Good morning, ladies and gentlemen, welcome to Axsome Therapeutics' conference call. Currently, all participants are in a listen-only mode. We will be facilitating a question and answer session towards the end of today's call, 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, Mr. Mark Jacobson, Senior Vice President of Operations at Axsome Therapeutics. Please go ahead.
Thank you, operator. Good morning, everyone, thank you for joining us on today's conference call to discuss the positive top-line results from the CONCERT Phase II trial of AXS-12 in patients with narcolepsy. A press release announcing that AXS-12 achieved the primary endpoint in the trial crossed the wire a short time ago and is available on our website at axsome.com. 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 investigational agents, our clinical and non-clinical plans, our plans to present or report additional data, the anticipated conduct and the source of future clinical trials, regulatory plans, future research and development, and possible intended use of cash and investments.
These forward-looking statements are based on current information, assumptions, and expectations that are subject to change and involve risks and uncertainties that may cause actual results to differ materially from those contained in the forward-looking statements. These and other risks are described in our periodic filings made with the Securities and Exchange Commission, including our quarterly and annual reports. You are cautioned not to place undue reliance on these forward-looking statements, which are only made as of today's date, and the company disclaims any obligation to update such statements. Joining me on the call today from Axsome's management team are Dr. Herriot Tabuteau, Chief Executive Officer, Dr. Cedric O'Gorman, Senior Vice President of Clinical Development and Medical Affairs, Mr. Nick Pizzie, Chief Financial Officer, and Mr. Dave Marek, Chief Commercial Officer.
On today's call, Herriot will provide an overview of today's announcement before turning the call over to Cedric, who will review in greater detail the top-line results of the CONCERT clinical trial. Following Cedric's presentation, we will open the line for Q&A. Following the Q&A session, Herriot will provide some concluding remarks. I shall now turn the call over to Herriot.
Thank you, Mark. Good morning, everyone, and thank you for joining us today on today's call. Earlier this morning, we announced that AXS-12, Axsome's novel oral investigational medicine for the treatment of narcolepsy, met the pre-specified primary endpoint and rapidly reduced the frequency of cataplexy attacks in patients with narcolepsy as compared to placebo in the CONCERT Phase II trial. The effect was highly statistically significant with a P value of less than 0.001. CONCERT was a Phase II randomized, double-blind, placebo-controlled, crossover, multi-center U.S. trial in which 21 patients with a diagnosis of narcolepsy with cataplexy were all treated with AXS-12 for two weeks and with placebo for two weeks, with the treatment period separated by one week of down titration and washout.
In addition to its effects on the frequency of cataplexy symptoms, AXS-12 in this study also significantly reduced excessive daytime sleepiness, assessed by the Epworth Sleepiness Scale and by the frequency of inadvertent naps or sleep attacks as compared to placebo. AXS-12 also resulted in statistically significant improvements in cognitive function. The improvement in the ability to concentrate with AXS-12 is especially relevant because the cognitive impairment associated with narcolepsy is one of the most distressing aspects of the disease for patients, as highlighted in the FDA's The Voice of the Patient Report on Narcolepsy. Finally, AXS-12 treatment resulted in improvements in sleep quality and sleep-related symptoms as compared to placebo. The beneficial effects of AXS-12 were rapid, being observed as early as week one. Overall, AXS-12 produced substantial improvements as compared to placebo on all symptoms of narcolepsy assessed in the CONCERT trial, reaching statistical significance on most.
AXS-12 was safe and well-tolerated, with no reported serious adverse events and no discontinuations due to adverse events. These positive results support initiation of Phase III trials for AXS-12 in narcolepsy, which we anticipate in 2020. Based on the clinical profile observed in this trial, we believe that AXS-12 could be a candidate as foundational therapy to meaningfully improve the lives of many people with narcolepsy. Narcolepsy is a chronic, debilitating neurological condition characterized by excessive daytime sleepiness, or EDS, and cataplexy. Cataplexy is a sudden reduction or loss of muscle tone while a patient is awake, triggered by strong emotions. Cataplexy is seen in about 70% of narcoleptics. Other symptoms of narcolepsy include disrupted nighttime sleep paralysis, and hypnagogic hallucinations. Narcolepsy is an orphan condition that affects nearly 200,000 patients in the U.S.
Existing treatment options are 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 EDS. There is therefore an urgent need for new treatments for patients, which address the unmet needs of patients and the limitations of current agents. Narcolepsy is caused by a loss of hypocretin neurons in the brain. Hypocretin neurons normally excite norepinephrine neurons, which promote wakefulness and help maintain muscle tone. Hypocretin loss leads to dysregulation of norepinephrine neurons, resulting in excessive daytime sleepiness and loss of muscle tone or cataplexy. AXS-12 improves norepinephrine regulation of signaling to affect the symptoms of narcolepsy. AXS-12 consists of reboxetine, a potent and highly selective norepinephrine reuptake inhibitor. It is orally administered, dosed during the day, has a well-characterized safety and tolerability profile, and is not expected to be scheduled.
AXS-12 has been granted U.S. FDA orphan drug designation for the treatment of narcolepsy. I would now like to turn the call over to Cedric, who will review the CONCERT top-line results in greater detail.
Thank you, Herriot. The CONCERT, or Clinical Outcomes in Narcolepsy and Cataplexy: An Evaluation of Reboxetine Treatment study, was a phase II double-blind, randomized, placebo-controlled, cross-over, multi-center trial of AXS-12 in patients with narcolepsy. A total of 21 patients with a diagnosis of narcolepsy and exhibiting clinically significant symptoms of both cataplexy and excessive daytime sleepiness were treated for two weeks with AXS-12 or with placebo, followed by a crossover to the other treatment after a one-week down-titration and washout period. Patients were dosed twice daily with a total daily dose of eight milligrams in the first week, which was escalated to 10 milligrams for the second week. Patients were randomized in a one-to-one ratio to either receive treatment with AXS-12 followed by placebo, sequence one, or to treatment with placebo followed by AXS-12, sequence two.
The pre-specified primary endpoint was the change in the weekly number of cataplexy attacks averaged over the two-week treatment period for overall treatment effect. Secondary endpoints included changes in excessive daytime sleepiness, or EDS, as measured by the Epworth Sleepiness Scale and the number of inadvertent naps or sleep attacks. Cognitive function is assessed by the ability to concentrate item on the patient-reported Narcolepsy Symptom Assessment Questionnaire, or NSAQ, and other important symptoms of narcolepsy, including sleep quality and sleep-related symptoms as measured by the NSAQ. Assessments were recorded daily using an electronic diary. Because of the crossover design, this study was effectively powered like an approximately 40-patient trial, since approximately 20 patients were treated with AXS-12 and the same number was treated with placebo. Here are the baseline demographics and clinical characteristics for the study population. The mean age was 32.6 years.
The mean time since narcolepsy diagnosis was 3.8 years. The average number of weekly cataplexy attacks at baseline was 30, or more than four attacks per day on average, reflecting a narcolepsy population with significantly impactful rates of cataplexy. The mean baseline score on the Epworth Sleepiness Scale was 18, reflecting moderate and severe EDS. With regards to cognitive function, all patients rated their ability to concentrate as very poor, or average. Taken in totality, the measures of cataplexy, sleepiness, and the ability to concentrate describe a narcolepsy patient population with significant disease burden. On the pre-specified primary outcome measure, AXS-12 demonstrated a statistically significant reduction from baseline in the mean weekly number of cataplexy attacks, averaged for the two-week treatment period for overall treatment effect, for a reduction of 13 attacks for AXS-12 as compared to 0.3 attacks for placebo, with a p-value of less than 0.001.
The mean reduction in cataplexy attacks with AXS-12 was statistically significant versus placebo as early as week one, the first time point analyzed, and maintained at week two. This highlights the rapid and significant reduction of cataplexy with AXS-12. When we look at response rates for patients who experienced a 50% or greater improvement in the weekly number of cataplexy attacks, at week two, 76% of patients were responders when treated with AXS-12 versus 30% of patients with placebo, with a p-value of 0.003. Looking at an even higher threshold for response, namely a 75% or more reduction in the weekly number of cataplexy attacks, at week two, 42.9% of patients were responders with AXS-12 versus 10% with placebo, which was statistically significant with a p-value of 0.018.
Assessing the effect on excessive daytime sleepiness, as measured by the Epworth Sleepiness Scale. From a baseline score of 18.1, reflecting moderate and severe daytime sleepiness, treatment with AXS-12 resulted in a clinically meaningful and statistically greater improvement as compared to placebo in excessive daytime sleepiness, with a reduction of six points as compared to a reduction of 3.1 points with placebo after two weeks of treatment, with a p-value of 0.003. When we assessed effect on excessive daytime sleepiness in terms of the reduction in the number of inadvertent naps or sleep attacks, AXS-12 treatment resulted in a statistically significantly greater reduction in the number of inadvertent naps and sleep attacks as compared to placebo, with a 31.8% reduction with AXS-12 versus a 5.3% reduction with placebo at week two, with a p-value of less than 0.001.
Now looking at responder rates for improvement in excessive daytime sleepiness with a response defined as a 50% or greater reduction in the number of inadvertent naps or sleep attacks. At week two, a significantly greater proportion of patients treated with AXS-12 as compared to placebo, 38.1% versus 10%, had achieved a response with a p-value of 0.036. In the CONCERT trial, we assessed cognitive function using the ability to concentrate item of the Narcolepsy Symptom Assessment Questionnaire, which was assessed daily. For this assessment, patients rated their ability to concentrate on a five-point scale ranging from one for very good to five for very poor. 0%, that is, none of the patients in our study, rated their ability to concentrate as good or better at study entry.
Treatment with AXS-12 resulted in a statistically significantly greater improvement in the ability to concentrate compared to placebo as early as week 1, with a p-value of 0.007, and this improvement increased at week 2 with a p-value of 0.002. Furthermore, at the end of the first week of treatment, 38% of patients had a weekly average ability to concentrate that was good to very good with AXS-12 treatment, compared to 15% of patients with placebo and 0% of patients at baseline. At week 2, these percentages increased to 43% for AXS-12 and 25% for placebo. Moving now to sleep quality and other sleep-related outcome measures, AXS-12 demonstrated important benefits on these core symptoms of narcolepsy, as measured using the Narcolepsy Symptom Assessment Questionnaire. 45% of patients reported improved sleep quality with AXS-12 treatment, versus only 5% of patients with placebo, with a p-value equal to 0.007.
30% of patients reported a reduction in the number of awakenings at night with AXS-12 treatment, versus only 5% of patients with placebo, with a p-value equal to 0.044. AXS-12 treatment also resulted in greater proportions of patients with reductions in sleep paralysis episodes and in hypnagogic hallucinations as compared to placebo. In this study, AXS-12 was safe and well-tolerated. There were no serious adverse events, and there were no discontinuations due to adverse events. The most commonly reported adverse events in the AXS-12 treatment arm were anxiety, constipation, and insomnia. In summary, in the CONCERT trial, AXS-12 met the pre-specified primary endpoint, demonstrating a statistically significantly greater reduction from baseline in the frequency of cataplexy attacks and demonstrated statistically significant reductions in excessive daytime sleepiness.
Beyond the improvements in cataplexy and excessive daytime sleepiness, AXS-12 also demonstrated meaningful improvements in the ability to concentrate, in sleep quality, and other sleep-related symptoms. AXS-12 was safe and well-tolerated in the study, with no serious adverse events and no discontinuations due to adverse events. We would like to thank the patients, the investigators, and the clinical site staff who collaborated with Axsome in the completion of this study as we strive to further the clinical development of AXS-12 in the hopes of bringing to patients a novel, well-tolerated therapeutic agent with the potential to effectively address several symptoms of narcolepsy. With that, I will hand the call back over to Ariel.
Thank you, Cedric. I would like to hand it back to the operator to open the line for questions.
Thank you. Ladies and gentlemen, at this time, if you'd like to ask a question, you will need to press star one on your telephone. To withdraw your question, press the pound or hash key. Please stand by while we compile the Q&A roster. Your first question here comes from the line of Marc Goodman with SVB Leerink. Please go ahead. Your line is now open.
Yes, good morning. A couple things. First of all.
The plan for phase III is to do multiple studies at first, or are you going to do one study? Just so we're clear, are you going to be going after both endpoints, cataplexy and EDS? Remind us also of the IP around this product and how we should be thinking about that. Maybe you could just give us a sense of how you think about the data relative to the products that are on the market right now. Thanks.
Thank you, Marc, for the questions. With regards to phase III, we do intend to move as quickly as possible into phase III trials. With the AXS-12, we would anticipate two studies, two registration trials. This is typical to get a product approved, we would anticipate launching those two studies simultaneously. With regards to the intellectual property, as a reminder, we have been granted orphan drug designation for AXS-12 for the treatment of narcolepsy. That's a minimum of seven years of protection. There's also NCE protection for AXS-12. In addition to that, we have filed patent applications, and obviously, should those patents issue, that would significantly extend the runway for the product.
You're pursuing both EDS and cataplexy endpoints?
Yes, we are. One of the things that we really like about the data is that it shows that the AXS-12 in this trial addressed both of the key symptoms of narcolepsy. That is both cataplexy and EDS. Related to that, you mentioned the other part of your question had to do with how we view AXS-12 with regards to the treatment landscape. What's nice about these data is that they do show that the effects on cataplexy and on EDS are very strong. The drug is also very well-tolerated. As a reminder, there is currently only one product that is approved to treat both cataplexy and EDS. We also like the fact that the data indicate that in addition to cataplexy and EDS, that sleep quality is improved.
We're also very glad to see that the drug also has a positive cognitive effect. Therefore, we think that there's no reason why, if AXS-12 is positive in phase III trials and the data are replicated, that it could not be a candidate for foundational therapy in narcolepsy.
The dosing in the phase III, what are you planning?
We would anticipate similar dosing in terms of total daily dose. The way that this trial was designed, during the first week, patients were dosed at eight milligrams. Even with that dose, there was a significant effect. In the second week, they were escalated to 10 milligrams. We would expect similar dosing in the phase III trials.
Thanks.
Your next question comes from the line of Charles Duncan with Cantor. Please go ahead. Your line is now open.
Good morning, Ariel and Cedric. Congratulations on the data. Lots of data that you shared. Really appreciate that. Wanted to ask you a little bit about the patient population and the treatment duration in this study, especially as it relates to the next steps or phase III. How would you characterize this particular patient population? You mentioned them as being fairly highly burdened, but do you think that the sample is representative of the overall population of patients with narcolepsy?
Thanks, Charles. I'll let Cedric answer that.
Thanks, Charles. Absolutely. The patient population, both in terms of their baseline sleepiness scale as measured by the Epworth Sleepiness Scale of a mean of 18 points, is very much in keeping with the baseline level of severity for patient populations for which narcolepsy treatments have been tested. That also applies then in terms of the cataplexy rates at baseline. In fact, in our study, the cataplexy rates, when you look at some of the trials that have been run with other agents, are on the higher side. We've definitely looked at a population that is burdened by cataplexy. In addition to that, given that they also had cognitive deficits, with the fact that no patients at baseline were reporting anything better than average ability to concentrate, and we also improved that.
One interesting difference is that our trial was over a shorter period of time, a two-week treatment period. It's also nice to have seen the effects demonstrated in that short period of time on all important core symptoms of narcolepsy, namely excessive daytime sleepiness, rates of cataplexy. Cognitive ability is measured by the ability to concentrate, other key symptoms of narcolepsy, sleep quality, and sleep-related symptoms like the hypnagogic hallucinations and sleep paralysis episodes, and number of awakenings at night.
As a follow-up to that question and the previous set of questions by Marc, for phase III, excuse me, what would you anticipate the treatment duration to be? Could you lay out a little bit more details on anticipated design of those studies?
Hello. Yeah. We're still digesting the data, obviously, one of the things that we like to do is to look at the data from prior trials very carefully, in this case, our phase II trial, to inform the design of the phase III trial. Just to give you a sense, we have not finalized any of this yet, registration trials in this disorder have been on the order of about four weeks in duration. That should help you think about the duration of the trial. A four-week trial or five-week trial. In terms of the sizing of the study.
Slightly bigger.
Yeah. Cedric is saying slightly bigger, look, when we run our registration trial, we'll make sure that it is very well-powered. What's nice is we're seeing definitely a large effect here with a small number of patients. That, I think, gives us a lot of room with regards to a powering of the trial such that it is manageable but still yields the results and the data that we would hope to generate for a registration package.
Yeah, the effect sizes are pretty notable here and should be capital efficient. Last question is, could you anticipate fully starting both trials in 2020? Would that be your goal?
That is our anticipation.
Okay. Good deal. Thanks for taking my questions this morning.
Thank you.
Your next question comes from the line of Joon Lee with SunTrust. Please go ahead. Your line is now open.
Hi. Thanks for taking my questions and congrats on the results. Could you remind us what the dose is that's used in Europe for depression and what you use as compared to what you use in the phase II CONCERT trial and other follow-ups?
The doses that are used in Europe for depression are in the range of what we studied in the CONCERT trial.
Okay. You said that the safety was clean, so you expect the scheduling to be not an issue. Would you also say that the mechanism of action are sufficiently differentiated from modafinil and XYREM to warrant it not being scheduled?
Yeah. Right now, our anticipation is that AXS-12 would not be scheduled. As you pointed out, it is approved in Europe, and it's not scheduled there. So far in the data and based on the mechanism of action, we would not expect it to be scheduled.
Great. The last question is, could you remind us what the baseline was for cataplexy and for excessive daytime sleepiness?
Absolutely. The mean baseline weekly cataplexy attacks were 30. That's on average more than four cataplexy attacks a day. In terms of the excessive daytime sleepiness, the baseline score was 18.1, which again reflects a moderate to severely afflicted population with excessive daytime sleepiness.
Great. Thank you.
Your next question comes from the line of Yatin Suneja with Guggenheim Partners. Please go ahead. Your line is now open.
Hi. Good morning, everyone, congrats on the results. Just a few questions on the baseline. Can you just comment on or help us understand the baseline scores a little bit better? It seems like the average cataplexy attacks at baseline was 30 for you. For XYREM, it is about 20-24. Does that mean these patients are really, truly refractory, harder to treat, or the higher baseline gives you a better chance to show a larger delta?
Well, first of all, thanks for the question. You want to make sure that patients have a level of cataplexy attacks which demonstrates that they are impacted by their symptoms and that they would need treatment for their symptoms. Certainly, the numbers you cited sound about right. We certainly wanted to make sure that we had a population of patients who had cataplexy attacks that had also been studied for agents that have shown efficacy. As we mentioned before, there's only one agent that has the approval for both cataplexy and excessive daytime sleepiness. In terms of baseline, we want to make sure that we were recruiting a population of patients that were moderate to severely afflicted by both of these key symptoms of narcolepsy, the cataplexy, and we got that as demonstrated by the baseline level of 30 on average cataplexy attacks per week.
Also in terms of a mean baseline score of 18 on the Epworth Sleepiness Scale. Again, right there on the cusp of moderate to severe excessive daytime sleepiness.
Got it. Just two more follow-up. With regard to the phase III program, is it fair to assume this is the type of patient population you would like to recruit? That's one part of it. The other part is that most likely it's going to be a little bit more extended or more longer in duration. Any potential safety issues that you could think of? With more extended use, do you anticipate the efficacy to sort of improve a little bit more? Just finally, if you can also talk about the market opportunity. I mean, the pricing in narcolepsy is a little bit different, more orphan type pricing than some of the other programs that you are running. Just help us frame the market opportunity also. Thank you.
Sure. Thanks for the questions. I'll let Cedric respond to the question around the phase III design and the population that we're looking for. With regards to the safety, what's nice about AXS-12 is that reboxetine is a very well-characterized agent, and it has been used for long periods of time. We don't expect any safety issues, any new safety concerns. The drug was incredibly well-tolerated in our trial. We had zero discontinuations due to adverse events. We're pretty proud of that. I'll let Cedric answer the phase III population question and then Dave Marek will talk about the market opportunity.
I think the answer is pretty short, really, just to say yes, exactly. It's the same population, the same degree of severity we will pursue in phase III. As you know, only one agent has an approval for cataplexy. The population that we're pursuing, both in the phase II and in the planned phase III, are comparable. That's the answer to that part. Dave?
Yeah, thank you for joining us this morning. Regarding the market opportunity, in short, we believe that this could be very significant. The first way we typically look at the market potential is to look at the impact on patients' lives. Given the very strong efficacy findings for both cataplexy, EDS symptoms, and the other endpoints Cedric mentioned earlier, if the phase III replicates what we see in CONCERT, we believe that this could have a tremendous benefit to a high number of patients with narcolepsy, both with and without cataplexy. Given there's about 200,000 people with narcolepsy in the U.S., we believe, as Ariel mentioned earlier, that this could be foundational therapy for a good number of patients. As we progress through the development program, of course, we'll fine-tune the commercial strategies to assess the likely patient and revenue forecast.
You asked a question regarding pricing. It's premature for us to really specify where our price would be. However, we would certainly consider the clinical benefit and the corresponding economic value of AXS-12 while we also look at the marketplace environment. What we would do is engage payers ahead of time to ensure that we find a price that we believe would provide fair and timely access for patients while rewarding innovation with what we believe would be a potentially superior profile to other market options.
Got it. Thank you very much.
Your next question comes from the line of Ram Selvaraju with H.C. Wainwright. Please go ahead. Your line is now open.
Thanks very much for taking my questions. Just a few quick ones. Firstly, can you comment on what you expect the timing to be of a formal end of phase II meeting with the FDA for this product candidate? In relation to that, also, whether or not you would specifically seek to obtain a special protocol assessment from the FDA for the phase III program. Wanted to ask about the duration of treatment effect that would likely be viewed as clinically meaningful by regulators in the phase III context, if you've had any initial indications from them on what their opinion might be on that front. Then two other questions that are market related. One is with respect to the scheduling. Let's assume that reboxetine winds up not being scheduled. Do you foresee that the only potential rival in the narcolepsy indication would potentially be pitolisant?
If so, what specifically do you anticipate are likely to be the edges that reboxetine might hold over pitolisant? Finally, from a market standpoint, can you give us a sense of how you draw the distinction between narcolepsy and excessive daytime sleepiness, or if you view those as basically being the same thing? Also, if you view reboxetine as potentially having a commercial opportunity at all in jet lag. Thank you.
Okay. Thank you for the multi-part question. With regards to the timing of an end-of-phase II meeting, we would be looking to meet with the FDA as soon as practicable. As you know, we've got a lot going on. We're fortunate to have a broad pipeline. There's a lot remaining between now and the end of the year, as I'm sure you're aware. We have a lot to do, but having said that, we are planning ahead and we will not be specific as to the exact timing of a meeting. We first have to request a meeting. You can imagine that we'd want to do that expeditiously. With regards to an SPA for our phase III trials, we will consider the benefits of an SPA. We don't think that it's necessary in every instance.
That's something that we will consider, obviously, especially after we meet with the FDA during an end-of-phase II meeting. In terms of the duration of effect which would be needed or required by regulators, we do know that registration trials for some of the currently approved products were of a duration of treatment similar to what we are contemplating for our planned phase III trials. I don't think that there are any surprises there. The other thing too is we did announce last year when we announced the AXS-12 product candidate that we had met with the FDA. During that meeting, we did get pretty specific guidance and feedback on the planned duration of our trial, and so we feel pretty comfortable with the timeframe that we're looking at for dosing.
Your next question had to do with how we would compare ourselves, I guess, to pitolisant, assuming that our product is not scheduled. I think what we can say is what we see in the product label for pitolisant. pitolisant is approved only to treat excessive daytime sleepiness. What we saw, though, in the CONCERT trial with AXS-12, is that we saw an effect that was robust, not only on excessive daytime sleepiness but also on cataplexy, two of the core symptoms. I would also point out that while we're focused on those two endpoints in the questioning so far, what's exciting about AXS-12 is that it also showed a benefit on numerous other symptoms. In fact, every single symptom of narcolepsy that we assessed there was a clear benefit.
For example, in terms of improvement in the quality of sleep, only about 5% of placebo-treated patients reported an improvement compared to about 45% of AXS-12 patients. It's still early days for us in terms of really looking at the data and delving into it. We tried to provide as much as we could in a very short period of time when we had 48 hours really to look through the data. So far what we're seeing would point to a very favorable profile versus currently approved drugs.
With respect to the distinction between narcolepsy and daytime sleepiness from a market perspective as well as the potential opportunity in jet lag, and I was hoping that maybe you could comment on that also specifically within the context of potential pricing paradigms that you might employ.
If I understand the question correctly, I think you're pointing out that excessive daytime sleepiness is seen not just in the narcolepsy population, but in other broader populations. Which is true. Right now, we are focused on the narcolepsy opportunity. That is the condition that we study the AXS-12 in. We're looking to move forward with that indication. Certainly, drugs which improve wakefulness may have a role also in jet lag or other medical conditions. Right now, we're focusing on the data that we have in hand in the indication that we studied in. With regards to pricing power, as Dave mentioned, certainly we would look to the price, the product based on the value that the product provides, while ensuring access to the product for patients. It's still early days on that front.
What we'd look to do is to try and replicate the findings of the phase II trial in phase III, as we think about pricing. Certainly, as you're aware, the current pricing for products that are approved for this indication would leave significant opportunity.
Then just curious about one aspect of the safety profile. The press release mentioned constipation. Was this known to be a potential side effect with reboxetine in the European real-world usage setting? If so, it didn't seem to be particularly severe, doubtless was well-controlled, but wanted to know what you believe the mechanism is underlying that. Thanks.
Well, this is Cedric here. One of the nice things about AXS-12, about reboxetine, in terms of its selectivity for norepinephrine receptors is that it tends not to hit off-target receptors and therefore actually has a reduction, has less side effect profile. Now, constipation does occur, and it has been characterized in terms of use of reboxetine. That's well-characterized previously, so yeah.
Yeah. The other thing that we would add to that is we reported obviously the most common adverse events, but the overall rate was relatively low and very similar to placebo. Importantly, the rate of discontinuation in this trial was virtually nil. I think only one person discontinued, and that was not due to an adverse event. We're pretty pleased with the product profile.
Okay, one last item is whether or not at this juncture you expect to need a distinct sales force to market this drug, or if you feel that a specialty neurology-focused sales force would easily and tacitly be equipped to market this drug alongside your other drug candidates? Thank you.
Hi, it's Dave, and thanks for the question regarding the sales force. I think we have a little bit of time here to understand not only what the ultimate profile would be for AXS-12, but the rest of the portfolio. We would ensure that we have a sales force that would maximize the opportunity for AXS-12 in this indication. We would also do it with an eye towards driving efficiencies across our entire commercial portfolio. As we see other programs advance, we would look at any synergies that we could glean across the portfolio to make sure that we're both highly effective, but also highly efficient in our promotional efforts, not only with sales force, but with non-personal promotion as well.
Our next question here comes from the line of Bert Hazlett with BTIG. Please go ahead, your line is now open.
Thanks. I have a couple. Congratulations on the data, first and foremost, but could you remind us, are there delivery technologies embedded in AXS-12? Anything to modify the PK?
Thanks for the question, Bert. Part of the patent applications that we have filed would be around the delivery.
Okay, that moves right into the other comments on patents that I had the questions. Could you just discuss the status? Do you have notice of allowance? Are these use patents? Just a little bit more on the general patenting strategy would be helpful.
Thanks for the question, Bert. We have filed several patent applications, and those patent applications would cover various aspects of AXS-12. As I mentioned, one set of patents that we are looking at to prosecute would be around the formulation. Other patents would also be around the method of use.
Just one or two quick ones. I think you mentioned eight milligrams and 10 milligrams. Have you decided on one of those doses to move into phase III? As you see a longer use in phase III, would you expect any CV AEs like tachycardia or anything to manifest themselves in a phase III study? Thanks. That's all for me.
With regards to the AE profile, reboxetine is very well characterized. It is very safe. We do not anticipate any cardiovascular signals. That remains to be seen. That's why you do clinical trials. What's nice is we know that the drug is incredibly safe with long-term use.
And the dosing-
With regards to the dosing in our planned phase III trials, it's still early days with regards to looking at the data. We wanted to look at the data and really understand it. Certainly, I think we've identified an effective dosing range. What we'd like to tease out is the lower dose which we gave during the first week and was titrated to the higher dose during the second week, how effective that is. What's nice is that both doses were very well-tolerated. That gives us a lot of leeway to maximize efficacy.
Agreed. Congratulations on the data again. Thank you.
Thank you.
Your next question comes from the line of Myles Minter with William Blair. Please go ahead. Your line is now open.
Hi, guys. Congrats on the data. Looks great. I was just wondering whether you can help put the rapidity of effect into context relative to currently approved therapies. I know you only measured one week out after treatment commencement, did you hear any anecdotal evidence from the patients when they came in for a visit that efficacy may have been brought forward from that time point? Just curious on, I think it's one patient that dropped out of sequence one in your trial. Just wondering whether that was due to adverse effects that was in the dose titration portion, or whether they switched back to placebo and just dropped out for efficacy reasons.
Then maybe one for Dave, just curious as to whether there's any broader sort of off-label usage of the SNRI class in maybe patients that have failed XYREM efficacy, and whether there's any learnings from that from the clinical side. Thanks, guys. That's it from me.
Thanks, Myles. With regards to the onset of action, we will look through our data to see how fast the onset of action was. We are able to look at that information. Certainly, the onset of action was very rapid and certainly at least at one week, there was a measurable effect. With regards to the onset of action of other agents that are on the market, I don't know if there are data at less than one week for some of the other currently marketed agents. We don't want to give you an inaccurate answer right now. The patient who did drop out, so that patient was just lost to follow-up. That was not a discontinuation due to any adverse event. With regards to SNRIs that are used off-label, what's nice about AXS-12 is that it addresses numerous symptoms.
Some of the SNRIs and the SSRIs that are used off label may be used for one symptom of narcolepsy, and that leads to polypharmacy, of course. With AXS-12, we have shown that for every symptom of narcolepsy that we assessed, there was a significant effect.
Cool. Thanks for the questions. Congrats.
Thank you.
Your last question here comes from the line of Matt Kaplan with Ladenburg Thalmann. Please go ahead. Your line is now open.
Hey, guys. Thanks for taking the questions, and congrats on the results. I guess one question, narcolepsy, what % of patients suffer from both EDS and cataplexy?
Well, if you look across narcolepsy, we see that up to 70% of patients that have narcolepsy also have cataplexy associated.
Okay. That's helpful. I guess, given the current treatment landscape, I guess specifically XYREM being the only drug approved to treat both symptoms and the cumbersomeness associated with using that drug, you have to dose it in the middle of the night, once before you go to bed and once in the middle of the night. It seems to me, with respect to the data that you gave us, that only 25% of patients of the 50% diagnosed are receiving treatment. It seems to me that there remains a significant unmet need in this patient population. Have you done any market analysis with respect to how you think with this product profile, if approved, will be used given the current treatment landscape?
Well, I think, with just receiving the data, many times what we would do is put the data in front in terms of a product profile to get a more specific kind of willingness to prescribe and willingness to use. We don't have those kind of results, given the fact that we're just analyzing the clinical data now. However, the way you characterize it, I think, is accurate. We look at narcolepsy with a significant disability. It's an incurable neurological disorder, and when you look at the current treatment options, we know that there is still significant unmet treatment need in the marketplace today.
We would certainly anticipate, as Herriot said earlier, if we can replicate the phase III data consistent with CONCERT, there's really no reason we can see at this point why this wouldn't be considered as a first-line or foundational therapy for a sizable portion of those patients.
Thanks, Dave. Brass again, guys.
Thank you.
There are no further questions. I will now turn the call back over to Mr. Mark Jacobson for closing remarks.
This is Herriot Tabuteau. Thank you all for joining us on the call. We're excited by the results of the CONCERT trial, and we're especially excited by what they potentially mean for narcolepsy patients who are living with this debilitating disease. I would also like to thank again the patients and the investigators, and especially our Axsome team. Our team has worked very hard to generate these important data, and we're looking forward to continuing to update you on our progress with the AXS-12 program. We also look forward to the remainder of the year, which will continue to be a busy time for us, as we're still expecting top-line results from our phase III trials with AXS-05 in major depressive disorder and with AXS-07 in the acute treatment of migraines. Thank you, and we look forward to speaking with you again throughout the month of December.
Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.