Hello everyone. Thank you for joining us at the 44th Annual TD Cowen Health Care Conference. I am Joe Thome, one of the senior biotech analysts here on the team at Cowen, TD Cowen. It is my pleasure to have with me today, CEO Herriot Tabuteau of Axsome Therapeutics. So thank you very much. Herriot, maybe just to, to kick things off, obviously a lot going on in the pipeline in the commercial setting. Hit the high points of, of 2023, and then what should investors be looking for for the duration of 2024, and then we'll, we'll dive into the specific programs. Right. Well, first of all, thanks, Joe Thome, for having us present at the conference again this year. So, 2023 was a transformational year. We had our first full year as a commercial company, and I think we're very proud as a team with regards to what we accomplished in 2023. So we launched two products, and in the first year we exited the year with roughly $50 million in sales for our lead product and for our second lead product, another $20 million. So a run rate of about $250 million exiting the year. So we're really proud of that given the size of our infrastructure. In addition to that, we advanced our late-stage pipeline, and for each of our product candidates that we initiated trials for, we made progress. So AXS-05, which is the same active ingredient as Auvelity, we advanced our ADVANCE-2 phase III trial in Alzheimer's disease agitation. Solriamfetol, which is the active ingredient in Sunosi, we actually launched our phase III trial in ADHD, which is a brand new indication. And in addition to that, we announced three other additional indications. So, MDD, binge eating disorder, as well as shift work disorder. So we really expanded the pipeline. Now, on the back of that, we also have our phase III program for AXS-12 and narcolepsy that we progressed in 2023. And then, we also made progress with regards to our NDA submissions for AXS-07 and AXS-14. So, a lot happened in 2023 with regards to the in-line products as well as the pipeline products. And then that sets us up really nicely for this year, for 2024. Perfect. Maybe we'll start with commercial Auvelity. Where are you seeing the most uptake in the treatment paradigm across the first, second, third line settings? And maybe how do you expect that to change over the course of this year or even beyond? So Auvelity, thus far, has seen, I would say, expanded use in the frontline setting. So when the product was first launched, as you can imagine, it was being used in patients who were in need of another treatment. So most patients, the vast majority of patients with MDD are drug treated. So as you can imagine, they probably, most patients, had been on an SSRI or an SNRI. And when a new product is launched, clinicians naturally think about their patients who are in greatest need, so for whom the current products are not working. And that's about two-thirds of patients who are treated with SSRIs who do not respond. So that's where we initially expected to see the use of Auvelity. What we've seen most recently is that it is being used as first-line or second-line treatment in about 40% of the prescriptions that are written today. So we like the way that's going, and the split there is somewhere north of 10% in the frontline setting and the rest in the second-line setting. We had our neuropsychiatric conference in the fall. Some of our docs indicated their primary care colleagues are actually seeing pretty good reimbursement, and are able to use the drug first-line. Can you talk a little bit about the importance of the primary care setting? I know you did the expansion of the sales force. What's sort of gonna be the balance there between the primary care docs and maybe the specialists? Well, you know, as you expand beyond the specialist, you will inevitably hit primary care. So when we launched the product, the focus initially was on psychiatrists. And that's where we saw the vast majority of the use coming from: psychiatrists or primary care psych-like primary care doctors, primary care physicians who treat a lot of patients for depression. So that's where we saw a lot of the use. And we did expand the sales force, and the reason for that is to expand our reach. So as you go beyond the high-decile prescribers, then you will inevitably reach prescribers who are more primary care. So that's expected, and we're ready for that. In terms of when the expanded, 100-person sales force should maybe be seen in the revenue line, are you guiding investors to a meaningful change? Is that gonna happen second quarter, third quarter? What, what will we start seeing the impacts, do you think, of, of those efforts? So the extra 100 reps, they're online, they're fully trained, and they're active, and they're in the field. So that status was going into the beginning of this quarter. So we would expect to see increasing contribution from the sales force expansion throughout the year. Perfect. Maybe we'll jump over to AXS-05 in Alzheimer's agitation. Maybe you can just give us an update as to where the ADVANCE-2 trial stands right now. You did just have the adjustment of the when we're gonna see data now is later this year or H2 2024. Maybe what led to that decision. Sure. So we're first of all very comfortable with the guidance of the second half of 2024 for the Alzheimer's disease agitation readout. And that guidance was a refinement of our prior guidance, and it's meant to incorporate any potential fluctuations in enrollment at the clinical trial sites as we enter this last leg of the study, while importantly maintaining quality of the patients who go into the trial. So we're comfortable with what we're seeing, and a lot of the tweaking of the guidance was meant to incorporate any potential changes going forward. So we're very excited about the program. I think we're probably more excited about the program than we've ever been. that's due to validation from both a recently approved product as well as some competitive dynamics, which stress the fact that this is high unmet medical need and the potential for Auvelity to actually fulfill that need. So we're really excited about the program. We wanna make sure that we have a quality package, and our team is working very hard to ensure that. Obviously Rexulti is launching. Maybe what are you hearing in terms of how that product is progressing, and how does your product compare? Do you think you're differentiated compared to what they have there? Maybe elaborate on that a little bit. So one of the things that we've been looking at has been the prescription trends, as you can imagine, for Rexulti. But we're really looking at it in terms of the channels. So what I say the channels, if you think about the indication in Alzheimer's disease agitation, is primarily a Medicare population. So we've definitely seen an increase in terms of scripts in that setting. So that's good. It means that there is receptivity towards a product to treat this disorder. And that is in the face of the fact that there are issues or challenges with the product since it is an antipsychotic and it does carry a black box warning against its use, specifically in that patient population. So physicians are forced to walk a very fine line. So that's what we're seeing with regards to that launch. Now, as it relates to AXS-05, AXS-05 is a different mechanism of action, and as you know, so it is not in that class. You know, so far, what we've seen from the ADVANCE-1 trial as well as from the ACCORD trial and also anecdotally from our open-label safety extension trial is very positive. We recently saw a Alzheimer's agitation failure in the space. Getting some questions on that. Maybe can you touch on potentially why investors shouldn't read through that program to yours? So it's, you know, we want to refrain from commenting too much on a competitor readout since we don't have access to the data, and it hasn't really been published. But we can make a contrast between that product and what's been disclosed, which is three trials, two of which were not positive, one of which was mixed. And we can contrast that to AXS-05, where we have had two controlled trials, both of which separated from placebo. So different profiles from that perspective. And then also, these are different products. The molecules are different. So both molecules, both products utilize inhibition of CYP2D6 to increase the plasma concentrations of another agent. And the inhibitor in AXS-05 and the other product are different. And then even what is thought to be the active ingredient in both is different. So dextromethorphan, which is, dextromethorphan in our product, and, deuterated dextromethorphan in the other product. So different products, different clinical trials, and also, a different pattern of results from controlled studies. Maybe with the breakthrough therapy designation meeting after the ADVANCE-1 trial, the FDA on the efficacy side said, you know, you would need one more placebo-controlled study, which obviously you do have with ACCORD. So, you know, hopefully ADVANCE-2 is a slam dunk. We see a real big benefit on CMAI. But how do you view the importance of actually hitting that on the efficacy standpoint with the current package versus just generating the placebo-controlled safety data that the FDA requested? Well, you know, you always want your studies to work, right? So, having said that, we do have, as you mentioned, in our pockets two positive controlled studies. So we think that that positions us very well going into the data readout for the ADVANCE-2 study. Maybe just last question on this. How easy is it to find these patients? When you think about the potential commercial opportunity here, I don't know if you wanna compare it to, to MDD, but how, how are you thinking about that? So there are 6 million patients in the US who have Alzheimer's disease, roughly 70% of them. So, you know, north of 4 million patients are thought to have agitation. So very large patient population. So the clinical need is there, for sure. And then, you know, with regards to for clinical trials, it's important to remember that one of the things that has been helping to drive enrollment in clinical trials for this indication was the lack of an approved product. And now there is, obviously an approved product, which has limitations, but that is a new dynamic. Perfect. We are gonna see the AXS-12 narcolepsy data this quarter. Maybe if successful on the current study, where do you see AXS-12 kinda slotting into the treatment paradigm for narcolepsy, you know, especially that you do have Sunosi as well? So we are on track to report results in this quarter for AXS-12 in narcolepsy. So we're very close to data, so we'll know a lot more in terms of the product profile. Some of the things which are static, which will not change, is the fact that this is an oral agent. It is dosed during the day. Assuming that the product is successful, we think that it will provide clinicians and patients another important option. If you think about the narcolepsy space, there are roughly 185,000 patients who have the disease. And in terms of the current leading agents, they are being used to treat a minority of those patients. So you have underdiagnosis, undertreatment, and also a majority of patients who don't tolerate the current treatments. So we're really looking forward, if successfully developed, to being able to provide another treatment option for these patients. And when we think about the contribution here, sort of the footprint necessary, if AXS-12 is successful, should this essentially just go to the top line, given that you already have the sales force with Sunosi, question one? And then second, can you just remind us if the trial is successful, what you would sort of need ahead of a regulatory filing, at this point? So, we'll take those two questions in reverse order. From a regulatory standpoint, in addition to the ongoing study and the completed efficacy trial, we will also need to complete the open-label safety extension trial. So we're on track to do that. So that study enrolls patients who are rolling over from the SYMPHONY trial. And then, in terms of marketing the product, one of the things that we like about our setup from a commercial perspective is that we already have a product, which is Sunosi, which is approved for narcolepsy. So, our field force is already detailing the docs who will be writing AXS-12. So there is a lot of operational leverage. You know, now will it all fall to the bottom line? You know, obviously, there will be some spend, but there is a ton of operational leverage. And we really like that about our setup, not just for AXS-12, but also for other potential indications that we're pursuing, for example, for Sunosi. So as I mentioned, for solriamfetol, we are in a phase III trial for ADHD. We are on track to launch a phase III trial in MDD this quarter, as well as one for binge eating disorder. Those are all psychiatry indications. And we already have a psychiatry sales force. And maybe on the MDD indication for Sunosi, with that trial starting soon, what's sort of the mechanistic rationale to study Sunosi and MDD? And maybe how would that play with, with Auvelity? So the mechanistic rationale is that solriamfetol is a dopamine and norepinephrine reuptake inhibitor. In addition to that, it is a TAAR1 receptor agonist. So those mechanisms of action have been shown in preclinical models to be relevant to depression. And actually, in antidepressant predictive models, it's been shown to produce antidepressant-like effects. So we think that, mechanistically, it makes a lot of sense. Now, the TAAR1 mechanism is very interesting because, should solriamfetol be successfully developed for MDD, it would be the first TAAR1 receptor agonist for that indication. So if you think about, you know, what we've done with our currently marketed products and also with the pipeline is we've tried to go after novel mechanisms of action. And the reason for that is, MDD is a very heterogeneous disease. So it's important for clinicians to have different tools to address different patients. So let's first see what the results of the study show. First, let's launch the study, which we're on track to do this quarter. And then let's see what the results show. And there's such a large patient population, and there's such great clinical need that we think that if it is successful, then it should also allow clinicians to treat patients differently. The GEMINI study enrolled, I think it was first patient dose to data within six months. I guess, is there anything different about the trial design for the Sunosi study that would make that not the case here? Any changes in the treatment dynamic, or when would you be in a place, I guess, to give us guidance on when we should expect data? What we'd like to do is initiate the study. Once we do that, take some time to see what the enrollment patterns are. At that point, we would be able to provide some guidance as to when data readout might be. Perfect. Maybe jumping over to AXS-07 'cause we, we chatted a little bit about that last night. Maybe where are you in regards to refiling the, the submission for AXS-07? And then second, where do you see this ideally slotting into the, the paradigm for, for migraine? So we are on track to refile the NDA in the first half of this year. In terms of where it would slot in, the rationale behind developing AXS-07 has always been to address the key unmet need in migraine, which is efficacy. New agents have been launched, and those new agents, while mechanistically they are interesting, what we've seen from the prescription data and reported back from clinicians is that the efficacy is not always there. It's about on par with what you see with triptans. What we've done with AXS-07 is taken a multi-mechanistic approach to increase efficacy. In fact, our clinical trials have been designed to look at patients with a history of inadequate response. That's where it's gonna slot in. It's gonna slot in for the many patients for whom the current agents do not provide adequate relief. In terms of the reimbursement dynamic there, I guess because of that positioning, do you expect the reimbursement to be relatively straightforward, or how are you thinking about that as well? The way that we're thinking about that is, first, demonstrate clinical benefit. And that's where you have to start. And so, I believe that we have done that. And let's wait to see what the label looks like once the product is approved. And obviously, our team internally is thinking very hard about exactly the question that you asked, pricing, access, and how we launch the product. And we will have more to say with regards to that, when the time's appropriate. Perfect. And then AXS-14, don't think gets a ton of attention from investors in fibromyalgia, but you are nearing the NDA submission here. Maybe can you just remind us on the package, what you have from an efficacy standpoint, and how confident you are that the FDA, you know, will accept the data that you have in hand? So what we have from an efficacy perspective are two controlled studies, both of which were positive: a phase III trial as well as a phase III trial. Those studies met their primary and secondary endpoints in terms of pain reduction, as well as improvement in function. There were also other differentiating aspects of the product, such as its effect, its positive effect, let's say, on fatigue, which is another symptom of fibromyalgia. So we're really excited about the clinical profile of the product. And we believe that it is one that if the product is approved, it will definitely address some unmet needs in that patient population. As a reminder, there are only three products currently approved to treat fibromyalgia in, and so this and there has not been a new approval in decades. This should be a very important product for the patient community. How difficult is it to find and treat these patients? Obviously, the patient population itself is relatively large, but because of the symptoms, they might be managed at rheumatologists or primary care doctors or what have you. I guess how can you go into the marketing effort here a little bit to find and identify the patients? So our team is doing a lot of work to figure out the optimal way to target the clinicians who would write the prescriptions to treat these patients. And, as you alluded to, the treatment path is more circuitous than it is for some other disorders. So patients who have fibromyalgia, they are diagnosed by rheumatologists, but it's not always the rheumatologists who end up managing those patients after their initial diagnosis. So there will be some work that's needed there, but it's work that we think is definitely doable. And we're working very hard to make sure that we have an effective launch strategy once the product is approved. Perfect. Maybe jumping back to Sunosi, I guess how penetrated are you in the narcolepsy and OSA markets, and how is the launch progressing relative to maybe your expectations when you acquire the asset? So we are—I mean, when we acquired Sunosi, the sales force was about twice what it is currently. So we acquired the product. We rationalized the sales effort. We used our Digital Centric Commercialization, or DCC, platform to better target the clinicians who prescribe the product. So we're really proud of what we've been able to do with the product. As a reminder, in the latest quarter, prescriptions grew 18% year-over-year. So very happy with what we've done thus far with the product. In terms of the penetration in each of these markets, for OSA, it's tiny, and so there's a lot of opportunity still in that current indication. And what we're really excited about is laying the groundwork for the future potential indications, which I've alluded to, which I've talked about. ADHD, we are in a phase III trial for ADHD, and that is on track to read out in the second half of this year. Maybe on the ADHD indication, what are you looking for in the adult setting, before moving into a pediatric trial? So, what we're looking for in the adult setting is obviously to demonstrate the potential effect of the drug versus placebo. So we've initiated that trial. Now, there has been one study that's been done with solriamfetol in ADHD, which was recently published in the Journal of Clinical Psychiatry. This was a controlled study. It was a single-center study, sponsored by us. And that study was positive, which is great, but it is a single-center study. So the current study, which is the FOCUS Phase III trial, that is a multi-center trial. It's a registration trial. So we're very much looking forward to seeing what the results of that show. And what would we like to see? Obviously, we want to see how the drug separates from placebo. We want to see what the effect size is and see how that compares to currently available treatments. In terms of the pediatric population, we do intend to initiate a trial also in the pediatric population that is necessary in order to be able to file an NDA or an sNDA for solriamfetol in that indication. Can you go into that a little bit more, to get the adult indication, the pediatric indications? You just need one trial each. And I know we talked a little bit about due to some abuse liability reasons, kind of why, why that is. But if you could touch on that a little bit, that would be great. So if you kind of step back, the FDA does require that any product for ADHD that you demonstrate efficacy both in the pediatric population as well as the adult population. And the reason for that is, the FDA is loath to approve a product just for adults for ADHD because it's likely to be used off-label in children with ADHD. So that's the regulatory path. And we think that we will need one study in each population, so one adult study and one pediatric study. And then you also alluded to the other indications for Sunosi. And on the R&D day, you indicated there's a tie between, I guess, narcolepsy and binge eating disorder. Maybe can you go into that a little bit and what gives you confidence that you'll be successful in the binge eating indication? So if you look at the currently approved indications for Sunosi, excessive daytime sleepiness and obstructive sleep apnea, and excessive daytime sleepiness and narcolepsy, both of those indications, both of those conditions, obstructive sleep apnea as well as narcolepsy, tend to be patients with higher BMI. So there is a positive correlation between high BMI and OSA. And there is also a high prevalence of eating disorders in patients with narcolepsy. Some of that is due to the disease, nighttime eating. And then what we've mechanistically in terms of the rationale for looking at binge eating disorder, it is thought that the pathways that solriamfetol targets, dopamine and norepinephrine, are involved in appetite control. So there is that mechanistic rationale in terms of neural pathways. And then, in terms of the clinical data that we've seen, if you look at if you mine the data from the completed trials in OSA and in narcolepsy, you could you could look at, for example, adverse events. And one of those adverse events is appetite suppression. And also, that has resulted in or, or is associated with weight loss in those studies. So there is some, clinical preliminary clinical, data not in the target patient population, but it dovetails nicely with the mechanistic rationale. Perfect. And obviously, the acquisition of Sunosi brought in a whole nother aspect of the pipeline. And you have a lot of things on your plate right now. But how are you thinking about additional BD for the platform? Is this a focus right now, or do you have everything that you can handle right now? Well, you know, fortunately, we have a pretty broad pipeline, and it's late stage. So there's a lot of work to do. So it's not anything that so we don't have to do anything right away. But having said that, you know, we're always looking for opportunities and for products and mechanisms of action that fit nicely into our pipeline and that help with our mission to develop new drugs for patients with difficult-to-treat CNS disorders. So, you know, we're keeping our eyes peeled. As you saw with Sunosi, we can be optimistic and act quickly if it makes sense. And we will continue moving forward and using that framework. Perfect. With that, we are at time. Thank you all very much for joining us. Thank you.