speaker-0: My name is Jennifer Smith Parker, Director of Insights at Biospace, and you're listening to Denatured. In this episode, I speak with Hans Erickson, Chief Medical Officer at Fundamental Pharma, and Steve Levine, Chief Patient Officer at Compass Pathways. We explore why treatment-resistant depression remains so difficult to address, and how new approaches, from rapid-acting antidepressants to psychedelic therapy, may reshape the treatment paradigm. Hi Steve and hi Hans. Thank you so much for joining this episode of Denatured. Pleasure to have you. If you can introduce yourselves, that would be great. Steve, why don't we start with you?

speaker-1: Thanks, Jennifer, and thanks for having me here today. Nice to see you, Hans. I'm Steve Levine. I am a psychiatrist by training, and I am the Chief Patient Officer for Compass Pathways.

speaker-0: Bring up puns?

speaker-2: Okay, so ⁓ hello everyone. Hi Steve, hi Jennifer. Happy to be here. I'm Hans Eriksson. I'm just like Steve a psychiatrist by training. Have spent ⁓ more than twenty five years in late phase track development in the psychiatry space and I'm now working as chief medical officer of fundamental pharma in Heidelberg, Germany.

speaker-0: Brilliant. Okay. So let's go ahead and start with our questions. So depression is often described as a heterogeneous condition. So how does that complexity shape why so many patients fail to respond to first and second line treatments?

speaker-1: Maybe

speaker-2: Can give that a stab, and I think it's very correct that depression is a very heterogeneous condition, and probably there are several different biologies at play. And ⁓ so far, the majority of the pharmacological treatments have been based on different versions of the same theme, mainly an attempt to overcome ⁓ perceived malfunctioning in monoaminergic neurotransmission. So practically all the Classical antidepressants have the same basic mechanism. And it may very well be that this is the best mechanism for a subset of individuals. But if there are several different biologies here, there are probably also, and we know that patients are not having very much help from these interventions. So what I think is promising now is that a number of different novel mechanistic approaches are being used. We we we we can see how ⁓ medications like psychedelics, like e ketamine-based treatments and several others are are making their way into the more general use ama among patients. And I think it will actually ultimately lead to more patients being able to get benefit from the treatment.

speaker-1: Yeah, thanks, Hans. And maybe just to build on that, ⁓ first starting with ⁓ as Hans said, the underlying biology of depression. Of course, in the diagnosis of depression, we have a syndrome, and the criteria are to meet five out of nine of the criteria to make a diagnosis. Well, with five out of nine, that means that there are many combinations and permutations. And so necessarily there may be different clinical pictures. And to Hans's point, that also might reflect some differences in the underlying biology and therefore what might be an effective mechanistic target for that subtype, which is not fully characterized at this point. Additionally, there is heterogeneity in the treatment course for these patients, which may have some bearing upon what might be effective treatment in terms of how many treatments have they tried previously and been failed by? How long has their current episode been? one of the more reliable predictors at this point of response to treatment is the length of the current episode, with the longer that goes, the more refractory the condition being. So there are many, many different facets to this heterogeneity that all leads towards a very complex picture of how we can effectively treat depression.

speaker-0: That makes sense. And the term treatment resistant depression, I know when I was speaking with with both of you gentlemen earlier, I understand more it's a classification than a diagnosis. So how should clinicians and drug developers think about that distinction?

speaker-2: It's very correct that ⁓ it's not a diagnosis in in itself. It's a subclassification of patients with major depressive disorder. Sometimes it is almost treated as if it were a a condition on its own, but every patient with TRD, treatment-assistant depression, has major depressive disorder as well. So there is a huge overlap. And ⁓ I think the ⁓ classification we are relying upon, which basically is that you should have failed Two adequate antidepressant treatments during the current depressive episode. There are s some variations on that, but that I think that's the basic idea. Is there in order to put up some rules about how these trials are being conducted and also to provide some guidelines for regulators? I think clinicians do not always think so black or white. Clinicians perhaps can see a patient who has only failed on one treatment, but who is suffering quite a lot, and almost treat that patient as if. He or she was ⁓ treatment resistant. There can also be patients who have milder depressive symptoms and failed several medications, but they are not necessarily treated by the clinician as if they had a T R D. ⁓

speaker-1: One of challenges though, clinically, is that clinicians often conflate the severity of the current episode with treatment resistance. And it's not the case that you necessarily need to have a severe depression in order to have a treatment resistant depression. The resistance refers to the number of lines of therapy that have been ineffective within this current episode. And so potentially even a mild or moderate depression could still qualify as a treatment resistant depression. The reason why the distinction is so important as based upon the number of lines of treatment is that evidence very much supports the fact that after a patient has been failed by two lines of treatment, the likelihood of a treatment being effective or efficacious within trials drops off a cliff. It is much, much more difficult at that point for someone to have an effective treatment at the point that they've met those criteria for treatment resistant depression. Regardless of the severity of the episode.

speaker-0: When we're talking about targets and most standard therapies, targeting serotonin, dopamine, or neuropinephrine, are we reaching the limits of that paradigm for a large subset of patients?

speaker-2: Yeah, I mean probably these targets are relevant for a subset of individuals. And ⁓ but I do think that we may have reached the end of how many different variations we can do on this theme. I mean the first modern antidepressants came during the nineteen fifties. ⁓ the first tricyclic in MiPR came in nineteen fifty-seven. It's it's still an efficacious medication. It has side effects that are perhaps not so acceptable today, but it it's still Is as efficacious as as more ⁓ modern medicines. And it's not until the the very last years I w I would say that we have seen ⁓ new mechanisms of action that are truly differentiated come coming out on the market. ⁓ but of course there are other thoughts one could have as well. So ⁓ typical treatment with an antidepressant is that you start the treatment with one, or sometimes more than one antidepressant can can can be added on top. And when you reach ⁓ a certain ⁓ improvement, you stop there and s stay on that dose and then you keep the patient normally on the same dose for six months or or longer. What we really don't know is whether the treatment algorithms could also be used in order to achieve better efficacy. So for instance, we know that some antidepressants are more effective on the serotonin side, others are more on the noradrenaline side. Maybe it's better to start with a serotonergic drug and switch to a noradren adrenergic, but That is an avenue that has not been ⁓ extensively researched. And and I think there are more variations one one could do, but I still think we are probably close to the limit of what we can do with these established medicines.

speaker-1: Yeah, and as Hans said, certainly many people have been helped by drugs with these mechanisms. We can't deny that. ⁓ but building upon what you've already said, Hans, I would agree that in terms of pursuing new development of monoaminergic drugs, we'd be beating a dead horse. ⁓ and not just in terms of the mechanistic approach, but also as far as the paradigm of care. This notion of needing to take a drug one or more times a day, every day, in many cases really rotely out of any other therapeutic context, has helped some patients but has its limitations. And that's why it's exciting to see that we're in an age of the development not only of new mechanistic approaches, but also new paradigms of care, which may be more rapidly effective and certainly more durable without the need to continue to take that treatment every day or on a very frequent basis.

speaker-0: So let's talk about these new mechanisms. That's a perfect segue here, Steve, what you're saying. So ketamine is provato, they showed rapid efficacy, but they common significant side effects, as we know in monitoring burdens. So what is the opportunity here to retain efficacy while improving tolerability and usability?

speaker-2: I think we have seen some examples in recent years how it seems as if antidepressant benefit can come from NMDA receptor modulators like ketamine without having that excessive burden of side effects that we see both with the nasal sprays that you mentioned as ketamine or spravato, and as we also see with infravenous ketamine, which is used off-label in some parts of the world. ⁓ so ⁓ I think the challenge now is to try to refine the concept of N MDM modulation and stare away from the dissociative experiences. And there could be different ways that that one one could do this, but I would not be surprised if we in three, four, five years' time we will see NMDA receptor modulators that have a much milder tolerability profile.

speaker-1: Yeah, and speaking from, and I agree with that optimism, speaking from the perspective of somebody who, going back to twenty ten, had ⁓ started to build the first infrastructure to deliver ketamine off label for treatment resistant depression. We ran a company between twenty ten and twenty twenty that operated these practices across the US. And then in the latter part of that decade, catalyzed by the FDA approval of S-ketamine, ⁓ some of the original Interventional psychiatry infrastructure that was built to be able to deliver in-office multi-hour treatments. The tolerability profile of ketamine and esketamine, I would say, was certainly an advance, an iterative advance upon what existed to that point in terms of SSRIs and other traditional antidepressants. And generally speaking, a pretty tolerable profile, the dissociative experience is something that is typically mild and tolerated by most patients. But the burden primarily in my mind remains in terms of the frequency of treatment. Esketamine, which is really the only pharmacologic treatment approved specifically in treatment-resistant depression and prescribed to patients today, is highly burdensome in the sense that it does require eight multi-hour treatments in the first month. It's twice per week, and then weekly in the second month, and maintenance is weekly or every other week, but many patients still reliant upon being driven by a caregiver to a two to three hour appointment on a weekly basis. That is a tremendous burden on patients and their caregivers. And with the data being generated in psychedelics today, where we are seeing evidence of much more durable response to single or or a few number of treatments, it does open up the possibility of paradigms that are are much less burdensome and ⁓ potentially more in the service of restoring quality of life.

speaker-0: Speaking of that, so let's talk about Steve about Comp three sixty. So you're advancing obviously a very different model here. So how does psilocybin therapy change a treatment paradigm compared to chronic antidepressant use, what we're seeing with sprovado? And I'm just curious what some of the challenges to clinical trial design and psychedelics compared to other psychiatric treatments.

speaker-1: Yeah, so a few questions embedded in there.

speaker-0: Within one. It's kind of a it's kind of it's kind of a multi question question. ⁓

speaker-1: Yeah, well, I'll start with just the background that at Compass Pathways, we are investigating a proprietary synthetic formulation of psilocybin. And we are studying this in a medically supervised context with one or more administrations. And at this point, across a large phase two B study as well as two phase three trials, we've now studied over a thousand participants in our phase three studies. We've already reported out. Highly statistically significant positive primary endpoints reached in both of those trials. And the emerging profile that we're seeing pending additional data that we're anticipating early Q3 is a paradigm where one or two initial administrations and potentially a retreatment at a later point may lead to durable efficacy out to at least six months, which is the furthest time point we've measured at this at this point. So this suggests a profile of an option that may be both ultra rapid as well as durable on a scale that we've never seen with a safety profile at this point that suggests one that is generally safe and well tolerated. We've begun the submission of our NDA on a rolling basis, which is currently undergoing rolling review. ⁓ Thank you. Thank you. So, you know, really, really excited about.

speaker-0: Congratulations.

speaker-1: the possibilities there of a a really a truly differentiated paradigm of care from what is available to patients living with TRD today. You also asked about the trial design. And certainly with psychedelics and with CON360 specifically as an example of a psychedelic, there are considerations of how do you blind studies where the participant can feel The drug, which is valid. This is something that FDA has acknowledged and has addressed through draft guidance on the design of these trials. It's also an area where Compass Pathrays has really been a leader, and in particular, Guy Goodwin, who's our chief medical officer, has been a pioneer in the space of how do you design trials to maintain the blind for psychedelics, or because this isn't really the unique domain of psychedelics, in fact, really for any psychoactive substance. Particularly where there's a subjective endpoint, there's the risk of unblinding. And we've managed this through a number of design elements, including blinded central raters, the reduction or the capping of the percentage of patients enrolling in the study or participants enrolling in the study who can have had prior psychedelic experience. And then, probably most importantly, the use of multiple active doses, a low, medium, and high. That enables you to give the prior instructions to participants that you will receive some dose of psilocybin. And when you combine that with their lack of prior exposure and an immersive day where they're wearing an eye shade and listening to music and lying down in the presence of a supportive monitor, that has been confounding. We've seen a clear dose response. And in the way that we measure the subjective experience to having psilocybin. We see a lot of overlap across the arms in the measurement of that experience, which which shows us that there clearly is confusion on the part of participants of what they've received.

speaker-0: Interesting. And as you're saying, this is definitely a very different design model ⁓ than what we've seen with standard antidepressants. I'm also curious when we're coming to real life burden, actually. I mean, Hans, let me ask you, ⁓ one of the aspects that Steve mentioned was the frequently taking pills. And I just wonder all from the psychological perspective, just patients, not like being reminded of their disease.

speaker-2: think that there are advantages in medications that you don't need to take regularly because the patient experience becomes much stronger if you know that you need to take a pill every day. I I think there may be some risks that with more irregular use that you may drop out of of the dosing schedule, which is also not a good thing. But I think there are s so many instances now where we have seen that daily treatment doesn't seem to be necessary. I mean for for ketamine It it does not seem to be necessary and for many of the psychedelic approaches that are in development to to see that as well. And this is not necessarily a first in medicine. Another efficacious treatment, electroconvulsive therapy, often have quite longstanding effects in many patients, but not in all. So it seems as if we are s moving into a a a set of treatment algorithms or treatment methods that are much more diverse than what we saw ⁓ in the past.

speaker-0: Interesting. Interesting. I'm wondering, is it possible that earlier intervention with novel therapies could be a key shift in how TRD is managed going forward?

speaker-1: That's a critical thing. Certainly we know a couple of things at this point. One, as I mentioned earlier, the longer someone goes ineffectively treated, the more refractory their condition, the less likely it is that they will benefit from everything. The more that comorbidities, whether it's other psychiatric conditions, medical comorbidities, those mount as well as the the costs of treating the comorbidities. And then the impact that it has on people's social life and their professional life, their ability to work. All of these things mount over time and it it ⁓ takes an incredible toll on the quality of life of patients and the potential for them to achieve wellness at some point. Additionally, we also see that with treatments that are specifically indicated for treatment resistant depression. Whether it's pharmacologic treatments like esketamine or neuromodulation techniques like TMS or electroconvulsive therapy that Hans mentioned earlier, these treatments are getting to patients with TRD too late. Even though somebody qualifies as having TRD after being failed by two treatments within the current episode, we most typically won't see the use of treatments that have demonstrated efficacy in this population until fifth, sixth, seventh, later lines.

speaker-2: Dad.

speaker-1: That is not okay. That's not ⁓ that's not in line with the evidence. And it is leaving people languishing and untreated and potentially having a negative impact on the more longitudinal course of their care.

speaker-2: We also know that early improvement during treatment is associated with better long term outcomes. So maybe it's more sensible to use these rapid acting medications earlier to actually overcome the depression and ⁓ not follow the normal path where you perhaps don't see full efficacy until after four to six weeks, sometimes even longer.

speaker-0: So, gentlemen, we have reached the end. Thank you so much, both of you, for speaking with me. It's been fascinating to learn more about the topic and about the great potential we have for patients going forward. And if you'd like to listen to more episodes at Denatured, please turn to biospace.com or shoot me a pitch at jennifer.smith-parker at biospace.com. Thank you very much.