Okay. Good morning, everybody. Welcome back to another session. Marc Goodman, one of the biopharm analysts at Leerink, and, thank you for joining us. We're lucky enough to have Axsome Therapeutics with us, Herriot Tabuteau, the CEO. It's been a great ride. I have to say, we've been, you know, following your company now for five or, or so years, and, you've done a great job and pretty amazing getting here. So, you know, kudos for all that. Obviously, everybody here who cares about what's the next five years are gonna look like over everything that you've done so well, it's like, okay, that's in the rearview. Let's start with probably the topic that I hear the most about from investors, certainly over the past, you know, couple of weeks, and that's the Auvelity, in AD agitation.
Just give us a little bit of some color behind the scenes on what. Okay, you delayed the data coming into earlier in the year into later in the year. Just give us an understanding of what's going on there.
Sure. So first of all, Marc, thank you for having us present at the conference. We've been focused over the last year on a couple of things. One is making sure that we advance the inline programs, the inline products, so Auvelity and Sunosi commercially, and then also making sure that we keep the pipeline progressing and expanding. One of those pipeline programs is Alzheimer's disease agitation. We're very excited about that indication. Lately, there's been developments in the field, which we think underscore how important of a disease this is and also the potential for AXS-05, which is the active ingredient in Auvelity in Alzheimer's disease agitation. So as a reminder, we initially had a positive phase 3 trial, the ADVANCE-1 trial in Alzheimer's disease agitation, as well as the ACCORD study, so two positive trials.
We launched the ADVANCE-2 study, which is ongoing. As we enter right now the last leg of that study, we wanted to make sure that we took into account any potential fluctuations in enrollment rates at the sites while also maintaining a very high level of study quality. We initially had guidance for the first half of 2024. We refined that guidance to the second half of 2024 in order to incorporate any potential fluctuations in enrollment during this last leg of the study.
Right. But originally, it was even supposed to be into the next year, right?
Yeah. Initially, we had thought that the study would read out in 2025. And that underscores one of the observations with this indication, which is that enrollment patterns can be a little bit harder to predict than it is for other indications. The ADVANCE-1 study that initially took about two and a half years to enroll. So based upon that, when we launched the ADVANCE-2 trial, our guidance initially was 2025. And then we saw that after that the study was actually enrolling even faster than we had expected. So we moved guidance to 2024 to the first half, and now we're just refining it to the second half.
I think it also I probably should have started with this, but take a second and just describe the data that you saw in the two studies that are done and the purpose of this third study that you're doing.
So the first study, the ADVANCE-1 trial, it was a parallel group study in patients with agitation associated with Alzheimer's disease that used the Cohen-Mansfield Agitation Inventory as the primary endpoint. That study separated very nicely. So it was a very positive study. We showed a rapid onset of action and also meaningful treatment difference versus placebo. The second study that we conducted was the ACCORD trial. That was a randomized withdrawal study design. So patients were treated with open-label AXS-05 initially. The ones who responded stably were then randomly withdrawn. And the point of that study is to look at relapse. And we also saw a separation so between AXS-05 and placebo. So we were happy with those results. The current study, which is the ADVANCE-2 trial, is a parallel group study.
It's designed exactly like the ADVANCE-1 trial is designed. One of the things that is important about that study is it will increase the body of data that we have with regards to the safety, so controlled safety data, which is really important in this patient population, which is a vulnerable patient population, and it is a new indication.
So we have this will be the third study. You have two studies that are positive for efficacy already.
Yes.
The third study, the main purpose is safety, basically.
That is, a very important element of that study, which is it will be the second study where we will generate controlled safety data in a parallel group fashion.
Yeah. Yeah. What's your thoughts about what's happening with Rexulti now? They have a new indication. Just the market dynamics and, you know, how that has evolved and.
It's a very important development in the space because initially, so when we started developing AXS-05 for Alzheimer's disease agitation, there was no product approved to treat this condition. So, the brexpiprazole approval is now the it makes brexpiprazole the first drug that's approved to treat Alzheimer's disease agitation. It's something it's a launch that we do watch, of course, 'cause we're very much interested in the space. And recently, we have seen an uptick in usage of that product in the Medicare channel. And we ascribe that to the new approval in Alzheimer's disease agitation. And that dynamic is important at the clinical trial site level as they speak to potential recruits into our study. And we wanted to also take that into account when we refined our guidance to the second half of 2024.
Let's presume your product is approved. They're both on the market, obviously, you know, Rexulti. How do you think about comparing the products?
There're different molecules with currently different profiles. Now, you know, obviously, everything's gonna depend on the final profile of the product and what the labels look like. But what we know from the data thus far that's been generated with AXS-05 is that the onset of action appears to be different. So, you know, we've shown separation after two weeks of treatment, so a faster onset of action. Also, AXS-05 is a different mechanism of action. So it works on the glutamatergic system, and the sigma-1 system. It is not an atypical antipsychotic. So some of the concerns with the latter class of drugs, the atypical antipsychotics, which has led to them having a black box warning against their use in patients with dementia should not apply to AXS-05.
Yep. And I also get the question quite often about Avanir's recent, you know, their 786 product that did not work recently. So some people say, "Well, are you concerned 'cause they're very similar mechanisms?" And your thoughts on that?
We don't view, obviously, any development in the field is worth watching and is worth noting. But it's also worth emphasizing that the products are different. In fact, both components are different. So the point of similarity is that is the dextromethorphan molecule. And you need to inhibit its metabolism in order to have high enough plasma levels in order for it to do what we'd like for it to do. However, our product, AXS-05, uses dextromethorphan. AVP-786 uses deuterated dextromethorphan. So the molecule is different and would be expected to act differently. And then, the inhibitors, the CYP2D6 inhibitors, they're also different. So our CYP2D6 inhibitors, bupropion, and AVP-786 uses quinidine. So different molecules.
And it's we can't say too much about what the reasons are for the clinical results that have been disclosed so far, which has not been great, but top-line results for AVP-786. But what we do know is we know that with AXS-05, the two controlled trials that we've had thus far have shown an effect versus placebo, and that they're separated. And the results with AVP-786 have not always been consistent.
Yeah. Yeah. Okay. Let's switch gears and talk about depression with Auvelity. Talk about you know, we're kinda moving into a new year, right? What are the new marketing strategies? Have you made any changes to the, the messaging or, you know, maybe we can start there.
So going into 2024 and we are now in 2024, what we wanted to do was take a lot of the learnings from the first year of launch and see if there was any refining that was needed in terms of messaging. So one of the nice things about Auvelity is the large body of data that's been generated. So there's data not just on the symptoms of depression but also on the extent of relief of those symptoms, so remission, for example, clinical response. In addition to having a fast onset of action, Auvelity has also shown significant improvements in terms of function. So we have functional outcomes data. We also have, importantly, you know, quality of life data. So Auvelity showed significant improvement in quality of life. It separated after one week.
And that's very rare in depression. So a lot of data and a lot of things to talk about. It's also a it also utilizes a new mechanism of action. It works on the glutamatergic system. So what we learned from the first year was that there's a lot to educate clinicians on. And in 2024, I think one of the things that we've done and we've done successfully thus far is to make sure that we simplify the message, initially to focus on some of the key attributes, so that clinicians can be educated on the mechanism of action and also that the key profile of Auvelity, which is that it works fast and that it lasts.
Right. What about payer discussions? I know that's been a, you know, an interesting strategy that you've taken. You've kinda not really signed a lot of contracts in year one. How is that, you know, strategy evolving?
That strategy is evolving the way that we anticipated that it would evolve, which is that negotiations do continue. You know, we do have, one.
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We fully expect that coverage will expand. One of the aspects of the payer landscape is the large consolidation. And so you do have three large group purchasing organizations, which control about a third of the commercially covered lives each. And so, in the background, while there is progress that's being made, the outcome of that will be seen as a step function. So we're.
Nothing, nothing, nothing, and all of a sudden, one big one gets signed.
Yeah. Yeah. Exactly. And so we're very happy with the way that it is progressing. And we fully expect that our current coverage, which overall is 70% of all covered lives, roughly 100% in the government channel and 48% in the commercial channel, is going to evolve and expand.
Yeah. And has the product been used in the way that you thought it was gonna end up being used? How's that evolved?
The way that seems to be evolving is that the usage is moving from later lines towards earlier lines of treatment. So we have seen that happening. Currently, 40% of the usage of the product is in second and first line. So of that 40%, 30% in second line and 10% in first line. So we think that bodes really well for the future of the product. And it also speaks to the fact that clinicians who have initial experience with it, based upon that experience, they appear to be using it in earlier lines.
Yeah. Let's flip gears to Sunosi, product on the market for narcolepsy. You acquired this product, a year plus ago. How is that going? What's kinda evolving there as far as how the product's being used and your strategies to market the product?
So we're really happy with the way that our team has taken Sunosi and put it into our digital-centric commercialization platform and been able to better target with fewer reps the prescribers for that product. And so, in the fourth quarter, for example, you know, we saw roughly a 20% improvement year-over-year in terms of prescriptions and sales for the product. So we're really happy there. One of the things that we're really excited about as it relates to Sunosi or the new indications.
Yeah. Let's go there.
So we last year we launched a phase three trial in ADHD. And we expect to have results from that phase three trial in the fourth quarter of this year. We also announced some other new indications, so major depressive disorder, binge eating disorder, and shift work disorder. And so we're on track to initiate a phase three trial in major depressive disorder and binge eating disorder this quarter. So we're very excited about those indications as they represent very large potential markets. And we think areas where the product could be differentiated.
You've started one study in each one of those three indications. How many studies will it take in each one, so just so we understand?
So we started a phase three trial in ADHD. And we will be starting phase three trials shortly in MDD, binge eating disorder, and shift work disorder. For ADHD, the study that is currently ongoing is in adults. And we anticipate starting a study in pediatric patients. We will need one study in each in order to file an sNDA.
For global companies. But look at the, for MDD and binge eating disorder, we would need two studies. For shift work disorder, we would need one trial.
Mm-hmm. So those have already been organized with FDA, and so you feel comfortable about that. Okay. Good. Good, good, good. I guess just on, on ADHD, I just, that's the one that I've just kinda migrated to 'cause I guess maybe also because you announced it first. But, how do you see that playing out, you know, in the space of ADHD? What's the hook there?
If you look at the current treatment landscape for ADHD, you can divide it up broadly into stimulant medications and non-stimulant medications. The stimulant medications are thought to have very high efficacy. So they work really well, but they're highly scheduled. And there are limitations to them based upon that, and related to safety and the fact that they're highly scheduled. On the other hand, the non-stimulant medications.
You and I joined the firm a year ago.
While they don't have those limitations, they're not thought to work as well. So lower effect sizes. And so there is this space in the middle, a very large space, where we think that solriamfetol, if it's successfully developed, could fit.
I see. And that's a good segue into AXS-12, which you're also pursuing in narcolepsy. Talk about that product a little bit and expectations for upcoming data.
So, AXS-12, which we are developing for cataplexy and narcolepsy, is in a phase three trial. That phase three trial is on track to read out this quarter. So,
Soon.
Yeah. So that's,
Tomorrow.
So that's soon. So we're, there's a lot that we'll learn, obviously, from this phase three trial. And we'll know very shortly the full extent of the profile of the product. And narcolepsy is—it's a very interesting space. It is an orphan indication. It's a large orphan indication. And currently, the agents that are available probably leave a lot to be desired, from at least the tolerability perspective. And secondly, if you know, if you look at the number of patients who are currently treated, it's still a minority of the patients who have narcolepsy. So still a lot of clinical need for drugs that are well tolerated. And that can address a larger segment of the market. So we're very much looking forward to the results of the study.
AXS-12, this is an oral medication. It's got daytime dosing. It's unlikely to be scheduled.
Mm-hmm. And it's for Cataplexy, whereas your other products are so you can kinda check those into the spaces.
That's right. So we already have one drug, Sunosi, which is approved to treat excessive daytime sleepiness in patients with narcolepsy. And AXS-12, this is to treat patients who have cataplexy.
Yeah. Same sales force you expect to sell both?
We do expect that there's gonna be a significant operational leverage, since we are already calling upon doctors and sleep specialists who treat narcolepsy.
Yeah. Give us an update on AXS-07. You know, a couple of years ago, everyone was focused on this product. It just seems to have been delayed a little bit. And when are we gonna see it?
So we did receive a complete response letter from FDA, as you know. And that was related to CMC. And we believe that those issues have been resolved. So we're on track to resubmit that NDA in the first half of this year. We expect that to be a Class 2 resubmission, so which would be a six-month review.
Okay. So this drug is for migraine. The product should be approved around the end of the year then, theoretically. So it will launch no later than early next year. Talk about the hook to that product in the migraine space, which I'm sure a lot of people know. You know, the CGRPs are been ramping for a few years now.
So AXS-07 is designed to provide greater efficacy. So if you in survey after survey, and of clinicians as well as patients, the high immediate need is greater efficacy. So that's the way that the product was designed, with a multi-mechanistic approach to deliver that. And this, our first phase 3 trial, it was also designed to demonstrate that effect in patients who have a history of inadequate response. So, and we did show that. So we showed, in patients with a history of inadequate response, a very large treatment effect.
We are.
The way that we intend to.
It's garbled/omit .
Make sure that the product gets to those patients who need it most is to focus on headache specialists, once the product is launched.
And so just remind us, it's made up of, of what?
So it's MoSEIC meloxicam and rizatriptan. So it combines a triptan, which is known to be active in migraine. And then Mmeloxicam is a COX-2 preferential NSAID, which has a very long TMAX. And we developed a technology, our MoSEIC technology, which allows it to be absorbed much more rapidly. So the TMAX is dramatically reduced. And so those two, the MOAs of the two agents combined, provide the ability to address several of the pathophysiological components of migraine.
When you say inadequate response, this is for people who triptans don't work, I presume, when you did the studies, right? Or was it CGRPs as well?
Yeah. So the study was designed. It used a scale, which is called the mTOQ, the Migraine Treatment Optimization Questionnaire. And that was used to screen patients who have a history of inadequate response.
Got it. Let's flip gears to fibromyalgia. Talk about that product and how you see that playing out 'cause that product is being filed.
It is being filed. So that's, this is, so AXS-14 is being developed to treat fibromyalgia. This is the S-enantiomer of reboxetine. There are two positive, controlled studies, a phase three and a phase two trial. We are on track to submit that NDA in the first half of this year.
In our uncertain business, roughly 11.
Fibromyalgia is a space where there are only three products that are currently approved. And it's been, you know, more than a decade since a drug has been approved and launched in this indication. We really like the profile of AXS-14 in this indication based on its effect on not just pain but also function. And also, one of the other components of fibromyalgia that was looked at with AXS-14 was fatigue. And in both studies, it also improved fatigue. So, very nice profile. And one which we think will be welcomed by the fibromyalgia patient community as well as clinicians.
Can you talk about what's approved for fibromyalgia and how your product is differentiated?
Yeah. So, the three agents that are approved for fibromyalgia, we don't think that they address all the symptoms of fibromyalgia. And, for example, I mentioned that AXS-14 has an effect on fatigue. And actually, some of these drugs actually cause fatigue, which is a so not a lot that's out there at all, to treat these patients. And so an area of high unmet medical need.
I mean, Forest launched melnazepram, like, 15 years ago. It's probably the last one, right?
Mm-hmm. Yes.
This product is better than milnacipran?
Look, there have not been head-to-head studies. But we, based upon the data that is available, AXS-14 had a very profound effect on pain, yeah, a very profound effect on function. And also, a significant impact on fatigue.
So it sounds like the data is just better data, is what you think?
The data are, we think are very compelling.
Yeah. One of the things that I overlooked, I wanna kinda come back to, and that's Auvelity or, or any of these products and how you're thinking about, outside the United States. Is there any plans to bring any of these products outside? And if there is, what's the what's the strategy?
It's always been part of our strategy to partner our products outside of the US. So that has not changed. And the one of the things that we've had to do with a lot of these assets that we've had and the size of the team is prioritize. And so we wanted to make sure that we prioritized, obviously, becoming a commercial company and launching in the US. Our team now has grown. And there's more bandwidth. And so that is allowing us to push development of our products, all of our products outside of the US in a more focused way.
Mm-hmm. And I think one of the programs I did not bring up was smoking cessation. Maybe you could talk about 'cause that's the same underlying product, Auvelity.
Yes.
For smoking cessation. Maybe we could talk about that.
Yeah. So we expect to initiate a phase 2/3 trial, a pivotal trial this year for AXS-05 and smoking cessation.
Yeah. What's the hook there? Just remind people.
So the rationale is based on work that was done at Duke University looking at the impact of dextromethorphan in animal models of nicotine addiction. And that showed a pretty profound effect. So there was a phase two trial that was run in conjunction with Axsome under a collaboration with Duke University that also showed a signal. So that's the rationale behind studying the drug in this indication. And again, very large market, very, very highly underserved, almost universal dissatisfaction with the current treatment options.
Right. I mean, we know the bupropion should work, right? So this is supposed to be working even better because of the dextromethorphan.
It, the bupropion in, is used at a lower dose. And it's used primarily to increase the plasma concentrations of the dextromethorphan.
Right.
So that's the work.
It's really the dextromethorphan is what we're doing.
Right. That's the workforce.
So in a way, it's kind of a new. It's a new.
Correct.
Way off, yeah. So just in the last minute, maybe you can, we've kinda gone through everything, right, as far as the programs. Have we missed any programs? I don't think we.
No, I don't think so.
So, as you think back to all of these programs, everything going on, and all the questions you get from investors, what seems to be, you know, just maybe underappreciated or, you know, it doesn't it people aren't you know, people are not thinking about it the way you're thinking about it?
You know, I think that, given everything that's going on and the new programs that have been introduced, that folks maybe are starting to do more work and to learn more about the potential for solriamfetol in these new indications. So, binge eating disorder, ADHD, MDD, and shift work disorder. So I think, and that makes sense since those are newer programs that have been recently announced.
Yeah. It's very similar to, like, what, what, Provigil, modafinil, kinda was doing, right? You're, your assets similar to modafinil, or?
They're similar from the perspective of the initial indications, excessive daytime sleepiness, in narcolepsy and in obstructive sleep apnea.
Yeah.
But in terms of the mechanism of action, they're very different mechanisms of action of the products. And the anecdotal feedback as well as results of network meta-analyses does suggest that Sunosi works better than that product.
Mm-hmm. Interesting. Thank you. Thanks for joining us. Appreciate it.
Thank you.
Yeah.
Thanks.
Good luck this year with everything.
All right. Thanks, Marc.
Yep.