R&D Day 2019

Nov 25, 2019

Slides

Good morning, ladies and gentlemen, and welcome to Axsome Therapeutics Conference Call and Webcast. Currently, all participants are in a listen only mode. Later, there will be a question and answer session and instructions will follow at that time. As a reminder, today's conference call is being recorded. Would now like to turn the conference over to your host, Mark Jacobson, Senior Vice President of Operations at Axsome Therapeutics. Please go ahead. Thank you, operator. Good morning and thank you all for joining us on today's conference call focusing on AXS-seven and the unmet needs in the acute treatment of migraine. During today's call, we will be making certain forward looking statements. These statements may include statements regarding, among other things, the efficacy, safety and intended utilization of our product candidates, our clinical and non clinical plans, our plans to present or report additional data, the anticipated conduct and the source of future clinical trials, regulatory plans, future research and development and possible intended utilization of cash and investment. These forward looking statements are based on current information, assumptions and expectations that are subject to change and involve risks and uncertainties that may cause actual results to differ materially from those contained in the forward looking statements. These and other risks are described in our periodic filings made with the Securities and Exchange Commission, including our quarterly and annual reports. You are cautioned not to place undue weight on these forward looking statements and the company disclaims any obligation to update such statements. Joining me on the call today from Axsome's management team are Doctor. Herriot Tabuteau, Chief Executive Officer Doctor. Cedric O'Gorman, Senior Vice President of Clinical Development and Medical Affairs Mr. Dave Merrick, Chief Commercial Officer and Mr. Nick Pizzi, Chief Financial Officer. We are honored to also be joined on the call today by Doctor. Stuart J. Tepper, Professor of Neurology at the Geisel School of Medicine at Dartmouth and Doctor. Richard B. Lipton, Professor and Vice Chair of Neurology and Director of the Montfiore Headache Center at the Albert Einstein College of Medicine. Before we hear from Doctor. Tepper and Doctor. Lipton, Herriot will first make some introductory remarks regarding our product candidate AXS-seven. Following the presentations by Doctor. Tepper and Doctor. Lipton, Cedric will provide a brief update on the clinical development of AXS-seven and the acute treatment of migraine, and Dave will then review the results of the mindset physician survey. We will then open the line and Doctor. Tepper, Doctor. Lipton and the ACO management team will be available for questions. I shall now turn over the call to Ariel. Good morning, everyone, and welcome to Axsome's R and D and key opinion leader conference call to discuss the unmet needs in the acute treatment of migraine and the potential of AXS-seven. AXS-seven is Axsome's novel oral investigational medicine consisting of Mosaic meloxicam and rizatriptan under development for the acute treatment of migraine. It is currently being evaluated in the Phase 3 MOMENTUM trial, which is being conducted in patients with a history of inadequate response to prior acute treatments. We recently announced completion of enrollment of MOMENTUM and remain on track to report top line results from this trial before year end. Based on FDA feedback, we believe that this trial, if positive, will be the only efficacy study needed to file an NDA for AXS-seven for the acute treatment of migraine. An NDA filing is targeted for the second half of next year depending on the outcome of this trial. For the many people who are disabled by CNS diseases like migraine, Axsome accelerates the invention and development of potentially life changing medicines. Our pipeline of differentiated CNS product candidates also includes AXS-five for the treatment of depression, agitation associated with Alzheimer's disease and nicotine dependence and AXS-twelve for the treatment of narcolepsy. We also remain on track to report top line results from the GEMINI Phase 3 trial of AXS-five in major depressive disorder and the CONCERT Phase 2 trial of AXS-twelve in narcolepsy before year end. Today's discussion will focus on migraine and provide important rationale and context for the development of AXS-seven in this condition. We are honored to have with us today 2 of the world's leading migraine experts, Doctor. Stuart Tepper and Doctor. Richard Lipton. Doctor. Tepper is Professor of Neurology at the Geisel School of Medicine at Dartmouth and Director of the Dartmouth Headache Center. He is Editor in Chief of the journal Headache Currents and Associate Editor of the journal Headache. Doctor. Tepper has published more than 350 peer reviewed manuscripts, editorials and books. He serves on the Board of Directors of the American Headache Society. Doctor. Lipton is Professor and Vice Chair of Neurology and Director of the Montefiore Headache Center, the Albert Einstein College of Medicine. He serves on the editorial boards of several journals, including Neurology and is past President of the American Headache Society. Doctor. Lipton has written 11 books, published more than 800 original articles, and is a 5 time winner of the H. T. Wolff Award for Excellence in Headache Research from the American Headache Society, a 2 time winner of the Enrico Grepi Award from the European Headache Federation. Doctor. Tepper will provide his perspectives on migraine and the emerging treatment landscape and discuss the mechanisms of disease, treatment targets and the rationale for AXS-seven in this condition. Doctor. Lipton will then discuss inadequate response to current acute migraine treatments and implications for the ongoing Phase 3 MOMENTUM trial of AXS-seven. Following Doctor. Lipson's presentation, we will turn the discussion over to Cedric and then to Dave. With that, I will turn it over to Doctor. Tepper to start the discussion. Hello. I'm Stuart Tepper. I'm a professor of neurology at the Geisel School of Medicine at Dartmouth. And I'd like to talk a little bit about migraine in terms of both its impact as well as its pathophysiology and how this might lead to a potential target for AXS-seven. Migraine is underestimated as a severe illness that cuts a broad swath in terms of disability and impact worldwide. And the degree to which it cuts this swath and has an impact was evaluated by the World Health Organization in 2017. And in 2017, the WHO ranked migraine among the 5 most disabling illnesses in the world comparable to quadriplegia. The problem for migraine is not only is it severely disabling, but people live with it for years. And the WHO then evaluated years lived with disability for all illnesses worldwide and migraine came in as the number 2 illness for years lived with disability. The magnitude of the problem is not appreciated adequately by payers, by regulatory authorities, by my colleagues and by those without migraine. This debilitating pain results in fear for the next attack and damages family life and social life and has tremendous pharmacoeconomic consequences. Depression and anxiety are twice as common in people with migraine than in those without And this widespread misperception of the seriousness of migraine contributes to its under recognition and undertreatment. There is an urgent need for new treatments to improve efficacy for this very serious neurological illness and more than 70% of patients are not fully satisfied with their current treatment. Fortunately, there is an emerging treatment landscape. This treatment landscape is divided into treatments that are used to prevent migraine and treatments that are used to treat migraine when it occurs. The preventive space has improved with the advent of the anti CGRP antibodies. The acute space is going to expand rapidly over the next year or 2 with oral anti CGRP medications called GPANTS and lasmiditan and it is in this area that AXS-seven fits. It's really worth remembering that all migraine patients, including those on preventive therapy need acute treatment. Every single patient who receives any of the new preventive therapies will require acute treatment and we need better acute treatment for our patients. In order to design the optimal acute treatment, it's worth returning to what the actual mechanisms of migraine are. This slide is to illustrate the pathophysiology of migraine, how migraine occurs. And I think it's useful to think about 2 aspects of migraine, the mechanisms of pain, which occur peripherally and the central processing. And we'll start with the mechanisms of pain on the left. What occurs in migraine in terms of pain generation occurs primarily in the meninges or the coverings of the brain or the dura mater, where CGRP is released and when it is released, it causes blood vessels to dilate and it causes neuroinflammation. On the top, you see the release of CGRP. This is on the left causing the blood vessels to dilate. When they dilate, windows open up in the vessels and inflammatory mediators pour out into the meninges. On the left at the bottom is a set of graphs which show you in bar form what happens when those inflammatory mediators are released. Cyclooxygenase and prostaglandins are released during the attack seen in red and that results in neuroinflammation via the arachidonic acid cascade. So on the in the periphery, the mechanisms of pain include CGRP induced vasodilation and inflammation and any acute treatment needs to reverse those events. The whole peripheral pain mechanism aspect hurts and pain fibers carry the signal back into the brain where there is processing. The processing of the migraine includes a condition called central sensitization in which patients become sensitive to all sensory stimuli and non painful stimuli hurt. When central sensitization occurs during a migraine, it's harder to treat the migraine, harder to reverse the migraine. Again, an acute treatment optimally should reverse central sensitization as well as those peripheral pain mechanisms. AXS-seven is a novel oral investigational medicine, which consists of MOSAIC meloxicam and rizatriptan and is under development for the acute treatment of migraine. The idea is to combine multiple mechanisms to terminate migraine more effectively. Meloxicam is a non steroidal anti inflammatory. It can turn off the neuro inflammation that occurs peripherally and it has central effects to reverse central sensitization. Rizatriptan is a serotonin 1b1d agonist. And as such, the activation of those subreceptors results in preventing CGRP release, in constricting the blood vessels that CGRP dilates and in preventing the signal from going back to the brain. Note that rizatriptan doesn't do anything for the neuro inflammation and little for central sensitization, but the meloxicam takes care of those particular aspects of the mechanism. In addition, the way AXS-seven was designed, it allows for rapid absorption, enhanced and consistent relief of migraine and reduced symptom recurrence. And I'll explain that in the next few slides. Here's a summary. The rise of triptan prevents the release of CGRP and constricts the CGRP dilated blood vessels. The meloxicam takes out the inflammation by inhibiting cyclooxygenase prostaglandins and inhibiting the arachidonic acid cascade. Rizatriptan also prevents the return of the pain signals to the brain. All three of those steps are peripheral. The meloxicam also reverses the central sensitization. So these multiple mechanisms of AXS-seven address the multiple disordered physiological processes that are observed in migraine attacks. This slide shows how the combination of MOSAIC meloxicam and rizatriptan optimizes the delivery of these medications. On the left in gray is conventional meloxicam and in yellow is the combination of Mosaic meloxicam and 10 milligrams of rizatriptan. The combination of the Mosaic formulation and the combination with rizatriptan results in a much faster rise of the meloxicam to a higher blood level. On the right, similarly for rizatriptan, in gray you see the conventional rizatriptan, in yellow rizatriptan mixed with Mosaic meloxicam in a combination pill and what you see is a higher and faster rate of rise of the rizatriptan. The combination then should work faster and reach higher levels, faster and better and higher blood levels as a result of the MOSAIC formulation and the combination with rizatriptan. In addition, the duration of the meloxicam activity can result in a long activity with a reduced likelihood of recurrence based on this pharmacokinetics. If one thinks about the chemicals that are triggering the migraine, CGRP and the prostaglandins and arachidonic acid cascade of neuroinflammation, what one sees in the AXS-seven is that it peaks right when the CGRP and PGE2 are being released. So the pharmacokinetics match the need. The idea would be that this combination would terminate migraine by targeting the release of the chemicals at the appropriate time, faster and higher. In summary, I wanted to make it very clear that migraine is highly disabling, characterized by debilitating pain that damages family life, social life and employment and is in the top 5 most disabling disorders in the world and number 2 for years lived with disability. There is an urgent need for new treatments that provide improved efficacy and especially acute treatments that can terminate migraine when it occurs. The physiologic changes during a migraine attack include the release of CGRP, which causes vasodilation and inflammation, which lead to the initiation of pain peripherally and central sensitization in which patients become sensitized to non painful stimuli called allodynia, which actually makes migraine more difficult to treat. The mechanisms of AXS-seven address these multiple physiologic processes that are so disturbed in migraine. The AXS-seven is rapidly absorbed with a PK profile, which aligns at the same time as the increases in CGRP and the inflammatory markers observed during migraine attacks. The rizatriptan prevents the release of CGRP and constricts the vessels that CGRP dilates as well as preventing the signal from returning to the brain, while the MOSAIC meloxicam terminates the neuroinflammation peripherally and reverses the central sensitization. The multiple mechanisms of action of AXS-seven combined with this favorable pharmacokinetic profile are likely to result in improved efficacy in the acute treatment of migraine. And as a provider, I am awaiting the study results with anticipation. Thank you. Thank you, Doctor. Tepper. I will now turn it over to Doctor. Richard Lipton, Professor and Vice Chair of Neurology and Director of the Montefiore Headache Center at the Albert Einstein College of Medicine. Doctor. Lipton will discuss inadequate response in the acute treatment of migraine and implications for the MIMENTO trial. Doctor. Lipton? I'm happy to be here today to discuss inadequate response to acute migraine treatment. The overview slide summarizes what I'm going to cover. First, new acute treatments for migraine must address unmet patient needs. 2nd, unmet needs for efficacy can be readily measured using the migraine treatment optimization questionnaire. 3rd, unmet needs are consequential both on a short term basis and a long term basis. 4th, combining a fast acting non steroidal and a fast acting triptan is a rational approach for addressing unmet efficacy needs. And finally, the MOMENTUM study enrolls patients with a history of inadequate response to their prior acute treatments assessed using the MTOC-four. One of the things I like about the MOMENTUM trial is that it enrolls the patients who will be candidates for the treatment once it's approved. And since this combination product will be for people whose needs aren't met by conventional monotherapy, there's an alignment in the design of the study and the planned pattern of use of therapy. The migraine treatment optimization questionnaire is a patient reported outcome that I developed to identify patients with an inadequate response to their usual acute treatment. And the goal really was to identify patients who might require a change in treatment. The MTOK 4 assesses 4 areas overall impact by asking people if they feel in control of their headaches, a global assessment which asks people if they become pain free 2 hours after treatment for most attacks, a consistency of response question that asks if one dose of medication relieves headache and keeps it away for at least 24 hours and an emotional response question that asks people if they're comfortable enough with their medication to be able to in the American migraine prevalence and prevention study. This is a large scale epidemiologic study where over 8,000 people with episodic migraine completed the MTOC. In this study, we found that 56% of people had an inadequate 2 hour pain free response to the usual acute treatment. We found that 54% had an inadequate 24 hour pain relief result. And we found that among those who were pain free at 2 hours, a full 25% did not sustain those benefits over 24 hours. So put simply the MTOC shows us that in the U. S. Population on their usual acute treatments, there's a very high level of unmet treatment need. In the headache world, we distinguish between episodic migraine, which is defined by less than 15 headache days per month and chronic migraine, which is defined by 15 or more headache days a month. And we've shown that people transition from episodic migraine 1 year to chronic migraine the next. The distinction is crucial because people with chronic migraine not only have more frequent attacks, they experience more headache related disability, they incur higher direct medical costs and they have higher rates of both presenteeism and absenteeism. In this slide, we classified individuals based on the quality of their acute treatment response from very poor to truly optimal and evaluated how treatment response 1 year predicted the new onset of chronic migraine the next. So we see in people whose treatment is very poorly optimized, they're 2.5 times more likely to transition from episodic migraine to chronic migraine. And we see a kind of dose response curve where reductions in treatment optimization are associated with increased risk of making that transition from episodic to chronic migraine. And of course, the implication is that acute treatment really matters not only for the attack a patient is treating today, but prognostically as well. In the AMPP study, we also identified predictors of having an inadequate response to treatment defined by 2 hour pain freedom. And we found that greater pain intensity, the presence of cutaneous allodynia, which Doctor. Tepper has told you about meeting criteria for depression, having an elevated body mass index or having a higher average monthly headache day frequency are all predictors of inadequate response to acute treatment. For aladenia, we contrasted treatment benefit for various classes of medication as a function of aladenia. So the dark purple bars represent patients with aladenia, the lighter bars represent people free of allodynia. And what you see is that across a range of medication classes, allodinic patients are less likely to have a satisfactory response to each of these classes of medication than those patients who are free of alodynia. These findings have implications for the MOMENTUM Phase 3 trial, where we evaluated patients with an inadequate response to treatment. So the MOMENTUM study specifically enrolled patients with an inadequate response to their current acute treatment assessed using the migraine treatment optimization questionnaire. We consider this a strong approach because we're targeting the patient population with the greatest clinical needs, the patient population that would be candidates for a combination product. To date in this study, the majority of patients who were screened also exhibited cutaneous allodynia and were therefore studying a population enriched for patients with difficult to treat migraine. The multiple mechanisms of this combination product may address 2 of the strongest predictors of an inadequate treatment response. Higher pain intensity is one predictor and the multiple mechanisms of this combination product may act synergistically to enhance pain relief and that will certainly be studied when the results of the trial become available. And in addition, there's evidence that cutaneous aladenia is a predictor of inadequate treatment response and that non steroidal anti inflammatories may reverse the central sensitization that results in alodynia. Finally, the MOMENTUM study incorporates an active comparator arm, rizatriptan. Rizatriptan is certainly considered one of the most effective and one of the fastest acting acute migraine therapies. So if the combination product outperforms rizatriptan that would be an impressive finding. In summary then, we've said that new acute treatments for migraine must address unmet needs and that unmet needs for efficacy can be measured very simply using the migraine treatment optimization questionnaire. We've said that ineffective acute treatment is consequential that it is a risk factor for medication overuse, a risk factor for quantification of migraine, meaning that transition from episodic to chronic migraine and that it's a predictor of poor long term outcomes. We've said that more than half of patients with migraine report inadequate responses to the usual acute treatments. AXS-seven by combining a fast acting NSAID and a fast acting triptan may address 2 of the strongest predictors of inadequate treatment response, specifically high pain intensity in the presence of cutaneous allodynia. By enrolling patients with a history of inadequate response to the current treatment, the MOMENTUM study is targeting the population where this combination product would have the greatest clinical utility and would most likely be used and inclusion of the active comparator in the MOMENTUM study will generate important comparative data, which will support both approval and clinical use. Thank you so much for your attention. Thank you, Doctor. Lipkin. I will now turn it over to Cedric O'Gorman, Axsome's Senior Vice President of Clinical Development and Medical Affairs, who will review the design of our ongoing migraine trials. Thank you, Herriot. I would like to provide an update on the status of our ongoing clinical trials in migraine. Firstly, I will speak about the MOMENTUM study. The MOMENTUM or maximizing outcomes in treating acute migraine study is a randomized double blind placebo and active controlled Phase 3 trial of AXS-seven for the acute treatment of migraine. The MOMENTUM trial is only enrolling patients who have a history of inadequate response to prior acute migraine treatments as assessed using the migraine treatment optimization questionnaire or MTOC 4. Patients are randomized in a 2:2:2:2:1 ratio to receive either treatment with AXS-seven, rizatriptan, mosaic meloxicam or placebo. The 2 co primary endpoints of the trial are the proportion patients who are free from headache pain 2 hours after dosing and the proportion of patients who no longer suffer from their most bothersome migraine associated symptom, nausea, photophobia or funophobia 2 hours after dosing for AXS-seven as compared to placebo. Superiority of AXS-seven to the rizatriptan and meloxicam arms, which would demonstrate component contribution will be established based on sustained freedom from headache pain from 2 to 24 hours after dosing, which is the key secondary endpoint. The trial is being conducted pursuant to an FDA Special Protocol Assessment or SPA. The first subject was enrolled in the MOMENTUM study in March 2019, and we recently announced that the study is now fully enrolled. Top line results are expected this quarter. Based on FDA feedback, the MOMENTUM trial, if positive, will be the only efficacy Now turning to our 2nd Phase III trial of AXS-seven for the acute treatment of migraine. Now turning to our 2nd Phase 3 trial of AXS-seven for the acute treatment of migraine. We recently launched the INTERCEPT or initiating early control of migraine pain and associated symptoms study, a Phase 3 randomized double blind multicenter placebo controlled trial evaluating the early treatment of migraine with AXS-seven. In contrast to the ongoing MOMENTUM study in which patients with a history of inadequate response to prior treatments are instructed to treat their migraine attacks once they have become of moderate or severe intensity. In the INTERCEPT study, patients are instructed to administer AXS-seven at the earliest sign of migraine pain, reflecting how they would be instructed in real world clinical practice. Approximately 300 patients will be randomized in a one to 1 ratio to receive treatment with AXS-seven or placebo. The 2 co primary endpoints of the trial are the proportion of patients who are free from headache pain 2 hours after dosing and the proportion of patients who no longer suffer from their most bothersome migraine associated symptom, nausea, photophobia or phonophobia 2 hours after dosing. Top line data for the INTERCEPT study is expected in the Q1 of 2020. Finally, in addition to our 2 Phase 3 efficacy trials, we are conducting a Phase 3 open label long term safety extension trial, which was launched in early July. With that, I would now like to turn the call back over to Herriot. Thank you, Cedric. I will now turn it over to Dave Marrick, Axsome's Chief Commercial Officer, who will discuss the findings of the mindset survey of migraine treating physicians and the implications for AXS-seven. Thank you. We know there's been plenty in the literature over the past decade and before that citing unmet needs in the treatment of migraine. And after many years of sparse treatment innovation, we know, as Doctor. Tepper mentioned, the environment has started to evolve with the development and the launch of new therapies. So we wanted to conduct a survey of migraine treating physicians to ensure that we had a fresh view of the unmet needs and the opportunities in the acute treatment of migraine. So to do that, we commissioned the mindset physician survey, which was conducted by Medicorp. Our objectives were 2 fold. 1st, to ensure within the acute treatment of migraine that we have a clear view through the physician lens of today's challenges and unmet needs to make sure that we're really aligned on what we're solving for. And second, we wanted to see if we were hitting the mark with the design of AXS-seven and the clinical development program with the primary indicator around physicians' willingness to prescribe should we meet our targeted clinical endpoints. Just over 100 physicians were surveyed with a good representation of neurologists who identify themselves as headache or migraine specialists as well as general neurologists and primary care physicians who treat migraine. So to participate, physicians needed to personally treat at least 100 people with migraine across a 12 month time period. And combined, the surveyed physicians treat more than 50,000 patients with migraine each year. So what did we learn? The first area we explored was difficult to treat migraine. Physicians report that nearly 1 in 3 or 31% of their patients experienced difficult to treat migraine attacks. The bar chart on the left depicts how physicians characterize those patients with 50% of them having experienced an inadequate response to prior acute treatment. And so why do physicians feel the need to address this significant patient group? Well, in addition to relieving the intense suffering of the patients, of course, when patients have a suboptimal response to 1 or more acute therapies, the vast majority of physicians, 76% are moderately to significantly concerned about those patients progressing to chronic migraine. And if we include those physicians who are somewhat concerned, then the percentage reach is 95% of physicians. So this potential progression was exactly what Doctor. Lipton was highlighting earlier. And this is one of the reasons that we believe the MOMENTUM trial is so important. By utilizing the MTOC to enroll individuals who've had a suboptimal response to their prior acute treatments, this is the patient population of significant concern to physicians. Next, we wanted to understand when considering a new acute treatment for migraine, what's the greatest unmet need in the prescriber community? And for the majority of physicians, the answer is clear. It's efficacy. We asked the question 2 ways. First, we wanted to understand why patients needed to switch from prior acute treatment and the bar chart on the left shows the reason is predominantly due to efficacy, 62% of the time and significantly more than any other criteria. And so when we look at the right, relative to all patients with migraine, the most significant unmet need was stated as efficacy by 85% of physicians. So when we put these elements together, the strong alignment on the unmet treatment need centered on efficacy, coupled with the MOMENTUM trial design in a patient population with prior suboptimal treatment response and the potential to generate comparative data for AXS-seven versus rizatriptan, physicians indicated that they would be highly to prescribe AXS-seven depending on the results of that trial. If AXS-seven does achieve the clinical endpoints planned in momentum, 56% of physicians indicated they are moderately to significantly more likely to prescribe AXS-seven over currently available treatments. And an equal number of physicians, 56% again, are likely to prescribe it over drugs in development inclusive of oral CGRPs who have not demonstrated superiority versus standard of care. And when we add those who would prescribe it slightly greater, then those numbers rise to 91% 87%, respectively. And we asked physicians which patients would be the most likely candidates for AXS-seven assuming it meets its objectives of the MOMENTUM trial. In the bar on the far left, those physicians would prefer AXS-seven for nearly a quarter or 22% of their treatment naive patients. And the percentage of patients increase as we move to the right for 35%, 40%, nearly 50% of those patients who have already endured at least one prior treatment failure would receive AXS-seven. So not surprisingly, those categories would be the greatest source of initial use for AXS-seven. So overall, what are the takeaways from the research? 1st, difficult to treat migraine is highly common and of significant concern to prescribers. 2nd, efficacy is clearly the priority unmet need in the acute treatment of migraine. And finally, if momentum is successful, there is a significant willingness to prescribe AXS-seven over current and emerging acute therapies. Thank you. Thank you, Dave. With that, we will now open it up for questions to Doctor. Tepper and Doctor. Lipton and of course to the Axsome management team. Operator? Thank you. And operator, while we compile the roster, I should add this is to everyone on the line that before we take the first question, while we have a number of late stage and mid stage product candidates, This call is focused specifically on AXS-seven and migraine. Out of respect for our physician experts who have given us their time, please limit your questions to our migraine program. Thank you. Your first question comes Thanks for hosting this call. They've been very helpful, Doctors Lipton and Tepper for sharing your thoughts. I did have a question for the KOLs and that is around the lines of or on what they would really like to see out of momentum in terms of understanding that efficacy bar that Dave just outlined, is it about exceeding what you see with rizatriptan at 2 hours or is it about exceeding placebo at 2 hours and then perhaps exceeding rizatriptan over the course of the remaining 24 hours? What would be a good result for you? Richard, do you want to take that? Yes, sure. So, I mean, the first thing to say is that for combination products, there's an FDA factorial rule that says to get a combination product approved, you have to show that the combination is better than its constituents. So as your question implies, the study clearly rides on the ability to show that the combination is better than razotriptan and better than MOSAIC meloxicam when given as monotherapy. I mean, I would hope to see an incremental benefit of the combination at 2 hours and I would hope to see that those benefits are sustained over 24 hours. Doing factorial studies in migraine is difficult. I think in terms of the ability of this product to separate from its constituents, the fact that the sponsor deliberately selected a responds perfectly to rizatriptan and you give them rizatriptan, responds perfectly to rizatriptan and you give them rizatriptan plus mozak meloxicam, it might be hard to separate. So I think the alignment on selecting difficult to treat patients who have unmet needs on current therapy coincides with who's going to use the drug, but also may well increase model sensitivity for demonstrating the difference between the combination and its constituents. Okay. That's helpful. And then my other question that I had and then I'll hop back in the queue is related to aladenia and really this idea of central sensitization. How easy is it to measure, call it the burden of alodynia? And what is the kind of consistency with regard to patients that also express nausea as the most bothersome symptom. Is it possible that this particular product may be great for patients with allodynia, but not so great with those with nausea or are you not concerned about that? Again, Richard, I think this is up your alley. All right. So, aladenia can be measured in many ways. One way of measuring it is with a questionnaire and some of the results I showed were from a questionnaire called the aladenia symptom checklist, which we used in the American migraines prevalence and prevention study. In AMPP, in that study, we find that about 2 thirds of patients with migraine have allodynia. When we talk about early treatment of migraine, when people talk about that, although everyone agrees that treating early is desirable and everyone agrees that the treating moderate or severe pain design that is required in Phase III studies doesn't align with practice patterns, not everyone agrees on what we mean by early treatment. So some people when they mean early treatment mean time from headache onset to taking treatment. Some people mean treating while pain is mild. Some people mean treating before allodynia develops. So we know that treatment a higher proportion of people get pain free if they treat while pain is mild than if they wait for moderate or severe pain and higher proportions of people get pain free if they treat before alodynia develops rather than after alodynia develops. There is some correlation between alodynia and nausea in population studies. And if nausea is mild or if you treat early before nausea develops then oral medications are certainly the option that patients prefer and they can be quite effective. There is a subgroup of patients who rapidly develop nausea, who sometimes need non oral therapies. I mean, I think it's worth saying that migraine is not a one size fits all condition. There's 7 atriptans. They're marketed combination products. And the armamentarium is going to be expanding as DITANs have already been approved and GPANs are likely to be approved over the next 4 months. My hope and belief is that having different tools for different patients will improve patient outcomes for everyone. And outcomes for everyone. And certainly, as Dave Merrick suggested, there is a high need and high desire for management team. With regard to NDA timing, would that be gated off of the results of momentum or would you wait for the open label extension study to complete? And when would you anticipate that to occur? Thanks, Jonathan, for the question. So we are targeting an NDA filing in the second half of twenty twenty. And now as Cedric mentioned and as also as I mentioned during my opening comments, should MOMENTUM meet its objectives, that is, should it meet its objectives with regards to the primary endpoint as well as the key secondary endpoint, then we believe that this would be the only efficacy study needed. Having said that, we also need a safety database. And we are compiling that safety database with an open label safety extension trial. We need 300 patients treated for 6 months and 100 patients treated for 1 year. So that 1 year anniversary would be the gating factor or the gating item to an NDA filing in the second half of next year. So right now, we're anticipating that we'll meet those timelines assuming that we have success with our ongoing clinical trials. Excellent. Thanks for taking the questions. Happy Thanksgiving to all. Thank you. Your next question comes from the line of Joon Lee from SunTrust. Your line is open. Hi. Can everybody hear me? Yes. Yes. Thanks for the question. Yes. So for the KOLs, in the real world situation, when someone doesn't respond to triptan, do you add on NSAIDs separately and does that work? And I have a follow-up. The answer to your question is yes. We do add NSAIDs and instruct patients to take an NSAID with a triptan. However, compliance with that is very poor. And there was a study, I think it was by Hu, but I'd have to look it up. But there was a study that evaluated patients who had been instructed to take NSAID plus triptan in combination. And the likelihood of them actually taking the 2 drugs together was incredibly low. It's extremely unlikely that they do it. What they end up doing is stepping as Richard Lipton, which is stepping in attacks, that is they will take an NSAID and then couple hours later, if it hasn't worked, then they might add the triptan at that point depending on the initial response, which also Richard has shown is associated with less good clinical outcome. And this is a real problem for us because when a patient doesn't do well with a triptan or doesn't do well with an NSAID, we don't we can't stand there and tell them, look, you've got to take these 2 together to get the synergy. And that's one of the great advantages of the combination tablet, which we would expect to see in the modified in the trial against the individual components. So that's the answer. Yes, we tell them. Yes, we're aware they're probably not doing it. And yes, we could really use a tool to have them comply because we think they'll get a better clinical outcome if they use the combination. It might be worth adding I'm sorry, it might be worth adding that the MOSAINT meloxicam combination as Doctor. Heffler already told you has a short Tmax relative to other NSAIDs that are currently available and certainly relative to MOBIC and also along half life. So the particular so what we want in migraine therapy is rapid onset of action and then sustained benefits. And the kinetic profile of this product looks very promising in terms of delivering on those benefits, although we'll have to wait for the results of the trial to see if the pharmacokinetic hypothesis that drove development actually delivers in a clinical trial. Thank you. That answers my other questions. But the other question I had was the company is running 2 trials for migraine, one is called MOMENTUM, where patients are instructed to wait until the pain threshold is, I believe, moderate to severe, if I'm correct. And then the INTERCEPT study, which is a real world study where the patients are instructed to take the medication as soon as the symptoms manifest. Do you for the KOLs, how much of an improvement in efficacy do you expect from this difference in taking the medication, like just the timing of the medication taking, if that is the main difference? Yes. So right. So I mean the first thing I want to say is that treating moderate or severe pain is currently a regulatory requirement. And so the design that the FDA requires for acute treatment studies and the practice pattern that most headache specialists recommend are at odds. Broadly speaking, everything that's been studied works better if people treat for mild pain rather than moderate or severe pain. It's true NSAIDs. It's true for triptan. It's true for GPANS. Early treatment is simply better. And the gains are quite large. So for sumatriptan where I happen to know the data, 2 hour pain free rates with sumatriptan for moderate or severe pain might be 30% and 2 hour pain free rates if you treat for mild pain might be 45% or 50%. So early treatment makes a huge difference. And ultimately, I would like to see a closing of the gap between how we recommend using drugs and how they're studied for approval. But a sponsor of any acute treatment trial doesn't really have a choice about doing moderate or severe studies at the moment, when it's simply the regulatory requirement. So I'll just add that if you consider MOMENTUM as a regulatory trial and the second study, the early intervention study as a real life trial. The advantage of the real life trial is you're evaluating patients who have already had a lack of success with previous acute treatment and they undoubtedly took that treatment early. So you want to create your trial to compare your new medicine with its synergistic components to patients who have had a lack of success optimally using MeraCue treatment and that's what this study does. And I would anticipate that it will be quite positive. Thank you. Your next question comes from the line of Marc Goodman from SVB Leerink. Your line is open. Yes, morning. I have a couple of questions for the physicians. I guess number 1, can you talk about just the CGRP injectables and whether they've met your expectations or not and how the prevention market has how you expect that to change now that we have acute medications coming in? And I guess the second question is talk about the orals and how you expect that to impact the injectable market and how this whole prevention in acute, do they come together or is there still going to be separate markets? And then 3rd, as oral CGRPs are there and this product AXS-seven is there, let's just presume all the products make it to market, how you anticipate the physician community to use the products? Do you just one get used after the other? Do they ever get used in combination? How do you think about this? Thanks. Well, it's a completely different session to talk about the prevention space. It's been a complete shift in our practice and it's exhilarating and it's been fantastic. But as I said, every single patient who's on prevention needs acute treatment and a rising tide carries all boats. So every single one of the patients who is on prevention is going to need adequate preventive treatment and it's nice it's going to be nice to have a palette of mixed colors from which we can paint. And for those patients who are eligible for triptans and NSAIDs, a combination tablet with an optimal pharmacokinetic profile offers the opportunity to achieve a sustained pain free response and the result of the sustained pain free response as Richard showed you is reduced likelihood of conversion from is likely a reduced likelihood of conversion from episodic to chronic migraine. So we see the varying acute entries as being opportunities for patients to match patient need to optimal acute treatment. And just to add a couple of points, GPants are drugs that have a number of advantages, but they are not drugs that would be used before a triptan. And GPANS I think will be used in people who can't take triptans because of cardiovascular contraindications, who don't respond to triptans and the hope is it's a novel mechanism where people who can't tolerate triptans. The reality is that AXS-seven is obviously not a drug for patients who have cardiovascular contraindications to triptans or who can't take triptans. And it may be a drug for people who have inadequate response to triptans because in combination with an NSAID, the hope and my belief is that we'll see a boost in efficacy. So the bottom line is there are 40,000,000 Americans who have migraines and maybe 3,000,000 of them with cardiovascular contraindications to triptans. And that's why I said earlier that acute migraine therapy and preventive migraine therapy is not a one size fits all condition, but the market is enormous and there is plenty of opportunity for options. Your next question comes from the line of Yatin Suneja from Guggenheim Partners. Your line is open. Good morning. Thanks for taking my question. My question is for Doctor. Aptepper. I think you talked about molyxicon and rizatriptan could be helpful in patient. But given that momentum is enrolling a more inadequate responder patient population, so could you maybe talk about how compelling is the biological rationale for using Bicambo in this group versus the patient that would have responded adequately to current therapies? And then I have a follow-up. Right. It's not momentum that's evaluating the patients that have had inadequate response. It's the second trial, which of course I can't remember the name of right now. But it's I'm sorry, Doctor. Tepper. Yes, so the momentum is the study evaluating an adequate response and incept in the early treatment study. So just a Okay, got it. A lot of me. Sorry about that. Yes, how stumbling can I be? So in the past, when there is a lot there are many, many studies that have shown that in patients who have inadequate responses to conventional acute treatment, combining triptan plus NSAID in a controlled setting in a randomized controlled trial is shows greater efficacy. So I would assume that that is what is going to be demonstrated here. And the reason that I assume that is number 1, we have a long track record of this combination showing synergy in modified factorial studies, in other kinds of studies, but also we have an optimized acute formulation here. So the MOSAIC meloxicam should hit earlier, the rizatriptan should hit earlier, they should hit a higher Cmax. And then as Richard said, meloxicam has a more protracted effect to reduce recurrence rates. So everything is lined up. The ball is teed up perfectly at this point to show us that the whole will be greater than the sum of the parts. Yes. So one other thing to add is that when you study a relatively treatment refractory group, broadly speaking, what happens is that response to active drug goes down a little, response to placebo goes down even more. And when you compare active drug and placebo, the magnitude of the treatment difference, the therapeutic gain actually gets bigger. So I'm and that's true across a range of treatments. So I'm hopeful that studying a treatment refractory group aligns with who the candidates for a combination product will be and that it will actually increase model sensitivity in terms of achieving statistically significant benefit. Got it. Two more questions, one for physicians. Given that it is a it has a very, very short Tmax or a very fast acting profile, any safety consideration that we should be watching for? And then the question for the company is, can you talk about the open label extension study? Is that already ongoing? And then how often do these patients needs to be taking the drug to satisfy the 1 year treatment requirement from the FDA? Thank you. Yes. So there's evidence that patients can tolerate very rapid rises in triptans and perhaps the best evidence comes from subcutaneous sumatriptan, which has a very short Tmax and a very rapid rise. So I don't think per se, I would expect the rapidity of the rising phase to cause safety problems. But obviously, I do think that a long term safety study is necessary to see what happens when people use a combination products over multiple attacks. Difficulty. And just to answer your this is Cedric here. Just to answer your question about the long term safety study, it is indeed ongoing and patients will treat migraines over the course of the year as they occur. So it's assessing the safety and efficacy of AXS-seven for the chronic intermittent use of migraines as they occur in this patient population. Your next question comes from the line of Myles Minter from William Blair. Your line is open. Thanks for taking the questions. Again for the KOLs, I'm just curious what proportion of patients you see in your headache clinics that have had inadequate response to prior therapies presumably prescribed by a primary care physician. And how are you thinking about AXS-seven? Would you want to put them on a generic triptan prior to considering AXS-seven or would this potentially be eligible for frontline therapy in treatment inadequate patients if momentum rates out as we think it will? And then I have a follow-up. Thanks. Well, in a headache center, almost everybody we see has had a lack of success with an oral triptan. And our job is to evaluate how many triptans have failed, whether they were legitimate trials, whether the patient whether we should go back to the well or whether we should move on. Very, very I would say the majority of patients we will probably move on. In general neurology and in primary care, there may be patients who have not been exposed to triptans. Payers will likely make a recommendation for step edits to branded acute treatments of 1 or 2 generic triptan failures and or contraindications or lack of tolerability with respect to triptans. So my anticipation is that a large, large number of patients in headache centers will be eligible for new branded acute treatments. And then the question is the nature of the lack of success. Was it inadequate pain free? Was it too slow a response? Was it recurrence? Was it tolerability? All of those need to be taken into account in picking the new treatment. And Richard may actually give you details as the percentage of patients who have had a lack of success with conventional acute treatments. Well, so I presented the data earlier showing that on their current therapy and these results are not stratified for what they were on, but 60% 56% of patients have an inadequate 2 hour pain free response and 54% have inadequate pain relief. So that is not on optimized current treatment. But I agree with Stu that before you get a branded combination product, you're going to have to sell 1 or 2 generic oral triptans. There are a whole lot of people who do that. That's helpful. And then my second question is related to 7 having a what looks to be an increased bioavailability of the rizatriptan component alone compared to Maxalt. In your clinical experience, do you ever push the dose of triptans? And do you see a change in efficacy there? Or that's just something that's not done for safety reasons or just because there's no expectation of additional efficacy with an increased dose? Well, it has to do with what is actually the dose response curve for a given triptan. And the dose response curve, which has been worked out by the pharmacologists in conjunction with clinical trials establishes an optimal dose with the greatest likelihood of efficacy and the lowest likelihood of adverse events. And when you go above what is the optimal dose, you get more adverse events without greater efficacy. And for most triptans, the dose response curve is pretty well established. There are a few little footnotes on dose response curves. But once you push above the optimal dose, you're not likely to get a lot of bang for the buck. I mean, there is an incremental advantage that may come from the rapidity of the rising phase. So broadly speaking, the impression is that drugs that have a short time to maximum concentration work better, subcut sumatriptan works better than sumatriptan tablets and the subcut dose is only 6 milligrams and the tablet dose is 100 milligrams, but the drug has a 14% oral bioavailability. So you're actually delivering more drug and getting less benefit because of the rapidity of the rising phase. My hope is that the kinetically optimized formulation here will deliver greater benefits, not based on how high the Cmax is or what the area under the curve is, but simply based on the rapidity of the rising phase. But that is a hypothesis to be tested when we see the results of the trial. Great. Thanks very much. I'll hop back in the queue. We have time for one final question. Your final question comes from the line of Matt Kaplan from Ladenburg Thalmann. Your line is open. Hi, good morning. I guess a question for doctors Liptan and Tepper. And I think Doctor. Lipkin, you might have addressed this to a certain extent already. But I guess given the population patient population in the MELANZEN study and the results that we've seen already, for example, that are in the rizatriptan label in terms of kind of a 60% to 70% response rate at 2 hours. What are you expecting and what are you looking to see given this patient population in the MOMENTUM study in terms of response rates at 2 hours for the combination and for the monotherapy? And then I guess similarly for the 2 to 24 hour pain freedom as well? Yes. Well, there are 2 kinds of response rates reported. There is pain free 2 hour pain free response, which is defined as going from moderate or severe to mild or no pain. And then there's headache response rates, which are defined as going from moderate or severe pain. I'm sorry, one is moderate or severe to mild or none and that's headache response. The other is pain free. So the pain free rate with rizatriptan is about 40%. The 60% to 70% numbers you quoted were response rates were going to mild pain counts as a response. So on top of an expected 40% response rate with rizatriptan, I would hope to pick up another 10% or more with the combination product for 2 hour pain free. And I'm not sure what I expect over 24 hours, but I expect a very low recurrence rate, both because the Mosaic meloxicam has a very because the Mosaic meloxicam has a relatively long half life. I don't know, Stu, do you have a different view? No, I completely agree with that. Well, thank you very much for the added comments. There are no further questions at this time. Mr. Jacobson, I turn the call back over to you. Great. This is Herriot. Thank you everyone for participating in this R and D event today. I would also like to thank Doctor. Lipton and Doctor. Tepper for their time and their insights. We remain excited about the potential of AXS-seven to address the unmet needs in the acute treatment of migraine and we look forward to top line results from our MOMENTUM Phase 3 trial of AXS-seven by year end. Thank you. Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.