Good morning. Welcome everyone to the Psychedelics Forum. We are indeed at an inflection point in the history of psychiatry, one where decades of stigma are giving way to serious science. We're gonna host four panels today, across the four panels, we're gonna have some of the most thoughtful people working at the intersection of neuroscience, clinical development, mental health innovation, and patient care. We're gonna be exploring several questions throughout the day. We are gonna spend the day digging into some of the important questions such as, you know, what will it actually take to get these therapies approved and into the patient hands? What does a variable clinical model look like? Do you even need psychedelic experience to get a therapeutic model?
You know, just last week, the momentum in the psychedelic space received a significant boost with President Trump signing the Executive Order, directing the FDA to accelerate approval of these drugs. The FDA moved swiftly to issue a Commissioner's National Priority Voucher to three companies, and we have representation from one of those companies today, and that's Kabir from COMPASS Therapeutics, and that's gonna accelerate approval of these drugs significantly. With that, I'd like to kick off the first panel, which will explore how drug developers are thinking about the path to approval, competitive pressure, and how do you scale this class for wider adoption. With that, I'd like to welcome Dr. Srinivas Rao from AtaiBeckley, Kabir Nath from COMPASS Pathways, Rob Barrow from Definium, and Dr. Atul from Helus Pharma.
Welcome everybody, and thanks for taking the time to participate in the panel today. Maybe if I could request you all to start us off with a quick overview of the company, maybe just a one-minute version, and then we can dive into Q&A. Maybe I'll just start with Kabir here, who's at the top of my screen here.
Thanks very much, Ami. It's a pleasure to be here. Thanks for the invitation. Yes, COMPASS Pathways is in the late stages of the largest psychedelic development program to- date. Over 800 patients in our two phase III trials. We have declared the primary endpoint of both those trials, highly statistically significant results in treatment-resistant depression. We are already aligned with the agency on a rolling submission and rolling review. That rolling submission is underway. I have a commercial team that can't wait to get going and to get this to patients. We are excited to be leading this field.
Okay, who'd like to go next? Maybe Rob?
Yeah, absolutely. Rob Barrow, CEO. Thanks so much for having us, Ami. It's great to see everyone again as always here. Definium's developing an ODT form of LSD or lysergide tartrate. We've taken a pretty expansive view of what we think can be done here as well, and I know we all share a view of how impactful these treatments can be for patients. We just announced last week a further expansion of that and have three pivotal readouts, one in major depressive disorder and two in generalized anxiety disorder, which will be coming over the course of the second and third quarters this year. We've been moving at a clip and we'll have some pivotal data coming very soon.
From there we'll be moving aggressively to follow regulatory pathway to filing and get these, well, product on the market here. Incredibly exciting times for the entire field and for us as an organization certainly.
Okay. Srini?
Thanks, Ami, for having me on and as always, great to see you guys. AtaiBeckley is a company that's really got a portfolio of compounds, taking a slightly different tack compared to the other companies. Two of the assets are short duration compounds, short psychedelic duration compounds. The first is BPL-003, which is 5-methoxy-DMT through an intranasal transmucosal route. We also have VLS-01, which is DMT through a transmucosal oral route. The third program, R-MDMA. The first two are TRD. The last one is social anxiety disorder. We're going to be initiating the phase III program for BPL-003 this quarter. We have a readout for a phase II-B for VLS-01 in TRD a little later this year.
We did provide some additional readouts, some additional data for EMP-01 when we had our top line roughly a month and a half ago. Had some additional data readout last week, and we'll be providing some guidance on where that program's going over the next little bit.
Okay. Atul?
Thank you very much for the invitation to speak here, Ami, and it's a pleasure being here on the panel. I'm coming from Helus, formerly known as Cybin. We are a, again, a clinical stage company with two assets, one of which I lead, which is a deuterated version of psilocin, currently in phase III. The other is a deuterated version of DMT. Just got some data from an earlier phase trial, and the plan would be to kick off first other trial later on this year, which would be in the anxiety disorder space. We are excited to see where the trials are moving along and looking forward to getting data in and working with the agency to get these to patients.
Okay. Maybe I want to start with asking about the most recent development, and it was a bit of a surprise to see the FDA come out with, you know, the Priority Vouchers. Obviously there's a lot of velocity on the political front here, and the immediate question that comes to mind is, could we, you know, are we ready? And you're at sort of, you know, front and center of kind of leading the way with, you know, in the space with the being the closest to that commercial readiness. Maybe, you know, talk to us about whether, you know, obviously, the approval will come earlier than what most of us had expected.
Are you ready, and what are you thinking, or what are the priorities for the company, to really go to market?
The first thing to say is we will be ready. Absolutely. As I mentioned earlier, right from when we got our first phase III data in the middle of last year, we'd actually engaged with the Agency about seeing what sort of potential accelerated paths there would be. We already had alignment on a rolling submission and rolling review. In fact, our messaging has been consistent now for a number of months that we will be launch ready by the end of this year. That is absolutely the case, and while we're of course delighted with the potential further regulatory flexibility, and we look forward to discussing with the Division what options that might give us, we're also excited to see whether in fact rescheduling can be moved up. That was, I think, another really important component of the executive order.
We will absolutely be ready. I have, as I said, a commercial team. We've filled out the commercial leadership. Really, whether you speak to providers, patients, or current or prospective employees of COMPASS, everyone is relishing the opportunity to get there. So we will be ready. Yes, it's putting a lot of pressure on the team. I obviously have folks who are engaged on the filing. We have modules already written, ready to be submitted. I have the commercial team ready to go, and we're signing up, as you know, all the third-party vendors you need left, right, and center because getting a launch together is complex. I have a tremendous leadership team. As I say, we've got real excitement at the level below. You know, it is amazing.
I kind of hoped and knew that we wouldn't have to work very hard to recruit the commercial team. We're not. It's actually, we have people flooding towards COMPASS who really want to be part of what is a once in a lifetime, once in a career opportunity to bring something really, really new to patients. We will be ready.
Okay. Great. maybe, Rob, you know, you're gonna have data from three phase III readouts this year, and one of them should be coming up, you know, later this quarter. With this sort of happening, you know, in the broader, sort of landscape, You know, as you have the data readouts, how does that, you know, influence sort of your discussions with the FDA with regards to how you're thinking about approaching, you know, sort of the regulatory review part of things? Srini if you'd like to add anything as well.
Yeah. I think, you know, at a very high level, I can't say enough about our engagement with the Division of Psychiatry and, you know, Clinical Review Division is one of the most important through regulatory process. While of course there's a lot of excitement and headline grabbing stuff is exciting certainly and gives some visibility to the field, I think all of us have benefited from a thoughtful, sort of detailed, coherent engagement from this division, and that sets us all up very well going into whatever on whatever timeline and whatever sort of indications, the fact that we have.
I can speak, you know, for our program from our first meeting, pre-IND meeting, Tiffany Farchione has been a party to every one of those discussions and has given, you know, an extraordinary amount of time and effort and energy. I think really set us up to have those thoughtful discussions and to develop a really thoughtful package to bring back to them. That positions, I think, us very well and we're gonna be moving very quickly upon positive data.
If we're fortunate enough to generate some positive data in phase III to get a file together and be moving forward with the agency, and we'll likewise be ready for that and everything that comes after that on a, you know, whatever timeframe, we're looking at.
Yeah. I actually just want to reiterate that point, Rob. I mean, we've had consistency across, you know, administrations. There's always been support at the FDA level that's, you know, that has manifested as a Breakthrough designations. It's been essentially, you know, one team with Tiffany, and it's been very constructive discussions all the way through. Really have a lot of respect for her and her team and, you know, really good input all the way through. From that perspective, you know, I think, at least for us, I mean, obviously we're a little bit further behind the other companies here. It's been very good and, you know, nothing's really changed in that regard. One point that they did raise, and I think it's an important one, is just the intra-agency communication, right?
I think that has been problematic in some situations, you know, particularly with the DEA. You know, we had sort of two different experiences with two different phase II trials, you know. One where there was sort of blessing with the, you know, the protocol at the top level, and that was it and didn't really impact amendments. Another trial, all of a sudden, everybody wanted to review everything every time there was an amendment. I mean, there's a bit of a lack of consistency. And how the DEA is approaching this. Anything that can clarify that, I think would be huge. Of course, that's all the way through to approval as well. I mean, there's obviously the statutory 90-day approval timeline.
Obviously, Kabir and Rob can probably speak to this better than I can, but there seem to have been some delays in the past where the statutory timeline's not met, and anything that can facilitate that discussion and get that through is obviously good for us and more importantly, good for the patients.
Yeah. I mean.
Yeah. Yeah. Go ahead, Atul.
Yeah. I was about to say that I certainly would echo what Srini has said. I think as having a BTD designation, we do meet with the Division of Psychiatry twice a year. They have been open, flexible, and it has been a give and a take, not just a directive coming from a regulator telling us what to do, but they do listen to us. I think the other point which Srini had made, which was with the DEA, I think what we've seen is that at any place where we're running our trials, there are state DEA approvals required and Federal DEA approvals required, and those two don't necessarily go in lockstep. That has been an issue for us.
I mean, we work through those, of course, but a better coordination of those would certainly have made things much smoother.
I want to follow up on this.
Yeah.
Yeah, go ahead. Yeah. I think maybe you were about to comment on the DEA scheduling, maybe.
I'm happy to get there, but I just to stress again something that I think, you know, speaking for COMPASS, and I believe every other company represented here, we are all doing really robust, rigorous clinical studies to the same scale degree with the same rigor as any other drug that's ever been approved in psychiatry. I think it's really important to note that this is not about exceptionalism or different standards, 'cause I think that sometimes gets lost in the messaging.
That's critical.
You know, we are all doing really rigorous, robust studies. We're doing two phase III for our lead indication, that's, you know, that's what we expect to be the standard that people adhere to.
Yeah. Maybe just to sort of follow up on that thread from earlier about, you know, the DEA scheduling and, you know, the recent sort of order from the Trump administration, does that change how one should think about how easy it is to get some of these drugs rescheduled? Or is it just that, okay, it at least sort of builds the confidence around that and the process and the timelines are expected to be pretty much kind of what we've seen in the past?
So I think-
I think the first thing is we don't know. Rob.
Yeah. The, you know, the devil is in the details always on these things, right? Even laws that get passed, you know, how they get implemented in the Code of Federal Regulations and in policy and in practice can both take time and, you know, changes can be made along the way. I think probably the full complete answer is we don't quite yet know exactly the impact, but certainly symbolically, directionally,
Right
moving in the right direction. I think people miss this sometimes, right? Topical cocaine was approved a few years ago. It's been subsequently scheduled.
Been around for long, yeah.
The scheduling process is not a new process. It is certainly something that has to be navigated and that we're all, I'm sure, preparing. I know we at [Definium] are very, very tuned into.
Agreed
We lose sleep over. This is something that we just know is ahead of us, and we're gonna be ready for.
It is relatively perfunctory. Yeah.
Yeah.
I mean, we know essentially FDA and DEA do the same analysis. You know, right now, by statute, they do it sequentially. You know, the extent they could do it, at least to some degree in parallel, seemed logical essentially since it's a similar analysis based on the similar fa-patterns. Again, as Rob says, until we actually see this kinda codified, we can't be sure.
Does it change anything in terms of when in your submission process you start to you know, share data with the DEA or start the interactions with the DEA?
It takes two to interact, so we'll have to wait to see.
In my experience, and this is going back to some atypical opioid work, much of the initial interaction, because it was sequential, as Rob or Kabir pointed out, it was actually the agency, the FDA, that does the initial outreach. What does Schedule I mean? It means high abuse potential, which one can debate with a psych doc, but more importantly, that there's no medical use, right? Once it's approved, it's got a medical use. Actually, the petitioning process historically has been from the agency to the DEA saying Hey, yeah, we've got a medical use now, and here's a so-called eight-factor analysis around abuse liability, and that just results in differential down scheduling of that product. You know, this has been what THC has been through.
This was back in the 1980's for, you know, anorexia associated with AIDS back in the day. Also for gamma-hydroxybutyrate, that's another name for that is sodium oxybate, but that was in the early 2000s, I believe. This is a known process, but at least historically, it's always been a direct connection between the agency, the FDA, and the DEA. Kabir, Rob, you guys are closer. You may have some additional insights on that, but that's certainly what I have.
I would say if we're doing our jobs, which we are, we will have all the data. Happy to present those data and make those arguments to whatever audience in the Federal government.
or state governments are interested in having those conversations.
Hear, hear.
Fair. Fair. I wanted to maybe just switch gears and maybe talk a little bit about trial design and, you know, the topic of sort of functional unblinding that still seems to be something that keeps coming up. You know, from a sponsor's perspective, what do you see as the most sort of material clinical risk, and is that functional unblinding? You know, to what extent is functional unblinding a true statistical or regulatory risk versus a theoretical concern?
Yeah.
I think, sort of I guess I'm happy to jump in and start that discussion and kind of
Sure
f ollow up with what Kabir had said. We are running rigorous clinical trials to the same standards as any other drug that has in the past. Which then brings us this question of, well, is this a psychedelic specific issue of functional unblinding? I think my answer is that no. Anybody, for many, many psychiatric drugs, there was very clear functional unblinding. So if you ran risperidone trials at 16 milligrams per dose, you had functional unblinding.
It's functionally unblinded, yeah.
Absolutely. Whether you're looking at other trials, lorazepam for instance, diazepam, any of these, of course. The functional unblinding as such is not an issue. It almost feels like it is more of an issue here, because of the bad press and rap and earlier experience that people have had with psychedelics, which is why it gets to be a little more of a perception than sort of the fact that nobody else has had it and this is the first time we're facing with it, which is not so. Now, how does one deal with it?
It is real, and we certainly, and all of us have approached these, sort of along a similar manner, where you're separating the people who are evaluating the efficacy from those who are experiencing and are seeing and would be able to assess whether a participant did get a drug, an active drug or a placebo. Central raters far removed from the sites, not knowing what dose, not knowing what treatment, not knowing what phase of the trial they're in, what visit they're in, would be the steps that one takes to address that issue of functional unblinding. Presenting those data, along with things like what are the expectations from treatment, and were people truly able to be functionally unblinded, because the set and setting in things that people get are also make a difference to psychedelic experience.
it certainly, it would not be a surprise where a small proportion of people who were, who received placebo didn't get a psychedelic experience and people who got drug did not get it. There, those would be some of the factors that we would present and say, Well, yes, it happens, but it is not as, it is not like flipping a switch with the darkness and light coming on.
Okay. I'll sum up. This is not an issue. We shouldn't spend a whole lot of time talking about these things because they don't have any real impact, and we should focus on doing our high quality research like we've done in the past. You know, someone who can point us to psych drugs that don't have this problem, I'm still waiting to find those.
Yeah
Every drug in psychiatry deals with this.
Given the sort of, somehow the you know, reputation or sort of some history with psychedelics, is there sort of a requirement or is the FDA interested in finding out, how many patients in each arm, you know, appropriately guessed what they were on, and is that relevant, to assessing the data?
It's data we should have. We will have.
Yeah, exactly.
What exactly that would tell you? Yeah.
I don't think it would be much with it.
Yeah. We're all measuring it. I mean, I don't know anyone else have any to share at this point. We certainly don't yet from our phase III. To Rob and Srini and Atul's point, this really is a non-issue. I mean, it really should be a non-issue. We're not naive either. That's why we are all taking these steps, you know, and using these tools like trial design, centrally blinded raters, measuring what people guessed and so on, just so that we have all this lined up, but it really should not be an issue.
We go to great lengths to operationally sort of mediate any sort of bias that could be introduced in the assessments. Patients who take these drugs, like any drugs, and psych, again, you can name, you know. The examples are endless, you know, in the areas we're working, right?
Yeah.
Benzodiazepines, generally. Someone taking 2 mg of Xanax reliably knows they are taking that. Someone who takes 20 mg of Adderall very reliably knows that they are taking that. This is something that has been a just fundamental truth forever and why that would suggest throwing out, you know, standards of research that are established for even longer is, you know, a thing that will never, I don't think, make a whole lot of sense. We try to mitigate, we measure, we go to great lengths, probably the greatest lengths of any psych programs in history-
Right
to interrogate this. At the end of the day, the reality is it has very little bearing on much of anything. I think the carry, the pull through here, though, is, like, what would this tell us about the real world? Patients in the real world get drugged, and they know they're getting drugged, you know, what exactly would Someone who doesn't getting drugged having a different... If we think that the placebo response is just too low, we should change tack and just set a threshold and say, You have to be better than this number of points. That's not the right way to approach this either.
What we always end up, you know, after a lot of discussion over years now, we end up coming back to the reality that you just have to do good trials and try to mitigate any systematic bias that could be interjected, and then live with the realities that this is just psychiatry and this is how trials work.
Yeah, I think that key point there is the bias, right? You know, one of the points that had been raised but kind of gets brushed under the rug sometimes with the Lykos NDA and the CRL was that it wasn't so much patient unblinding, though there was that because, you know, there was expectations that were set with people that had. You know, it was 40% of folks had taken MDMA. It was more about the therapists being unblinded, right? You had the person in the doing a lot of therapy before hanging out in the room with the patient. They have a pretty good sense of whether or not the patient got drug, and then adjusting their therapy post-drug. That is a totally different thing that no one has ever done before, right?
That is new, and that is what was harped on a little bit inappropriately so. That's not the same as patient unblinding. I mean, I think sites are always. You know, and the olanzapine trial is a perfect example. If patient A comes in with no weight gain, patient B comes in having gained 10 lbs in two weeks, you pretty much know which one's which, right? I mean, that's pretty obvious. Same kind of thing. The site has always got a pretty good sense of what's going on, but that's where central rating comes in.
Okay. Yeah. That, that makes sense. Okay. Let's, you know, try to think about what is the efficacy bar. You know, do you think that, you know, what's clinically meaningful from a commercial perspective here? You know, is the bar to demonstrate a statistically significant study? Is it sort of effect size, or is it relative to what's out there in the market today? As you think about, you know, designing the trial and picking the right sort of endpoints, et cetera, how do you think about that? Anyone can go.
I mean, You have to have statistically positive results to get an approval.
Yes.
That's pretty low. You know, that is also a function of how many patients you put in the trial, though. You can statistically power for almost zero difference if you put enough people in studies. The reality is all of those dynamics are going to play into both regulatory and clinical perception. The larger the effect, the more people who are significantly better, the better the perception is and, you know, the better data it'll ultimately go on the label. All of it stacks up to, you know, driving some different degree of confidence in the reliability, robustness, and the magnitude ultimately that physicians treating these patients can expect to achieve, hopefully. I don't know if that's very. Generally speaking, yes, statistically positive, bigger magnitude is of course better.
Approval, as Ami s aid, right? I mean, that's kind of what you do need, right? The agency doesn't want you overpowering studies. I mean, you could do on the MADRS a 0.1 point change and get stat sig if you wanted to. You might have 50,000 patients per arm, you could do it theoretically, right? The agency wants it to be clinically relevant, and that's typically on the order of two or three in the placebo group. Like, if it's an individual patient, a 3-point delta is considered minimum clinically important difference. I mean, Typically, when it's, you know, a placebo delta, people think about it sort of in the same way. It's around 3-ish.
Mm-hmm.
Anything-
It obviously depends on the indication. I mean, you know, MDD and TRD are very different indications, yes?
there have only ever been two drugs approved, of which only one is actually used, yes? There have been multiple failures in TRD.
Mm-hmm.
In MDD, there are over 50 drugs approved. Clearly, you know, in terms of the bar, you would expect it to be somewhat different, even if not to everyone's point from a regulatory perspective necessarily. Clearly from a clinical and commercial perspective, you would expect those to be different.
I mean, to a certain extent, if you think about this, Ami, what does the treatment involve? If you have a treatment that has a easy to use, not very difficult, not very complicated, you go home, you take a pill, and you're doing okay. Here, I'm not speaking of a regulatory approval, as opposed to a supervised treatment where you need more resources from the treatment side, where you've got one person at least tied up making sure that the person who's taking it is safe for a number of hours.
One would think that the bar for adoption and commercial use for there would be to say that the treatment that needs more resources, to an extent, needs to show that it is better than something that needs a whole lot less resources to be administered. That would be something that we'd have to look at. How do you measure it? You know, all the measurements you said, you know, a drug-placebo difference, a standardized effect size, the response response and remission rates, all of those factors come in. We sort of have to balance it with what's needed to get the treatment and how useful and how effective that treatment would be.
That would be a sort of a balance that I think of. That's kind of an onus on us to show that, look, these are treatments that need more resources involvement from the treating aspect. The return that you get with the benefit that patients get from getting this is equal to commensurate or better than what you put in. That's what we've got to show.
Yeah. The next question I wanted to talk about is just sort of translation risk from phase II to phase III. In general, when we think about MDD as an indication, sometimes, you know, I think it's even hard to know whether a second trial will work even if the first one worked. If both are phase III, right? How do you think about translating a signal that you saw in phase II into phase III? Is it different as when we think about psychedelic treatments as opposed to, you know, some of the oral therapies like SSRIs, et cetera, that we've seen?
How much of kind of that maybe deterioration or sort of return to the mean is acceptable, but or how do you design trials to sort of manage around that?
Well, the first answer to that is that, yes, there is a difference between phase II and phase III, the trials that we see that you run. I mean, you know, you just take a look at, you know, FDA's analysis showed that approved drugs for MDD at approved doses, 48.5% of those trials failed at those drugs. Obviously, all of those had gone in with successful phase II data. That difference is there. What are the reasons for that? That's a whole another discussion. How does one mitigate it? What does one do to make sure that those things don't apply?
I kind of think of this as a leaky boat with efficacy leaking out of a boat or data, you know, coming in as you go from phase II to phase III. There are a number of small things that one needs to do to make sure that you're not seeing those loss of efficacy as one moves into phase III. Some of those are as simple as picking the right kind of sites, making sure that you're working with them, close enough oversight because you have the variability is so much more with many more sites coming in. How much of a difference are you able to replicate your inclusion and exclusion criteria to the same extent in phase III as in phase II?
What are you willing to give up to be able to generalize your data to a larger population? The compromises that you make in that are what are the things that impact your processes in designing your trials. What you want to be able to do is look at generalizable data without compromising too much on what and here. As we're running the trials, whether it's our clinical operational colleagues who say, If you do this, we'll be able to recruit a trial, otherwise it won't get done. Or our commercial desires wanting things to be included which do not help you in gaining your efficacy. It's a blend of all of those that one does then. Would we expect to see some changes in data between phase II and phase III for psychedelics?
I'm approaching these are drugs. There's no other difference. If that's the pattern that you see in other drugs, there's no reason why you shouldn't expect to see some of that in phase III trials as well.
Okay.
So.
Srini, Rob, anything to add?
Yeah. I mean, I think Atul's kind of hit the nail on the head. I mean, this does tend to happen. There is, you know, typically these trials are larger, right? 'Cause you're trying to hit a safety database, you're trying to hit other things. There tend to be more sites, and that invariably increases variance. You know, in general, what you're trying to do, if you to a degree you can, is not change too many variables between phase II and phase III. The more variables you change, the more unknowns you introduce, typically the greater the variance as well. I mean, that is always something that I've tried to stick by.
I mean, change as little as you can within the constraints that Atul outlined, you know, other commercial constraints and more generalizability, et cetera.
Maybe if you could sort of shift gears, you know, try to think about sort of the commercialization of these drugs. I think as I sort of think about the drugs that each of your companies are developing, they're all similar but also different from each other in many respects. Maybe it would be helpful for the listeners to hear from you on what do you think is, you know, a necessary for differentiating your drug in this market where, you know, hopefully in the next two years we're gonna have, you know, four, five, six, different options? How do you know, what is your current view on what is going to be, you know, important from a commercial success perspective?
maybe, Kabir, since you're closest to launch.
Mm-hmm.
We'll start with you.
Yes. I somehow thought that was coming. I think a few comments here. First, let's start with what is clearly to the benefit of everyone moving into this space, which is the infrastructure for what we still call interventional psychiatry, which is not a particularly nice phrase, but I think people understand it, these kind of potentially multi-R treatments. That infrastructure has scaled incredibly rapidly since the launch of Spravato. From 2019 to now, you now have somewhere between 7,000 and 8,000 centers that can, at least in theory, deliver these sorts of treatments.
1,000 or so of them are still providing the bulk of that, but both that number and the overall number are continuing to grow rapidly, and you have to give credit to J&J for ultimately, after a few stumbles out of the gate, really putting a lot of effort behind that. Clearly that is very favorable for all of us because while ultimately I think all of us will probably get there at the end, have a vision of where psychedelics and drugs like them are used much more broadly. I think we also acknowledge that that existing infrastructure, you know, those adopters as Spravato today are likely to be among the earliest adopters of some of our drugs, and that makes a lot of sense. To your question, I mean, the answer is it's really too early to tell.
I mean, to your point, these mechanisms differ radically in terms of patient experience, in terms of potentially durability in the clinic, potentially utility across different indications and so on. I think, you know, right now all of us are at the point of generating really compelling data in the indications we're looking at. I think there will be, and this is not kind of pollyannaish, I think there will genuinely be space for a number of different approaches. Again, you know, I'm sometimes asked if I'm going after Spravato. Absolutely not. I actually think Spravato sales will benefit from a positive inflection point if and when we're actually approved, because there will just be more focus on driving patients towards these sorts of treatments. There'll be another company out there educating, working with providers and so on.
So we're too early to tell at this point, which is not to say I'm needy. It will be a competitive space in the long run, and we completely recognize that. But right now we're all in the business of actually generating those profiles.
Rob, you're next.
Yeah. I, how much better people get for how long tends to be the biggest driver, right? If you can get more people more better, and they stay that way for a long time, for anything that requires some effort to get done, that's going to be a huge advantage. We look at those dynamics and all, you know, regularly here, all of us, I'm sure, are talking about the challenges of what patients face today, even when they're going out to get intranasal esketamine or ketamine. You're talking about a visit a week, right? I still challenge everyone, you know, put a two-hour Zoom on your calendar for every week for the rest of the year and see how well that goes, and it's not viable right now.
Drive somewhere back and forth twice a week for the next month, and then do it once a week for the rest of the year. The fact that they're getting that kind of uptake for a treatment that is that burdensome is remarkable, and it speaks to how, how strong the desire is for patients and providers to do something new and meaningful. And that gets back to what Kabir's saying. You know, they're... I mean, c-competitive, yes. At the end of the day, the drugs that, uh, for whatever population and subsets of those populations are most, uh, well-received and they're going to have the best positioning are the ones that drive the best outcomes on a, on a risk-adjusted basis for patients and providers. They can do it and make people better.
It's hard to see why, especially in these areas where there have been so few. I mean, we can talk about how many treatments are approved for. There's not really new drugs in these indications for the last three decades, right? That's why Spravato is having some uptake is because it offers a different profile. People get better faster, and even though they have to come back a bunch, they can stay better. Those that stick with it, which aren't all that many in the long run. You know, again, I think, yes, we always focus on the sort of what is the p-value of a study and of course, needing to get great outcomes.
if we can really meaningfully change the trajectory of illness for patients who have had very little historically, it's gonna be a big driver of what brings both providers to the fore of wanting to deliver this and brings patients in the door to get better, hopefully.
Srini?
I mean, I take the point that, you know, we don't have the full data set, and there are gonna be points of differentiation for sure between these compounds. I mean, I think just pragmatically, AtaiBeckley's focus, particularly with the two leads that are in depression, has been something that is short duration and fits very cleanly in a Spravato paradigm, right? What I mean by that is the entirety of the psychedelic experience does wrap well within two hours. Potentially allows for a label that is very similar to Spravato's, which is go in and get dosed and then monitored for two hours. That's something that we have aspired to do. The Agency has been pretty comfortable with that.
In fact, even within the phase III for BPL-003, they were comfortable with a discharge at two hours, assuming that the patient meets discharge criteria. Obviously, that was very encouraging. You know, just one of the key points from the phase II-B that we re-read out middle of last year was, if you have a short duration compound, what does that do to magnitude of efficacy on the MADRS, as well as durability? At least with that phase II-B trial, it didn't seem to have much of an impact. In other words, it was pretty comparable. I mean, you know, the results were very similar to the phase II-B with COMP360 and the same indication as an example. I think that was encouraging. If that replicates, I think that'll be pretty positive.
You know, certainly in talking to both patient groups as well as providers, there's enthusiasm for that short duration. You know, again, we'll have to see how that ultimately does impact efficacy and durability.
Atul?
I mean, you know, I mean, to any certain extent, if you take a look at parallels between other second generation, say antidepressants, antipsychotics, so many of these we say, Well, these seem to be similar mechanisms, but when you take a look at what happened out in the marketplace, each of them were able to have enough patients who would need it, that not only were they all commercially successful, but they all had people who would say, you know, This is a, you know, this is a patient I think will do better on X drug versus Y, without claiming any names. I don't see a reason why this group of treatments, psychedelics, should be any different than any other that have been there.
The heterogeneity in a psychiatric disorder, the treatment responses are such that, yes, while we may be looking for the same big broad indication, when you start taking a look at people and patients and patients' responses, we will all be addressing significant needs for patients.
I wanna touch upon what's the risk in all this. I think we hear from everybody that, Look, this is such a large patient population. You look at MDD, GAD, and there are lots of other indications beyond that. It's not lost on anybody that the market, target addressable market is huge. The question is, what's the risk that this psychedelic space is not gonna be a billion-dollar opportunity? Is the risk around payer adoption, or is it around scalability of these drugs? Maybe, you know, I'd like to kind of hear from you kind of what that is. Maybe attached to that, I think, you know, like, when we talk about payers, right?
Upfront, like, unlike a SSRI where you get a 30-day prescription and then the patient, you know, if there's no response, the patient drops off. Here, now we are looking at treatments where the upfront payment is higher, the cost to the, you know, system through the infrastructure is more, how do payers look at that? Maybe a two-part question, but I also wanted to touch upon the payer side of it.
Maybe I'll start because we are closest. I mean, I think the first part I would build on Rob's comments, which is today, a clearly suboptimal treatment for TRD in terms of frequency of visit and so on, and required to be delivered in an office, is still getting pretty significant traction, which tells you that, you know, for something that offers the potential for profound relief from symptoms that's durable or maybe needed, and none of us quite know yet, maybe two to four or five times a year, whatever it turns out to be, and for some lucky people, maybe even less frequently than that. I think, you know, the initial evidence is that office-based procedures are absolutely scalable and can ultimately address a very, very large population. Obviously, all of us are thinking about how we do ultimately expand beyond those treatment centers.
How can we make this available on a geographically more dispersed, basis? Also, you know, ensuring broad and equitable access across all parts of the population, which brings to your second part. Payers are absolutely aware of this coming class. They are completely aware that there are new options potentially coming that are transformative in what they mean for patients in terms of treatment outcomes. Clearly, they need to see the data. Clearly, all of us are building the economic models that actually say why these really are highly relevant and can indeed help to transform their cost structures. Patients with chronic refractory depression, sadly, spend a lot of time engaged with the healthcare system. Yes, they are, you know, in just pure economic terms, expensive patients for payers.
There are very robust arguments to be made, and we will be doing that, and that's, you know, obviously a key part out of commercial planning as we develop the profile is to actually have those engagements.
Yeah, I mean, I, the biggest risk probably is that we as a you know, a lot of the things that have been done historically were more informed by tradition and sort of a non-standard approach to how drugs are developed, and the extent to which those things persist and are carried forward as requirements out into the real world could be a barrier to adoption. Like, you know, I know that everyone has a different lexicon and approach on these things. You know, and again, there's like a lot of historical academic approaches here that kinda got carried forward in the early days of research.
If those are required, if that's what's being done and that's gonna be pushed out onto the world, who pays for that? How that gets done is gonna be a huge hindrance. The other, just broadly speaking, every drug has potential benefits and potential risks. There's certainly a variety of scenarios that have to be considered that balance those sides, right? Being overly cautious in terms of safety and REMS requirements and the things that go into that simply serve as a barrier to access. In many cases, those sort of surrounds the things that, you know, the additional people being required to be on site are things that have not been tested historically in any of our clinical research, right?
We've been sort of all handed a thing in a particular way. We don't see it as a barrier to sort of what would by any external view, I think be measured as a commercial success. When we think about the opportunity here, the thing that's always striking to me is that we talk about these drugs being sort of transformative and this incredible potential, if we collectively in our programs and as a field and as, you know, the whole healthcare system don't actually do the things to try to get it out at that scale, then we'll never get there.
Mm.
You know, if we really take an ambitious view of what can be done and think about changing the face of what it means to have a depressive episode or to be diagnosed with generalized anxiety disorder or PTSD, and we want to reshape that and the promise it holds for patients, we have to take an expansive view of how this can be done and invest in risk mitigation and approaches to everything from labeling to development to how do we support this getting out in the world that enables that. That's probably a bigger response than your question because it's not going to impact what I think realistically by any measure likely gets us all to a, you know, good top line, bottom line over a period of time.
But, um, that isn't enough in terms of what we hope to achieve with this category of drugs.
Srini, anything to add?
No, I think it's worth expanding on one point that was raised there, that there is a long history here that has perhaps colored how these drugs are, you know, how one approaches and tests these drugs, right? So I don't think a priori there would've been this focus on having two people in the room, et cetera. Um, you know, you're giving a dissociative anesthetic in one case, which is esketamine. You're not that worried about it, right? I mean, you're monitoring the patient, but that's kind of all you're doing. The patient is susceptible to stuff. I mean, they're just like with a psychedelic. But, you know, there is a history here and there's, uh, you know, a bit of a sordid history in some situations as well with respect to psychedelics, that's kind of put these weird constraints on things.
I mean, we do hear, and again, I welcome the opinion of other folks, but certainly in the context of clinical trials, what quote, unquote therapist or sitter or whatever the term you want to use of person in the room, that can be a bit of a rate limiter at times, right? Hopefully in time, or even just based on the REMS, if we can move it towards a more Spravato-like paradigm where the patient is monitored over, you know, AV and with some basic telemetry blood pressure and pulse oximeter, that'd be great, right? I mean, you can tell if someone's got an issue, and then you can go in there and make sure that you can address that.
I think it is a bit strange to have these other odd constraints around someone sitting in the room with the patient, et cetera. I don't know how the rest of you feel, but that always has struck me as being somewhat peculiar.
Yeah. I mean, drug labels aren't where the practice of medicine that typically gets sort of directed, right? I mean, you sit with plenty of volatile anesthetics where people, you know, take them, get put on life support and, you know, cut open, things get taken out or put in, sewn back up and they head home. While there certainly are there's for care and how that should be provided, it's not a labeled thing. So there's, again, there's a balancing act here of wanting to be absolutely dedicated to the responsible and safe use of these
Absolutely
drugs. That cannot be, that cannot ever be set by the wayside, but that balance also requires a sort of level-headed view of what risks can and cannot be mitigated. One cannot mitigate people out in the world from, or cause them to behave exactly the way we would like them to at all times. We just need to take a very clear, you know, again, level-headed view of how we make sure that access is enabled in a way without compromising safety, but recognizing that there is a balance here. That there's a balancing act between being overly cautious in a way that stands in the way of patients actually getting access to the drug.
I think we're gonna get there, I think the conversations have been moving dramatically in the right direction acutely over the last decade. We've gotten to a much sounder, you know, thought process around this in the way we're conducting trials these days and in discussions with regulators. You know, that's just a thing that probably is the most, you know, the most unique aspect of this field historically and something that moving in a more standard fashion unlocks an even bigger opportunity than folks appreciate today.
So we have just a couple of minutes left, and I, uh, and I've, you know, at least sort of in the last question, I've heard a lot of comments from everyone around kind of the operationalization of it and setting, uh, reasonable expectations in terms of what would be required from monitoring patients and following kind of the REMS requirements, et cetera. Uh, I also wanted to touch upon from a, um, from an economic model perspective for the clinics. Um, I think a lot of questions that we get from investors is, you know, how is this gonna work? Is it gonna be attractive enough for clinicians to maybe expand clinics or even sort of, you know, utilize these drugs?
You know, we've heard from COMPASS about obtaining kind of CPT codes. From your perspective, maybe just, you know, what more needs to be done to make it obvious or clear from a clinician's perspective that, you know, this is attractive? Are there certain other things that you would like to see get, you know, done or achieved to make that even smoother in terms of the adoption? Maybe again, start with Kabir.
Yeah. I mean, I think clearly the work that COMPASS led to get a CPT code that's specific to the provision of psychedelic medicines that can be built up over hours and so on and is unique for this, I think that is an absolutely helpful, useful, foundational step. You know, and we've done a lot of work around practice economics, and it is actually very easy to demonstrate that particularly if we see the sort of durability from limited administrations that we're seeing in our trials, that this is actually a very compelling economic model because, you know, this enables providers to fill a room to get reimbursement for it.
Obviously, as all of us get to commercial approval, potential approval and commercial launch, there's a whole host of other things, how we enable buy and bill and so on and so forth, and there's a whole series of steps that all of us will need to put in place, but none of those are particularly new or different. I mean, I think that's what people tend to kinda see. There's this view that somehow this is gonna be. This is not that different from where drug and procedure go together, and that happens in all sorts of fields of medicine right now.
I think what you can actually see and what you're actually seeing through this growth of interventional psychiatry, of physical infrastructure is, you know, psychiatry frankly turning into much more of a business in the way historically rheumatology or cardiology or oncology have done, and I think that also is a very favorable prospect for us.
Yeah.
I mean, folks typically anchor on something that feels concrete. There's a ton to be done. It is. Nothing is actually all that novel here, I think is at the end of the day. There are unique combinations of things that, like with any drug, are going to be unique to that field and that category of drug and the drug or program specifically. There's still going to be the mechanics of a commercial drug launch and of mental healthcare practitioners doing their jobs that have to be navigated.
You know, while there will be new codes maybe specifically, like they still have to bill, they still have to get paid, and we have to make sure that they're incentivized in a way to actually do this, which we don't see being something that is all that challenging to overcome. Takes a lot of effort, a lot of thought, a lot of intention, a lot of data, a lot of discussions, That's just sort of par for the course in launching a drug.
Okay. Srini.
Not too much to add.
Anything more? Okay.
Yeah.
All right. Well, we are at the top of the hour. This was a great discussion. Thank you so much for sharing your thoughts and thanks to all our listeners for joining. Really appreciate you taking the time today.
Thank you for the invitation.
Thanks, Ami.
Thank you. Bye.