Study Update

Sep 21, 2020

Press Release

Good morning, ladies and gentlemen, and welcome to Axsome's Therapeutics Conference Call. This call is being webcast live on the Webcast and Presentation page of Axym's website at axim.com@acxim.com .com. Later, there will be a question and answer session and instructions will follow at that time. Please note that today's conference is being recorded. I would now like to turn the conference over to your host, Mark Jacobsen, Chief Operating Officer at Axsome Therapeutics. Please go ahead. Thank you, Good morning and thank you all for joining us on today's conference call. This call is to provide an update on our AXS-twelve product candidates. A short time ago, this morning, a press release crossed the wire announcing the expedited development plan for AXS-twelve in the treatment of narcolepsy based on the outcome of our recent breakthrough therapy meeting with the U. S. Food and Drug Administration or FDA. We will begin this call with prepared remarks by Doctor. Herriot Tabuteau, Chief Executive Officer, and then open the line for questions. 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 other things, the efficacy, safety and intended utilization of our investigational agents, our clinical and non clinical 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 shall now turn over the call to Ariel. Thank you, Mark. Good morning, everyone, and thank you all for joining Axsome Therapeutics' clinical update conference call. This morning, we announced an acceleration in clinical development for AXS-twelve for the treatment of narcolepsy. As a reminder, AXS-twelve is Axon's novel, oral, highly selective and potent norepinephrine reuptake inhibitor under development for the treatment of narcolepsy. AXS-twelve has been granted FCA Breakthrough Therapy Designation and orphan drug designation for the treatment of narcolepsy and Axon has pending patent applications covering AXS-twelve. Narcolepsy is a chronic debilitating neurologic condition characterized by excessive daytime sleepiness and cataplexy. Cataplexy is a sudden reduction or loss of muscle tone while a patient is awake, triggered by strong emotions, and it is seen in about 70% of narcolepsy. Other symptoms of narcolepsy include cognitive difficulties, disruptive nighttime sleep, sleep paralysis and hypnagogic hallucinations. Narcolepsy is an orphan condition that affects nearly 200,000 patients in the U. S. The serious condition interferes with cognitive, psychological and social functioning, increases the risk of work and driving related accidents and is associated with a 1.5 fold higher mortality rate. Existing treatment options remain limited, do not address all symptoms, provide variable efficacy, have significant side effects and are mostly controlled substances. Only one agent is currently approved to treat both cataplexy and excessive daytime sleepiness. There is therefore an urgent need for new treatments which address the unmet needs of patients and the limitations of current agents. In August, the FDA granted Breakthrough Therapy Designation for AXS-twelve for the treatment of cataplexy and narcolepsy based on positive results from our previously completed Phase II CONCERT trial, which was a randomized, double line, placebo controlled, crossover, multicenter U. S. Study. In this trial, AXS-twelve demonstrated rapid, substantial and statistically significant improvement in cataplexy, excessive daytime sleepiness and the ability to concentrate for AXS-twelve as compared to placebo. Pursuant to AXS-twelve being granted breakthrough therapy designation, we recently had a breakthrough therapy meeting with the FDA to discuss the development program and regulatory path forward for AXS-twelve for the treatment of MarcoEssi. Based on the outcome of this study with the FDA, we are pleased to announce that the development plan for AXS-twelve in the treatment of narcolepsy has been expedited. The expedited development plan includes a single Phase 3 efficacy trial, which along with the previously completed Phase 2 CONCERT trial will be used to support the filing of an EMEA or approval of AXS-twelve for the treatment of cataplexy and narcolepsy. The planned Phase 3 trial will be a randomized double blind, placebo controlled, parallel group study. We intend to initiate this trial in or before the Q1 of 2021 and look forward to providing greater details about this study at that time. Patients completing a Phase 3 trial will be eligible to enroll in an open label safety extension study. Also, as part of the expedited development plan, clinical and non clinical data with Revoxetine, which we previously obtained through our exclusive license agreement with Pfizer, can be used to support the NDA filing for this new molecular entity. Specifically, the existing short term and long term safety database of more than 2,500 patients treated with riloxetine along with the safety data from the completed and planned studies of AXS-twelve in patients with narcolepsy would be sufficient to support an NDA filing for AXS-twelve. Certain existing completed clinical pharmacology studies with reboxetine are considered sufficient to support an NDA filing for AXS-twelve and the extensive package of completed non clinical study for avoxetine are considered sufficient to support an NDA filing for AXS-twelve. Our expedited approach for the development of AXS-twelve for narcolepsy reflects our commitment to accelerating the innovation of potentially life changing medicines for many patients living with serious CNS disorders. We are very pleased with the FDA feedback from the breakthrough therapy and look forward to frequent and collaborative interactions with the UGC as we execute on this expedited development plan. Based on its clinical profile to date, we believe that AXS-twelve is successfully developed to be a candidate as foundational therapy to meaningfully improve the lives of the many patients living with narcolepsy. With that, I'd like to open the call to Q and A. Operator, can you please have our first question? Your first question comes from Mark Goodman from SVB Leerink. Your line is open. Hi, this is Rudy on the line for Marc. Congrats on the news. I just have a quick question for Alfon, the filing for EXO-twelve. So what would be the gating factor for the NDA? I guess you talked about that you have the data, preclinical data and safety data from Pfizer. Just wondering if you need additional data on top of that. And would you include the open label safety expansion study data for the NDA filing? Thanks. Thanks for the question. With regards to the gaining we will need some our Phase 3 trial. Now, we will need some additional patients obviously in the safety database who have narcolepsy. Those patients will come from our completed CONCERT trial as well as the planned Phase 3 trial. And then those patients coming out of the Phase 3 trial will go into the over label safety extension study. So we think that it significantly reduces the number of patients and the things that we need to do in order to file the NDA once we complete the Phase III trial. So obviously, once we launch the Phase 3 trial, we'll have more to say in terms of all of the various things that go into an AG filing, which are extensive. But this absolutely contracts, if you will, the items that we need to check off. So this is a new kind of remedy and one of the things that would need to be done typically would be a 2 year carcinogenicity study. And so as a result of the Pfizer collaboration, we actually don't have to run that. So we have that information. So that's not going to be a gating factor. Other items such as pharmacology studies, which are typically needed, those are also largely done and completed with regards to the package. So that's now I think this is a question for the better answer as we get closer to completing a Phase III trial. But overall, we're very pleased with the acceleration and the timelines. Thanks. That's very helpful and congrats again. Thank you. Your next question will come from Ram Selvaraju from H. C. Wainwright. Your line is open. Thanks very much for taking my questions. I was wondering if you could comment on the length of the evaluation window in the planned Phase III trial? And also if you could comment on whether the adjudication by the FDA that the preclinical and clinical safety data package from Pfizer has any potential read through to the possible path forward for AXS-fourteen in fibromyalgia? Thank you. Thanks for the question, Ram. With regards to the length of the Phase III efficacy trial, now this will be a short term trial. We have not given the exact length of the study. But if you look at past trials that have looked at cataplexy or that have looked at excessive daytime sleepiness in this indication. They've ranged anywhere from 2 weeks in the capable of a CONCERV trial to 12 weeks. So we will provide the exact length of treatment once we launch the study. But I think those two brackets should provide you with a good approximation of what the length of the trial will be. With regards to your question around the outcome of the FDA's assessment of the preclinical and clinical package with roscenic reboxetine for AXS-twelve and its implications for AXS-fourteen, which is esproboxetine, the SS and Atrium, which is being developed for fibromyalgia. It's too early to tell, but I think certainly it bodes well. There is some overlap in terms of the preclinical work that was done for AXS-fourteen, I. E, Roboxetine and AXS I'm sorry, for AXS-twelve, I. E, we're seeing at Roboxetine and AXS-fourteen, I. E, Thanks for taking the question and congrats on the progress, Herriot. And I wanted to just ask you about that more in the future. And then if you have a sense of the time to enroll the trial at this point? Can you gauge that at all? So thanks, Charles, for the question. I mean those questions are related to the trial design in terms of numbers of patients and the time that it will take to enroll the study. So the study design, as we stated in our announcement this morning, will be a parallel group design. And in terms of the number of subjects, we'll provide that once we launch the study. But just to give you some framework through which to think about this, if you look at our CONCERT trial, so that was a 21 patient trial used across our design. So translating that to a parallel group design would be roughly 21 or so patients per treatment arm. Now I'm not saying that that's going to be the number of subjects in our Phase III trial, but it is good to look at that because we certainly are looking at that from a powering perspective. And in the CONCERT trial, the results on the cataplexy were highly statistically significant using that patient number. So we'll be north of that in terms of the numbers of patients per treatment arm and we'll provide more granularity and more precision around the size of the trial once we actually launch it. With regards to the length of time that it will take to enroll the trial, that depends obviously on the size of the trial. And to give you just again a sense of what we know from our experience, the CONCERT study, which was 20 patients, we did enroll that in less than 6 months or about 6 months across roughly 12 clinical trial sites. Again, not saying that this is necessarily predictive. Of course, it's not predictive because it's not the cycle of the Phase 3 trial will be different. What I'm saying is the metrics that you can extract from that experience, I'm not saying that they're necessarily predicted, but it's data that we do have and that we'll be looking at and that you should look at. Yes. That makes sense. It's all very helpful. I guess the other thing to think about is the effect size that you're thinking about and the types of patients that you'll be enrolling. Maybe if you could help. If you think about the sample that was enrolled in the CONCERT trial, how would that compare roughly to the sample, the enrollment criteria that you'll be using for this trial? Our goal would be to enroll similar patients in the Phase III trial, in the Phase II trial. Okay. That's helpful. And then the last question that I had, probably the only guy on the call that knows both Orphan Medical, which became Jazz and then also covers Ceflon. But I'm wondering if you think about the residual unmet need here in treating cataplexy, would your intent to be able to treat both cataplexy and excess of daytime sleepiness, would that be part of the label? And then how would this would an approval of AXS-twelve leverage the planned sales force that you haven't that you're planning for psych and neurology? So in the CONCERT trial, we show a profound effect not only on cataplexy, but also on excessive daytime sleepiness. And so that was an endpoint in the CONCERT trial that will be an endpoint also in our Phase III trial. And in the CONCERT trial, it was a secondary endpoint. And in the Phase III trial, excessive daytime sleepiness would be at least a key secondary endpoint. And then with regards to the sales force, the way that we think about our sales effort right now is that our CNS franchise is divided between psychiatry on the one hand and neurology. So if you look at our product candidates for which we plan to file on the AEs, shortly. On the psychiatry side, you have AXS-five for depression. And on the neurology side, you have AXS-seven 4 migraine and AXS-twelve would fall under the neurology bucket. So the answer is the short answer is yes. Our business model is to focus on CNS and to leverage operationally everything that we're doing. Makes sense. Thanks for taking the question. Congrats on the progress. Thank you. And your next question will come from Joseph Thelma from Cowen. Your line is open. Hi, there. Thank you for taking my questions. Just first maybe a little bit of a broader question on kind of if you're able to provide any additional information on what the FDA saw in the available data package, I guess, 1st to award the breakthrough therapy designation and then second, kind of to go ahead with the single Phase 3. Is there a certain aspect of the data that stood out to them? And then second, do you anticipate the drug would have any scheduling or based on the Phase 2 in the existing data package, do you have enough information to show that there's no withdrawal symptoms? Thanks. So when we ran the Phase 2 CONCERT trial, the point of that study was to see if there was a signal. It was a dual panel test of our hypothesis that selectively targeting norepinephrine in the way that AXA-twelve does would result in anti cataplectic effects as well as effects against the accepted daytime sleepiness. And so we were very pleased with the results, which showed some very strong outcomes on those two measures. And we applied to full rate conservative designation based upon those results. As a reminder, cataplexy is still narcolepsy is still a very much underserved therapeutic area. There's only one agent which is currently approved to cataplexy. And the agents that are available to treat excessive daytime sleepiness, most of those agents are controlled substances. So we were very pleased that the FDA found the results of the CONCERT trial compelling in order to award a strict therapy designation. And also we're very pleased that the data are strong enough that they can be used to support the filing on NDA along with a single Phase III trial. With regards to scheduling, we do not expect AXS-twelve to be scheduled and that is based upon the extensive clinical experience with the product. And there is we do have access to a lot of data. As a reminder, the number of patients in the safety database is more than 2,500. This is the safety data, which we obtained through the Pfizer license. And those data do not show signs of abuse potential or growth. And that is in addition to the extensive amount of post marketing experience in Europe with the product. Excellent. Thank you very much. Congrats again. Thank you. Your next question comes from Yatin Sumja from Guggenheim Partners. Your line is open. Hey guys, just a couple of questions from me as well. Can you maybe just talk about some of the benchmarks that you are looking at as you are thinking about the following the assumption both for cataplexy and EDS? And what you are thinking about? I think, I don't know, I've shown somewhere around 12 to 14 attacks per week improvement over procedure. Is that how you are thinking of howling? So that's one part of the question. The second is, you mentioned the foundational therapy. What are you getting from KOLs? Like what level of improvement do you need to show for you to become a foundation therapy? Yes. Well, thanks for the questions. And please do let us know if we don't answer them all. With regards to the powering for the Phase III trial. One of the things that we're looking at very clearly are the effects that we saw in CONCERT trial. And so in that study, cataplexy, we were able to show an effect that was highly statistically significant. At week 1, p value was less than 0.001 and at week 2, the p value was 0.002 and that was with 21 patients using a crossover design. So that would translate to roughly 21 patients per treatment arm if it's more powerful group design. So now that's not necessarily precisely predictive, but certainly it gives us a comfort that there is a large treatment effect here. And we'll certainly be looking at that data very closely as we power our Phase III trials. And with regards to your questions around foundational therapy and what level of effect we will be looking for to support that, the reason why we say that this could be foundational therapy is if you look at the symptoms that AXS-twelve improved in our CONCERT trial, these are the key some of the key symptoms in narcolepsy. So there was a found effect on cataplexy. That's one. There was also a profound effect excessive daytime sleepiness and we measured that using more than one measure. So we have ortho sleepiness scale as well as a number of inverted naps. And then something which is not usually measured or assessed, but which affects patients with narcolepsy profoundly is the ability to concentrate. So this is a symptom which patients feel all the time as a result of their narcolepsy. And AXS-twelve did show a very significant effect on the ability to concentrate that is improving the ability to concentrate. And then lastly, you look at several measures, several sleep related measures such as quality of sleep, nighttime awakenings, sleep paralysis, episodas and the nausea hallucinations, Those were also positively affected by AXS-twelve. The magnitude of the effect on cataplexy and on excessive daytime sleepiness are similar to what has been seen with the only currently approved agent for both of those indications. You can't do cross crop comparisons, of course, but it is instructed to look at the historically reported 9 disease effect. So those are the access of the data which support that AXS-twelve could be foundational therapy should replicate these results in the Phase III trial. Got it. Just one more question for me. Can you remind the IP and anything you're doing on the European front for narcolepsy? Thank you. So X as well is a new cap quantity, so it does have NCE status in the U. S. We also have orphan designation, So it has been granted orphan drug designation, so that's 7 years exclusivity from launch. In addition, Exome has filed and is prosecuting patent applications, which would significantly extend the runway. And in Europe, we are not developing in Europe. Europe. And your next question will come from Myles Winter from William Blair. Your line is open. Hi, guys. Just wondering whether the regulators made any specific comments about enrolling patients that may not be naive to Xyrem treatment or now that we've seen WACX approved for excessive daytime sleepiness and Harmony's intent to submit an sNDA to get that cataplexy indication, whether or not they want patients that might be experienced on that therapy to be enrolled in your trial? So, Mayav, we have not that has not been an issue that has come up and that was not an issue in the enrollment also of the CONCERT trial. Okay, beautiful. And then just on the CONCERT trial study sites, are you anticipating that the vast majority, if not all of them, would be used in the proposed Phase III trial? Well, we'll certainly be looking at those sites, and that's what we've done historically. So the experience in enrolling one study, we always try to use in selecting sites for the next study. So I would anticipate that there would be at least some overlap. And final one for me. Do you have a handle on how many top one electives out there are also comorbid with depression just given the mechanism of action of AXS-twelve? About 57% to 60%. Beautiful. Thanks for the questions. Thank you. Your next question will come from Joon Lee from Truist Securities. Your line is open. Hi. Thanks for taking my question. So do you have any plans to do any real world studies similar to what you did for INTERCEPT or migraines to support commercialization? What do you think will be the key differentiator? I know safety is 1, but do you also hope to differentiate on efficacy? How do hope to position it commercially? Yes. So a couple of questions there With regards to real world studies, yes, I would anticipate that we would do what we've done now historically, which is to try and get as much data as possible from any kind of clinical trial that we run. And certainly, any kind of open label experience would provide some level of real world data. With regards to differentiation, you mentioned that we could be differentiated on safety. So that is true. But just to be clear, one of the key across the full range of new Gordon symptoms that affect patients with narcolepsy. Who were oxidate experienced. We can get back to you with that exact percentage. I don't know if Cedric knows off the top of his head. But there weren't any material difference in response based on the those experience versus NICE. Is that fair to assume? So we'll confirm that, but we do believe that, that is the case. Great. Thank you. And your final question for today will come from Matt Kaplan from Ladenburg Thalmann. Your line is open. Hey, guys. Good morning and congrats on the regulatory progress. Just wanted to dig in a little bit more in terms of the work that you've done when you analyze the market for narcolepsy cataplexy and how potentially AXS-twelve could fit into the treatment continuum and where you see that where you see it playing a role? Do you think it will be, I guess, as a frontline treatment or as a given that a large percentage of patients don't tolerate sodium oxybate, would it be after the Trabasta use of sodiumoxetate for the treatment of narcolepsy cathelepsy? Catch up? Thanks, Matt, for the question. With regards to where it would fit in the treatment paradigm, we based on the clinical data thus far and the clinical profile of AXS-twelve, we think that it could be foundational therapy for patients with narcolepsy. Now you did mention patients who may have been treated with the oxybate. And but the reality of it is that the current number of patients who are treated with oxybate is represent a very small percentage of the total number of narcoleptics that are out there currently. So if you assume around 200,000 or close to 200,000 patients with narcolepsy in the U. S. And knowing that the number of patients who want SIRGMRX-three is about 14 is there are a lot of patients out there who are in need of treatment. And what's nice about AXS-twelve in addition to the potentially strong efficacy across a range of symptoms of narcolepsy is the fact that it does not share a lot of the side effects abuse related issues that are currently seen with the oxidate products. So the however, again, that is not how we plan to compete in the marketplace. And in fact, there are so many patients who are currently underserved, who are not taking oxybate. That's where we intend to go to. The fact of the matter is that patients with CNS disorders and patients with narcolepsy deserve better treatments. And that is our goal here as a company. And so we want to make sure that we develop therapies that address not just the symptoms that the industry is looking at, but the symptoms that patients say are important to them. So if you look at our data, for example, we've looked at the ability to concentrate, cognitive difficulties is an area which patients with narcolepsy state is one of the most bothersome symptoms. And at least thus far, we've shown that that is also improved with AXS-twelve. So a lot of different ways that we can help to address the medical need in this relatively large orphan condition, which is underserved. Great. Thanks so much for the added color. This is Julian with our Q and A session. I turn the call back over to Harriet Tubineau for closing remarks. Well, thank you all for joining Axsome's conference call this morning. We are excited about the expedite development of AXS-twelve in the treatment of narcolepsy. So Axsome is committed to advancing the development and commercialization of all our strong late stage CNS product candidates, which now number 4 across 6 different indications. As we strive to provide improved therapeutic options for patients living with serious and difficult to treat CNS disorders, we will keep you posted on our continued progress throughout the rest of this year. Thank you again for joining our call. Thank you, everyone. This will conclude today's conference call. You may now disconnect.