Good morning, ladies and gentlemen, and welcome to Axsome Therapeutics Conference Call. Currently, all participants are in a listen-only mode. This call is being webcast live on the webcasts and presentation page of Axsome's website at axsome.com, back arrow, http://axsome.com, forward arrow. 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 Jacobson, Chief Operating Officer at Axsome Therapeutics. Please go ahead.
Thank you, operator. Good morning, thank you all for joining us on today's conference call. This call is to provide an update on our AXS-12 product candidate. A short time ago, this morning, a press release crossed the wire announcing the expedited development plan for AXS-12 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 Dr. Herriot Tabuteau, Chief Executive Officer, 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 plan, our plans to present or report additional data, the anticipated conduct and the source of future clinical trials, regulatory plans, future research and development, and possible intended 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 Herriot.
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-12 for the treatment of narcolepsy. As a reminder, AXS-12 is Axsome's novel, oral, highly selective, and potent norepinephrine reuptake inhibitor under development for the treatment of narcolepsy. AXS-12 has been granted FDA's Breakthrough Therapy Designation and Orphan Drug Designation for the treatment of narcolepsy, and Axsome has pending patent applications covering AXS-12. 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 narcoleptics. Other symptoms of narcolepsy include cognitive difficulties, disruptive nighttime sleep paralysis, and hypnagogic hallucinations.
Narcolepsy is an orphan condition that affects nearly 200,000 patients in the U.S. This serious condition interferes with cognitive, psychological, and social functioning, increases the risk of work and driving-related accidents, and is associated with a one-and-a-half-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-12 for the treatment of cataplexy in narcolepsy based on positive results from our previously completed Phase II CONCERT trial, which was a randomized, double-blind, placebo-controlled, crossover, multi-center U.S. study.
In this trial, AXS-12 demonstrated rapid, substantial, and statistically significant improvement in cataplexy, excessive daytime sleepiness, and the ability to concentrate for AXS-12 as compared to placebo. Pursuant to AXS-12 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-12 for the treatment of narcolepsy. Based on the outcome of this meeting with the FDA, we are pleased to announce that the development plan for AXS-12 in the treatment of narcolepsy has been expedited. The expedited development plan includes a single Phase III efficacy trial, which along with the previously completed Phase II CONCERT trial, will be used to support the filing of an NDA for approval of AXS-12 for the treatment of cataplexy in narcolepsy.
The planned phase III trial will be a randomized, double-blind, placebo-controlled, parallel group study. We intend to initiate this trial in or before the first quarter of 2021 and look forward to providing greater details about the study at that time. Patients completing a phase III 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 reboxetine, 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 reboxetine, along with the safety data from the completed and planned studies of AXS-12 in patients with narcolepsy, would be sufficient to support an NDA filing for AXS-12.
Certain existing completed clinical pharmacology studies with reboxetine are considered sufficient to support an NDA filing for AXS-12, and the extensive package of completed non-clinical studies for reboxetine are considered sufficient to support an NDA filing for AXS-12. Our expedited approach for the development of AXS-12 for narcolepsy reflects our commitment to accelerating the innovation of potential life-changing medicines for the many patients living with serious CNS disorders. We are very pleased with the FDA's feedback from the Breakthrough Therapy and look forward to frequent and collaborative interactions with the agency as we execute on this expedited development plan. Based on its clinical profile to date, we believe that AXS-12, if successfully developed, could 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&A. Operator, can we please have our first question?
At this time, if anybody would like to ask a question, please press star one on your telephone keypad. Again, that would be star one on your telephone keypad. Your first question comes from Marc Goodman from SVB Leerink. Your line is open.
Hi, this is Rudy on the line for Marc. Congrats on the news. I just have quick questions from the filing for AXS-12. 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 it include the open label safety expansion study data for the NDA filing? Thanks.
Thanks for the question. With regards to the gating factor, what is nice about this expedited path is now really the gating factors are minimal. It's essentially completing our phase III trial. 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 III trial. Those patients coming out of the phase III trial will go into the open label safety extension study. 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. Obviously, once we launch the phase III trial, we'll have more to say in terms of all of the various things that go into an NDA filing, which are extensive.
This absolutely contracts, if you will, the items that we need to check off. This is a new chemical entity, one of the things that would need to be done typically would be a two-year carcinogenicity study. As a result of the Pfizer collaboration, we actually don't have to run that. We have that information, so that's not going to be a gating factor. Other items, such as clinical pharmacology studies, which are typically needed, those are also largely done and completed with regards to the package. For VEXA, I think this is a question which will be better answered as we get closer to completing the phase III trial. Overall, we're very pleased with the acceleration of the timelines.
Thanks. That's very helpful. Congrats again.
Thank you.
Your next question will come from Raghuram 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-14 in fibromyalgia. Thank you.
Thanks for the question, Ram. With regards to the length of the phase III AXS-12 trial, this will be a short-term trial. We have not given the exact length of the study. 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 two weeks in the case of our CONCERT trial to 12 weeks. We will provide the exact length of treatment once we launch the study. 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 racemic reboxetine for AXS-12 and its implications for AXS-14, which is esreboxetine, the S,S-enantiomer, which is being developed for fibromyalgia, it's too early to tell.
I think certainly it bodes well. There is some overlap in terms of the preclinical work that was done for AXS-14, i.e., racemic reboxetine, I'm sorry, for AXS-12, i.e., racemic reboxetine, and AXS-14, i.e., esreboxetine.
Thank you.
Your next question will come from the line of Charles Duncan from Cantor Fitzgerald. Your line is open.
Thanks for taking the question and congrats on the progress, Herriot. I wanted to just ask you for any additional color with regard to trial design in terms of dosing or the sample size. I know you'll talk about that more in the future. If you have a sense of the time to enroll the trial at this point, can you gauge that at all?
Thanks, Charles, for the question. Those questions are related. The trial design in terms of numbers of patients and the time that it will take to enroll the study. The study design as we stated in our announcement this morning, will be a parallel group design. In terms of the number of subjects, we'll provide that once we launch the study. Just to give you some framework through which to think about this. If you look at our CONCERT trial, that was a 21 patient trial. It used a crossover design. Translating that to a parallel group design would be roughly 21 or so patients per treatment arm. I'm not saying that's going to be the number of subjects in our phase III trial. It is good to look at that because we certainly are looking at that from a powering perspective.
In the CONCERT trial, the results on the cataplexy were highly statistically significant using that patient number. We'll be north of that in terms of the numbers of patients per treatment arm. 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'll take to enroll the trial, that depends, obviously, on the size of the trial. To give you just again, a sense of what we know from our experience. The CONCERT study, which was 21 patients, we did enroll that in less than six months or about six months across roughly 12 clinical trial sites. Again, I'm not saying that this is necessarily predictive. Of course, it's not predictive because the size of the phase III 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 predictive, but it's data that we do have and that we'll be looking at, and that you should look at.
Yeah. 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 to the phase II trial.
Okay, that's helpful. The last question that I had, I'm probably the only guy on the call that knows both Orphan Medical, which became Jazz, and also covers Cephalon. 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 excessive daytime sleepiness, would that be part of the label? How would an approval of AXS-12 leverage the planned sales force that you're planning for psych and neurology?
In the CONCERT trial, we showed a profound effect not only on cataplexy but also on excessive daytime sleepiness. That was an endpoint in the CONCERT trial. That will be an endpoint also in our phase III trial. 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.
Okay.
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. If you look at our product candidates for which we plan to file NDAs shortly, on the psychiatry side, you have AXS-05 for depression. On the neurology side, you have AXS-07 for migraine. AXS-12 would fall under the neurology bucket. 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.
Your next question will come from Joseph Thome from Cowen. Your line is open.
Hi there. Thank you for taking my questions. First, maybe a little bit of a broader question on if you're able to provide any additional information on what the FDA saw in the available data package, I guess first to award the Breakthrough Therapy designation and then second, to go ahead with this single phase III. Is there a certain aspect of the data that stood out to them? Second, do you anticipate the drug would have any scheduling or based on the phase II in the existing data package, do you have enough information to show that there's no withdrawal symptoms? Thanks.
When we ran the phase II CONCERT trial, the point of that study was to see if there was a signal. It was the original test of our hypothesis that selectively targeting norepinephrine in the way that AXS-12 does would result in anti-cataplexic effects as well as effects against excessive daytime sleepiness. We were very pleased with the results, which showed some very strong outcomes on those two measures. We applied for Breakthrough Therapy designation based upon those results. As a reminder, narcolepsy is still a very much underserved therapeutic area. There's only one agent which is currently approved to treat cataplexy. The agents that are available to treat excessive daytime sleepiness, most of those agents are controlled substances.
We were very pleased that the FDA found the results of the CONCERT trial compelling in order to award us Breakthrough Therapy designation, and also we're very pleased that the data are strong enough that they can be used to support the filing of an NDA, along with a single phase III trial. With regards to scheduling, we do not expect AXS-12 to be scheduled, and that is based upon the extensive clinical experience with the product. 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. Those data do not show signs of abuse potential or withdrawal. 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 Suneja from Guggenheim Partners. Your line is open.
Hey, guys. Just a couple 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 powering assumption both for cataplexy and EDS and what you are thinking about? I think Adam has shown somewhere around 12 - 14 attacks per week improvement over placebo. Is that how you are thinking of powering? That's one part of the question. The second is, you mentioned the foundational therapy. What are you hearing from KOLs, like, what level of improvement do you need to show for you to become a foundational therapy?
Yeah. Well, thanks for the questions. 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 the CONCERT trial. In that study, with regards to cataplexy, we were able to show an effect that was highly statistically significant. At week one, P value was less than 0.001, and at week two, the P value was 0.002, and that was with 21 patients using a crossover design. That would translate to roughly 21 patients per treatment arm if this were a parallel group design. Now, that's not necessarily precisely predictive, but certainly it gives us a comfort that there is a large treatment effect here.
We'll certainly be looking at that data very closely as we power our phase III trials. With regards to your question around foundational therapy and what level of effect we would be looking for to support that. The reason why we say that this could be foundational therapy is that if you look at the symptoms that AXS-12 improved in our CONCERT trial, these are some of the key symptoms in narcolepsy. There was a profound effect on cataplexy. That's one. There was also a profound effect on excessive daytime sleepiness, and we measured that using more than one measure, so the Epworth Sleepiness Scale, as well as a number of inadvertent naps. Something which is not usually measured or assessed, but which affects patients with narcolepsy profoundly, is the ability to concentrate.
This is a symptom which patients feel all the time as a result of their narcolepsy. AXS-12 did show a very significant effect on the ability to concentrate, that is, improving the ability to concentrate. Lastly, if you look at several sleep-related measures such as quality of sleep, nighttime awakenings, sleep arousal episodes, and hypnagogic hallucinations, those were also all positively affected by AXS-12. 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 comparison, of course, but it is instructive to look at the historically reported magnitudes of effect. Those are the aspects of the data which support that AXS-12 could be foundational therapy should we replicate these results in the phase III trial.
Got it. Just one more question from me. Can you remind the IP and anything you're doing on the European front for narcolepsy? Thank you.
AXS-12 is a new chemical entity, so it does have NCE status in the U.S. We also have Orphan Designation. It has been granted Orphan Drug Designation, so that's seven years of exclusivity from launch. In addition, Axsome has filed and is prosecuting patent applications which would significantly extend the runway. In Europe, we are not developing it in Europe.
Thank you.
Your next question will come from Myles Minter from William Blair. Your line is open.
Hey, guys. Just wondering whether the regulators made any specific comments about enrolling patients that may not be naïve to XYREM treatment, or now that we've seen WAKIX 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.
Myles, that has not been an issue that has come up and that was not an issue in the enrollment also of the CONCERT trial.
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?
We'll certainly be looking at those sites, and that's what we've done historically. The experience in enrolling one study, we always try to use in selecting our sites for the next study. I would anticipate that there would be at least some overlap.
Final one from me. Do you have a handle on how many type one narcoleptics out there are also comorbid with depression, just given the mechanism of action of AXS-12?
About 57%-60%.
Beautiful. Thanks for the questions.
Thank you.
Your next question will come from Joon Lee from Truist Securities. Your line is open.
Oh, hi. Thanks for taking my question. Do you have any plans to do any real-world studies similar to what you did for INTERCEPT or migraine to support commercialization? What do you think will be the key differentiator? I know safety is one. Do you also hope to differentiate on efficacy? How do you hope to position it commercially?
Yes. A couple of questions there. With regards to real-world studies, yeah, 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. 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. That is true. Just to be clear, one of the key points of differentiation of AXS-12 is around the efficacy which we've seen thus far, and its efficacy across the full range of the important symptoms that affect patients with narcolepsy.
Great. Just a follow-up question. In your phase II, what percentage of the patients were oxybate-experienced versus naive?
There were certainly patients who were oxybate experienced. We can get back to you with that exact percentage. I don't know if Cedric knows off the top of his head.
There's not.
There weren't any material difference in response based on those experienced versus naive. Is that fair to assume? We'll confirm that, but we do believe that is the case.
Great. Thank you.
Your final question for today will come from Matthew 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-12 could fit into the treatment continuum and where you see it playing a role. Do you think it will be, I guess, as a frontline treatment or, given that a large percentage of patients don't tolerate sodium oxybate, would it be after the use of sodium oxybate for the treatment of narcolepsy, cataplexy?
Thanks, Matt, for the question. With regards to where it would fit in the treatment paradigm, based on the clinical data thus far and the clinical profile of AXS-12, we think that it could be foundational therapy for patients with narcolepsy. You did mention patients who may have been treated with oxybate. The reality of it is that the current number of patients who are treated with oxybate represent a very small percentage of the total number of narcoleptics that are out there currently. 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 are on sodium oxybate is about 14,000 or so. That would imply around 7% penetration. What that means, I think to your point is, there are a lot of patients out there who are in need of treatment.
What's nice about AXS-12, 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 and abuse-related issues that are currently seen with the oxybate products. However, again, that is not how we plan to compete in the marketplace. 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. That is our goal here as a company. 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.
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. At least we know thus far, we've shown that is also improved with AXS-12. A lot of different ways that we can help to address the unmet medical need in this relatively large orphan condition which is underserved.
Great. Thanks so much for the added color.
That brings us to the end of our Q&A session. I turn the call back over to Herriot Tabuteau for closing remarks.
Well, thank you all for joining Axsome's conference call this morning. We are excited about the development of AXS-12 in the treatment of narcolepsy. Axsome is committed to advancing the development and commercialization of all our strong late-stage CNS product candidates, which now number four across six 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.