Episode Transcript
[00:00:00] Speaker A: We did a lot of work back at the beginning of 2019 around psychedelics and as a company reached clinical conviction pretty quickly, we decided that one day these could be really important tools for psychiatrists in the treatment of serious mental illness.
[00:00:19] Speaker B: Well, Kabir, thank you so much for taking the time to have this conversation. I'm really excited to be speaking with you today. I've been looking forward to this conversation for quite some time. For the audience, Kamir is the CEO of Compass Pathways. Compass Pathways is a breakthrough drug development company focused on psilocybin for treatment resistant suppression. Before I rattle on about Kabir's successes, I'm actually going to pass it over to you. Could you give us maybe just a thumbnail sketch of your career and how you ended up here?
[00:00:42] Speaker A: No. Thanks very much, Brandon, and thanks for the opportunity to chat today. So, yes, as you said, I've now been CEO of Compass Pathways for the last couple of years and I came to that through a career in pharmaceuticals and even before that in medical devices. So career wise, a fairly traditional career. I am, as you may guess, British by background and indeed am now back living in London since March of this year. But over the last 30 years have spent most of my career abroad in Asia, Singapore and China and India and in the US for the last 15 years before this.
From a personal perspective, having grown up in the uk, you know, my life has been touched by serious mental illness. My father died by suicide. I had two very close friends, one from school, one from university, who died by suicide. And over time, as I built my career in the pharmaceutical industry, I think I always knew that at some point I would come to this field. I had a fairly typical adventurer in big pharma at Bristol Myers Squibb was lucky enough to do global roles, run China, run the Asia Pacific region. When BMS became a completely oncology company, I decided that's not where I wanted to be and I went to Otsuka Oatsuka within the industry is a well known Japanese pharmaceutical company, a storied pharmaceutical company that in fact has made very significant investments in serious mental illness. They were the discoverers of Aripiprazole Abilify, which went on to be one of the best selling antipsychotics. And I joined Otsuka to run the US and ultimately run their global business with that strong focus on serious mental illness. And I'm going to pause there because the next piece of the story tells you how I came to Compass.
[00:02:26] Speaker B: Yeah, and this is a fascinating story. As I was kind of digging in here, heard that you actually helped participate in one of the early rounds of financing over at Compass. Tell me a little bit more about that.
[00:02:38] Speaker A: Sure. So I think, as many of the listeners will be aware, really the kind of the psychedelic renaissance started maybe 15, 20 years ago. Small academic studies, NYU, Johns Hopkins, Imperial and London and so on. And while there was clearly interest among many, there was philanthropic interest and so on, the whole process was to many people catalyzed by Michael Pollan's book in 2018, how to Change youe Mind. And that brought it to a much broader group of people. Like many other people, I read that book and I was then also fortunate to meet Robin Carhart Harris very soon after that. Otsuk is a Japanese company that takes a very long term view and we were absolutely committed to mental illness for the long term, but cognizant, like many, that there was a lack of really interesting good new options. I went back to the team and said, look, we have to find out if this is real. And so we did a lot of work back at the beginning of 2019 around psychedelics and as a company reached clinical conviction pretty quickly. We, we decided that one day these could be really important tools for psychiatrists in the treatment of serious mental illness. Having reached that conclusion and convened AD boards and so on, we said, now, now what do we do? And we'd identified this with a small company called Compass in London that had some early data. And so we literally went and called on them. And I arrived in London in 2019, met the Co founders, George, Katya and Lars at the time. And over the next few months it became very clear that we shared a vision for the fact that there needed to be significant change, There was the opportunity for significant change in how serious mental illness could be treated and that psilocybin could potentially be a really significant breakthrough. And as we aligned on that vision, Compass was still a private company. George actually asked if Otsuko would be interested in leading the Series B as a strategic investor. And that's exactly what happened. And it was not necessarily a smooth process as you can imagine. It was still quite far out there for a global pharmaceutical company in 2019. But ultimately Otsuka did end up leading the Series B. One of my colleagues joined the board and that's how I came to know Compass and build my relationship with the co founders.
[00:04:51] Speaker B: As you looked at the market, as you looked at the various options, how did you get conviction around Compass specifically? Presumably there is maybe a few other spots you could have picked. So how did you think about that?
[00:05:03] Speaker A: Truly at the time COMPASS was the most advanced and will perhaps come on to talk about maps and maps pbc, because clearly that was out even then as a not for profit and moving into a slightly different structure. But really in terms of the data that had been generated at that point, COMPASS had some pretty robust early stage data. We're already well into the execution of the Phase 2B. We obviously did meet in other companies as well, but it was a combination of where they were, plus the credibility of the team, plus our conviction that they were running really rigorous, robust studies. And I think it's an important point there because this is a field that in the last 20 years has had a lot of experience and a lot of anecdote, but not necessarily that much evidence. And you know, a big part of what George and Katya had already set up to do and what I've continued to build on is that focus on generating rigorous, robust evidence. And I think if you look the, the Phase 2B that they were planning or actually in execution at the time was 233 patients across 10 countries, across 22 sites for a phase 2 study in neuropsychiatry. That is a very large and a very robust study. So we were convinced by what we saw there. And I think the other thing is, you know, psilocybin, we believe has, for certain patients, it has unique properties that make it uniquely well suited for some patients with treatment resistant depression and potentially other indications as well. I think the final thing was indeed that choice to start in treatment resistant depression. So this, where we're working today is with patients who by definition are both diagnosed and have somehow entered the medical system. But everything that's out there right now, SSRIs, SNRIs, even antipsychotic augmentation, is simply stopped working for them. It's a population in really serious need and a population that at the time, back then, before the approval of esketamine, there was just one old drug approved which had limited uptake. So really a population with very few options and again, that attracted Oatsuker and ultimately me to this. They have taken on one of the most challenging populations, one of the ones that's most in need.
[00:07:17] Speaker B: Since you mentioned it, tell me a little bit more about, you know, the kind of focus on, on treatment resistant depression. You know, we had Doug on the show as well, focusing on MDD instead. How are you thinking about the, the kind of indications to go after?
[00:07:30] Speaker A: If you think about it, it's, it's a fairly typical paradigm that you start with the hardest to treat, you know, end of a disease. And again, when you think about what's called treatment resistant depression, and I'll be the first to acknowledge that's not a really very nice phrase that let's say difficult to treat depression, the definition is people who have failed at least two other antidepressants in their current episode. So while theoretically it can be first episode depression, in practice, this is really a proxy for people with chronic refractory long term depression, people who have had multiple episodes over many years. And if you look at the populations that we're recruiting into our trials, it's typically that it's people who have had depression for many years have had many episodes. And again, we know from STARD and from some other trials that right now in that third or fourth line, the kind of response rate you get are very, very low. They're 10, 12%. So most people truly have very few options. So I think the decision that Compass made, that George and Katya made, and they made it in discussion with regulatory authorities, with psychiatrists, with Pisces, to start in that population because they really wanted to show that this could be a paradigm shift in that very hard to treat population, I think that's exactly the right place to have started. I'm actually delighted that now there are others, like Cybin, that are looking at the fuller spectrum, because I don't for a moment believe that psilocybin's value is limited to treatment resistant depression or the hardest to treat cases. I think it has huge potential. And look, I think we're still truly just at the start of this true psychedelic renaissance. I mean, other than Maps, now, like us, we're the first company to have got into phase three, to be in phase three. There is room for all of us across this spectrum of diseases. And as you're well aware, beyond just classical depression now, there are people generating signals in a host of other serious mental illnesses. And I just think that's really exciting and really shows great potential for the field. Sure.
[00:09:36] Speaker B: Is MDD on the radar?
[00:09:38] Speaker A: So we're thinking that through the other phase two data that we have published so far has been ptsd, which is also another very significant unmet need. We have a phase two ongoing in anorexia, again, where there are no drug treatments today, but clearly where we go strategically is something that's an open question.
[00:09:53] Speaker B: I saw the phase two in ptsd, the phase two in anorexia. How did you think about those as the next two indications as opposed to. I said it a little bit Tongue in cheek with, with mdd, which might have felt like maybe the more obvious follow.
[00:10:06] Speaker A: Yeah, no, it's a great question. And I'll look at them in two separate ways because they really are very different. So PTSD clearly travels very significantly with treatment resistant depression. Yes, there's a significant amount of comorbidity both ways, but a PTSD population, you're perhaps up to 50% also with treatment resistant depression. And what we thought about as we designed that study, as we thought about that study, was looked. This is a population again, that has very few treatment options. There are a couple of old drugs approved, but people recognize that for most people there's nothing that works very well. And what we were intrigued and wanted to understand, which was why we thought it was important that we do this study before other people get. There was a concern whether a profound subjective experience could actually potentially be triggering or have some sort of safety impact in a population with ptsd. And therefore we thought it was important that we do a study before other people got there. What we showed in that phase 2 study, 22 patients, open labels, so I'll recognize it's a limited data set, was indeed a very strong signal potentially for efficacy. But most importantly, we showed that it didn't have any significant safety impact so that it was safe to study this in that population. And I think looking forward, as I said, this is treated by the same physicians in the same settings of care, you can clearly see a strong synergy between PTSD and treatment resistant depression. Anorexia is obviously different. And if you look back at our history a few years ago we supported a number of investigator initiated studies actually in a whole variety of domains. Some were in depression, but some went well beyond that, including two in anorexia, one on the west coast at UCSD and the other at Imperial in London. And out of that first one we saw again 10 patients, open label. So a very small study, but a very intriguing signal that suggested for at least a significant number of these patients, this did lead to profound changes in their relationship to eating or to their eating disorder, with some return to normality in terms of their relationship to food. That's what made us decide to take that into a phase two, I will say, and we have been very public around this, anorexia is a very difficult disease to recruit patients into. In contrast to, let's say, treatment resistant depression, where most patients are seeking something else, most patients are going to seek a new treatment. With anorexia, the vast majority of patients actually have no desire to seek treatment and so recruiting patients into a randomized trial in anorexia has been challenging, and we've acknowledged that publicly. That said, we see it as really important that we continue to try to push the science there and see whether there is something that could bring potentially relief for some patients in anorexia. Obviously, again, commercially, it's a very different setting. This is treated in specialist centers, it's treated by specialists. But I think that from our perspective, in terms of really pushing the science and seeing if there's something that could be done there is very important. Back to your question. Clearly, we've also supported studies in bipolar. MDD is of interest and so on. So I think you can see around the core depression side, there continues to be opportunity that we'll go on to pursue.
[00:13:31] Speaker B: Of course. Now, I wanted to pull on the thread you just left there. Why did you feel it was so important to do this work in PTSD before others? Tell me about what the counterfactual was that maybe you're guarding against there.
[00:13:44] Speaker A: We recognize that these are powerful drugs and that we are working with vulnerable patient populations in doing this. It is candidly in all our interests across the sector that studies are done, number one, with the safety of patients in mind, and that as the companies that are now established themselves as public companies, raised a lot of money from investors and so on, while absolutely we are pursuing large, robust trials to try to get to regulatory approval, that has to be front and center the safety of patients. The fact that acknowledgment that we are working with vulnerable patients and putting them into even more vulnerable settings by nature of the experience that they may have, and I think, therefore, for something like ptsd, where there were real safety questions, it was important to do that. It was exactly the same question with bipolar 2. That's why we supported a small IIS in bipolar 2. Again, the concern there that that could potentially the strong subjective experience could trigger mania, hypomania, suicidal thoughts. What we saw again in 15 patients, there was not only a strong signal of efficacy for 12 out of those 15, but absolutely none of those safety signals either. And again, in time, you could imagine that replicating that in a much larger controlled setting for bipolar 2 would be important.
[00:15:07] Speaker B: One thing I'd love for you to maybe to opine on a little bit here is we've seen MDMA for ptsd. You're naturally looking at psilocybin for ptsd. How do you think about these different kind of approaches for this one indication and why one over the other?
[00:15:22] Speaker A: The place to start Is these are very, very different drugs with very different pharmacology. So MDMA is not in fact a classic, classic psychedelic, though I acknowledge the world at large just puts it in the same bucket as a psychedelic. But it is not a classic psychedelic. It does not produce the altered state of consciousness and so on. What MDMA does is that in pathogen, if you like, opens you up in a different way emotionally and therefore it does seem. And certainly the evidence from Maps now like us, is that that does require an active therapeutic component that needs to be integrated with MDMA in order to achieve the outcomes. Now, interestingly, there are companies working with derivatives of mdma. We're seeing to what extent that's really true and to what extent the therapy is truly required. Psilocybin is a very different drug. So the experience on psilocybin is highly on a substantial dose as the 25 milligrams of synthetic that we are delivering as the active dose is, is a highly inner directed experience. As you know, we have somebody who sits in the room during the entire session. We are recording those sessions. We were required by the agency to record those from a safety perspective. So we have those anonymized transcripts. I can tell you that the vast majority of those are silent in as far as interaction between the patient and the facilitator, the sitter in the room, because it truly is an inner directed experience. It's one that actually where you process your own emotions and it can be positive. It could be challenging. There could be a lot of personal history that's uncovered, but it's not one that requires active direction from a therapist in the room for the outcome. So these are very different approaches and I would not want to say one is better or worse than the other. We simply don't yet know whether for given patient groups, one is going to be more profoundly efficacious than the other. What I do know is that our study, and again 22 patients, open label, so small was this was simply a single administration of COM360. And what we saw is profound responses out to 12 weeks for the vast majority of the patients. In that I will acknowledge this was simple ptsd. So we chose single index trauma. So it was again a selective patient group. And one of the big questions for us right now, which we're working through is we would love to move that into a more robust proof of concept, but to what extent do we expand the patient group and so on. And I guess a final point, which is we all learn the hard way. We don't do direct cross trial comparisons. And again, I think, you know, Lycos, the MDMA trials they've done, was a much first, much bigger, but also a much broader set of patients in terms of trauma.
[00:18:16] Speaker B: Let me play that back to you just to make sure I understand, because MDMA is an empathogen, it's almost needed to be coupled with psychotherapy, whereas because psilocybin is a traditional psychedelic, it's more of an internal experience during the kind of patient experience. Is that about right?
[00:18:33] Speaker A: That's exactly right. And therefore does not need during the act of the drug experience itself to be coupled with therapy. And that's an important distinction because that's different from saying that the patient may not benefit from psychotherapy outside the specific setting of the drug administration. But yes, and that's what we know so far. And that's again, Lycos very clearly position their MDMA therapy that way as MDMA assisted therapy. I mean, they use the phrase that MDMA catalyzes therapy, obviously partly in the light of what happened with them, but also there were people, as I say, seeing whether there are derivatives of mdma, to what extent can you actually push the envelope on that therapy? But certainly from what we know today of the pharmacology and how these drugs work, how you characterize it seems to be the case.
[00:19:25] Speaker B: So Dan from MindMed was talking a lot about the challenges of a psychotherapy assisted model, but potentially the benefits of coupling with traditional psychedelics. Talk to me a little bit more about how you think about that potential coupling challenges associated with it. Would you ever consider a coupling?
[00:19:41] Speaker A: Yeah, so I think what's really important, and again, this is kind of really gets into how we or mindmed or anyone else needs to develop drugs. So just as a reminder as a step back, the FDA regulates drugs, it does not regulate psychotherapy and not as it regulates clinical practice. So we're very clear that what we are developing is the administration of psilocybin 1 or repeat dosings. It's clearly critical that there is adequate education of the patient as to what to expect, what a psilocybin experience can be. But that's really the frame of the intervention that we are seeking to get approved. And again, for psilocybin for lsd, that actual administration itself does not require therapy for, for us to have the effect. And again, what we showed was on day two, the very following morning, before there was even any integration. And I'll come back to that in a second, that's where we showed the maximal response. So it really was the drug effect on that day. That said, there is plenty of evidence out there that even SSRI benefits can be enhanced by good psychotherapy as well. So again, we're not anti psychotherapy. It may well be to the patient's benefit that there is a therapeutic alliance either preceding or following up from that. But the focus of the intervention we are trying to get approved, which is the psilocybin administration itself does not actually require therapy. And I think that's a really important distinction. And that again, is the contrast with mdma.
[00:21:11] Speaker B: There's a purity in isolating the effect.
[00:21:13] Speaker A: Yeah. And I think when you look at, we call it psychological support. And I actually think Dr. Guy Goodwin, our CMO probably takes credit for first really introducing that phrase. And now just some extent, you know, mindmed Cybin and other companies following behind, and that's how we address it, psychological support. But again, it's in the context of the administration of Comp360 itself.
[00:21:35] Speaker B: Take me through the patient experience for Comp360.
Imagine I'm showing up to participate in this phase three study. What would I expect to kind of happen here?
[00:21:47] Speaker A: So what we have per protocol is clearly first, this is a treatment resistant depression trial. And so the first thing I have to say is we work very hard to ensure the patients truly meet the criteria so that they have actually failed at least two antidepressants in the current episode. We do. These trials are monotherapy trials. So we do actually ask that patients wash off if they are on something. Already. Roughly 70% of patients in our trials have been normally an SSRI. They've had to wash out of that. We have had very, very few patients who have not been able to do that. And part of that, let's be honest, is that these drugs are typically not working in this population. In fact, they are not responding to the SSRIs, but they're there as a kind of crutch and so on. But we recognize in a clinical trial context that's a significant ask. We're making the patients, in order to do that, in terms of the protocol itself, we have two sessions of what we call preparation with the therapist who will be in the room. And that, as I say, is really about helping people understand the nature of the experience they're going to have. But it's not about. It's not therapy in the sense of actually trying to set intentions or to try and establish a preferred outcome for them. It really set expectations. We clearly have a bunch of physiological measures. We do also need to Check that people are not actively or recently suicidal because again, unfortunately in this population there is a very high incidence of suicidal, aviation, suicidal thinking and so on. So that's really important that people are, shall we say, prepared for the experience. But again, to make clear, this is not therapy in the sense of setting a frame for outcomes or what people expect to get out of it, acknowledging that it is a long day, it is a tiring day, there are some transient potential side effects like headache and nausea and so on, and that the experiences could be challenging on the day itself. So the final preparation session is the day before. So again, just to make sure that everyone is aligned, that this is going to be okay. The day itself. Patient will come in, taken to the room, meet the therapist again, vitals are taken, and then there's a patient with the rooms. And we have again, for a trial setting, we have actually put certain standardization around the room. And that was really in the context of we're attempting to minimize all the other variable elements here because this is a trial setting. And again, we'll get on to how trial to real world is a very different inflection point, but it is a trial setting. So yes, we do say a certain standardized setting, comfortable couch somewhere for the therapist to sit in the room, blindfolds are offered, and then we have a curated playlist which again is, I'm afraid you have no choice about the playlist. It is our playlist. And again, that was because we are trying to control variables in a clinical trial setting. And then the drug is administered and again, it will depend on, you know, which arm you're on and so on. And obviously all that has been communicated beforehand. Again, if we're talking about, let's say somebody is in fact on what we take as the active dose, 25 milligrams. That is typically for most people, an experience, you know, an intense experience for three to four hours and then a countdown after that over a couple of hours. So it is five to six hours, shall we say, in the room, potentially a little longer. As I said, for the vast majority of people it will be a largely in a directed process with very little interaction with the person sitting in the room. Obviously there is somebody in the room there for both practical safety, if you need to go to the bathroom or whatever, but also for physiological safety, for psychological safety. So if there is concern or if it is a challenging experience, they can just redirect you back. Obviously there is no touch unless that's been pre agreed upfront and so on. And you try to Avoid that. So this is the day itself. As the experience ends, as somebody comes down from it with the therapist, they determine when they're free to leave. But you have to be driven home. Yes. You cannot take yourself off. You know, somebody else has to be there to drive you the following day, come back. And that's where we, you know, the madras is taken by a centrally blinded rater. So nobody you've interacted with, who will then take the depression score on his head. We have seen that on the start of day two, that is actually the maximal response. That's when we get the strongest scores on that. And then we have what we call an integration session. But again, perhaps, you know, over time, we need to change that because that implies that it is, if you like, a. A therapeutic experience. It's not. It's a safety check. Again, it's for you to say, this is what I experienced. And really, just to be sure that no kind of extreme behaviors or actions are contemplated as a result of the experience. Not very common with psilocybin, but nonetheless, we think it's really important to have that safety check on the day afterwards as well. And then per protocol, another session is offered a week later. Again, similarly with the same therapist. So I think what we, again, have tried to do clearly, in the clinical trial setting is ensure adequate understanding what's going to happen, ensure safety in the room, and then ensure a safety check thereafter. But again, to be clear, this is not a psychotherapy intervention. And we would expect, both in that setting and in the real world, the patients may have an ongoing therapeutic alliance with a therapist, but outside the trial.
[00:27:22] Speaker B: Setting, where can we find this playlist?
[00:27:25] Speaker A: So, just. Just to acknowledge that George, our co founder, that is one of his passions, and George was very invested in that and will continue to be as we go forward.
[00:27:34] Speaker B: Is the playlist going to have to be a part of the standard treatment design? No.
[00:27:39] Speaker A: No. I mean, again, as I said, you know, what we. What we were very clear was it was important in a trial setting in order to say we believe this is the drug that's working, that we standardize everything else. But no, I think in the same way, the physical set and setting is not going to be part of any protocol in the future. But obviously, we would hope and work with the initial treatment centers we work with to ensure that it was appropriate in terms of putting the patient at ease and in terms of playlists, whether that's a. Bring your own. Again, to some degree, that's clinical practice. Yes. And we are not trying to dictate clinical practice, but certainly anecdotally and talking to patients and so on. The vast majority actually welcome the music and it does become a key part of the experience. As ever, there'll be happy in a handful who hate the playlist and for whom it's actually not a positive experience. But in general, the feedback has been very positive around that.
[00:28:37] Speaker B: So one takeaway from this is generally great music taste. Over on the Compass team, I do want to touch on maybe the elephant in the room here. You've been very specific in calling out the distinction between mdma, psilocybin. Let's talk about the Lycos experience and maybe some of the things that you're learning, watching kind of that initial path forward and how you're reflecting and maybe potentially changing some decision making in the face of that.
[00:29:00] Speaker A: So I think a couple of factors. I mean, first, let me be the first to say that without Rick Doblin and his pioneering spirit, many of the rest of us would not be here at all. So Rick was on his own for a long time, pushing both publicly and behind the scenes for people to understand the potential benefit of these medicines. And we must acknowledge that. Second, we must acknowledge, because it's been going a long time actually, the studies, the maps pbc, then Lycos designed for their phase three, were actually designed and finalized around seven years ago. And one thing that is very clear is that the FDA has developed their thinking significantly over the years since then and how they think that psychedelic drugs should be studied. So, you know, the draft guidance came out in the summer of 2023. We and the other companies that you've been talking to are well aligned with that. That guidance did not exist six years ago. So we need to recognize that. With that as background, a couple of areas. I mean, I do think the biggest area of distinction is what we've already addressed, which is therapy as opposed to psychological support. Because it's clear that the agency does not regulate therapy and because Lycos permitted individual choices around therapy, because there was, you know, while there was a manual, there was a very wide range of different approaches that therapists could choose to take with their patients, you ended up with something that is hard for the agency to interpret. And I think if they're going to move forward, they're going to find that something that truly streamlines, narrows that down is going to be important. The second big bucket then is around execution. And part of that dates back to a design that was finalized six years ago that clearly the agency would not accept today. As the design for two phase three studies. And that became very clear and partly execution more broadly. I mean, without getting into the details, there were issues around safety events and so on and so forth, which again, specific to lycos, a couple of other areas, which again, are going to be important to all of us. So this whole question of expectation and functional unblinding clearly occupied a lot of time. And how are we and others dealing with that? So actually, if you look back, even at our phase 2B design, we had three doses of psilocybin in that 25, 10 and 1. And Dr. Guy Goodwin, who at that time was the advisor and author of that protocol and PI subsequently joined us as our chief medical officer. Guy came up with that design, anticipating precisely some of these challenges. There would be what we saw in that. And another important point, which is a distinction from us. We studied both in phase two and in phase three, patients who are largely naive to classic psychedelics. And when I say largely naive in the phase two, only 6% of them had any prior experience. In the phase three, we're capping it to only 15% who can have any prior experience of classic psychedelics. Why is that important for that person? Coming in for the first time genuinely distinguished between 10 and 25 is pretty well impossible. Even on the 1mg, a number of people have a full blown psychedelic experience.
On the 25, around 30% had a very limited psychedelic experience. There's a great deal of intersubject variability, even though the means separate very clearly. And so that says, as a naive population, having those three doses does work as effectively as anything we can find to blind patients to what they're actually on. That same design is behind one of our phase three studies, the one that has two doses. The other study we have to acknowledge is against true placebo. And that was at the agency's direction to establish a true safety baseline in that we are going to be asking people's expectations ahead. We are going to be asking them after the event what they think they got. We acknowledge the majority of people with placebo will probably determine that they actually got placebo. But to the point, there are a fair number of people on the 25mg who may or may not have an experience as well. So there is still some mix there. So I think we've addressed that expectation, functional unblinding to the best we can through the design we have and with the fact that we have an overwhelmingly naive population. And that's really important. But clearly, having listened to the whole ADCOM having continued to review that with a continuous process of dialogue with the agency through breakthrough designation, there may be areas not so much about design and conduct of the trials, but more about reporting of the trials and how we think about unblinding the data in the long run that will be informed by how that ADCOM and that process went.
[00:33:45] Speaker B: I want to talk a little bit about this phase three, then. In doing some of the work before this, it kept coming up that this is perhaps the largest phase three ever run in psilocybin and potentially in psychedelics as well. Was that a conscious decision to run the largest? Was that an important kind of milestone to hit?
[00:34:02] Speaker A: No, I can assure you that we're not. That wasn't done as a badge of honor or a badge of pride. That's a consequence of the design, not an input to the design. So, as I said, the 2B was very large for a 2B. And that was a deliberate choice because it's well known that in psychiatry in general, going from phase two to phase three is high risk. And there are all sorts of examples of drugs, typically oral, daily drugs, which clearly have a very different dosing paradigm. But there are plenty of examples that have had a robust phase two and failed in phase three. So George Katira and the team at the time made the brilliant decision to do a really large phase 2. The phase 3 trial sizes are driven by the design, by powering, by what we want to see. I think perhaps less than the size in terms of the N. What I would focus on is some of the other bold choices, and these were more deliberate. So these are running fully blinded for 26 weeks. Primary endpoint at 6 weeks, fully blinded to 26 weeks. That is unusually long in any form of depression trial. And that was a deliberate choice to see what sort of durability we can establish up to 12 weeks and beyond. Second, they both have an open label portion from weeks 26 up to weeks 52, where everyone is eligible for a dose of psilocybin. And that was a really important design choice because we recognize that people who do not get an active dose, to expect them to stay in a study for 26 weeks will be very challenging. That, shall we say, incentive to stay in the study has been ineffective, and we've. We're seeing a low rate of dropout. So it really is, you know, keeping people in. So I would say in terms of durability, robustness, yes, we were keen to establish a standard. The size kind of fell out of the funnel as the Necessary outcome. And that certainly wasn't the objective. But again, this will mean, obviously, as the first kind of classic psychedelic to move forward. Safety is really important, as well known. I mean, the agency has expectations around the size of the safety database and so on. And that also was factored into the thinking.
[00:36:20] Speaker B: Now, all this work is, if I can be crude, expensive. As a small company leading the charge here, how do you think about bearing the burden of needing to prove all of these points along the way?
[00:36:32] Speaker A: This is the world of biotech. Yes, I mean, this is the world of biotech. This is what we do. People take really interesting science and they put everything they can behind seeing that this could be seen to work. But certainly, I mean, these are. Psychiatry is on. On the scale more complex because it requires more studies. You can't. I always joke with my oncology colleagues, you can do a seamless phase 1, 2, 3, and do it on a single arm, open label, and it's just fine. We clearly are investing very significantly in it. But what drives us is the belief that we have the potential to produce something that is profoundly, paradigmatically changing for some patients. Yes, these trials are complex. Yes, they're expensive. We have raised significant money. We will need to continue to raise significant money. That's a big part of my job. But what motivates and powers us on is the belief in what we're doing. And I think, Compass, we're 200 people, but every one of those people is here because we believe we're doing something profoundly important that could bring benefit to a lot of people. And yeah, will I pretend it's easy? Do I sometimes worry about where the next chunk of money is coming from? Absolutely, I do. But we're committed to seeing this through.
[00:37:44] Speaker B: As we say, internally with our team. If it was easy, somebody else would be doing it. Now, given the capital requirements of this, is this a natural monopoly? Do you like, do you think of this as all the value kind of occurring to scale here?
[00:37:56] Speaker A: Yeah. So it's a great question. So first, I mean, no, there are. I mean, you've spoken to none of them for this podcast. There are none of us moving through. And I think the promise here for a sufficiently large number of patients is there that ultimately capital will come in. I mean, again, if we look at TRD where we're starting, a third of all patients who are diagnosed and treated for NDD will end up not responding to two or more. So that is, you know, in the US alone, that's roughly 5 million people. Yes. And that's you know, as you can imagine, as more people are pulled in at the top of the funnel into treatment, that number's only going to grow. And similarly, across ptsd, high prevalence and so on. So I think there are very large patient numbers here. And so, no, I think, you know, we may end up being the first, you know, now, assuming, like us, does indeed have to do another study and so on, the chances are we will. I think there's room for multiple different approaches and so on here. And I think, let's be honest, you know, many of the really interesting questions around durability, redosing, induction, maintenance paradigms, what else you combine this with and so on, those answers are only going to emerge over a number of years. Yes, phase three trials do not answer all of those. Clearly, from a commercial perspective, potentially being the first is both an opportunity and a challenge. And I would say that the team is clearly very cognizant of both of those elements of it. But let's remember, we're not actually quite the first because esketamine spravato is out there, it is getting significant uptake. And again, we could get into the argument about whether esketamine is a psychedelic or not. But I think it does have dissociated properties. It does put patients into a vulnerable state where they need to be cared for and monitored. So let's call it a psychedelic. For all intents and purposes, the spravato, what JJ has been able to do, the infrastructure that's been set up and so on, there is a lot of that that we can leverage.
[00:40:00] Speaker B: I understand that there's a significant kind of government affairs challenge upcoming, provided this, this goes well. Public affairs challenge, getting things descheduled, having the states then come into compliance. How do you think about maybe just looking around the corner a little bit, knocking on wood, that things go well.
[00:40:16] Speaker A: Couple of thoughts around that. I mean, first, you know, we're obviously not doing this in a vacuum. I mean, you can't kind of open your newsfeed without seeing something else written about psychedelics right now. Yes, it's really part of the zeitgeist. And that has both positive and negative elements to it. I mean, the positive is the acceptance that these potentially could be an important tool for some patients is increasingly there, at least among some sectors. But obviously we have a lot of work to do and we're doing that along a number of different dimensions. There's a very tactical one which is rescheduling, as you say, so that if we are fortunate enough to get approved Federal level rescheduling is automatic, but state level absolutely isn't. We're already working to see how we can ensure that state level would be in place pretty soon after any federal level. So that's kind of tactics. It's working lobbying level really at grassroots, at state level and so on. But there's clearly the broader policy piece there and there. I think, you know, to a large extent, you know, some of the companies that you've already talked to, we are starting increasingly to work together as well. I think that's important. I mean, all of us have this interest in showing why the medical model makes sense from a safety perspective, from a quality perspective and so on. But also because that's really the only way to drive broad and equitable access, because that's the only way that you can push for reimbursement, be by that CMS or by commercial payers, because the informal sector is always going to be cash pay for the foreseeable future. So again, I think building alliances around that medical model is really important. But yes, I mean, back to a comment earlier. I wouldn't be here if I thought this was going to be easy. If I thought it was as simple as hiring 500 reps and sampling, I'd be doing something else. And I know it's going to be much more challenging. But I know what we can bring to patients is of much greater value.
[00:42:05] Speaker B: You mentioned that, hey, this is in pop culture now. It's in the zeitgeist. You can't open your Twitter feed without seeing something about this. Is that frustrating for you? Is it causing noise or is it actually a tailwind?
[00:42:17] Speaker A: My answer depends on which article I read that morning. No. So I think clearly the destigmatization, the acknowledgement that serious mental illness is something very troubling. The fact that people are being more nuanced about setting it in the right social context and acknowledging that this is not just a physiological thing, but there are social and other determinants acknowledging that bringing forward treatments that for whatever reason went underground for a long time and truly trying to understand their safety and what they can bring, all that's great. The hype is not so. The articles that say solution, magic bullet, cure, that's clearly unhelpful. First, because it's self evidently not true. Nobody is talking about curing depression. And second, because not just in a trial context obviously, but in a real world context, we don't want to create false expectations. These can be powerful tools for some patients in the hands of a treating physician. But we fully expect that for many of them there will be ongoing, whether it's psychotherapy, cbt, potentially even other drug therapy or whatever. And also one of the things we're trying to establish in phase three is potential frequency of dosing, but it's very unlikely to be one and done for most patients. So again, the hype piece is not helpful. Similarly, the post Lycos the world has fallen in part of this is not helpful either. And so, you know, what we and my colleagues in these other companies are trying to do is to steer that balance road that says here is huge opportunity and huge potential. But it absolutely behooves us to do this extremely rigorous, robust, expensive studies to determine safety and efficacy. And that's exactly where we are.
[00:44:02] Speaker B: Yeah, in some ways, all press is good press because it gives you an opportunity to get on a platform and talk about the thoughtful ways that you're approaching this.
[00:44:10] Speaker A: To some extent, yes, but there is some bad press mixed in with that good press too. But no, look, we can't alter that narrative. We can't alter some of those elements. But what we can do, as I say, is provide a very balanced, honest perspective and focus on the things we bring to it, which is, I say, a real understanding of how to develop these things and hopefully in time, how to make them available to patients if we're lucky enough to get approved.
[00:44:35] Speaker B: I want to bookend this conversation with maybe where we started. You are not the founding CEO of Compass. How did this come to be? Talk to us about the kind of transition.
[00:44:43] Speaker A: George was the founding CEO. So George, Katya and Lars Vilda together founded the company and George was chairman and CEO through the ipo. In the first couple of years of the phase two, the board made the decision in to do be very much with George. Part of that, that George is an entrepreneur, a visionary, has built many businesses. We would not be here without his vision, his and Katya and Mars application. But the board felt with George's complete agreement that the time was coming to bring somebody in with a background in drug development and commercialization, somebody who was kind of perhaps a little close to some of the nuts and bolts that were needed. So actually once they made that decision, I was the first person they called. And for various reasons, it went to and fro over a period of time. But after around nine months, once the 2B data was in hand, it became clear to me that this kind of job was made for me. I had George and Katya's trust and so I ended up joining two years ago. In August. And we thought very hard around the transition. We did a lot of planning and I would say from an operational perspective and from the perspective of the people in the company, it went as smoothly as it possibly kind of done. And you know, I give huge credit to George for that and the rest of the leadership on the board for ensuring that. But it's been a very effective transition. He remained chairman until earlier this year. He and Katya are both now off the board and determined to do their own next thing. I think probably still in the area of serious mental illness, but it was a very effective transition. And yes, that was the relationship I built, starting with that initial meeting of strangers in an office in London five years ago that blossomed into us leading the series B and so on. Ended up with me joining a CEO.
[00:46:23] Speaker B: What an incredible story. How did you think about making this on the surface, one could say quite a significant career bet in this kind of transition?
[00:46:33] Speaker A: Yeah, it's a good question. So I think the first thing to say is I'm clearly not unique. I mean, most biotech companies are either still helmed by a founder, somebody with a scientific vision and so on, or by somebody like me who's made the decision to jump from bigger pharma at the right point and so on. So I think like most of those people, I would say while the bigger companies bring incredible skills, resilience and so on, they're big companies. Yes, there comes a point in your career where you want to actually trade some of the bureaucracy and the decision making for something much more flexible and nimble, but it had to be. But what brought me to Compass specifically was what we are doing. The idea that we can bring psilocybin forward for patients in serious need, the fact that it absolutely was not going to be straightforward, that this is going to be challenging both through the drug development and potentially going to market and the opportunity to really make your mark on something in a way that in a bigger company, nobody's indispensable. In a bigger company, I'm not indispensable now either. But there's an opportunity to actually shape something for the future in a much more profound way. And yes, other element, I'm lucky enough to be at a point in my career where I could trade some of the certainty of income for some of the theoretical upside which, given the biotech markets of the last couple of years, it remains strictly theoretical, Maybe.
[00:47:56] Speaker B: On behalf of the kind of patients on our platform, thank you for taking the plunge and leading the charge into this market here. It's been such a pleasure getting to know you and having this conversation. Is there anything I haven't asked that I should have asked about?
[00:48:09] Speaker A: No. Well, first, thank you for the invitation, Brandon. I very much enjoyed it as well. No, I would just leave this with a final, final thought, which is, yes, what we're doing is difficult, but patients with serious mental illness so much deserve the opportunity for this new paradigm to be introduced. So much deserved new approaches to treatment and so on. And that's what we're completely committed to, providing a compass.
[00:48:31] Speaker B: Absolutely. Well, again, hey, Kabir, thanks so much for taking the time for this conversation. I've so enjoyed it. Just a heartfelt thank you.
[00:48:38] Speaker A: No, thank you. Thank you for the invitation, Brent. It.
