that view?
Yeah, a few things. One of them, as you may know, in our Phase I-B data, we didn't see, we dosed with higher doses in NT2 and in idiopathic hypersomnia and didn't see additional increase in adverse events compared with the NT1 population. That's a large one. That's likely what we've seen with other molecules as well. That's something that we're looking at closely. Some of this is based on just the known concept that the patients with zero or very little orexin in the NT1 group are likely to be hypersensitive to exogenous orexin. Whereas the NT2 patients and the idiopathic hypersomnia patients are not going to be in that same category because they do have some degree of orexin on board.
Thank you. Our last question comes from the line of Troy Langford with TD Cowen. Please proceed with your question.
Hi. Congrats on all the data today, and thanks for taking our question. In the patients that did step down in their dose in the open-label extension, can you provide any additional color around whether these decisions were driven by any specific AEs seen in the open-label extension?
No. As we said, the incidence of AEs in the open-label extension was low. This was largely driven by investigator and patient preference.
Okay. That was the end of our question queue. Thanks, everyone, for joining us on this busy morning. We're, of course, available at the company if you have any follow-up questions. Thank you.
This will conclude today's conference. Thank you for your participation. You may now disconnect your lines at this time and have a wonderful day.