Thank you for joining us for the corporate presentation and guided Q&A session for Pathways here at the 45th Annual TD Cowen Healthcare Conference. I'm covering analyst Ritu Baral, and joining us for the presentation, we have CEO Kabir Nath. Kabir, I'll have you come up to the mic for the presentation, then we'll do Q&A. If you could, introduce your colleagues at. Of course. at the beginning of the Q&A. Thanks very much indeed. Thanks, Ritu. Thanks for the invitation to be here. I am just going to spend a few minutes giving a high-level overview of Compass Pathways before we get into Q&A. There are our disclosures. Just draw your attention to those. Who are we? Compass Pathways is a company devoted to generating robust clinical evidence for innovative treatments in mental health. Our lead candidate is COMP360, our proprietary synthetic formulation of psilocybin, and we are studying that in treatment-resistant depression. The phase II-B study was published in the New England Journal in 2022, and that showed a robust signal of efficacy in treatment-resistant depression, with roughly a quarter of patients in remission after a single dose at 12 weeks. We are now very much in the midst of our phase III program with two pivotal trials. COMP005, our first trial, we are expecting top-line six-week primary endpoint data next quarter. For our second pivotal trial, COMP005, the 26-week data is expected in the second half of 2026. Last week on our annual earnings, we reconfirmed those timelines. We also published data from a small open-label study in phase II in PTSD in quarter two of last year, and we are now in the process of designing a late-stage PTSD program to capitalize on that. Again, a very significant unmet need in PTSD. At the end of last year, our cash position was $165 million. At the beginning of this year, we have raised an additional $150 million in gross proceeds, and that gives us cash runway through that COMP006, 26-week readout in the second half of next year. Why are we choosing to study treatment-resistant depression? Treatment-resistant depression is a huge unmet need. The prevalence of MDD in the States is around 21 million people. Around 10 million of those are drug-treated, and at least a third of those treated for MDD ultimately fail two or more antidepressants sequentially. That is the population that has a regulatory definition of treatment-resistant depression. It's not actually a DSM definition, but it's something that physicians clearly recognize. There are only two drugs approved in TRD. One is an extremely old combination that is not prescribed, and the other is esketamine, and I'm sure we'll come on to talk a little bit more about esketamine and what that means for this market. Very significant market, huge unmet need. Compass's decision originally, seven years to go into this, was first recognizing that unmet need at the time esketamine was not approved. There was literally one old generic drug approved in TRD, but also a recognition that if we could show significant benefit in that population, as is typical in many other therapeutic areas, you can move upline into easier-to-treat populations. The current treatment pathway, as you can see, is typically first-line pharmacotherapy, traditional antidepressants, second-line, you either switch, add, maybe switch to yet another one. From third-line onwards, you can see a range of possibilities. Again, as I said, most of those switching, augmentation, and so on leave the vast majority of people unsatisfied. You see now esketamine as an approved drug in here, and also now increasingly somatic therapy as well. Again, we can talk more about that and what that means for the rise of interventional psychiatry as a discipline. Here then is just a schema of the two phase III trials that are currently underway. COMP005, as I said, is reading out next quarter, the primary endpoint at six weeks. That is 25 mg, the active dose, against true placebo, randomized two to one. The reason for that is, as we came to debate with the agency, the design of a full phase III program. While they very much applauded and understand the design of our second phase III, which replicates the design and the three arms of our phase II-B, they were also adamant on getting a true safety baseline through a placebo-controlled study. The first study, as I say, is what's reading out next quarter. The second study then takes the same three doses that we employed in phase II-B, which we saw as an effective way to mask from a patient perspective what dose they were on, so an effective way of blinding in this otherwise hard-to-blind population. What we have done is added a second fixed dose at three weeks. The hypothesis there coming from the phase II-B is that that second dose could potentially improve response rates, both in terms of who actually goes into response or remission, but also potential durability. Both studies, as you see, run blinded for a full 26 weeks, which is almost unprecedented in depression trials. In the second part, there is an opportunity for retreatment for patients who either have not responded or who have remitted and then relapsed. That is an option for retreatment with the same dose as their original assignment. At week 26, there then is the option of a dose of COMP360 in open label for every subject. That was designed as a way to really incentivize people, particularly in the inactive arms, to stay on what is a long study through that time. That, based on what we're seeing, has been effective in actually maintaining a significant level of patients through into Part C. Full 52 weeks of safety, therefore, we will have, which again, when you look at the FDA's draft guidance for the development of psychedelic drugs that they put out in June 2023, they look for both a design like this of two complementary studies. They're looking for durability. Actually, they mention 12 weeks, and you see we run blinded to 26 weeks. They are also looking for 52 weeks of safety in these programs. Actually addresses all of those requirements from the agency. Finally then, in terms of what we will see, in a few weeks' time, recognizing, as I've just said, that the studies do run blinded through 26 weeks, we have made the decision for a very limited disclosure of top-line data with the six-week data. What we will see is the primary endpoint, which is the MADRS effect difference changed from baseline between the 25 mg and the placebo arms, the p-value and confidence intervals that are associated with that, and then a high-level safety assessment from the DSMB, which is seeing unblinded safety data on a regular basis. With that, Ritu, that was all I wanted to present, and so happy to get into Q&A. As we do so, I'm joined by Dr. Guy Goodwin, our Chief Medical Officer, and Dr. Steve Levine, our Chief Patient Officer. Great. Thank you, Kabir. Can we talk about, you will not, with the top line, talk about secondary endpoints, but you will talk about some safety detail. Can you speak to the qualitative, can you speak to the breadth of the safety data that you will disclose with top line, given that that is the FDA focus essentially of this study? Yeah, it will be a very limited disclosure. It will be a summary statement from the DSMB around safety, but it will specifically, if there is any clinically concerning imbalance around suicidality to be called out, it would call that out. Is this a case where no news is good news? If there is no statement on suicidality, either ideation or activity, the assumption should be that no signal was seen or no separation was seen? Correct. Okay. This is the fun question. Why has everything been failing in depression recently? Across mechanisms in many, you know, MDD, TRD, what's happening with trials, conduct? You know, we talk about the issue of professional patients and these professional sites. Could you address that and maybe what you've been doing in your trials to prevent that? Sure. Oh, let me start and then clearly Guy can add to that. First, I'm not sure this is a new phenomenon, unfortunately. Yes, we seem to have some recent cases, but this is not exactly new news. I will actually hand to Guy to talk specifically about trial con and so on. The one thing I would say, of course, is placebo in this context is very different from placebo in the traditional context of a daily oral. Somebody who is taking a pill every day for six weeks, and I agree we have seen some very confounding placebo responses around that. This is going to be a single administration, very limited interaction with the site or with physicians between then and the six-week primary endpoint. I'll hand to Guy to talk a little more about site selection and some of the other things we're doing. Yeah, I mean, site selection is basically, we've included people with experience from the phase II. That's an important quality marker because we know that these people delivered. We've been careful not to recruit too many sites into certainly the COMP005 study, which is the placebo control study. Of course, our criteria for entry for patients is very exacting in that they have to have failed two approved antidepressant treatments at an adequate duration with proof of failure of effect. That in a sense is partially a guarantee against this professional patient issue because these people have to have a validated medical history, which is in some ways the most exacting criteria. You can go into that medical history and look for red flags that indicate a professional patient, other clinical trials, other clinical trial screenings, that sort of thing. That's correct, yes. The other important thing, given we're talking about a psychedelic, it was to exclude psychedelic seekers. As a reminder in the phase II-B. How do you do that? In the phase II-B, we capped prior experience to 10%, and we actually had 6%. In the phase III, we're capping it to 15%, and that's a stratification criterion. So across the arms. Clearly, there's an element of self-report in that. We have to acknowledge that. I think nonetheless, with that discipline, with the work we've done with sites, with the PIs and so on, we've been keen to ensure that we do exclude that kind of psychedelic seeking. Is there anything in a patient's record that could, I guess, inform whether they are truly psychedelic seeking or not? Only a record of them having taken the drugs. Okay. For example. It would have to be self-reported. Yeah, or, you know, there may be documented hospital visit because of adverse effects in a recreational setting. You know, you could have that kind of thing. In which case, yeah. Probably more important than anything is that through medical record and pharmacy records, demonstration that this patient truly meets criteria for treatment-resistant depression. Of pharmacy records as well. Okay. Got it. What do you expect from your placebo? You will report it with top line. We understand that you will only give the delta as well as, no, not the effect size, just the difference. Just the difference, correct. Just the difference, correct. What is a safe expectation for what that will ultimately show once you open the book up completely on the dataset? Is there a potential for a nocebo effect, essentially? There is always the potential for a nocebo effect, but I think what we would say, and this is, as you'll recall, when we designed the study and spent some time talking about the size and the powering, there are a few datasets you can look at here. Usona, the Von Rotz study in Zurich, Usona was using niacin, but effectively that's the placebo. The Von Rotz study in Zurich used a true placebo. As we discussed at the time, when we looked at the one milligram arm from our II-B and looked at those patients who did not report a subjective experience and looked at that as a proxy for something more like a placebo, what you see is modest drops on MADRS, certainly significantly smaller than what we saw with the one milligram overall in the phase II-B. That is kind of what we would expect. Yeah, I think I don't, I haven't really got much to add to that. We would expect, we don't see as valid a placebo response as you would expect to see in a conventional trial, but we get over that, I think, by having the one milligram arm in the COMP006. Are you, what are you doing or even able to do, to minimize functional unblinding with this, with this therapy? There is the, you know, very well-documented psychoactive, side effect seen in this treatment window. In the preparatory session, are there, are there tools and tactics that you can use with patients to help minimize functional unblinding? I think it's partly about expectation. We are very clear with the therapists that they need to address with equanimity and with equipoise the probability of treatment success and also the probability of experiencing a psychedelic, intense psychedelic experience. That works very well when there is no drug placebo contrast in the consent form. When you have that, it's difficult because the expectation of the patient is very binary. In COMP006, and indeed in the phase II, and the reason we did the phase II, the patients all know they will get a dose of the drug. They do not know, of course, what dose it will be. Everybody's getting the warning of the severe psychoactive. Everybody has been talked to about a severe effect. They've been taught, yeah, they have. They have that expectation, but they've also been told that it's very unpredictable and that they would not be able to deduce from the intensity of the experience what dose they've had. Really it's COMP006 that has peak, protection against functional unblinding. Peak validity. I think, and we have to accept that if you put in an inert placebo, you are not going to see the usual kind of response associated with placebo. It is going to be an unblinded study. Okay. It's not to say that if you don't see an effect on 25 mg, which is sustained, I would still argue that that's a pretty useful clinical effect because bear in mind, all clinical practice is unblinded. Understood. This is supposed to be a guided Q&A, not a monopolized Q&A. If anybody has questions, please, please feel free to raise your hand and I'll pass the mic. I can keep going. Another key concern that emerged from the [LICOADCOM] is the impact of psychotherapy on the treatment response. What do you need to provide to the FDA so that they can clarify that, at least within the COMP360 application? Yeah, so I'll start and then Steve and Guy can build on that. I mean, first, to be clear, I mean, Lycos, we're putting forward psychotherapy. So, you know, unfortunately for them, it was truly a drug therapy combination. We are not. We are going to be seeking approval for a drug. And with that context and what we are doing by way of working with the patient, I'll hand to, I don't know who wants to lead and who wants to build on it. Okay, well, I mean, you know, essentially what we've said is that we're preparing patients, we're supporting them, and we're following them up. Those are the elements of the contact they have with someone who is a psychotherapist required by the FDA in the U.S., but someone who has been trained under clinical trial discipline, not to intervene, not to behave like a therapist. And indeed, the nature of the experience is in our favor from that point of view because there's very little interaction with a patient undergoing a psychedelic experience, unlike the empathic experience they get with MDMA. That said, we think we have to justify that choice of words and that choice of approach by documenting exactly what does happen and to prove, if you like, that our training was successful in making these people behave in a very consistent way in all three arms of the COMP006 and in both arms of COMP005. I mean, in COMP005, essentially, everybody's getting some sort of therapy, correct? Like, well, they're getting the support. They're getting the wraparound support the day before, they're getting the consolidation session. We try as far as possible to standardize exactly what that support looks like through all the three phases. Of course, we think we're simplifying the choice, the decision for the FDA to the difference between the two, which is accounted for by the drug. That's the way we're thinking about it. To be clear, you know, as part of that standardization, it is the reason why we characterize psychological support. The use of that term is really primarily to differentiate it from psychotherapy. The reality is that what's happening in the preparation of patients, supporting them during and then following them up is quite similar to what you would do to support a patient receiving any treatment. You're saying that the psychological support is like a therapy session or does it? The opposite. It's the opposite. What is, can you walk us through what a psychological support or like the consolidation session entails? Sure. In the meetings prior to the drug administration, the primary aims there are to build some trust and rapport between the participant and the person supporting them to provide psychoeducation. That is to inform them of the range of possible outcomes and expectations associated with participating in the trial. Again, quite similar to what you would do in studying or delivering in the real world, any treatment, you're always going to have that discussion with the patient, provide that education and build some therapeutic rapport. On the administration day, they are primarily there just to safeguard the patient. These are largely silent sessions. They're aiming to help maintain the participant's attention to the experience itself and to be that safe, supportive presence. In following them up, it's an open-ended opportunity for them to just talk about their experience. Is it guided? Is it prompted? It is not prompted or guided. It is non-directive. The consolidation session, it's really the. It's a follow-up. It's a follow-up. It's a safety-led follow-up. Just as you would with any treatment. Guiding or, you know, I think many investors have this impression that it's like, you know, cognitive behavioral therapy where somebody's guiding. I'm glad you're correcting the record. It's a safety follow-up. It's to allow the patient to talk about what happened and truly to ensure that nothing, they're not planning something dramatic or different, but it is not guided. It's not prompted. There's no therapeutic exercises or psych. Absolutely not. That's actually, that's very helpful. Let's switch gears to commercial prep. Can you discuss your current state of commercial prep, commercial access prep? Should we expect more network partnerships this year for you guys to figure out, yeah, care outlets? You talked about the somatic therapies and interventional psychiatric units as part of your prep. In a moment, I'll hand to Steve talk to all about that. Just to add one thing that we include in commercial, because it clearly is about market preparation, which is rescheduling. We have a very active stream of work on state-level rescheduling, because as many will be aware, if the drug is approved, the DEA is required to reschedule federally within 90 days, but that does not mean it's automatic at state level. We have set ourselves the objective of ensuring that there are legislation or whatever is needed in place in every state for rescheduling as quickly as possible. That work is on a long lead time. That's one piece within commercial. How long will that take, Kabir, like to roll out over the major market states? By starting in, I mean, to get it ready for two years' time, it can take more than two years, which is why we're doing the work now. You can start now. You don't need to wait for the DEA scheduling for that. We've already started. We've already started with sponsoring legislation and so on to do that. That's been picked up, which is as we would expect. That's one piece that we put into commercial. I'll turn to Steve to talk about the network side. Yeah, in terms of traditional market access activities, that will begin in earnest with phase III data in hand. For the moment, although we're not investing directly heavily in commercial, as you alluded to, as you're aware, we have been engaged in deep work in bilateral information exchange with our network of research collaborations. You asked the question if we will grow that network this year. You know, part of the intention behind the representation within this network is, number one, to represent prototypical sites where SPRAVATO is being delivered today, which are primarily the interventional psychiatry networks. There are two collaborations within our network that would very much be considered interventional psychiatry networks. We also include hospital systems, integrated delivery networks, decentralized models. In terms of future consideration of adding others to that network, it'll be an ongoing assessment of whether we have optimal coverage of the treatment delivery landscape that we think best reflects delivery at launch and then a period beyond launch when we scale. Do you have an estimate right now of snapshot in time, two years before approval, how many feasible outlets there will be either now or two years' time? Yeah, we do. You know, already within our collaborations, although it's a handful of organizations, that represents hundreds of sites. Looking at SPRAVATO, which of course. Is it like close to like north of 500 or like a couple hundred? It's a few hundred. A few hundred. Okay. If we look at SPRAVATO, which is not a one-to-one analogy in the market, but is the closest analogy currently in the market, that is currently being delivered in more than 5,000 sites by more than 4,000 prescribers. That is probably concentrated, the majority of that clustered within 600-800 sites. With engagements that we've had with sites, learning from them beyond our research collaboration, it also includes a significant portion of them. These SPRAVATO sites, are they also treatment settings that can be renovated, augmented, et cetera, for COMP360? They are. They're really built to be platforms to treat patients with treatment-resistant depression, not to specialize in delivering one treatment. They typically also will deliver somatic treatments like TMS, maybe ECT, and already have the physical infrastructure and current planning to be able to deliver psychedelic treatments. Got it. We have about three minutes left. I wanted to be sure to talk about next steps in the TRD program after your really, really encouraging phase II data. Do you mean PTSD? I'm sorry, PTSD. Sorry. As we've said, we are in the process of designing the next studies for PTSD. Just as a reminder, the scale of the unmet need here, something like a prevalence of 13 million, no drugs have been approved for more than 25 years, so all generic drugs are all that is approved in that. Yes, the trade-offs here are, it is a very tough population to study with multiple comorbidities. You clearly need to be in the VA at least partially for those studies, but we're right now kind of actively designing what those could look like. Yeah, I mean, I think we were impressed by the data and we're impressed by the accounts the patients themselves gave. It's very interesting that patients. What sort of accounts can you? We interviewed all the patients post hoc just to get the sense of their total experience of the treatment itself and also the contrast with treatments they've previously had, both psychologicals, like psychotherapies, and also drugs. There was a dramatic sense of difference in the latter case. Also, the description of finding an autonomous way of getting through the issues that they'd had through the experience of the drug with the drug that didn't require the same kind of revisiting the trauma, which is kind of the assumed model for psychotherapy. Exposure model. Exposure, yeah. That didn't occur in about 50% of the cases of the patients. They still felt they'd somehow gained a perspective on the symptoms and a freedom from, particularly from, the most crippling of the symptoms. Without revisiting the original trauma. Which is very interesting because that's one of the reasons why it's quite hard sometimes to engage patients in psychotherapy. Got it. From a patient perspective, how do you view the draw of COMP360 as a PTSD drug versus TRD drug? Like if, you know, it's hard to compare and contrast across indications, obviously, but you know, how motivated are PTSD patients versus TRD patients to seek treatment and to undergo sort of a three-day process? PTSD is such a heterogeneous patient population. I'm sure we can't give an answer that characterizes all, but there are certainly plenty of PTSD patients who are desperately seeking another treatment option, just as there are plenty of TRD patients. Yeah, I mean, bear in mind it's a condition that tends to be very chronic. The average length of the symptoms is eight years from the trauma in our adult population. Furthermore, there is a tendency for the dysfunction to get worse over time. There is a sense in which people come to want treatment through time rather than very close to the traumatic event. I'll just add that the conditions often tend to be highly comorbid. They tend to be treated in the same settings of care. PTSD and depression. TRD, yes. And you know, unlike some other conditions, perhaps like psychotic disorders or some eating disorders where there is less insight into the condition, less of a subjective sense of distress and desiring treatment, like in TRD, patients with PTSD tend to be acutely suffering and interested in treatment. As self-aware that there's insight into the problem. Great. Any questions from the audience? The last minute? Great. In the II-B trial, what was the experience with folks redosing? In the II-B trial, what was the experience for redosing for the way? There was no redosing in the II-B. This will be the first retreatment. That we, Compass, have conducted, yes. There is, yeah, there is the Imperial study from four years ago, five years ago that has a second dose. Sarah Carhart-Harris piece, yep. Yeah. There are a couple of more recent small data sets, but this will be the first really large, robust trial of repeat treatment. How do they, how can a patient decide to read that? What do they have to meet? They have to meet a threshold on the MADRS. They are eligible for a re-dose. Yeah. When they get to part C, if they've shown no benefit, they can get a third dose. Correct, yeah. Or a fourth in the case of the COMP006, potentially. Or if they've previously responded and then relapsed. Yeah. Great. All right, thank you, everyone. Thank you, gentlemen. Thank you, Richard. Thank you.