Become a Creator today!Start creating today - Share your story with the world!
Start for free
00:00:00
00:00:01
Compass Pathway's Dr. Steve Levine
142 Plays4 days ago
Fresh from Psychedelic Science 2025, Dr. Steve Levine, the chief patient officer at Compass Pathways, talks to us about new Phase 3 results for psilocybin in treating depression.
Recommended
Transcript
Introduction and Guest Overview
00:00:09
Speaker
Welcome to Cognation. I'm Joe Hardy. And I'm Rolf Nelson. And on this episode, we're joined by a very special guest, Dr. Steve Levine.
Dr. Steve Levine's Career Path
00:00:20
Speaker
Steve is the chief patient officer at Compass Pathways and a board certified psychiatrist who has spent his career focused on improving access to innovative treatments for people living with serious mental health conditions.
Interest in Psychiatry and Mentorship
00:00:33
Speaker
Before joining Compass, he founded Actify Neurotherapies, a national network of clinics delivering interventional psychiatric care across the US. Steve, thanks for joining us.
00:00:44
Speaker
Thanks so much for having me. Absolutely. So we'd like to start off just getting your story a little bit. How did you get interested in psychiatry? how did that What was your path to finding that profession?
00:00:56
Speaker
I think we only have maybe 45 minutes or so here, so I'm going to have to make a very long story relatively short and hopefully I'll be succinct. But the the gist of it is, i mean, first of all, I've always been really interested in people and their stories.
00:01:12
Speaker
And I wound up going to medical school. I thought that what I wanted to do going out of medical school was to be a surgeon. But something I tried to do as I was going through my medical training was to put myself in the shoes of the doctors I was working with and try to understand what it was about their profession that drove them. What was their motivation?
00:01:34
Speaker
Were these my people? And would those same motivations be interesting to me over hopefully a decades-long career? And with the surgeons, it seemed like it was primarily the competitive element for them.
00:01:46
Speaker
And it's not that I'm not a competitive person, I am, but for that to be the thing that was fairly shallow to me, it certainly wasn't going to be you know something that that kept me engaged. And then with the primary medical specialties, it seemed that it was this body of knowledge, whether it was a disease or an organ system, and these doctors could sit in a room for hours without a patient present and just talk about that.
00:02:11
Speaker
And there seemed to be a bit of hubris in that to me in the sense that we don't know what we're talking about. And so to be so attached to a body of knowledge that is necessarily incomplete and probably incorrect also just didn't really grab me.
Psychiatric Care and Private Practice
00:02:25
Speaker
But I got lucky. I built some relationships with a couple of psychiatrists who became mentors. And even though I didn't really get a clear sense of what psychiatrists do because it's practiced in such a private way, they seem like my people and they seem to share that basic sense of curiosity about people and how they travel through this life and the idea that two, six, 20 people could have the same diagnosis and all have a very different experience of it and a very different story.
00:02:54
Speaker
And that just made sense to me. And so I went in that direction. I then got lucky again because I landed in a residency training program that really trained us to be therapists first and medication prescribers second.
00:03:08
Speaker
And I feel lucky because, you know number one, pharmacology in psychiatry at that point, and largely to the extent still today, is is fairly simple.
00:03:20
Speaker
you know There are 50 some odd antidepressants, but most of them are me-tos of each other. It's a a pretty simple pharmacology. But people are complex. And developing a model of the mind is complex, as you both know as cognitive psychologists.
00:03:36
Speaker
And so it made sense to me that that's where we should be spending our time in you know learning to taking to take care of people with their mental health conditions. And so that was really what I was rooted in.
00:03:48
Speaker
And then i went from there to a fellowship across the street at Memorial Sloan Kettering Hospital. And there I was learning to be a a psychiatric consultant to the oncology and medical teams. And so it it taught me some things about team-based delivery care models and this intersection between psychiatry and and the rest of the medical field.
Ketamine Clinics and Actify's Holistic Approach
00:04:10
Speaker
And so I took that and left, went out into private practice and was part of a very typical problem, which is i set up a private practice that didn't accept insurance, charged fees that I couldn't afford myself, mostly psychotherapy focused, but prescribing you know when necessary.
00:04:30
Speaker
And in addition, I did a couple of other things. I had a grant to to start a relatively early model of collaborative care within a federally qualified healthcare care center in Trenton, New Jersey.
00:04:42
Speaker
I did something similar in a women's health program after that. And that taught me a bit more about equitable access to care. In the meantime, I had this background dissatisfaction with the medication options that we had.
00:04:57
Speaker
And so making a very long story short, I became interested in the early research looking at the repurposing of ketamine in anesthetic for psychiatric indications, and in particular for people with highly refractory depression.
00:05:12
Speaker
And at the time, there had only been a few small academic studies. This wasn't available clinically. And after a lot of to and fro, i ultimately couldn't convince myself not to start to offer this to patients, at least to those who had no other options.
00:05:31
Speaker
And that was the start of something I feel pretty ambivalent about at this point, given kind of the wild west that ketamine has become, but starting the first ketamine clinics in this country.
00:05:44
Speaker
And originally that was just an offshoot of my private practice in New Jersey. Eventually it became a national company that was originally called Ketamine Treatment Centers. We later rebranded as Actify.
00:05:56
Speaker
We operated around the country and Really the the goal of that company was not to try to treat as many people with ketamine as possible.
00:06:07
Speaker
It was a few things. Number one the recognition that although not the end all be all, ketamine did represent a novel approach to treating depression and some hope for those who had exhausted other options.
00:06:22
Speaker
Personally, I really liked the idea of a treatment that was in person, really high touch, the ability to spend more time with patients. and in some sense kind of rejoin this bifurcated field where therapy tended to sit over here and medication over there with little communication in between, so a much more holistic approach, and one delivered as a team.
00:06:45
Speaker
And I think there's you there's something about multiple nice people being nice to you with with significant and frequent contact that makes it more likely that that your treatment may be effective and in ah in a more durable way.
00:06:58
Speaker
Another thing that was attractive about it to me was looking ahead at the pipeline, what was in development. It seemed that many of the more promising potential options were going to require a similar infrastructure in terms of the physical space as well as the team approach to deliver them as ketamine, and that wasn't yet built.
00:07:18
Speaker
So it was an opportunity to build for today at that time, as well as for the future. A lingering problem was still that as an off-label treatment, and one in most cases not directly covered by insurance, this was something that wasn't really affordable and accessible broadly.
00:07:37
Speaker
you know Once again, delivering treatment that I couldn't afford myself. and that was not okay. And so the you know the next step on that journey was looking ahead to when there would be FDA approved products that would be covered by insurance.
00:07:50
Speaker
And the first of those wound up being S-ketamine, J&J Spravato product, that was approved in 2019.
Transition to Compass Pathways and Psilocybin Research
00:07:57
Speaker
And that was the opportunity to shift the business from one that was focused on ketamine out of network, patients paying at the point of service,
00:08:07
Speaker
to one that was a broader-based interventional psychiatry platform that delivered a range of FDA-approved and insurance-covered treatments, at the time being primarily Spravato and TMS, which is transcranial magnetic stimulation, with, again, an eye towards the future and there being additional you know later approved products that would fit within this model.
00:08:31
Speaker
All was well and good, but the initial commercialization of Spravato was challenged, to say the least. It was it was quite rocky in the beginning. ah And that along with a few other challenges around the same time and then the pandemic, which you may have heard of, that that has given me the COVID that I have at this very moment, hit in early 2020 and we wound up closing Actify, which was a really difficult thing, both professionally and personally.
00:09:05
Speaker
But I knew the co-founders of Compass Pathways and was intrigued but about what they were developing as far as Comp360, the synthesized form of psilocybin that they were starting to investigate for treatment-resistant depression.
00:09:21
Speaker
And it was pretty clear that if J&J stumbled out of the gates with Spirato, that there were going to be some similar challenges to access for patients if Comp360 received an FDA approval.
00:09:33
Speaker
And so it was kind of a natural segue to move into Compass Pathways to start working early on many of the considerations that that will have a significant impact on whether the millions of patients who are currently underserved living with treatment resistant depression are able to get timely access to a new option if it's approved.
00:09:57
Speaker
Great. So before we get into the recent news and the information about the clinical trial, um so your inroads to this were via ketamine, and um now you're working more with psilocybin. I wonder if you could say anything about um mechanistically how these two drugs differ and are are are used towards the same end towards treatment of depression, PTSD, and several of these things, um how they might be used differently in terms of, well, mechanistically, but also in terms of what kind of therapy might accompany them?
Understanding Depression and Treatment Mechanisms
00:10:39
Speaker
It's a great question. And as you are probably aware, as you ask it, a difficult one to answer because we bump up against the limits of what we know. when We start off, I think, having to acknowledge that we don't even know what depression is.
00:10:53
Speaker
you know and it's As far as our diagnostic manual, the DSM, we have syndromes. We don't have diseases. So they're just you know collections of symptoms that we draw a circle around and we give it a name. And every once in a while, we erase those circles and draw new ones and maybe change the names.
00:11:09
Speaker
And so by by the very definition as a syndrome, we don't really know its etiology. We don't know the the pathological process. And it's probably likely that when we get around to knowing what we're talking about that It may be more heterogeneous than than we realize. There may be you know multiple pathways to get to this final common picture that we call depression.
00:11:31
Speaker
So with all that hand-waving and preamble said, what we what we think we know, at least at this point, about the mechanisms of of ketamine or psilocybin or other classical psychedelics primarily come from preclinical research, not necessarily looking at the the impacts on the brains of of people themselves, but in animal models or in petri dishes or you know test tubes.
00:11:56
Speaker
Although we you know we do have imaging data at this point in humans as well. but In any case, what what we do know are the receptor targets of these drugs, right? We know the the initial actions of them. And so in the case of ketamine, it's impacting a glutamate receptor called NMDA. It's an NMDA receptor antagonist.
00:12:17
Speaker
With psilocybin and other classical psychedelics, it's a serotonin receptor called 5-HD2A.
00:12:25
Speaker
That sets off a cascade of events, though, and i don't think we we fully know yet what the pathway is that's responsible ultimately for the building evidence of antidepressant effects for for both of these classes of drugs.
00:12:42
Speaker
ah you know There are many very interesting theories at this point about the desynchronization acutely of certain brain networks and remodeling of pathways in the brain, speculation about you know various you know mechanisms of change that may happen after the experience of of drugs like these.
00:13:05
Speaker
ah Ultimately, yeah we don't yet know. you bring up the the issue of therapy. And you know I think one of the reasons why there's a lot of interest in in many of these types of compounds is the recognition that after exposure, there may be a period of time where people are more receptive to new learning or to shifts in in thinking or perception of themselves and the world.
00:13:32
Speaker
It's often known as plasticity. And you know it's a very exciting area of research. you know Certainly ketamine or psychedelics aren't the only things that that enhance plasticity in the brain.
00:13:45
Speaker
And enhanced plasticity isn't always a good thing either. And so you know I think there's there's a lot more to learn there. but you know it It does you know naturally provoke the questions of might combining some kind of psychological intervention in the period after exposure to an agent that increases plasticity have a beneficial and long-lasting effect.
00:14:09
Speaker
And it's certainly been ah question here where it seems that these these these molecules may have lasting benefits long beyond the time that it's actually in the body.
Clinical Study Design for Psychedelic Treatments
00:14:21
Speaker
And so it's also people trying to explain that.
00:14:25
Speaker
you know In the case of how we're studying Comp360 right now, ah we are not including psychotherapy. We use psychological support, which is really aimed at safeguarding patients through this process.
00:14:39
Speaker
So before administration, providing some treatment education about what they you know might expect during the study, ah you know how they'll be supported by a therapist in the room on that day of administration, trying to build some trust and rapport, setting an intention for for the participation in the trial.
00:15:01
Speaker
On the day of administration, it's quiet. you know Unless somebody is really having a challenging time, then the role of the person in the room is is really just to maintain psychological and physical safety and and not in any way to be directive or intervene.
00:15:18
Speaker
And even in the case that somebody is having a challenging experience, it's it's they're really their role just to support them and try to maintain their focus on the experience and not avoid that. And then there's follow-up sessions, which just give people an opportunity to talk in an open-ended way about that experience and and follow up on safety and so on.
00:15:38
Speaker
And you you know we've designed our trials in that way for a couple of reasons. you know Number one, first and foremost, you know we are committed to the safety of the participants in our study, so we really want to focus on that safety.
00:15:53
Speaker
Number two, you we want to minimize the variables in these studies so that they are rigorously designed and they answer the necessary questions about the risk-benefit profile of these drugs, which leads into recognizing that what we hope to do is submit an application to FDA for approval as a new option for patients.
00:16:15
Speaker
And the purview of FDA is evaluating the safety and efficacy, ultimately that risk-benefit ratio, of a drug, not the practice of medicine or psychotherapy.
00:16:26
Speaker
So we need to make sure that there is you know a profile that they can evaluate. With that, it's not that we don't think that psychotherapy might not have some role here.
00:16:37
Speaker
It probably does not, and almost definitely does not during the day of, because it is an internally focused, quiet experience that people shouldn't be distracted from. But after after treatment, it's entirely possible that they may be helpful.
00:16:51
Speaker
And that will be a next opportunity post, hopefully, an FDA approval as ah as a required step one to to learn more about. And you know we think it's likely that that psychologists, master's level therapists, others that that practice psychotherapy will have an interest in delivering psychotherapy after these treatments. And certainly it'll be you know an interesting set of research questions to follow.
00:17:17
Speaker
Yeah, and do you see any trade-offs here between, so as you designed a clinical study like this, obviously, you know, you talked about the expense of it too. So um obviously looking to deploy something that's going to be cost effective.
00:17:32
Speaker
At the same time, you talk about the amount of therapy that may be optimal for a patient here. Do you see any trade-off in this situation where, you know,
00:17:43
Speaker
Optimal treatment might include something that's more expensive, but but there's sort of ah a sweet spot that you can aim for.
00:17:53
Speaker
it's It's a really important question. you know And again, our our aim is broad and equitable patient access. So that's at the front of our minds and in any decisions we're making and certainly what's guided the approach that we're taking of an FDA approved pathway for reimbursement by insurance.
00:18:10
Speaker
When you think about the costs involved in these or any treatments, it's primarily people time, professional people time and drug cost. And I think the ketamine-Sketamine story is a great ah analogy for this because with ketamine, off-label ketamine, ketamine's a cheap old generic drug.
00:18:32
Speaker
A typical dose is about a buck, maybe. know it's It's relative pennies. It's the people time that's really expensive there because it's typically delivered in office. It should be delivered in an office, I think.
00:18:46
Speaker
And so it involves a lot of professional time. Those people, of course, are entitled to be reimbursed for their time. But the as an off-label treatment, that people time typically is not reimbursed by payers.
00:19:00
Speaker
Enter S-ketamine Spravato as an FDA-approved product that was that's been broadly covered by payers, even though the drug is much more expensive, to many orders of magnitude more expensive than generic ketamine.
00:19:15
Speaker
Because both the drug and the professional services time are paid for by insurers, the out-of-pocket costs for patients are many orders of magnitude lower. Right? ah You know, often just a $10 copay for patients as opposed to paying hundreds of dollars or more per treatment for off-label ketamine.
00:19:35
Speaker
So we have an analogous situation here in a sense.
00:19:40
Speaker
To the extent that there will be actual therapy added on to this treatment, you know, fortunately, there is an existing framework for insurance companies to reimburse therapy.
00:19:55
Speaker
And relative to the other types of services that insurers tend to cover, therapy therapy is relatively inexpensive, and so typically not over-limited in terms of you know access for patients if they're insured.
Synthetic Psilocybin Development and Benefits
00:20:09
Speaker
on On the drug side, you know we certainly are aiming in the the completion of our phase three studies in treatment-resistant depression to present a profile of a drug that is attractive to payers in the sense that you know we hope to demonstrate that it's differentiated from existing options by both being rapid acting but also just one or two initial treatments being quite durable and therefore representing significantly less burden burden on patients, on their caregivers, on the healthcare system at large.
00:20:44
Speaker
We do also recognize, though, that unless healthcare providers can be reimbursed for their services, then it would be difficult for them to provide this. And so another thing we've already done was a couple of years ago to partner with several other groups, some professional societies as well as another manufacturer,
00:21:03
Speaker
to apply for new reimbursement codes that are specific to psychedelic treatments, the administration day for a psychedelic. And those were approved. They went live in January of 2024. So the reimbursement framework is already essentially laid for the eventual reimbursement of these products if approved.
00:21:21
Speaker
That's really interesting. So the the particular medicine that you're working with, Comp360, is a synthetic form of psilocybin, which is the active ingredient in magic mushrooms.
00:21:34
Speaker
Why did Compass Pathways choose to go the route of ah creating this synthetic compound. And what do you think the differences or advantages, disadvantages, so on and so forth of this synthetic form relative to say, just taking a magic mushrooms?
00:21:53
Speaker
Yeah, it's a question we get a lot, of course. you know are Our aim was to have an FDA-approved product because that essentially is the key that unlocks insurance reimbursement and then uptake and delivery within the existing healthcare system.
00:22:12
Speaker
Now I'll be the first to acknowledge that we do have not have a perfect healthcare system, far from it. But 92% of Americans are insured in some way. Most do rely upon their health insurance coverage to afford, accept, and access their care.
00:22:28
Speaker
And so if we are sincere about equitable access, then that was really the only option as a pathway. We do recognize that there are many ways for people to access psychedelic substances, including taking natural products.
00:22:44
Speaker
ah But going back to the requirements for an FDA approval, what FDA is evaluating is safety, efficacy, and quality of a drug product.
00:22:55
Speaker
And it's that quality side which includes you know standardization of dose, purity, the the safety of the product i means having what's called a GMT product.
00:23:08
Speaker
And it's pretty difficult to do that, particularly at scale with a natural product. And so it typically requires a synthesized product to be able to meet those standards so that everyone knows that the medicine they're getting is the same as what person B got, it's the same medicine they got a year ago, that it's, say it's 25 milligrams, it's 25 milligrams.
00:23:33
Speaker
That's really, yeah, that makes a lot of sense. And I'm curious about the differential effects, if you see any, particularly where where my mind goes with this, you know, clearly if you go to ah vendor, for example, you know, here in the Bay Area, there are there are places you can go to buy these, you know,
00:23:53
Speaker
mushrooms and you know off the shelf and there's a variety of different strains that are available and so you know there's there are options there but of course it's a it's a mushroom you know it lots of different things can happen and in the in the growing of the mushroom so you end up with different um you essentially the the compound that you're dealing with there is different the the the product that you're dealing with is going to be highly variable in that way And one of the ways I'm particularly interested in is the difference in GI effects. So effects in the stomach and the gut, um you know because obviously serotonin receptors in the gut are, there are a lot of them.
00:24:34
Speaker
And so there there this is an active you know process in the gut and this is sometimes a negative side effect for people having GI distress or issues. do you notice a difference in the compounded formulation there relative to say dried magic mushroom psilocybin?
00:24:55
Speaker
It's a smart question. and We can't answer it because we're not comparing 60 head to head to a natural product. I will say that, you know, in with the data, almost complete data set, which was our phase 2B study,
00:25:11
Speaker
that we released that data a couple of years ago. If you look at the adverse events from that study, nausea was one of the most commonly reported adverse events you know for a subset of people. So certainly, nausea isn't eliminated because it's a synthesized product versus know an actual mushroom.
00:25:30
Speaker
But whether there's a relative difference, I couldn't say. Yeah, I mean, um but my guess would be that it would be better just because there's probably a lot of other things in the mushroom that may be, you know, not great for the gut.
00:25:42
Speaker
But I guess it's it's an open scientific question at this point. Yeah. One that will be interesting to follow up on. Yeah. So, I mean, maybe we could get into some of the results from that phase three trial.
00:25:52
Speaker
Well, first of all, could you talk a bit about what is a phase three trial? You know, kind of how did you get to this point? Why is it important? but you know Who are the patients that you're trying to help and what are you finding?
00:26:08
Speaker
Happy. Yeah. let let me me Let start from the from the beginning. so we yeah ah When you talk about drug development, it's typically conducted in multiple phases.
00:26:22
Speaker
They're, even before you get into testing in people, you know, oftentimes you're doing preclinical research to understand just the mechanism of your drug, the impact in animals perhaps, studying the toxic the potential toxicity of the product, et cetera. But once you move into human trials, they are numbered one, two, three.
00:26:44
Speaker
That leads you up to the the point of a potential FDA approval. And then if it's approved, sometimes there are phases of studies beyond that, like phase four studies. um In terms of phases one, two, three, ah you are kind of gradually progressing your understanding of your product and asking different questions along the way.
00:27:06
Speaker
In phase one, tends to be in a relatively small population. You're primarily interested in the the potential safety of your drug in humans. maybe starting to gather some early information about a dosage range that you might want to be testing.
00:27:22
Speaker
As you move into phase two, you start looking at efficacy more and narrowing down what you think will be your your ultimate dose that you want to test that you think is the most efficacious.
00:27:35
Speaker
and start testing in more people to to build more of that evidence. um And phase three are essentially your confirmatory trials in larger populations seeking to replicate the efficacy that you found in phase two and complete the ah the the evidence you need to submit to FDA as an application for review and hopefully approval.
00:27:58
Speaker
So we're currently in phase three, considered late stage trials, that final phase before submission. We have two pivotal phase three trials, and we just announced the top line data from the first of those two.
00:28:13
Speaker
And this is in a group of people living with so-called treatment-resistant depression. And that means that they have major depressive disorder and within this episode of depression have not benefited from at least two trials of antidepressants.
00:28:28
Speaker
Sadly, that's a lot of people. There are 20 million U.S. adults that have depression each year in the U.S. About a third of them would be considered to have treatment-resistant depression.
00:28:40
Speaker
So we're talking about roughly 3 million people. And by the way, there's only two products right now approved for treatment resistant depression, really only one of them is prescribed at all, and that's Spirato.
00:28:54
Speaker
And that's only getting to about 50 to 60,000 people right now. So that's a big gap of 3 million people waiting for treatment, 50 to 60,000 Spirato. so that just gives us a sense of the unmet need here.
00:29:08
Speaker
So again, we were studying treatment-resistant depression in these phase three trials. The one we just reported on looked at our 25 milligram dose versus a true placebo sugar pill.
00:29:23
Speaker
And this was in 258 participants, a US-based only study done in 32 sites. It was what's called a monotherapy study where patients were not on other antidepressants.
00:29:37
Speaker
So we're just studying the effects of COMP360 alone. And what we looked at was a single administration of either 25 milligrams or placebo, single administration with some preparatory sessions ahead in a supervised setting with a therapist present during, with those follow-up sessions with the therapist after.
00:30:02
Speaker
and then measured the change in their depression scale score from baseline to six weeks later. And the scale used is one called the Montgomery-Oseberg Depression Rating Scale, MADRAS.
00:30:15
Speaker
It's a very commonly used depression rating scale. And what we found is that ah there was a clinically meaningful difference between those two arms after the single administration six weeks later.
Placebo Effect Challenges in Trials
00:30:31
Speaker
Now, we don't have much more information at this point because the study is still blinded out to week 26. So the both the patients, participants, and the study team and us won't know much more about this until that 26-week period is completed because during that time, under certain conditions, patients may also be eligible to get a retreatment.
00:30:55
Speaker
And so we want to maintain the integrity of the study. So all we know so far is the difference between those two arms at week six. We know that it was statistically significant that these results were you know not just due to chance.
00:31:11
Speaker
And we also got a statement from a board that reviews safety outcomes from our studies, saying that there was no clinically meaningful difference in the safety between the two arms in our study.
00:31:25
Speaker
Yeah, the the placebo effect, of course, becomes a topic right away when you're doing psychedelic trials. And just to kind of go back over that you know story, which was something we've talked about on this show before, but I think it's worth kind of just reviewing it because it's an important issue and I'm sure it will come up in the discussion of this trial and other trials as well.
00:31:48
Speaker
And you know I sort of refer to the new york the New Yorker cartoon where you have the patients like ah so Some of them are like sitting on the psychiatrist couch, just kind of calmly having a conversation. Then you've got the other group that's sort dancing around and in this wild bacchanalia kind of scene.
00:32:09
Speaker
And the one patient turns the other patient says, think we're in the control group. And the basic idea is that when you're in the control group of a psychedelic trial, you you sort of know that you're in the control group. And when you're in the treatment group, you sort of know that you're in the treatment group because it's psychologically very acute.
00:32:26
Speaker
Like you have it an experience, you go on a trip or a journey and, you know, there is, ah was introduced to an idea I was at the psychedelic sciences conference recently called the placebo suppression effect in psychedelic trials, where actually people who are in the placebo group improve less than you would typically see in a placebo arm of like an SSRI trial, for example, you know serotonin selective v-uptake inhibitor, like your standard, current standard antidepressant trial.
00:33:04
Speaker
you see a smaller placebo effect in psychedelic trials than you do in SSRI trials. And the hypothesis is that it's because there's sort of a disappointment effect of patients.
00:33:16
Speaker
you know They're enrolling in a psychedelic trial, and they're interested in that. And so they they could end up in the control arm, and they're aware of that, and it's somewhat disappointing.
00:33:27
Speaker
So do you have thoughts or ah any anything any comments on that? I do have thoughts. Yeah, first of all, yes, there has been a lot of discussion of the the role of placebo in psychedelic studies and the the know sort of the inherent nature of the unblinding effect of a psychedelic experience. And so what does that mean in terms of interpreting the data that that results from these trials?
00:33:54
Speaker
mean, I think it's worth pointing out first that it's certainly not the unique domain of psychedelics. Really, any Any neuropsych drug is going to be unblinding to some extent. It's just that we're really paying attention to it now as psychedelics. All psychiatric trials rely upon subjective endpoints.
00:34:19
Speaker
They're clinician-rated scales or patient-rated scales that ask for a subjective report of symptoms or an evaluation of symptoms. And so when you combine that with the recognition that you feel any of these drugs, you feel an SSRI, it's obvious if you've had an SSRI versus a true placebo, of if you know the gastrointestinal side effects as an example.
00:34:43
Speaker
ah With antipsychotics, you would certainly you know feel them and and feel the difference between that and a placebo. So it's not really the the unique domain of psychedelics, but that's not to discount it as something that we need to control for.
00:35:00
Speaker
you know One way we manage this in our phase IIb study, which we've carried over into the second of our phase III trials, is to use three active doses, a low, a medium, and a high.
00:35:13
Speaker
Because one of the challenges with the true placebo is that it's a binary. Patients are told they're going to receive something or nothing. And it's to be easy to tell if they got something or nothing.
00:35:26
Speaker
But in ah population that is mostly naive to psychedelic experiences, and we've we've capped the number of folks who can have had these experiences before so that most have not, who are wearing an eye shade, listening to music, lying down in a room, having a very immersive experience, and they're told you're gonna receive some dose of psilocybin, a psychedelic drug, then it actually creates a a fair bit of confusion.
00:35:53
Speaker
And what we saw in Phase IIb was that ah significant subset of our one milligram group, a dose which should be sub perceptual, you know many of them reported with the scale that we used to measure that experience that they had a psychedelic effect.
00:36:11
Speaker
And on the other end of the spectrum, you know a subset of the 25 milligram group reported no like its significant psychedelic effects. And what we wound up seeing was a ah pretty nice dose response, which was you know very supportive of the fact that there is a drug effect and that it's dose dependent.
00:36:30
Speaker
With this study that I was just talking about, our first phase three trial that's versus a true placebo, you know yes, that is going to be unblinding. We did that because we had to. you know FDA is interested in a placebo-controlled trial to establish a true safety baseline.
00:36:48
Speaker
It was part of guidance that they put out in June of 2023 for guidance for manufacturers to design psychedelic evaluation programs.
00:36:59
Speaker
But even you know with what I said before about the binary of something or nothing being unblinding, although we don't know the absolute numbers of how our placebo arm or the 25 milligram arm change, we only know only know the relative difference at this point.
00:37:17
Speaker
It would not be surprising if there was a non-zero placebo response because, again, it is ah highly immersive day. There's a lot of TLC from the study staff, and there's always that effect of you know multiple nice people being nice to you and and being in this caring,
Future of Psychedelic Psychiatric Treatments
00:37:36
Speaker
supportive environment. And so you know some people may have gotten a bit better just because of that.
00:37:43
Speaker
Yeah, that makes sense. And I think it's important to mention also that, you know, in this context, you know, talk about side effects and, you effects in general, that you're aware of things. ah SSRIs certainly do have side effects and people are often aware that they are on SSRIs if they are.
00:37:58
Speaker
And some of the side effects are quite nasty, actually, for some people. And that's actually one of the potential areas of benefit for psychedelics is as a different profile, not necessarily that it's all good, but, you know, there's a different profile of effects and side effects.
00:38:14
Speaker
Thinking about that and just the the sort of spectrum of options that may be available to patients in the future. I mean, how do you think about that in the context of you've got ketamine for treatment of treatment resistant depression, potentially you'll have psilocybin.
00:38:31
Speaker
um There's also now some research in 5-MeO DMT that's coming out that's looking like things are moving in a positive direction there. mean, how do you think about how that might play out as you have a toolkit that's now, I mean, after a very long time of very little innovation in this space, in the pharmacological domain, at least for psychiatry, in the treatment of depression specifically, but also in anxiety and other related syndromes, as you say.
00:39:03
Speaker
How do you think about that toolbox opening up and where do you see, like say, Comp360 fitting into that relative to other things?
00:39:12
Speaker
I think this is great for everyone, frankly. yeah The unmet need is so huge that this is not a winner-takes-all environment. you know This isn't you know which new option is going to win and be the one that you know patients take. and you know We're often asked about competition within the space, and we genuinely just don't really see it that way.
00:39:33
Speaker
and I quoted some numbers earlier of 3 million U.S. adults with treatment-resistant depression and only 50,000 to 60,000 of them getting Spravato right now. If you also include neuromodulation like TMS, transcranial magnetic stimulation, or ECT, that still brings that number only up you know somewhat over 100,000 last year So there's tremendous unmet needs. We need as many new options as possible.
00:40:00
Speaker
So yes, psychedelics are being developed in the same indication that we we've just studied in phase three, treatment-resistant depression, many other indications as well. We need new options across all of these.
00:40:16
Speaker
And the likelihood is that at least in the early days, these will be delivered in the same centers. I mentioned before the interventional psychiatry infrastructure and these platforms that deliver you know multiple treatments know today, mostly for treatment resistant depression patients, but that probably will expand as there's options available for other diagnoses as well.
00:40:38
Speaker
And they tend to be treatment agnostic in the way that they offer these treatments. It's, you know, largely a function of, you know, ah an appropriate match based upon a patient's symptoms, any medical comorbidities they may have.
00:40:55
Speaker
There's a large element of patient preference here. And I think that in the future, that's likely to come to bear on this. You know, we're going to have shorter acting options and longer acting options and ones that may be pretty short but quite intense or you know longer and a bit gentler and more meaningful.
00:41:15
Speaker
We'll have to see as the profiles of these drugs are better characterized through phase three studies how durable they are. But that may be something that comes into play when when treatments are being recommended or or patients are selecting ah amongst multiple options.
FDA Approval Journey and Compass Pathways' Plans
00:41:32
Speaker
But again, i think the more options, the better. Okay, so phase three looking good. um What are the next steps towards eventually aiming towards FDA approval?
00:41:45
Speaker
um Any he salient hurdles that are ahead? What's the time horizon like here? We have a few steps ahead ahead of us. So this was the top line primary endpoint of the first study, week six.
00:42:01
Speaker
We will still have to complete and report out on the full blinded portion, the 26 weeks of this study. And then we also have our second study, the three-dose 110 and 25 milligram study, where we're getting two initial administrations instead of one.
00:42:19
Speaker
And what we've said in terms of the timeline of all of this is that we will report the 26-week data of the second study. in the second half of 2026.
00:42:33
Speaker
And we will report the 26-week data from the first study when it's available, but we we will time that based upon the completion of the first part of the second study. I know this starts to get kind of complex.
00:42:48
Speaker
But the the second study, ah the first part is nine weeks, and we don't want to release the 26-week data of the first study before everyone's enrolled in that because we want to preserve the integrity of that study.
00:43:01
Speaker
Uh, and so, yeah, there, there's some time dependencies here, but ultimately to answer your question, we're, we're expecting the bulk of the data from our two phase three studies by the second half of next year.
00:43:17
Speaker
Now we've expected, we've guided that we will need all of that data in order to file with the FDA. Probably worth mentioning though that we do have breakthrough therapy designation, which means that we have the opportunity to have dialogue with the agency.
00:43:36
Speaker
We will be speaking with them now that we have this top line data in hand from the first phase three study. And there seems to be a growing recognition in FDA, in HHS, within the administration that there are big unmet needs.
00:43:52
Speaker
that so far there's a lot of demonstrated potential with psychedelic treatments. And so, you know, us and other manufacturers will see if there there may be some opportunities for acceleration, but our base case assumption is we'll need both studies.
00:44:11
Speaker
Yeah. So recently the FDA had an opportunity to look at MDMA treatment for post-traumatic stress disorder and they, you know, in committee decided to not move forward with that approval.
00:44:26
Speaker
And there was some, you know, controversy around the studies involved there. i mean, how does that impact your process and and have you like are you looking at what happened in that and that process and what you're doing and thinking about how to maybe avoid stepping on some of the rakes that that were stepped on in there?
00:44:49
Speaker
yeah We, of course, you know all within Compass watch that advisory committee. We follow that process closely. you know Ultimately, it was disappointing that, at least so far, they received a complete response letter and MDMA was not approved for PTSD.
00:45:07
Speaker
There were some concrete reasons that were pointed to excuse me for for that initial complete response letter. And, you know, ultimately there were some some gaps in the application as far as certain toxicity studies, liver toxicity, cardiac toxicity.
00:45:27
Speaker
They had had what's called a SPA with FDA, a special protocol assessment where they had pre-agreed on elements of how they would study their product. but it's clear that FDA has been learning like all of us along the way. This is a new area of science. Their thinking has evolved over time.
00:45:48
Speaker
And they had, I mentioned before, published guidance in June of 2023 for what they expect to see in the design of these studies. And unfortunately, Lycos didn't have the benefit of having that guidance before designing their trials.
00:46:04
Speaker
And so that may have accounted in some ways for some of the the criticisms of the package they submitted. But if you do look at that guidance, it it maps very nicely to the design of our trials.
00:46:15
Speaker
And you know we we are generating a very complete package that we believe includes all of the elements that will be required for an approval. So ultimately, although that was you know a disappointing thing for the field, certainly for patients, it didn't change any of our plans or or any of the ways that we are conducting our studies.
00:46:37
Speaker
Great. um So ah just to move sort of into future directions too. um So um Compass Pathways is also working on using the same substance, Comp360, in other treatments, ah notably for PTSD and for anorexia, both of which are in phase two.
00:47:02
Speaker
um I'd love to hear some comments about just the the thoughts about the usefulness of Comp360 in these situations, and then you know similarities and differences, especially in terms of and patient care in that direction.
00:47:20
Speaker
yeah we're We're particularly excited about the potential of Comp360 PTSD. It's another area of huge unmet need, particularly in the wake of lychosis CRL for their MDMA program.
00:47:36
Speaker
We conducted a ah relatively small study that we reported data from last year in 22 patients, open label, single administration of 25 milligrams of COMP360 using a very similar model of psychological support that we used in our treatment-resistant depression studies.
00:47:56
Speaker
And it was primarily a safety study. you know We didn't have previous experience with Comp360 for those living with PTSD. And so we you know had some initial questions about safety and tolerability in that condition.
00:48:11
Speaker
We did also have an efficacy endpoint in that study though, which was the PCL5, or excuse me, the CAPS5. PCL5 is the the patient rated scale.
00:48:21
Speaker
the CAPS-5, which is clinician-administered. And we were really encouraged by what we saw. You know, the the safety and tolerability were very encouraging.
00:48:32
Speaker
Response remission rates were were also, you know, quite impressive. you know the The caveats being that a small study, not ah a randomized controlled trial, but open label.
00:48:45
Speaker
But it was yeah essentially a pilot to to to better understand the population prior to moving into a later phase study. But that's what we're doing right now. We're in the process of finalizing designs for a late stage PTSD study, and we will be progressing that work through this year and really excited to move forward there.
00:49:06
Speaker
You mentioned the phase two study that we've had in anorexia as well. We should have data from that this year.
Hopes for the Future of Psychiatric Innovation
00:49:14
Speaker
Well, great. Well, Steve, yeah, thank you so much for for taking the time with us today. We're running out of time here, but really appreciate your pushing through your COVID as well.
00:49:24
Speaker
Yes. Super appreciative. It's been a fascinating conversation. We like to ask people a final question, which is just simply like, what are you most excited about in terms of where the research is going or where the field is going or like where your work in particular is going?
00:49:38
Speaker
what's what What's really lighting you up right now?
00:49:43
Speaker
Going back to you know when I was telling my story earlier, you know the things that have been most important to me through my career are having effective treatments that are acceptable to patients to offer them and for them to be available in an affordable and accessible way.
00:50:03
Speaker
And for decades now, we've been stuck with okay options that help some people, but certainly have left millions with with tremendous unmet need.
00:50:15
Speaker
And there's been really very little innovation to address that. And to the extent that there have been you know small sparks of innovation, they have been widely accessible. And so across the psychedelic space right now, you know with a number of positive trials recently, not just from Compass, but from others,
00:50:34
Speaker
it It really is promising that you you know one or more of these products may eventually receive an FDA approval, that there may you know truly be new options for patients who are waiting at some point in the near future.
00:50:50
Speaker
And because we are pursuing it through this route, through FDA approval, that they will be covered by insurance and affordable. ah Well, Steve, thank you so much for for being on the show. And yeah, good luck with all your efforts. And, you know, really appreciate all that you're doing. and Thanks so much.