Axsome Therapeutics, Inc. (AXSM) Earnings Call Transcript & Summary

Good morning and welcome to the Axsome Therapeutics Conference Call. [Operator Instructions] As a reminder, today's conference call is being recorded. I would now like to turn the conference over to your host, Mark Jacobson, Chief Operating Officer at Axsome Therapeutics. Thank you. Please go ahead.

Thank you, operator. Good morning and thank you all for joining us on today's conference call to discuss the approval of SYMBRAVO for the acute treatment of migraine with or without aura in adults. 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 investigational agents, our clinical and nonclinical 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 plans, commercial plans and possible intended use of cash and investments. 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 reliance on these forward-looking statements, which are only made as of today's date and the company disclaims any obligation to update such statements. Joining me on the call today from the Axsome team are Dr. Dr. Herriot Tabuteau, Chief Executive Officer; Ari Maizel, Chief Commercial Officer; Hunter Murdock, General Counsel; and Nick Pizzie, Chief Financial Officer. Also joining on the call today is one of the leading experts on migraine, Dr. Stewart Tepper, Professor of Neurology at the Geisel School of Medicine at Dartmouth; and Vice President of the New England Institute for Neurology and Headache. Herriot will first make some opening remarks. Ari will provide an overview of our commercial plans. Dr. Tepper will provide an overview of migraine, treatment needs and will then discuss the profile of SYMBRAVO. We will then open the line for questions and questions will be taken in the order they are received. And with that, I'm pleased to turn the call over to Herriot.

Thank you, Mark. Good morning, everyone. [Audio Gap] Slide 6. Yesterday afternoon, we announced that the FDA has approved SYMBRAVO for the acute treatment of migraine. We are pleased that this approval came early, 1 day prior to the PDUFA goal date. SYMBRAVO is a novel multi-mechanistic approach to treating migraine that targets multiple pathways underlying a migraine attack. SYMBRAVO can rapidly eliminate migraine pain and return patients to normal functioning with efficacy that is sustained through 24 and 48 hours after only a single dose. SYMBRAVO is engineered with Axsome's patented MoSEIC or Molecular Solubility Enhanced Inclusion Complex technology, which increases the rate of absorption of meloxicam enabling its use as a new molecular entity for the acute treatment of migraine. More than 70% of patients experience an inadequate response to current oral acute treatments. Based on its demonstrated efficacy, SYMBRAVO has the potential to address this unmet medical need. The Axsome team is proud to deliver this important new treatment to the estimated 39 million patients living with migraine in the U.S. Next slide. We are pleased with the broad label for SYMBRAVO. The label highlights are shown on this slide. SYMBRAVO is indicated for the acute treatment of migraine with and without aura in adults. In the control trials, SYMBRAVO was very well tolerated with the only adverse reactions with an incidence of 1% or more being somnolence and dizziness, which were reported each in 2% of treated patients compared to 1% for placebo. Next slide. SYMBRAVO was evaluated in 2 pivotal Phase III control trials. The INTERCEPT trial which treated patients when the initial pain was mild and the MOMENTUM trial, which treated patients when the migraine pain was of moderate and severe intensity. The efficacy of SYMBRAVO was, therefore, demonstrated across a broad range of settings including at the earliest onset when the pain was mild in patients with moderate and severe migraine pain and in those with a history of various responses to prior acute treatments. Next slide. Both the MOMENTUM and INTERCEPT trials met their co-primary endpoints. In both studies, patients receiving SYMBRAVO rapidly and significantly achieved pain freedom and freedom from the most bothersome symptom 2 hours after dosing compared to placebo. In the MOMENTUM trial, 3x as many patients treated with SYMBRAVO achieved 2-hour pain freedom compared to placebo. And in the INTERCEPT trial, twice as many patients achieved pain freedom at 2 hours compared to placebo. Freedom from the most bothersome symptom, phonophobia, photophobia, or nausea at 2 hours was achieved by approximately 40% of patients treated with SYMBRAVO. Next slide. The benefits of pain freedom was sustained for 24 hours as shown on this slide. 24 hours sustained pain freedom was achieved by 3x as many patients treated with SYMBRAVO in the MOMENTUM trial and twice as many patients treated with SYMBRAVO in the INTERCEPT trial compared to placebo. In a head-to-head comparison, SYMBRAVO also significantly demonstrated superiority compared to rizatriptan on sustained pain freedom. Results were similar for sustained pain freedom through 48 hours. Next slide. Notably, the demonstrated efficacy was achieved with only a single dose of SYMBRAVO. Importantly, 85% of patients treated with SYMBRAVO in the INTERCEPT trial and 77% of patients treated with SYMBRAVO in the MOMENTUM trial did not require rescue medication within 24 hours. These results demonstrate that the vast majority of patients achieved significant benefit with just a single dose of SYMBRAVO. Overall, these results demonstrate that SYMBRAVO can rapidly eliminate migraine pain across a broad range of migraine severity, allowing patients to quickly return to normal functioning with efficacy that is sustained through 24 and 48 hours after a single dose. SYMBRAVO is protected by a robust patent estate, extending out to at least 2040. With that, I would like to turn it over to Ari, who will review the commercial opportunity for SYMBRAVO and our launch plans.

Thank you, Herriot and good morning, everyone. On the next slide, you see that SYMBRAVO is entering a migraine market in which significant unmet treatment needs exist among patients and providers. Even with multiple approved medications available, more than 80% of migraine patients discontinue their acute migraine treatment in the first year. Migraine remains the leading cause of disability among neurological disorders for the more than 39 million migraine sufferers in the U.S.. And the devastating consequences of recurrent pulsating, severe and disabling head pain leave patients in constant search of therapeutic relief. Unfortunately, patient dissatisfaction is extremely high in this market due to limited efficacy response or burdensome side effects associated with existing treatment options. These dynamics present a clear opportunity for a product like SYMBRAVO to offer hope to the millions of patients in search of a new treatment approach. Next slide. Looking closer at the market opportunity, there's a large base of over 22 million prescriptions written annually, dominated by generic triptans that make up 3/4 of total prescriptions. Market penetration of newer agents over the past 5 years reinforces the potential for a novel multi-mechanistic medicine like SYMBRAVO to create a meaningful impact on the overall acute migraine market by offering the potential for improved patient outcomes. Importantly, the provider audience is highly concentrated among high-decile prescribers in headache centers and large neurology practices which will enable a targeted sales force effort for SYMBRAVO during our commercial launch. Next slide. As we prepare for market entry, we have been very pleased with the response to SYMBRAVO's compelling clinical profile, with future HCP targets highlighting SYMBRAVO's rapid and durable efficacy, novel mechanistic approach that targets the 4 key pathways underlying a migraine attack and well-established safety and tolerability profile. Three out of every 4 providers we engaged in market research expect to use SYMBRAVO as an acute migraine treatment for their patients. Next slide. We are planning to launch SYMBRAVO commercially in approximately 4 months. At Axsome, we believe in taking a strategic and focused approach to commercializing our products. And for SYMBRAVO, that will include a targeted selling effort that prioritizes headache centers and headache specialists who care for the vast majority of migraine patients in the U.S. In addition, SYMBRAVO will be Axsome's third product to leverage our digital-centric commercialization platform, enabling us to engage with providers across the migraine universe in a highly targeted and efficient way. Patient education will also be an important part of our promotional mix with unprecedented digital and traditional media channels available to educate patients throughout their migraine treatment journey. Finally, we are actively engaged with payers across channels to educate on SYMBRAVO's unique value proposition in anticipation of securing access for the product in its launch year. We will share more details around our commercialization plans soon. Next slide. I'd now like to hand the call over to Dr. Stewart Tepper, Professor of Neurology at the Geisel School of Medicine at Dartmouth and Vice President of the New England Institute for Neurology & Headache. Please go ahead, Dr. Tepper.

Well, thank you very much and it's really a great honor to be able to talk about the acute treatment of migraine and the advent of SYMBRAVO. And what I want to do is, sketch for you how we got here in terms of the understanding of migraine, some specific aspects of SYMBRAVO, I was one of the investigators in these studies and then where this might fit in from a clinical standpoint. Next slide, please. This slide takes you through what we know now about migraine pain and the genesis of migraine. Migraine pain is actually a noninfectious meningitis. That's why it hurts so much. And if one begins at the upper left in these set of diagrams, migraine itself begins in the brain and then activates the mechanisms of pain in the meninges. Activation of the migraine within the brain leads to CGRP release in the meninges and in the second frame at the top, the CGRP is released in the meninges during the migraine. And then in the upper right, what happens is 2 major events. Blood vessels dilate, because of the CGRP effect. CGRP is a profound blood vessel dilator. And when the blood vessels dilate, they open up and outpour the mediators of inflammation. And you can see on the lower left, the inflammation occurring, this is typical inflammation. And then in the second frame at the bottom, one sees the actual migraine pain mechanisms which were caused by the blood vessels dilating and the inflammation in the meninges. That hurts. Signal goes back into the brain and it's processed. So the pain signals are processed in the brain. That's when people receive the pain when they get nausea and sensitivity to light and noise. One way to approach this, of course, is to take out CGRP. But there are lots of opportunities for reversing migraine pain that are afforded by coming in from different mechanisms. Next slide, please. SYMBRAVO combines MoSEIC meloxicam and rizatriptan for the acute treatment of migraine. So let's take this apart. Rizatriptan prevents the CGRP release in the meninges at the very beginning. It prevents the CGRP release. Then it reverses the blood vessel dilation in the meninges, second mechanism. Then it prevents the pain signal from moving from the meninges back to the brain. The meloxicam terminates inflammation in the meninges as a nonsteroidal anti-inflammatory. And nonsteroidal anti-inflammatories have also been shown to reverse the central processing of the migraine pain. Nonsteroidals work both peripherally in the meninges and centrally to stop the migraine. And what SYMBRAVO combines, is a new formulation of the meloxicam, MoSEIC meloxicam to increase the speed of onset and the overall effectiveness. On the right, you see this MoSEIC delivery technology which enhances solubility and absorption. Regular old meloxicam takes a very long time to be absorbed. It's really more appropriate for preventive effects in various kinds of arthritis. It's a molecule with low solubility and poor absorption. But with this new formulation, there's a pH modifier, there's a drug inclusion complex formulation and this improves the drug release and enhances the absorption. So you -- on the 1 hand, you have this new MoSEIC meloxicam in a different dose than generic meloxicam to maximize the onset. And then rizatriptan actually is the triptan, the oral triptan was the fastest onset and the highest 2-hour pain-free numbers, which is further enhanced by MoSEIC technology. And with the combination of the MoSEIC meloxicam and rizatriptan in 1 tablet, the whole is greater than the sum of the parts. And the FDA, in one of the regulatory trials, MOMENTUM, required that the SYMBRAVO be tested against the individual components as well as placebo. Next slide, please. This is a slide that the pharmacokinetics of the drug, superimposed on what actually happens during migraine. If one follows across a migraine, the bottom you see the time in hours, CGRP peaks at about 1 hour and prostaglandin E2, which is an inflammatory mediator, peaks at about 2 hours. And in gold, you see what happens with the SYMBRAVO rizatriptan, it peaks in about 30 minutes. And the MoSEIC meloxicam peaks at between 45 minutes and 1 hour and the combination of the 2 medications combined in the medicine, all peak before the CGRP and the PGE2 and that enables the drug to terminate the attack so effectively. And remember, with the rizatriptan kicking in early, it's also preventing the release of the CGRP. So these components align with the increase in the key mediators of migraine. And the pharmacokinetic here actually predicts the clinical effectiveness of this combination medication. Next slide, please. Now a word about optimal acute treatment in migraine. When we teach, we really we really focus on getting an optimal acute treatment for patients. The best acute treatment for migraine is one and done. Patient is pain free within 2 hours without significant side effects and most of the time without any headache recurrence after the successful treatment, one and done. And there is a large prospective population-based study by Richard Lipton's group which was able to show over several years in thousands of patients that inadequate acute treatment effectiveness was associated with an increased risk of transforming to chronic migraine over the course of 1 year. And let me explain that. What was done was to evaluate the acute treatment effectiveness in people who had discrete episodes of migraine and then see what percentage of them actually got worse and got a higher frequency of migraine, greater severity of migraine transformed to greater than 15 headache days per month. And it turned out that optimal acute treatment was more than twice as likely to not be associated with this transformation, inadequate acute treatment was more than twice as likely to be associated with this adverse event of the natural history going from episodic to chronic migraine. And this enabled us to tell each other and patients that we want treatment that gives a sustained and complete response in order to prevent the onset of chronic migraine and medication overuse headache. And the advantage of the SYMBRAVO is that it combines the peripheral and central effects of meloxicam on the 1 hand, with the blood vessel effects and some of the neuronal effects of the rizatriptan on the other hand, to offer the prospect of a complete response. I showed you why it should have early onset, why it should have optimal efficacy. It has very low adverse events. You can see that the adverse events that were recorded were only 1% over placebo, very low recurrence, sustained response and sustained pain freedom were documented at 24 and 48 hours. So the pivotal trials were very encouraging. And remember also that SYMBRAVO was studied in one of the regulatory trials, MOMENTUM, on those for whom patients had, had a lack of success with previous acute medicines. These were more difficult to treat patients and SYMBRAVO showed excellent results in these harder-to-treat patients. What we really want to do and this we hope is the future, is to match patient need to treatment for the acute treatment of migraine. And that matching a patient need to appropriate treatment is referred to as stratified care. Next slide, please. Stratified care is actually going worldwide. The American Headache Society consensus statement states that individualizing acute treatment plan should be based on medical need and treatment history and across the world, physician statements and consensus statements confirm the idea of matching patient need to treatment. I put the UAE consensus statement there, the Polish experts' consensus statement, which says that we should be considering migraine-specific treatments as first-line therapies. So the future for acute therapy of migraine is migraine-specific acute treatment that focuses on multiple mechanisms of action to achieve a complete response. SYMBRAVO by combining MoSEIC meloxicam with rizatriptan allows for additive benefit for patients. And that's why we've been quite excited in the development of this particular medication. I thank you.

Thank you very much, Dr. Tepper. And at this point, we'd like to open the call for questions. And to do that, I'll turn it over to the operator to manage the line. Thank you.

[Operator Instructions] Today's first question is coming from Leonid Timashev of RBC.

Congratulations on the approval. Really exciting to see. I had a question on sort of the market and at what point in a patient's treatment journey, you're going to intervene and try to get them on SYMBRAVO. You talked about the high willingness to prescribe as well as sort of the failure of patients to respond to treatment. But what's the churn like in the market? At what point would a patient or a physician consider switching therapies? You do have a broad label. So would you try to use this upfront after they failed some other prior therapy? Yes, that's it.

So I'll answer part of it. Then Dr. Tepper, would love to hear your thoughts just about intervention with inadequate response. But from our perspective, we see SYMBRAVO as being a great treatment option when a patient is in need of a prescription treatment. And whether that is as an initially diagnosed migraine patient or somebody who has tried 1 or more existing agents and had either inadequate efficacy or intolerable response to treatment, SYMBRAVO will be a great option. And obviously, market access will be an important factor here. We'll have more to share about that as we get closer to the commercial launch. But Dr. Tepper, any thoughts from you in terms of when you think about switching a patient or initiating pharmaceutical intervention for migraine?

The first point, I think, is that it's the position of the American Headache Society that everyone with migraine needs an acute treatment. So we're starting on that premise. I think it's also useful to look at which kinds of patients are appropriate for SYMBRAVO without regard to what the payers are going to require, then circle back. And the fact that the nonsteroidal anti-inflammatory can reverse central sensitization requires us to look for patients that are at the peak of their migraine where this kind of a medication could reverse it and where a triptan alone or where a gepant alone might not. And 1 example of that that's really common is morning -- is migraine upon awakening that is morning migraine. And almost half of attacks occur in the morning. And triptans don't really get people back to functioning in morning migraine and gepants are a bit slow. And so I think SYMBRAVO is going to be very useful in patients who awaken with a full-blown attack. Because of the speed of the rizatriptan and the MoSEIC meloxicam, it also can be useful in patients who have a quick time to peak intensity from the time they notice the pain to the time they're disabled is rapid. And again, gepants tend to be kind of slow and this medication should be excellent for that. It also should be used in people who have a need for an anti-inflammatory and I was thinking about menstrual migraine, which occurs in 2/3 of women with migraine. So it's a huge number of patients and using a medication that combines an anti-inflammatory with a triptan should prolong the benefit, menstrual migraines tend to be long, the anti-inflammatory has -- various anti-inflammatories have been shown to be useful in menstrual pain. And so there's an overlap there as well as this reversal of central sensitization. Since the payers are likely to require previous trials, the MOMENTUM study, which evaluated patients who had various inadequate responses to acute treatment in the past shows that this medicine works. And the late Ninan Mathew published a paper on combining triptan plus NSAID in people who had, had a lack of success with triptans. And interestingly, when one combines the NSAID with the triptan, it usually works in people for whom the triptan alone has failed. So I think we have a lot of clinical circumstances in which this combination will be useful.

Our next question is coming from Charles Duncan of Cantor Fitzgerald.

Super. Congratulations on the approval. And Dr. Tepper, great to hear your voice and reconnect. I had a question for you, Dr. Tepper and that is probably related to the last question. It seems like you appreciate some of the synergies in the mechanism of action. But do you think that prescribers, KOLs and certainly general prescribers will see this as just another triptan or will they appreciate some of the synergies and mechanism? And you mentioned stratified care. I guess I'm wondering if you would place this before or after the oral anti-CGRPs. And what is the evidence you base that on?

I'm trying to remember the first question but let me deal with the second question first and then you can remind me. I don't think -- I think individualizing acute treatment and matching patient need to treatment or matching the treatment to patient need is really the key. There are going to be people for whom gepants are appropriate. They have low AEs similar to SYMBRAVO and they're gentle. And ubrogepant has been shown to be effective in prodrome. So they have some interesting utility and the more frequent that somebody use -- more frequently somebody uses a gepant, the more likely they are to get prevention. So they have some rather unique properties. But there are circumstances in which gepants may not be appropriate and I mentioned a few of them central sensitization, morning migraine, quick time to peak intensity, with a lack of warning that a headache is coming in, aura person for whom the gepant has been inadequate. And so I think sitting as a prescriber, there are going to be people for whom the combination therapy is appropriate from the get-go, assuming payers allow it and others for whom gepants or triptans will be appropriate from the beginning. And I do remember your first question, which was, how are we going to educate our compatriots that -- that this is not just another triptan. And that's really up to those of us who are teaching to explain that combining multiple mechanisms does afford increased effectiveness. We know that the combination is superior to the individual components as well as placebo. And we have those data and it's our responsibility to teach our colleagues that this is not another triptan. This represents an advance.

Very helpful. And if I may, just 1 quick follow-up for the company. I guess I'm wondering when you might pursue beyond adults. So for example, to include adolescents, given some of Dr. Tepper's prior comments with regard to menstrual migraine that might be of use. And then what would you anticipate -- or when is the data coming from the post CGRP trial that's being run. I think that's later on this year. Could you provide additional color there?

Charles, this is Mark. So the work for an adolescent -- the adolescent work is underway and we'll have more to say there. And with respect to the EMERGE trial, we anticipate results this quarter.

And I want to just chime in on this, I want to chime in on the adolescent part of this. One of the characteristics of adolescent migraine is quick time to peak intensity. When one asks an adolescent, how fast did that migraine get bad, they say that fast, they start to snap the fingers. And so -- and rizatriptan is actually already FDA approved for acute treatment of migraine in adolescents. And since the combination with the MoSEIC formulation moves the rizatriptan and meloxicam even earlier in the pharmacokinetics, this -- as you point out, this is a medication that could be very effective in adolescents. And so I look forward to seeing the results of that study.

The next question is coming from Ash Verma of UBS.

Congrats on the approval here. I guess I wanted to get a sense of what do you see broadly as the peak commercial opportunity here? I mean in migraine, there's definitely a strong precedent for drugs reaching several billion dollars peak sales type opportunity. So as you look at it, sort of early in the launch here, what is your expectation? Could this be a blockbuster? Could it go beyond that? Just would love to hear any thoughts that you have on that.

Sure. Thanks, Ash. We are very optimistic about the potential for SYMBRAVO. In our current corporate presentation, we have a peak sales range of $500 million to $1 billion. We firmly believe that, that range is achievable. But obviously, there's a lot to learn as we get out into the market and see the ramp of the product over time. But that said, we are very optimistic and do believe that SYMBRAVO has blockbuster potential and we look forward to educating the marketplace in a few months.

The next question is coming from Ami Fadia of Needham & Company.

Maybe my first question is for Dr. Tepper. You mentioned that there's going to be need for education kind of in the broader physician community. Outside of that, how do you see the utilization of the drug assuming that payers will require patients to have failed at least 1 other treatment. How often do you see the patients churning? And maybe kind of talk about sort of just receptivity of physicians to kind of try newer products? And then just for the company, from a sort of payer strategy perspective and maybe a launch curve perspective, could you give us kind of some initial parts around where do you see the product placed with payers? And then what could be a good analog for us to think about for the launch?

Well, very briefly, I think that when physicians or providers ask patients about whether they're getting a one and done response with tolerability and whether they can use a medication when they need it during the day, for example, at work and be restored to normal function, when practitioners ask that question, the number of patients that have inadequate response to particular treatment turns out to be remarkably high and persistence data in multiple, multiple studies on triptan use is very low. It's extremely rare for patients to remain persistent with single triptan therapies. So I think there's the prospect of improvement in patient care with this combination medication. And I'll turn it over to the company.

Ami, this is Ari. To answer your questions, from a market access standpoint, we're obviously in active negotiations right now and we recognize when products enter the market for the very first time, there's going to be different appetites in terms of utilization management or unrestricted access for new products. And so we recognize that not every payer is going to necessarily treat the negotiation in the same way. That said, we're discussing a variety of different access approaches. It could be as first line, it could be with 1 or 2 prior treatment failures. And so we're going to be open-minded because we recognize this is a long-term play in terms of the growth of the brand and profitability of the brand. And so we'll have more to share with that as we get closer to the commercial launch. I think in terms of launch curve analogs, obviously, the nearest launches in this space are the oral CGRPs. So I think those are fair comparators. However, there are some meaningful differences. Obviously, those products were launched by larger companies with larger initial sales force footprints, which we recognize. But that said, we're very optimistic about our ability to grow demand in this space and we'll look forward to sharing more details around those plans as we get closer to the commercial launch.

[Operator Instructions] The next question is coming from Marc Goodman of Leerink Partners.

This is Basma on for Marc Goodman. We'd like to know if there's any plan to go after prevention as an additional indication from SYMBRAVO, as this may help with the uptake. And then if there's time, we have a follow-up question to Dr. Tepper.

So we'll take that question. So SYMBRAVO is approved for the acute treatment of migraine. So it is not approved for prevention of migraine. Having said that and maybe Dr. Tepper could comment on this, one of the important aspects of SYMBRAVO, we feel is making sure that patients are adequately treated in order to prevent chronification of migraine. Dr. Tepper?

Yes. I think I would think about this as an optimal acute treatment and not one -- probably not one suitable for prophylaxis.

The next question is coming from Joon Lee of Truist Securities.

Congrats on the approval. Dr. Tepper, it was really interesting to hear you describe migraine as a noninfectious meningitis with activation of the inflammatory pathway with uncontrolled or under controlled migraine have some lasting damages to the meninges and/or worsen subsequent migraines. And if so, how critical is it to rapidly [indiscernible] the migraine pain? And would SYMBRAVO play a role there? And a quick follow-up for management. Have you disclosed the pricing of SYMBRAVO?

I don't think the issue is damage in the meninges there are people for whom migraine becomes a progressive disease. That is they gradually increase the frequency of their attacks and transform from episodic migraine having less than 15 headache days per month to chronic migraine having 15 or more days per month and then gradually and they can actually progress all the way to continuous headache. And we have lots of chronic migraine people with continuous headache. And that progression is linked to inadequate acute treatment and to the frequency of headache days per month. So if you have an optimal acute treatment, let's say, you have a person who has a 3-day migraine and they take a medicine one and done and instead of a 3-day migraine, they have a 2-hour migraine. They're going from 3 days of migraine to less than a day of migraine. The likelihood of progressing and transforming to chronic migraine goes down. That's probably why optimal acute treatment is associated with decreased risk of transformation. There are MRI changes that occur in migraine but these changes are reversible and are not permanent. So we don't think of migraine as a disorder like multiple sclerosis, where there's a gradual increase in lesions and a burden in the brain that develops. Rather, we think about this as a reversible neurologic disorder in which there is the prospect for bad progression and in which optimal acute treatment might prevent that.