quickly.
Thank you.
Back to back is a challenge, as anyone knows. We now have Dr. Herriot Tabuteau, who's actually the more interesting guy to speak to. Welcome to the second day of the Cantor Global Healthcare Conference. My name's Charles Duncan. I'm a senior managing, or a senior, biotech analyst here. Some people would say the most senior biotech analyst. I cover neuro-innovators broadly, and I have to tell you that I've really been fascinated to watch Axsome evolve over the course of several years. Herriot was an investor, and I remember, you know, pitching stocks to you, and you always had very good questions. And then you became involved in Axsome, and have gone from a development stage company to a full-line revenue generator, which has a very novel antidepressant drug. Herriot, thank you for joining us.
Great to see you.
Yeah, great to see you, too. Thanks for having us.
So Herriot, I think you're gonna tell us a little bit about Axsome.
Yeah.
We'll have a seat. I might have a few questions for you. So the first kind of softball question that I've been starting these meetings with is, you know, Herriot, if you look at the last year, what your company has accomplished, what is the one thing that you are most proud of having accomplished?
I think for us, it's managing the growth. We have so many assets under development, and we also have a commercial portfolio, so it's a lot to manage. You know, we entered the first full second year of launch for Auvelity, and we're able to grow sales sequentially 29% in the second quarter versus the first quarter. So that gives you a sense of the type of growth that we're seeing, but underlying that means growth in the organization in terms of all functions to support not just the commercial operations, but also the growing and broadening portfolio of products.
So it's quite a challenge to manage that growth and do it successfully, so I'm really proud of our team to be able to so far navigate that switch from being a developmental stage company to being a successful commercial company.
That growth comes not only in terms of top line and commercial, but it also comes from the standpoint of the pipeline and the clinical opportunities that you have with the existing and future drugs. So yeah, hats off to you. Not a lot of companies can manage that growth. I know a company that still has just one very successful drug in psychosis, but not a lot of companies can go to that next stage, and you're there. So-
Yeah, we're happy.
The question that I wanted to ask you, follow on softball question, is: what is the one thing that you will be most excited to see turn, you know, the one card turn over in the next?
Well, so next year is kind of far away.
Yeah.
So let me put myself in the mindset-
Next 12 months
... of investors-
Next 12 months
... who have a shorter time horizon in terms of events. We have so many products in development, and we've been advancing this year so many important clinical trials, that we're now at the point where we will have readouts between now and the end of the year and also going into next year. So there's a lot going on. There's a lot to do. The rest of this year will be very busy, and you know, as you alluded to, we'll have readouts. So if you look at our current pipeline, we expect to have clinical trial readouts for our Alzheimer's disease agitation program.
Yeah.
So we have two pivotal trials that are currently ongoing. So that's the phase III, ACCORD-2 trial, as well as the phase III, ADVANCE-2 trial. So two different studies, both pivotal, two different designs. One is a parallel group study, the other one is a randomized withdrawal study. So we're very much looking forward to turning those cards and also getting the required patient safety database that we will need in order to be able to file that indication with the FDA. So and then-
That's with Auvelity or AXS-05 in the clinicals?
That is with the AXS-05.
Yep. Yeah.
So, you know, other important clinical trial readouts will be solriamfetol in ADHD, so that is a phase III trial. So phase III trial's always important, obviously, right? Because it's the last stage of development, and these are typically registration trials. So, and if they're positive, then they portend potential regulatory approval and access to and availability to patients. So, so those studies, obviously, we are focused on and making sure that,
That's in adult ADHD, which is not well treated, not well recognized, and that's an important TAM expander for Sunosi.
It is in adults.
Yeah.
Just as a reminder, if you look at the ADHD market, there are 17 million patients in the US. That's both adults as well as pediatric patients, so a very large market and one that is a growing market. And right now, the treatments or such that you have broadly stimulants and non-stimulant medications, each of which has an advantage. Efficacy versus tolerability.
Mm-hmm.
So, it's gonna be interesting to see what the readout is of this first multicenter trial of solriamfetol in ADHD, and we think that it has the potential to potentially fill an important need somewhere along the treatment spectrum. So we're looking forward to the clinical trial readout, to understanding the profile and its potential use in ADHD.
So you want efficacy, but not with the liabilities of being a stimulant?
You know, we know what the safety profile is-
Yeah
... of solriamfetol. It's already approved.
Approved, yeah.
It's approved. It's widely used, so the label is very clear. It's nice to go into a pivotal trial already having an established safety profile. So now, and which we think is very favorable, and clinicians would echo that. So now we're looking for its potential efficacy in ADHD.
Mm-hmm. And other readouts?
So, uh-
Paroxetine coming or-
So, in terms of
AXS-12.
Yeah, in terms of other readouts, so AXS-12, this is our product for the treatment of narcolepsy. As a reminder, we did have a readout for the phase III efficacy trial, the Symphony trial, earlier this year. So we're very happy with that readout, which was positive. And there is the ongoing long-term safety extension trial for AXS-12. That will read out also this year. Also, other readouts, we are conducting a trial of AXS-07.
Mm-hmm.
This is our migraine product, and this is a study which is being conducted in patients who have failed oral CGRPs.
Yeah.
So that study, we expect to read out also by the end of this year.
So I want you to unpack some details on a couple of the trials that you mentioned. Certainly the last one. Migraine is a space we've done a lot of work in, and you know, we've had previous debates on that, and you've recently refiled AXS-07. I also wanna come back to AXS-05, which is probably our biggest focus with regard to the pipeline. Not dismissing at all Sunosi or solriamfetol and AXS-14 and 12, et cetera. So I'm gonna ask you kind of a silly Wall Street question, sell-side question: how do you feel about Auvelity and its traction in the market? What differentiates it in your mind? What's the most important differentiator in treating depression for Auvelity?
The profile of Auvelity is that it is, first of all, a different mechanism of action. So this is an oral NMDA receptor antagonist, and a sigma-1 receptor agonist. So,
Very different than an SSRI or SNRI.
So the mechanism of action is different.
Yeah.
So based upon that, it allows clinicians now a different treatment option. The vast majority of patients are treated first line with SSRIs.
Mm-hmm.
These are agents which work primarily on monoamines, which are important, but we think that the mechanism of action of Auvelity, which has now been tried by clinicians, and they can see for themselves how patients react to it. We think that the MOA backed by the rapid onset of action-
Yep
... as well as the clean, relatively clean tolerability and safety profile-
Mm-hmm
... we think that those are important points that resonate with clinicians.
And so the rapidity of onset, is it durable? I mean, shouldn't it be used first line if that's the case?
What we've seen is, in our clinical trials, that there was a separation as early as one week.
Yeah
... and then also, at two weeks, and that was maintained throughout the entire, duration of the study. So this is a drug with an effect which is fast and which appears to last. And we've also studied the product in long-term safety studies, but we've also during those studies, we had the opportunity to also collect efficacy data, and it appears to be maintained in those trials. And what we're hearing from clinicians also is that the drug does appear to work per the label. So in terms of its usage in terms of lines of therapy, what we're seeing right now is that roughly 50% of the use is in patients who are either first-line or second-line patients.
So that's what we're seeing, and the breakdown is about 15% first-line use and 35% second-line use.
So we've been very excited to track scripts. Things seem to be going well, and this may sound like a fishing expedition, but it's not really meant to be. It's more strategy or thinking. How do you feel about the kind of market uptake thus far, and are you seeing persistence that perhaps could have adoption, and then persistence that could exceed expectations or are exceeding your internal patients or not?
It's still early days.
Yeah.
The way that we think about it is, let's make sure that we react to the marketplace.
Okay.
In other words, what we've seen is that there's a lot of interest in terms of for the product, so that means that making sure that we educate clinicians. And then the... So that's how we look at it. So it's we know eventually what the potential of the product is based on the size of the market and based on the differentiated profile. And, you know, the exact trajectory of that is always hard to predict, as you know, so we watch it like you, and we use that information to inform promotional efforts.
And provide guidance perhaps next year?
So right now, you know, we have not committed to providing guidance. That is a point that we'll revisit and we'll think about. We think it's a decision that needs to be made carefully.
Yeah. Yeah, you don't want to have analysts get out over their skis. I know one who does that well, so. Let's stick with 05 or Auvelity. We're gonna call it 05 because the development or the TAM expansion opportunities for development, and that is Alzheimer's disease agitation. Something I'm very familiar with, quite interested in. There's one other drug approved, and that's a classic atypical antipsychotic, brexpiprazole, right? So the question that I have is: what's the opportunity there, and what gives you confidence? What's the kind of mechanistic or clinical rationale that you have to take Auvelity or AXS-05 into Alzheimer's disease agitation?
So, you know, where we stand right now in the clinical development is we've already completed two phase III trials.
Yep.
So, one was the ADVANCE-1 trial, which was a positive study, and then we had the ADVANCE-2. And then we had the ACCORD-1 trial. That study was also positive. So from a clinical perspective, it makes sense, obviously, to continue to develop the product. And in terms of, you know, mechanistically, what may be driving the efficacy, we think that there is a link between the pathology of Alzheimer's disease and a lot of the symptoms. So you do have cognitive symptoms, which people are very well aware of.
Mm-hmm
... in terms of, you know, memory issues. But, you know, the brain also controls behavior, and so, patients with Alzheimer's disease also have a lot of neurobehavioral symptoms. So, the underlying pathology may be relevant to both the psychiatric manifestations as well as the cognitive implications of the disease. And, you know, some treatments for Alzheimer's disease focused on treating the cognitive symptoms, share a mechanism of action or mechanisms of action with Auvelity, so NMDA receptor antagonism and say-
Yes
... sigma-1 receptor antagonism.
Yeah. So you make a profound statement that the brain controls behavioral symptoms. It's not... or behavior, that's not always the case. But I definitely believe it is the case, certainly in Alzheimer's patients, particularly later-stage Alzheimer's patients. So the types of patients that you're enrolling in these studies, you've conducted two phase III, so why do two more? Any differences?
We did conduct two phase III trials. The history is, we conducted the ADVANCE-1 trial, which was a positive study. We launched the ACCORD-1 trial.
Yeah.
That study, we stopped early. This was a randomized withdrawal study.
Yeah.
This was the first time that we looked at relapse. So we stopped the study because the relapse events that we saw were lower than what we were expecting. We didn't know exactly what was driving that, and as a risk mitigation measure, we did initiate the ADVANCE-2 trial, which is another parallel group study.
Yes.
But at the same. But then once the ACCORD-1 study read out, it turned out that the reason why we were seeing a low number of relapse events, a lower number than what we had projected, was it was that the relapse events in the drug arm, in the AXS-05 arm, were very low. So-
It's a good thing.
It's a good thing, and the study turned out to be a positive trial.
Yeah.
But we did stop it early. So we had the opportunity to initiate the ACCORD-2 trial.
Mm-hmm
... based upon the knowledge and information from the ACCORD-1 trial. So now we have four phase III trials. We think that that puts us in a very good position to have a regulatory package-
Yeah
... to enable approval of the product, should the studies bear out.
It kind of sounds like you jumped the gun with regard to that second randomized or the second double-blind trial. But the good news is, you're gonna have some readouts here that speak about not only the effect size, the ability to reduce agitation in Alzheimer's patients, but also maybe the durability or the ability to speak to reducing the costs or the burden of relapse. And that seems like it's really valuable potentially to the market. Is that the real readout, the real interest in these studies?
You know, we think that having different types of studies designed differently.
Yeah.
does provide different types of information.
Yeah.
All of which are important to regulators as well as to, from a commercial perspective.
Mm-hmm.
So the ADVANCE-2 trial, one of the reasons for conducting that study also is that it does provide longitudinal control, placebo-controlled safety data.
Mm-hmm.
And we know that that is something that the FDA is very interested in, especially in this patient population.
Yeah.
Regardless of whether or not it's a needed trial from an efficacy perspective, it's an important study from a safety perspective.
Yeah. I would argue that Acadia's Nuplazid or pimavanserin really suffered on the safety side with regard to the views of the agency. And so I know it's a little bit different, Alzheimer's psychosis versus agitation, but you wanna get that right going into this patient population. Do you feel good about treating elderly patients over time with Auvelity? I mean, do you have experience in clinic, experience with that, with depressed patients?
Auvelity is approved to treat MDD in adults, so that includes everyone. There are definitely elderly patients who are being treated with Auvelity. In terms of you know collecting data specifically in that patient population, that's not something that we've done yet, but it is being used in the elderly.
If I did a survey of a hundred investors, what would I get back in terms of an answer, in terms of what is the most important pipeline driver for Axsome? Would it be AXS-05? Would it be AXS-07? Would it be something else?
I would say that you're probably closer to that.
How many questions do you get?
- than I am, in terms of, you know, in terms of speaking to investors on a daily basis.
Yeah.
From the meetings that we've been involved in recently, clearly there's a lot of focus on the upcoming Alzheimer's disease agitation readouts.
That's what-
That's one. There's been also increasing numbers of questions on AXS-07, probably because we just refiled that NDA, and now we have a PDUFA date.
So, good segue. Thanks for that. I wanted to talk to you about that because, as you know, we've talked about migraine in the past.
Yeah.
Was proved to be a little bit of a headache, AXS-07 did, 'cause you had a complete response letter. What really was the new information that you could provide to the agency to refile?
It was manufacturing, so the Complete Response Letter dealt with the manufacturing of AXS-07. The agency wanted to see more, in their mind, a more robust process. You know, we think that we provided the information to answer their questions.
When would you anticipate that PDUFA date to be?
That PDUFA date is January 31st, 2025.
Okay, so it's a short review.
It's a six-month review.
Yeah. Yeah.
Mm-hmm
... Type 2 submission, correct?
That, that's correct.
Okay.
It's a Class 2 resubmission.
Yeah. So why do we need a new migraine drug? We have the oral CGRPs seem to be working well. Allergan, AbbVie likes them. The Pfizers like them. Why do we need a new migraine drug?
If you ask patients, they'll say that, they need drugs that work better, so it's efficacy, really.
Work better than the new, the oral CGRPs?
The meta-analyses of oral CGRPs have shown that their efficacy is probably in line with triptans. And, you know, some may suggest that it's slightly lower. So what you have is, you know, you have a new class of drugs, but still the same need with regards to efficacy. So in survey after survey, the majority of patients say that they would like drugs that work better. And if you speak to headache specialists and clinicians, that is still a need. So what do you do, you know, when a patient actually does not respond to the current treatments or fails? And given how debilitating migraine is, I think people think of it as a headache, but a severe migraine attack is classified according to the World Health Organization on the same level of disability as quadriplegia.
Yeah.
So it knocks you out.
Yeah.
So we know that the clinical need is there, and it's with that in mind that we actually designed the AXS-07 to be a multi-mechanistic approach to treating migraine that targets each of the pathophysiological reasons.
Mm-hmm
... for migraine attacks. We then tested that hypothesis in clinical trials, where patients came in, and they had a history of inadequate response. So that was our first phase III trial, and what that showed was a positive study. And we then also looked at how the drug would perform in a clinical trial setting if it were given the way that clinicians are trained to instruct their patients, meaning treat at the early sign of a migraine attack.
Yeah.
That study, which was our INTERCEPT study, was also positive. We think, as with all of our products, you know, what we aim to do is to provide something to patients and to clinicians which is not currently available that might increase their treatment armamentarium.
I want to ask you about the commercial implications in one second, but I did want to ask you one more question about the mechanism and the target product profile of AXS-07, because you are soon to be able to provide data that will speak to the utility of the drug post CGRP, oral CGRP use, and so I guess, what would you like to see out of this study? It's an open label study, so what's gonna convince you that you have a drug that's a winner, that can treat patients beyond those drugs?
It is an open-label study, but the way that the study is designed is that it does allow a comparison because these are patients. So the way that the study is designed is that data is gathered for these patients prior to AXS-07. So they must have been on an oral CGRP-
Yeah
... and they must have had inadequate responses to the oral CGRPs. So it's really comparing. It's a switch study, so then what happens when you then switch those patients who have not been getting adequate relief to AXS-07? So that's the design of the study, and we're looking forward to seeing what the readouts are, but we think that it'll provide insights.
You alluded to mechanistic differences. One of the things or one of the components of AXS-07, which I find intriguing, is meloxicam. So you may treat not only typical triptan type profile, but also be able to treat inflammation. Could that, over time, actually reduce the frequency of migraine? Could that have a disease-modifying activity associated?
Yeah, what we know is that if you treat migraines inadequately, so this has been shown, then that leads to inadequate treatment. Inadequate acute treatment leads to chronification.
Yeah
... of migraine.
Yeah.
So yeah, we do think that it's very important, not just from the perspective of relieving patients' pain acutely, okay, and adequately, but also by doing that, potentially reducing the chronification of migraine. So long term-
Mm-hmm
... then patients should have a low incidence of migraine, based on the data.
We'll look forward to that. I will personally look forward to that. I suffer migraine. I take a drug that is sold by Pfizer, and gonna look forward to an addition, additional thing in my medicine cabinet. Let me ask you about the commercial implications and how you might leverage an approval for AXS-07 across your current commercial establishment, because you really deal with psychiatrists. Do psychiatrists treat migraine? Is that an opportunity?
Before our psychiatry, so for Auvelity-
Yeah
... so, you know, we target psychiatrists, who are a very important base of prescribers.
Mm-hmm.
But then we also target HCPs.
Mm-hmm.
The PCPs. We target the primary care providers, and you know, we've been able to do that with our expanded sales force. The other important point to note is that there's a lot of comorbidity between migraine and depression.
Oh, for sure.
So for example-
Yeah
... so in fact, you know, it's one of the largest comorbidities-
Yeah
... migraine, in patients who have depression. So we do think that our clinician audience will be receptive to an agent that can treat these disorders in a single patient.
Excellent. We look forward to the next year for you. It's been fun to chat with you this morning. Appreciate all your insights and your ability to drive a growing neuro innovator. Thank you, Herriot.
Yeah, and thank you, but I'll say that, you know, we have an amazing team at Axsome.
Yeah.
They're the ones who are driving all the growth that you're seeing.
Excellent.
Thank you.
Thank you. Thank you, Herriot.