Good morning, ladies and gentlemen, and welcome to Axsome Therapeutics Conference Call. 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. I 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. This morning, our press release providing details of the company's financial results for the first quarter 2019 recent clinical and regulatory achievements and upcoming milestones crossed the wire a short time ago and is available on our website at Axsome.com. We will being this call with prepared remarks by Dr. Herriot Tabuteau, Chief Executive Officer; Dr. Cedric O'Gorman, Senior Vice President of Clinical Development and Medical Affairs; and Nick Pizzie, Chief Financial Officer. We will then open the line for questions from analysts. Questions will be taken in the order that they are received. During today's call, we will be making certain forward-looking statements. These statements may include statements regarding, among of things, the efficacy, safety and intended utilization of these investigational agents, our clinical and nonclinical plans, our plans to present or report additional data, the anticipated conduct in the source of future clinical trials, regulatory plans, future research and development, 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 weight on these forward-looking statements and the company disclaims any obligation to update such statements. I would now like to turn the call over to Herriot.

Thank you, Mark. Good morning, everyone, and thank you all for joining us on the call today. The first five months of 2019 have been very productive for Axsome. So far this year, we have reported positive efficacy results in the Phase 2 trial of AXS-05 in major depressive disorder, or MDD, as well as a Phase 2 trial of AXS-05 in smoking cessation. We received FDA Breakthrough Therapy designation for AXS-05 in MDD, and earlier this week, we announced the expedited development and pivotal status of AXS-05 in MDD following our recent Breakthrough Therapy meeting with the FDA. During the quarter, we also launched the Phase 3 MOMENTUM trial of AXS-07 in the acute treatment of migraines as well as the Phase 2 CONCERT trial of AXS-12 in narcolepsy. I would like to take a moment to review the current status of AXS-05 in light of the recent Breakthrough Therapy meeting before turning it over to Cedric, who will detail the status of our ongoing clinical trials, and then to Nick, who will follow up with a review of our first quarter financial results. As a reminder, AXS-05 is Axsome's novel, oral, investigational NMDA receptor antagonist with multimodal activity. AXS-05 was internally developed at Axsome and was covered by more than 30 issued U.S. patents, with coverage extending to 2030. Based on the Breakthrough Therapy meeting, the previously completed active controlled ASCEND trial in MDD is now considered pivotal, meaning it is sufficient along with the ongoing STRIDE-1 Phase 3 trial in treatment resistant depression with TRD, if positive, to support the filing of a new drug application, or NDA, for approval of AXS-05 in the treatment of MDD. Alternatively, Axsome may also file an NDA for AXS-05 for the treatment of MDD with the completed ASCEND trial and…

Thank you, Herriot. I am pleased to provide an update on our ongoing clinical programs. I would first like to spend a moment on AXS-05 in smoking cessation. Last month, we announced that Duke University had completed its top-line analysis of the Phase 2 trial of AXS-05 for smoking cessation treatment. The analysis showed that AXS-05 met the pre-specified primary endpoint and significantly reduced daily smoking as compared to the active comparator bupropion. The trial was a Phase 2 randomized, double-blind, active-controlled study to evaluate the efficacy and safety of AXS-05 for smoking cessation treatment. The preliminary clinical findings with the AXS-05 for smoking cessation are important because they provide additional data of the biologic activity of AXS-05. We are evaluating the next steps in the clinical development of AXS-05 as an aid for smoking cessation and look forward to providing an update in the near future. Turning now to our depression program with AXS-05, the ongoing STRIDE-1 trial is a Phase 3, multi-center, randomized, double-blind, active controlled trial to assess the efficacy and safety of AXS-05 in the treatment of treatment resistant depression. As previously mentioned, screening and enrollment in the STRIDE-1 trial will continue in order to build the safety database required for an NDA filing. We expect top-line efficacy results for STRIDE-1 in the second half of 2019. In the second quarter, we plan to launch a randomized double-blind, placebo-controlled, Phase 3 trial of AXS-05 in patients with MDD and anticipate top-line data from this trial in the second half of this year. As previously mentioned, this placebo controlled trial, if positive, may be used in conjunction with our completed ASCEND trial to support an NDA for the treatment of MDD. In the second quarter, we also planned to initiate an open-label safety extension trial to build…

Thank you, Cedric, and good morning, everyone. I will now cover the first quarter of 2019 financial results. Starting with our balance sheet, we had $42.6 million in cash as of March 31st, 2019, an increase of $28.6 million from our December 31st, 2018 balance of $14 million. This increase is primarily due to proceeds received from the at-the-market equity financing completed in January, and our new growth capital term limit with FCB entered into in March. Turning to the statement of operations, the company incurred a net loss of $10.6 million, or $0.32 per share, for the quarter ended March 31st, 2019 as compared to a net loss of $4.8 million, or $0.19 per share, for the quarter ending March 31st, 2018. Operating expenses in the first quarter of 2019 increased by $3.2 million to $10.4 million as compared to a $7.2 million in the first quarter of 2018. Research and development expenses were $7.6 million for the period ending March 31, 2019, as compared to $4.8 million for the period ending March 31st, 2018, an increase of $2.8 million. The increase is primarily due to the initiation and rapid progress of our MOMENTUM study, continued progress of our STRIDE-1, ADVANCE-1, and smoking cessation studies, along with the manufacturing cost related to our AXS-07 product candidate, which is partially offset by reduction in the cost of our previously completed clinical trials and non-clinical work. General and administrative expenses for the quarter ending March 31st, 2019 were $2.8 million, as compared to $2.4 million for the period ending March 31st, 2018, an increase of $0.4 million. The increase was due to higher legal costs, external fees associated with operating as a public company, and personnel costs. Interest expense in the first quarter 2019 was $0.2 million as compared to $0.3 million for the first quarter of 2018. We anticipate that our current cash position will be sufficient to fund our anticipated operating cash requirements into at least the first quarter of 2021. This guidance includes the new planned Phase 3 trial in MDD with AXS-05, as well as the planned AXS-05 open-label, safety extension study. Importantly, this runway extends beyond the data readouts for all of our ongoing and planned clinical trials with our CNS product candidates. That concludes our first quarter 2019 financial review. I will now turn the call back to Mark to lead the Q&A discussion.

Thank you, Nick. Operator, can we please have our first question?

Thank you. At this time, we will be conducting our question-and-answer session. [Operator Instructions] Your first question comes from the line of Marc Goodman with SVB Leerink. Marc, your line is open.

Morning, guys. One of the questions I've gotten several times from investors is just related to the ASCEND trial and the dose that you chose to use for bupropion, the fact that it was 105 mg rather than the higher dose that's normally used. Can you just comment on the strategy there and how you think about it, and how physicians are going to view this with respect to how efficacious this product is? And then the second question is can you just give us an update on your latest thoughts on commercialization for all of these opportunities? Thank you.

Thanks, Marc, for the question. So, for the first question, I'll turn it over to Cedric, and then I'll take the commercialization question.

Hey, Marc, thanks for the question, and that question does come up. So, the full daily dose that was used in ASCEND was 210 mg of bupropion SR, sustained release, and this is in fact a dose that's within the approved range for the treatment of major depressive disorder. And further, GlaxoSmithKline, who originally developed the drug, also had part of their submission for the NDA filing, including doses that were shown to be effective at that dose and lower. So, if you look back over the literature, there's also evidence showing that 150 mg, 200 mg, and upward have been effective in treating depression. So, then, you look at the actual results from ASCEND, and you ask yourself whether the magnitude of improvements seen with bupropion reflects a clinically meaningful expected antidepressant effect, and as you can see, it does. So, after six weeks, you see a 12.7 point improvement, and essentially, that does reflect an antidepressant effect that you would expect to see.

And if I just may add too, just to further stress one of the points that Cedric alluded to, the fact of the matter is that the study was against an active comparator. Most trials are against placebo. And so, it is definitely interesting to think about what the placebo-corrected reduction in the madras might've been, assuming that we had conducted a placebo-controlled trial. With regards to commercialization, it is definitely our intent, as we've stated in the past, to partner outside of the U.S. In the U.S., we do intend to launch these product candidates ourselves. Having said that, we are open to partnerships if they would increase the value of the franchises that we plan to file NDAs for and eventually launch. Given the fact that the paths to NDA for potentially both of our two lead product candidates appears to have been expedited, as you can imagine, this is a key area of focus for us, and we are acting to build the organization on the commercial side.

Thanks.

Your next question comes from the line of Ram Selvaraju with H.C. Wainwright. Ram, your line is open.

Hi. Thanks very much for taking my questions. Firstly, just a point of clarification, your cash burn guidance, does that include additional clinical development for reboxetine, AXS-12, or not?

Hey, Ram. This is Herriot. Our cash guidance includes the current trials, which are ongoing, and also, it includes the planned trials with AXS-05, so the new Phase 3 MDD trial, which is placebo-controlled, as well as the open-label extension. It does not assume new studies for AXS-12.

Ram, just to be clear, for AXS-12, it does include the Phase 2 study for reboxetine, so just to make sure that that clarification is made. And as Herriot stated, it also does include the Phase 3 study that is planned for MDD, as well as the open-label safety study for AXS-05. So, they have been included in our new cash guidance.

And then just as a point of clarification, let us assume that the Phase 2 AXS-12 study is positive. What would be the logical, theoretical next step there for development of that compound?

So, for AXS-12, we fully intend to initiate and launch a Phase 3 trial with AXS-12, should the Phase 2 study be positive. And so, that is part of our plans. We stated that intention in the past, so we're looking forward to the readout of that study.

And then pursuant to your comments, Herriot, regarding commercialization within the United States, and Axsome stated intent to pursue commercialization of these candidates independently, how do you see the framing and development of the commercialization effort and the establishment of sales and marketing infrastructure across these multiple therapeutic areas? And what kinds of synergies might you be able to exploit, assuming that two or maybe even three of the candidates in your current pipeline arrive on the market in roughly the same time frame, but obviously are targeting different therapeutic areas within the broader scope of mass market neurology?

So, if you look at our pipeline, and you look at the indications, which we are targeting, they do fall into two broad buckets. One is neurology, and the other one is psychiatry. And so, if you look at the indications, for example, for AXS-05, if you look at the mood disorder indications, those would fall under psychiatry, and then if you were to look at Alzheimer's disease agitation, there is overlap there. Alzheimer's disease is treated primarily by neurologists, but the behavioral symptoms are treated by psychiatrists, so there is overlap there. And then you have our neurology indications. So, if you look at AXS-12, that's neurology and the acute treatment of migraine that is neurology. Having said that, there's also a lot of comorbidity, a lot of psychiatric comorbidities with both of those indications. So, we do look at those two pieces, if you will, with regards to building a sales force, psychiatry and neurology, keeping in mind that there is an overlap there in the Venn diagram.

Very helpful. And then just a point of clarification regarding the prior inadequate responses to migraine therapy for patients being enrolled into the MOMENTUM study. Can you elaborate on that a little bit further and maybe give us a sense of whether these patients have been cycled through multiple [indiscernible] already or they only failed one [indiscernible] or if they failed other migraine therapeutics beyond the [indiscernible] class. Thank you.

So, I'll put it over to Cedric to answer that question.

Thanks, Ram. So, you can hear me OK, Ram?

Yup, I can.

So, patients who are enrolled in the MOMENTUM trial, we use a validated questionnaire called the mTOQ-4, and this assesses efficacy response to prior acute treatment. So, to your point, it's not specific to any particular one class, but generally, the acute migraine treatment. And there are four different aspects in the mTOQ-4 which evaluate prior response, and that's whether patients had two-hour pain freedom, whether they've had efficacy that lasted a full 24 hours with one dose of the medication, whether they've been able to plan daily activities, and whether their daily activities have actually been disrupted as a result of not getting adequate response from their treatment. And then it's scored basically, and for those patients who have inadequate response, it's a score of 7 or higher, and they're essentially deemed then to be inadequate responders and are eligible to be enrolled into the MOMENTUM trial.

Great. Thanks very much for that clarification, and congrats once again on all the progress.

Thank you.

Your next question comes from the line of Maria Skoboleva with Cantor Fitzgerald. Maria, your line is open.

Hi. It's actually Charles with Cantor. First of all, morning, Axsome team. Congrats on the progress. Thanks for taking our questions. I may have missed this because I'm on a train with spotty cell service, but with regard to AXS-05, there is other clinical studies such as tox studies or preclinical studies, and then in terms of manufacturing, will you be prepared to support the filing of an NDA by, say, this time next year or even earlier? Thanks.

Good morning, Charles, and thank you for the questions. With regards to the additional requirements for an NDA filing, in terms of preclinical studies, this is a 505(b)(2) NDA, so we can reference some of the more onerous clinical studies that normally would need to be done such as carcinogenicity studies, which take a long time, so that is definitely a positive. There are the bridging toxicity studies, which are required, some of which we conducted and which are under way. So, we're in good shape there, and we do not anticipate that being a gating factor. And in terms of manufacturing, we also are in really good shape with regards to manufacturing. It is not a straightforward process, but it is one that we've been working on for a while, and so therefore, we do not anticipate that there would be any sort of delay whatsoever. The manufacturing process is finalized and optimized, and we should be in good shape to be able to fulfill that part of an NDA package by next year.

And then as a follow-up question with regard to AXS-05, I mean, it's hard to pick your favorite child, but I'm wondering if you had at all to do it over again, would you perhaps had emphasized MDD over TRD, or as you think about that right now, what would you see as bigger opportunity? It seems like MDD is a larger prevalence or incidence challenge, but what do you think is the better indication [indiscernible]?

So, I think one thing to remember is that MDD encompasses what normally people talk about as MDD as well as the TRD. So, treatment resistant depression is simply major depressive disorder but in patients who failed at least two prior treatments. So, they are definitely more difficult to treat. So, with the broad MDD indication, it does allow us to target the general MDD population. Now, with regards to your question about if we had it to do all over again, would we have maybe emphasized MDD before TRD? I would say no. I think we're very happy with the sequence of clinical trials, so the Phase 2 trial, and the Phase 2 ASCEND trial in MDD did show the potential of the product, which is great and which is tremendous. We ran that study in a frontline population in order to be able to more clearly delineate potential benefits of AXS-05. But also, with TRD, because we are running that study in a very difficult to treat patient population where there is a high clinical need and we're the bar, we're showing efficacy is much greater. We think that that is a great position to be in with AXS-05, given that it is an oral, NMDA receptor antagonist with multimodal activity. So, it allows us to essentially demonstrate the efficacy of the product candidate in the hardest to treat population, and we think that that can only be positive for the broader MDD indication.

Thanks for that color, Herriot. I just have one last question over the AXS-07, which is coming back from the AAN-19, and it just seems like a rapidly evolving space-acute therapy for migraine. And I'm kind of wondering if you could share with us some further thoughts on differentiation of the molecule in what you are assuming to be the treatment paradigm in a couple of years? And then finally, do you anticipate running a long-term safety study with [indiscernible]?

So, thank you, Charles, for the question on AXS-07. We're very excited about the progress that we've made and the MOMENTUM Phase 3 trial with AXS-07, and as we stated, we now expect to have data this year. And with regards to what we view as some of the key differentiating features of AXS-07, now the MOMENTUM clinical trial will delineate that profile further, but the product is designed potentially to provide fast onset of action. We have a unique PK profile with MoSEIC meloxicam that results in rapid absorption of the product candidate, and because of the distinct dual mechanism of action of AXS-07, we do expect that the efficacy should also be strong and more consistent in current migraine therapies. Lastly, the meloxicam in our formulation does have a long half-life, and the point of that is to reduce symptom recurrence. In fact, that is one of the secondary endpoints that we are looking at is sustained pain freedom. So, now, all that is nice to say we look forward to the results of the clinical trial to see if our thesis bears out, and we like to make things a little bit more difficult for ourselves up front, and in order to do that with this study, we designed a very stringent trial, which is enrolling patients that aren't known to be difficult to treat. So, patients who have a prior inadequate response and who also have certain symptom tautology that is predictive also of worse outcomes with current migraine drugs. And we've also used a known potent active comparator, rizatriptan, and so what you have with the MOMENTUM trial is if we do have success, it should be able to clearly delineate the differentiating factors of AXS-07, especially since with the rizatriptan active comparator, we're essentially conducting also [audio cuts out] that compares the AXS-07 to currently available therapy.

That's helpful. And regarding long-term safety, if this trial reads out, what do you anticipate having to do in terms of exposure to patients over time?

With regards to long-term safety, we definitely would anticipate and we expect that we will need to look at repeat dosing over an extended period of time, so six months and certainly for one year. And we will be in discussions with the agency to find out exactly what that safety database requirement will be.

Thanks for the added information, and congrats on the recent BTD and interaction with the agency.

Thank you.

Your next question comes from the line of Matt Kaplan with Ladenburg Thalmann. Matt, your line is open.

Thank you. And good morning, guys.

Good morning, Matt.

Thanks, thanks. I wanted to dig into some of the new moving parts that you announced recently with respect to AXS-05 and the planned now Phase 3 in MDD and the open-label extension studies. Can you give us a sense in terms of the design that you're thinking of there and how you're going to achieve the timelines that you've laid out?

Thank you, Matt, for the question. I'll turn it over to Cedric to talk about the design of the planned Phase 3 trial, the new Phase 3 trial, and the open-label extension study.

Thanks, Matt. So, we've had a lot of experience now with having run the successful ASCEND study and the ongoing STRIDE study, which is fully enrolled, but we're going to keep screening and enrolling STRIDE to build the requisite safety database. So, we've built a very strong infrastructure and have established relationships now with numerous sites. We've run our feasibility analysis on running a placebo-controlled trial, and how many sites it would take, what the screening expectation in enrolling would be, and how long it would be to generate top-line data. So, with regard specifically to the design of the placebo-controlled MDD study, well, the key point really is that we're excited that this can be placebo-controlled given that ASCEND has demonstrated additional antidepressant effect for AXS-05 over bupropion, so that's the good piece of news. And then everything else based around the design of the placebo-controlled trial will be very similar to how we approach ASCEND, so keeping a lot of things the same and hoping to build on what was successful strategy, successful recipe previously. And then in terms of the open-label extension, which will comprise both patients who have MDD coming from our planned placebo-controlled trial as well as patients with TRD are coming from our STRIDE-1 study. We anticipate to have a rich database of patients with depression treated long-term up to 12 months with AXS-05 at the requisite numbers for six months and one year.

Thanks. That's very helpful. And then kind of a follow-up question on Ram's when he was asking about cash and runway, given the planned clinical trials that you have, how do you plan to or think about funding the company going forward?

So, thanks for the question, Matt. So, let me turn it over to Nick, who will talk about how we think about financing plans.

Thanks, Herriot. Thanks, Matt, for the question. As I said in my opening remarks, our current cash takes us into at least the first quarter of '21, which is well beyond the anticipated readouts of all of our current and planned clinical trials. So, aside from potential opportunistic use of our ATM, we do not anticipate an equity offering prior to readouts of the pivotal trials in AXS-05 and depression.

Thanks. That's very helpful, and congrats again on the progress.

Thanks, Matt.

Gentlemen, your final question comes from the line of Bert Hazlett with BTIG. Bert, your line is open.

Thanks. Just a quick question regarding timing. In terms of the AXS-05 placebo-controlled study in MDD, the Phase 3 that's upcoming, just thinking about how long it took to run the active control study, and having this, and thinking about IRB approval and other things, is it -- how do I wanna say it -- is it realistic to really think you're going to have data in 2019 for this study? It seems like a tall order. I just wanna make sure that we have our timelines correct. Thank you.

Bert, thank you for the question. So, maybe it would help for us to kind of tell you how we think about it in terms of the numbers, and that would help you to also come to your own assessment. So, if you look at the ASCEND trial which we conducted last year, and as a reminder, as Cedric stated, the new Phase 3 trial that will be placebo-controlled in major depressive disorder should have a similar design to the ASCEND study. We launched that study last year roughly at about the same time and were able to complete it at the end of last year, and we announced data, as you know, at the beginning of this year. That study comprised 80 patients, and it was conducted in approximately four centers. So, that gives you a sense now in terms of Phase 3 trials, there will be an increase in the number of centers and to give you a sense with the ongoing STRIDE-1 trial we're currently conducting of that study in more than 60 centers. So, applying really any kind of reasonable number of centers to the rate for the ASCEND trial last year, that'll give you a sense of how we think about the enrollment rate potentially and the ability to generate and report data by year end.

And Bert, if I could just add one thing as well, you had made the comparison to the STRIDE-1 study, and of course, another important distinction for the placebo-controlled MDD study is that these subjects do not need to have demonstrated a failure to one or two antidepressant treatments in their current depressive episodes, so you're getting a very straightforward depressed patient into the study, which would enroll more quickly than a TRD population.

Thank you for the clarity.

This concludes our question and answer session. I will turn the call back over to Axsome's CEO for any concluding remarks.

Well, thank you all for joining our call this morning. We've had a highly productive start to the year, and we expect to continue this momentum through the balance of the year. We look forward to keeping you updated on our progress, including multiple top-line data readouts and clinical trial initiations. Thank you again for joining our call.

This concludes today's conference. Thank you for your participation. You may now disconnect.