All right. Thank you, everyone, for joining. My name is Frank Brisebois. I'm one of the biotech analysts at Oppenheimer. Our next presenting company here is Compass Pathways. Compass has been one of the leaders here in psychedelic therapy, for sure, in the past couple of years. So I appreciate you guys taking the time. I know it's a busy, busy time for Compass this year. So with that, in terms of format, I think we'll do a fireside chat. Feel free to send in some questions in the Q&A. If not, you can also send them to my email, and I will do my best to get to them. But with that, thanks again, guys, and maybe just a quick background on the company.
For those that don't know, I think most people are pretty familiar with the company at this point, but it sure is an interesting time in the space again this year. And there's sure been some developments, without getting too political, that have sparked more interest in the space. So a little background would be super helpful. Thank you.
Sure. Thanks, Frank. And thanks for the opportunity. And just a reminder, we will be making some forward-looking statements. So I refer you to the risk statements in our various SEC filings. So thanks, Frank. Yes. So Compass, where are we today? We are in Phase 3 with COMP360, our proprietary synthetic form of psilocybin for treatment-resistant depression. We have a Phase 3 program of two pivotal trials. And I'm sure we'll get into more detail about them in a moment. But in terms of upcoming catalysts, we will see the six-week data, which is the primary endpoint from the first of those studies in the second quarter of this year, to be followed by the 26-week data from that study, likely early next year. And then the 26-week data from the second study, we call 006, in the second half of next year.
We have consistently guided, in line with the guidance in the psychedelic drug development from the FDA, that we will need both of those Phase 3 trials, supported by a very robust Phase 2b for a filing. And so that lays out kind of three catalysts over the next 18-21 months and the sort of timetable you can expect for us coming up. So to your point, yes, indeed, a very exciting time, and looking forward to the delivery of what will be the first kind of really significant Phase 3 data set in psychedelics.
Okay. Great, and yeah, I guess for those that maybe a quick review just of the Phase 2b. The Phase 2b was such a big milestone and then a big publication out of it for the space, so maybe just a quick reminder to people that don't know about the Phase 2b readout and learnings from it.
Got it.
Yeah. I mean, it was a study that was designed to anticipate some of the problems that we're now seeing more clearly expressed about the use of psychoactive drugs in general and psychedelics in particular. So we wanted to choose a population that was largely naive to the drugs because that had been a criticism of previous studies. We focused, obviously, on treatment-resistant depression as probably the most important of the unmet needs in psychiatry. We used a design which entailed comparison between different doses of psilocybin. So we didn't use an inert placebo because we thought that would be inherently unblinding. And we used remote ratings. We used a centralized system for determining the outcome, which was the MADRS rating scale used in all depression trials. So those are the key features of the design. In addition, it was a relatively large study. 232 patients eventually were entered.
And they were entered in over 20 sites, multiple countries. In other words, offered a certain amount of comfort that there would be generalizability. The actual results were highly statistically significant at the primary endpoint, which was at three weeks. And it showed reasonable durability out to 12 weeks, which was the duration that the study ran for. So we kind of felt that we had got a pretty good proof of concept, that we had a good design. We had a dose that we thought looked effective. That's 25 milligrams. And we had evidence of durability and acceptability of the treatment. So that essentially were what we learned from the Phase 2 study.
You mentioned TRD, difficult population. Why start with TRD? What were the pros and cons of doing TRD versus MDD, I guess?
It was partly the advice we got from regulators in the very early days. That was both in Europe and in the U.S. It was also common sense that basically MDD is a GP, a primary care problem. That's where the treatments are offered. We were doing something that was clearly more interventional than even psychiatrists are used to because we clearly saw the need for preparing patients, supporting them on the day, offering an environment that was basically going to be conducive to maximizing the immersive effects of the drug. Those things do not come in an average GP or psychiatrist's office. We were clear that this was going to be a specialized intervention. It was going to be a challenge for conventional services. It really made no sense to start, as it were, at the bottom with primary care MDD.
It was going to be for patients who had failed treatments and were therefore a considerable area of unmet need, and we had the data from STAR*D, for example, that really established that refractoriness really set in after two failed treatments, so two or more, up to four, in fact, failed treatments were the criteria for entering the study.
And I'd just add, as a reminder, of course, this all started before esketamine was approved. So at the time in TRD, there was just one very old combination drug that wasn't being used. So it truly, from an unmet need and a lack of therapeutic options, that was the obvious place to go as well.
Yeah. And I think that's a nice segue into esketamine. I think it's impossible to not think about Spravato when you look at these drugs and these companies. And I think that's great. There were some hiccups at the start, but a lot of learnings and some success here, which has been good for the space, I think. So can you help us understand maybe Spravato for TRD? A lot of people mention it, but they don't quite understand how rigorous or how many treatments you need and what it requires. So just a little background on Spravato before we kind of go in from the learnings.
Sure, so I'll ask Guy to kind of just talk about the protocol, and it's using clinical practice, and I can kind of comment on what that means from a business perspective. Guy .
Yes. I mean, it requires repeated administration. I think that's the key feature that differentiates it from the modern approach using psychedelics. Some people would argue that it has psychedelic properties, but those were really never emphasized in its original development, but the clinical trials that were conducted established its efficacy when added to an antidepressant. That was an additional feature of the development program, that it was developed as an episodic adjunctive treatment, but it required administration over a number of weeks, and that went twice a week for the first four weeks and then at lower frequency subsequently, and it's turned out that that often is a long-term treatment that patients often have difficulty stopping, so essentially, that is an important difference, but it is, of course, required administration in settings that are highly relevant to what we're doing now.
Yeah. So I mean, I think what we learned from esketamine's success, and I think now most people would use the word success now that it's a blockbuster, though I'll remind you that's still only treating around 45,000 patients. And we'll come back to that from an addressable market perspective and a competitive perspective. But I think what its success tells you is the overwhelming need for a rapid-acting antidepressant, particularly in some of these later lines of therapy. But what we also see is it is being held for later lines of therapy. So the typical use today is fifth line or later. So we are still struggling with the fact that there is too much cycling through things that are unlikely to work, even in people who have had multiple episodes of depression and so on. You're still seeing that.
To Guy's point, clearly, the fact that it's interventional, the fact that it requires a physical location, it requires some HCP resource, it requires a REMS, and so on, all of these are favorable factors in terms of how it compares to psychedelics. We know that we need to evolve beyond that, and so the work we at Compass are doing, and we've talked about the commercial collaborations we have, these are really two-way learnings as to what it's going to take to build on the successes, what's worked for Spravato in these settings, to actually adapt to be successful for COMP360. Spravato is currently available in something like 4,500 treatment centers, but there's an 80/20 rule. 600-800 of those account for the vast bulk of the delivery today.
Clearly, we have time ahead of any potential launch to be actively engaged with most of those 600-800, and that is part of our plan.
That's super helpful. It's interesting. You don't see a lot of fifth-line therapy in this space, blockbusters kind of thing. It just shows you the size of the market here, and so if we jump into Phase 3, as there's some readouts coming out, just a little more on the design, the choices for the design. Obviously, the duration has been poor. There's monotherapy. There's repeat dose, the thought that another dose would help. Just a little details on the Phase 3s before we jump into those.
Yeah. So there were two studies. The first we're calling 005. My apologies, not very original. And that is a comparison with an inert placebo and 25 milligrams single administration of COMP360. Essentially, of course, the COMP360 single administration is what we used in the Phase 2. The inert placebo is really to allow us to establish a safety baseline, which is something that the agency has expressed interest in. Patients will be assessed in the same ways, very much the same entry requirements. So in all ways, it's essentially a replication clinically of what we did in the Phase 2. But the one difference is that the primary endpoint will be at six weeks. So those patients who will be assessed at six weeks and subsequent to six weeks, those patients who have not responded will be eligible for retreatment with what they received originally.
And that runs out, blinded out to 26 weeks. So we have a long extension where we have unprecedented in this particular treatment of depression for looking at the contrast between the two arms of the study. At the end of that time, they're eligible for open-label 25 milligrams because that's, in a sense, a reward for staying long-term with the study. So the second study, somewhat different but related more closely to the one, 10, 25 milligram doses in the Phase 2, now offered twice at a three-week interval. So all patients receive two treatments, either of one, 10, or 25. Again, the endpoint is at six weeks. And then patients become eligible for a third treatment, again, with the original dose after nine weeks into the study. And then they are also followed double-blind for 26 weeks.
They have the same opportunity for retreatment with either non-response or with relapse in the subsequent phase up to a year. These are long studies. They're designed to answer important clinical questions of frequency of dosing. We think that they meet the criteria for an adequate proof of the efficacy of the drug, which is replicating what we saw in Phase 2.
Okay. Great. And so if you do respond, you don't get access to the repeat dose.
That's the intention of the trial. Yes, exactly. And so the criteria for retreatment is set so that it will only happen if people meet a symptomatic level.
Interesting. And so do you think some patients that responded would be disappointed by it? They would want a repeat just to see what could happen? Or is there too many things to answer here? Let's just answer one question at a time.
I mean, they're offered. They have the opportunity to have a second treatment. If they're disappointed with what happened the first time, then they can elect to go back onto an antidepressant or onto an antidepressant again. And so that's going to enable them to continue in the trial, perhaps giving some comfort to the clinician and to themselves that they have some sort of protection. But essentially, the offer is there for patients. They don't literally have to accept it, but that's what they're offered if they meet the criteria.
It was more like if the patient responds and feels great off the first dose, want another dose.
No, they wouldn't meet that. They wouldn't meet the criteria. But of course, if they're in the second study, the 006, they might be in the position of having responded, and then they get the second treatment, whether or not they've responded.
Interesting. Okay, so you'll answer a lot of questions here, and then just one word that is a difficult word, but it has to come up in your trials, and if anything, it probably means you have the right patients. Can you help us understand suicidality and suicidal ideation versus attempt, and TRD patients, just to help us maybe understand the amount, the percentage of patients that are TRD that actually have suicidal ideations coming into the trials and what that means with this trial?
Yeah, sure. So in the Phase 2, I can't give you the data for our trials yet, obviously, in the Phase 3. In Phase 2, about 60% of the patients coming into the study had previous suicidality endorsed with the scale that we use, which is the Columbia Rating Scale. And what that scale is used for is to look for change, as well as simply to exclude people who are clearly suicidal at the time they're assessed because that's not the convention to enter into studies. That means that we are detecting really quite low threshold changes, which may very well be simply part of the fluctuations in symptomatology in depression. Suicidality as a thought of the desire to be dead, the desire to end one's life, unfortunately, is part and parcel of becoming depressed.
It's usually estimated that 90% of patients at some point with a lifetime of depression will experience suicidal ideation. Whether or not that's important, of course, is whether it's translated into actions. And we have to assess those and regard those as serious. And that's what was thresholded in our trial and indeed in the esketamine trial. And so that will be reported as a serious adverse event, even though in a sense, nothing may happen. In our Phase 2 trial, there were no attempted suicides or suicides. But we had changes in this scale, which we interpret and others have interpreted as being evidence of suicidality. So that's the way the trial technically works. And what we'll be looking for with the large database is to what extent there's any imbalance between the arms of the trial.
The Phase 2 really wasn't large enough to reach any statistically meaningful conclusion. The increased number of patients should allow us to be more confident when we make generalizations from the data in Phase 3.
Okay. Okay. Great. But in this space, in terms of expectations around label or whatnot, a Black Box Warning would be in line with expectations.
We expect that. I mean, every antidepressant essentially has it. So we would not be surprised or concerned, candidly. And again, I think it's because there has been a lot of discussion about the Phase 2. It's important to note, obviously, that was thoroughly discussed with the agency. That hasn't led to any significant changes in how we've thought about or designed the Phase 3. And they do recognize everything that Guy has said. Unfortunately, this is simply a facet of this population.
And I hate to do this because this was a question from years ago. And I feel like we kind of moved past it. And then it came back. Functional unblinding, how do you guys answer that one? Because this is almost like the psychotherapy and support discussions that we had years ago. But with developments on a recent AdCom, that was difficult. I don't even want to throw in RFK yet. But how do we feel about functional unblinding and how we're approaching it, I guess, in terms of FDA guidance?
I mean, we accept many drugs that are submitted to the FDA are functionally unblinding in the sense that people probably can recognize they've got the active treatment rather than the passive one, the inert one. We think that this will be clearly an issue in 005 and the first of the studies. Whether it matters is a moot point, but we maybe don't have time to debate that. But we know that there will be unblinding in 005. 006, there will be less unblinding because we know from the data that we got in the Phase 2 that the subjective impression that patients get from different doses is very overlapping, surprisingly so. So it's not like you've got a very clear experience that is the 25 milligram experience versus the 10 versus the one. They're surprisingly overlapping.
And that was what we got back also from the sites who told us they were very uncertain what patients had received. So we think that the unblinding will be pretty minor in the Phase 3 006 study. But obviously, we're going to ask patients this time what they thought they were on. And we're also going to look at expectation because in a way, most people think that expectation should operate through the unblinding. So it's not just knowing what you're on shouldn't make much difference unless you have different expectations. So expectation is going to be something we measure, and we'll see whether that affects outcome. The data so far is interesting in that there are at least two studies I know of where expectation has not predicted the outcome in the psilocybin arm of a study, but it did in its control arm.
So we know expectation, for example, drives SSRI responses. So we'll just have to see. It may or may not be the case that expectation is an issue. And if it isn't, it's going to be hard to argue that unblinding is important. But that's for when we have more data on this.
No, that's super helpful. And on the therapy side versus support, your job is not to be therapists here, correct?
In the U.S., we have therapists doing the work of support for the patients. That's something that is sort of historical and has been driven by FDA advice and so on and influenced, I think, by MAPS. Essentially, we have to, in many ways, train therapists to be trialists, which is really a different job. That is to remain within rather constrained behaviors, to limit what they say to the patient, and we've identified items of behavior that we want to see and things that we don't want to see. In order to make sure that that training has worked, we're monitoring the actual transcripts from the trial exchanges between the patients and the therapists. We will be able to say the percentage of compliance with the training that we see in the therapist's behavior.
And we can be reasonably confident of an absence of the sorts of things that would really be described as therapy. So we think we will be able to offer evidence of how the therapists were trained and how they actually behaved with the patients with the different doses that the patients were exposed to. And I think this, again, is a groundbreaking approach to establishing the validity of the support model.
And I think if I may just build on that, Frank. I think where this becomes critical also is as we start to think about commercial because one comment that I know a lot of people are concerned about or one aspect is if truly there needs to be a licensed therapist in the room, that is clearly a bottleneck. So I think a few things to clarify here. First, even in their discussion of Lykos, it was clear that the agency said that they were not in a position, they don't have a mandate to actually regulate therapy, nor were they inclined to do so because that's part of clinical practice. Now, for Lykos specifically, that led to difficulties given that the therapy and the drug are fully integrated.
But I think our dialogue with the agency is clear, therefore, that they expect to see an HCP in the room who has a license at stake. So somebody who is sufficiently trained to identify a safety issue or whatever. But from that perspective, that could be a nurse, that could be a physician's assistant. Obviously, it could still be a physician or a therapist if they choose to do that and be trained for that. But we believe with that, you will see a much, much larger pool of potential monitors, people who can sit in the room. And as I think we've spoken about in the past, indeed, outside the U.S., even in the trial setting, we've been able to do that, working with nurses in some other settings.
We are now starting to push in some settings, some specific areas of study here, whether we can do the same in the States. So I think that's important in terms of how we think about scale and commercial scale.
I don't know, it's always tricky to discuss other companies, but the time of sitting in the room obviously changes depending on the time of treatment. There's been a recent update on the GH side with the DMTs, kind of the quicker onset, I guess, depending on how many times you have to trigger the right dose, I guess. Any comments on the developments there and where psilocybin can kind of stand in the paradigm here?
Yeah. I mean, I think so the first thing to say is clearly, we're all waiting for much larger data sets across a number of these other modalities in terms of number of patients and so on and understand really durability of effect and so on. Because I think the length of a single procedure is one element, but clearly, durability, repeats, the intensity of the experience, the nature of the patient experience, there are a whole set of other factors that come into this.
And I think certainly the idea that given the unmet need, given the literally millions of patients who potentially are going to be seeking new treatments for TRD, that a two-hour as opposed to a six-hour experience is going to be the determining factor of choice, I think we're a very long ways off from actually making that determination because there's so much more data to be had. And the nature of the experiences is very different. We know psilocybin is a particular type of experience. But again, what we have seen, at least in our trials thus far, is for the majority of those patients, it is a positive experience. It does enable some form of transformation, while recognizing there will always be some who have challenging experiences as well.
Yeah. Interesting. And then I'm sure you guys have talked about this. Do you have kind of prepared remarks? If I say RFK, what comes to mind? There's interest. It's a tricky one. But I think people want to know where things stand a little bit, or maybe these are very prepared remarks.
No, I mean, frankly, it is a question that comes up all the time. So I think the first thing to say is we have no idea. I mean, just to be absolutely clear, I have no idea what it means over the next one year, three years, five years. But I think our interpretation is at worst, it's neutral. And there's a good chance it gives us some positive tailwinds in a number of areas. I don't think that necessarily means in kind of the core risk-benefit decision around a Phase 3 program. I actually don't think it's in anyone's interest that we see significant changes to the way the agency thinks through that. Though obviously, we can continue to talk about unblinding and some of these other elements that we need to get clarity on and how they think about therapy. I think there are areas around that.
I mean, everyone knows it's hard to do studies with Schedule I drugs. If there were regulatory ways to make it, frankly, easier to get these studies up and running, if it was easier to look at the kind of bridge from clinical trials to commercial, so for most conventional drugs, early access programs, whatever you want, are relatively straightforward with a Schedule I drug, they're almost practically impossible, yes, because of the nature of what every treatment site would have to be able to do and so on. So I think there are areas around that. We, as you know, with our financing at the beginning of the year, have recommitted to PTSD, and I think clearly, there could be tailwind support from within VA/DoD in this new administration to really some urgency about studying PTSD, so I think that could be helpful to us.
But who knows? It's the straight answer.
If you didn't know, I'd be concerned.
Right.
Okay, and then I think the only other thing, the difference here is remind me, I think there's a difference in the inclusion/exclusion criteria from the Phase 2b to the Phase 3 in terms of prior experience on psychedelics, the cap. Why is there a difference there? And what do you think that can lead to?
I mean, it was partly it grew out of discussions with the agency. A slightly higher number has a practical advantage that one can realistically stratify on that, so that allows us to ask a separate question about whether this subgroup are indeed more or less responsive than people who are naive to the drug. So both of those were the increase in number allowed us to do that meaningfully. And of course, it's reflecting the reality that probably the increased awareness has resulted in increased exposure, so both those things seem to be common sense, really.
Okay. Great. And then, Kabir, you just talked about the recent raise. Can you remind us what's the balance sheet looking like?
Sure. So at the end of quarter three, we had $207 million. We then raised $150 in the beginning of the year, just short of that net. So until then, we've been guiding as a runway into 2026. This clearly comfortably takes us through the key readout of the 26 weeks of 006 and the second half of 2026, and also allows us to reinitiate some work in PTSD that otherwise have been put on the shelf.
Okay. I think we're up on time. Is there anything else I should have asked that we didn't have a chance to speak about?
No. Again, thanks for the opportunity, Frank.
Appreciate it. Thank you very much.
Thanks.