Hi, good afternoon, everyone, and thank you for joining us for this lunch session of Baird's Global Healthcare Conference. I'm Joel Beatty, one of Baird's biotech analysts. I'm pleased to have MindMed with us, and we have Dan Karlin, Chief Medical Officer. Dan, thanks for joining us today. Yeah, my pleasure. Thanks for coming, everybody. To begin, could you provide an overview of MindMed for those who might not be familiar with the company? Sure. MindMed is a clinical stage, brain health-focused biotech who... We have two assets in the clinic currently. Our lead asset, MM120, is a pharmaceutical formulation of LSD, and we are developing that, for the treatment of GAD primarily, and have just announced that we will also be kicking off an MDD program. So we're targeting both anxiety and depression, which are obviously, largely overlapping diagnoses, about 80% construct overlap. So we think by picking up both of those labels, we'll sort of be a, the best go-to option for all comers in the clinic, if and when approved. We've also got an asset we call MM402, which is the right enantiomer of MDMA. Folks will be familiar with, MDMA from Lykos development program, where they're developing MDMA as a session-based therapy, much like, what we're doing with MM120. But 402, in our case, is intended to be a daily drug for the treatment of autism spectrum disorders, so a sort of PK-dependent prosocial effects that will treat the core symptoms of ASD. Then we've got some unannounced, you know, preclinical, early pipeline activity as well. Great, so let's begin with 120 for GAD. Could you summarize the clinical data to date? Yeah. So LSD has a tremendous amount of data dating back to the '50s and '60s. The original psychedelic renaissance was largely driven by the discovery of the effects of LSD in Switzerland. Of course, due to some factors outside of the medical or clinical domain, access to LSD and other psychedelics was largely restricted for a number of years, starting in the early '70s until the last decade or so. What we saw over the past decade of increasing interest in clinical research in psychedelics was that psilocybin largely came to the forefront. You know, folks sort of explained this as when some of the original psychiatrists and researchers who wanted to bring psychedelics back into clinical research were going to their academic department chairs to say, "Hey, I'd like to develop psychedelics." They were met with a degree of skepticism, and found it easier to make the case to do psilocybin research than to do LSD research, despite the history of LSD being as rich as it was. We saw the opportunity to develop a drug in a space that other people weren't looking. So we picked up LSD and also saw the opportunity in generalized anxiety disorder, even though many of the companies in this space were looking at MDD instead. And so what we know now from the modern research is that in academic studies of LSD, in both depression and anxiety, we see rapid and durable efficacy. Academic colleagues of ours at University Hospital Basel have now described up to two-year efficacy from a two-dose regimen of LSD. What we saw in our own Phase 2B research was that in participants starting with moderate to severe GAD, an average HAM-A score of about 30, which puts people well into the severe category of GAD, we saw efficacy in response to a single dose of drug. We tested four doses versus placebo, and in both our 100 and 200 microgram dose groups, we saw efficacy that began as soon as 24 hours after dosing. At week four, we saw a 50% remission rate in GAD, and that remission rate and efficacy persisted out to 12 weeks after a single dose. It should be noted that we are giving drug as a monotherapy, so we tapered people off of background therapy and provided no additional psychotherapy alongside the drug. This is a single dose of drug in the absence of any other therapeutic agent, creating a 12-week remission in folks starting with moderate to severe GAD. Great, and then so thinking ahead, what are your plans for the pivotal trial program for 120? Yeah. So we've got three pivotal trials that we've announced. Our first study, which is called Voyage, is another study in GAD. It will be largely similar, or if not identical, to our phase II study, except that we'll test only two different arms. So we'll have a placebo arm and a hundred microgram dose arm. A hundred micrograms was the dose that we ultimately decided to bring forward because it had the best efficacy of any dose we tested and better safety than the 200 microgram dose. So we'll bring forward a hundred micrograms into that Phase III study. It will be just as phase II was. It'll be a twelve-week double-blind period with a primary endpoint at twelve weeks. We'll also look at day one, and we'll look at some longer-term efficacy in an extension phase that goes out for an additional forty weeks, so participants who are enrolled in the double-blind period will then continue into the forty-week extension, where they will be eligible for up to four additional open-label doses. We'll follow that, so that study will start this year and read out in the first half of 2026, and then early next year, we'll start a similar pivotal study. The only difference is that, or there are two differences, really. The first study will be U.S. only and have the two arms. The second study will be identical in design, with the exception of having a third dose arm, which will be a 50 microgram dose arm, included to be able to mitigate some of the effects of functional unblinding by having a confounding dose, so that folks who get the hundred microgram dose, will not know for certain that they got the treatment dose, 'cause they may have been allocated into the, less efficacious or inefficacious fifty microgram dose group. And that second study will be, US and international. Great. How has breakthrough therapy designation helped MindMed with the development of this? Based on the four-week data that we were able to bring to FDA from our phase 2b, we were granted breakthrough therapy designation, as you say, and breakthrough therapy designation does a few things. It obviously creates some reassurance among investors and observers that FDA is aligned with our evidence generation strategies and sees the potential for the drug. What it also enables is closer engagement with the agency, so that as we think through all of the nuances of a drug development program, we're able to go have one-off meetings, have email exchanges, have the ability to really be sure that we're in lockstep across our entire program with what the agency wants to see. You know, for reasons that I'm sure we're about to get into, that, that's increasingly relevant in the world today, because the agency has now had to make some decisions around another company's program that, while not a classic psychedelic like MM120, has some parallels that I think are relevant. So our ability to engage our regulators to ultimately feel like we're sitting on the same side of the table, looking out into the future and imagining what a package could be like that would give the regulators the confidence to say, "Yeah, go ahead, bring this into the world. Yeah. So let's dive into that a little bit more. One of the questions we get more commonly from investors, it relates to the Lykos MDMA CRL for PTSD. You think that's what I was talking about? Yeah, and it may have been. I'm not sure. Yeah. And, you know, how does the development approach at MindMed compare? Yeah. So we watched the Lykos AdCom with great interest and attention to detail. The general reporting, maybe for folks who aren't following the space as closely, a company called MAPS that has been around since the 1980s and is now MAPS persists, but their drug development arm has become Lykos. In 2017 kicked off pivotal programs for the development of racemic MDMA in a session-based format for the treatment of PTSD. MDMA is an interesting molecule in this regard because sessions with MDMA do not, on their own, produce lasting clinical change. MDMA was in its initial development and persists as a psychotherapy enhancer. I'm a psychiatrist and a psychotherapist myself. I trained with folks who were doing psychotherapy when MDMA was available for psychotherapy, and everyone describes the same phenomenon, which is that psychotherapy with MDMA essentially allows you to progress the therapy at a rate that is not usually achievable without MDMA. So it creates a sense of rapport, trust, openness with the therapist in the patient that allows for, as it was described to me, skipping the first dozen sessions of therapy. That's great, right? A drug that helps people do good psychotherapy is, I think, a boon and could be helpful to a lot of people. The trouble, though, when it comes to drug development, is that you're actually testing a dual intervention, that the drug on its own is not gonna make anybody better, so you need to test the drug plus psychotherapy. That's really hard to do. It's hard to do for a couple of reasons. One, studying psychotherapy is hard. That's how we've ended up with cognitive behavioral therapy as the dominant modality because it's easier to study. It's not better, it's just easier to study. And as with anything, we tend to pay more attention to things that are easier to measure, rather than things that might actually work better. And so if psychotherapy is hard to study, then you look at this problem of studying a combination intervention. So you've got drug versus placebo with a psychotherapeutic intervention. Now, you've got psychotherapists in your study, as your study therapists, who are believers in MDMA-assisted psychotherapy. That's right, why they participate in the study. Those therapists end up unblinded to the drug condition. You can't sit with someone for eight hours doing psychotherapy and not, well, yeah, I guess you could, but you'd have to be pretty bad at your job to not notice if the person you were talking to was on a treatment dose of MDMA or not. So not only do you have variability in the drug condition, you now have an induced variability in the therapist condition. It's not to say that this is impossible to study, but it's difficult to study. Lykos faced that challenge, starting admittedly, you know, we're talking eight years ago, before a lot of what we now know about the regulatory stance toward the drug classes, is before we got the experience of watching a bunch of other people work through how to design studies in the class and this core MDMA problem. And so, at the AdCom. FDA clearly presented a case for approval. It seemed clear to us watching the AdCom, and this doesn't get reported this way, by the way. The reporting on the AdCom is like it was a travesty, and the AdCom itself came out strongly negative toward the NDA, but FDA, you know, Tiffany and the Division of Psychiatry, seemed to be presenting a case for approval. Maybe a narrow label, maybe a fairly strict REMS. They actually presented a proposed REMS, but it seemed like they wanted things to go a different way, in light of... Now, who knows what would've happened with a different AdCom, right? The counterfactuals are easy to guess at, but not super meaningful, with the AdCom having gone the way it did, ultimately, FDA issued about a month ago, almost exactly a month ago, a CRL to Lykos. Now, we can't know what's in the CRL because no one's released it. We know what they said in a PR, which is that they're gonna go try to continue a negotiation with the agency around getting a label. But the reality is that when people look at what they consider to be the class that is psychedelics, MDMA-assisted psychotherapy gets lumped in with, say, MM120 in isolation. We, from the outset of our development program, have engaged in methodological mitigation strategies that avoid many of, if not all, of the pitfalls that Lykos encountered. So while it's certainly not good for patients that this, you know, potential treatment has been delayed, there were safety concerns that emerged, and there were some issues with the way that safety was monitored in the Lykos trial that was raised at the AdCom. So one could imagine that FDA had some commentary on safety in the CRL. But we were heartened by the fact that it seemed clear that the division itself wanted to find a path to approval. And we happened to have an end-of-phase two meeting the week after that AdCom, where we got to sit with the division, look at our program, and talk with them about how we are mitigating the concerns that were raised around the Lykos program. So while it's certainly a setback for Lykos and potentially a setback for folks with PTSD who could benefit from this treatment, it is not truly a practical setback for us. Effectively, everything we would have done in our phase three is what we will be doing because, again, we've been looking to mitigate these risks from the outset. Thanks. That's helpful context. And maybe thinking about the market opportunity, could you help frame how large GAD is and how many patients might be addressable by 120? Yeah, and of course, we've got GAD, and now we've got designs on MDD as well. So we've got the whole set of neurotic illness. The current estimate for the GAD population in the U.S. is 18 million people, 13 million of whom are receiving some form of treatment. The MDD market is 30 million, about half of whom are getting some sort of treatment. So we're talking about a massive population of people with diagnosed disorder. Some really interesting things that we've been doing recently, looking at the epidemiology of these illnesses, is that when you look at national surveys that effectively look at the symptom burden that is consistent with GAD, it seems likely that about twice as many people are walking around with symptoms of moderate to severe GAD, having never been diagnosed for the condition. I said at the beginning that we were sort of looking at this landscape of psychiatric illness and thought that GAD was a good target, and there are some reasons for that, which is that the MDD-heavy psychiatry market that we've seen since the early 1990s is not a reflection of real symptom burden. Now, that's not to say that there aren't people with depression. There are. But the history of psychiatry prior to the early 1990s was really focused predominantly on anxiety disorders. You go back as far as the late nineteenth century, and the concern for folks with neuroses was anxiety. There were a smaller population of people who had cyclical depressive disorder, who had true neurovegetative, anhedonic, melancholic depression, and they'd have episodes of this. That was a recognized thing, but the majority of patients with neurotic illness suffered from some form of anxiety. This was true through the barbiturate era. This was true into the benzodiazepine era. But what we see in the early '90s is what? The sudden emergence of this new class of drugs called serotonin reuptake inhibitors. SRIs, and I shy away from saying SS and SNRI because those are just marketing terms. SSRIs aren't that selective, and SNRIs, you know, how much more they do on norepi is not entirely clear. So the SRI class, not super efficacious, right? Effect sizes of zero point three-ish, if you're lucky. They also induce anxiety early in treatment, and that's... You know, when we think about the black box warning for suicidality, whether or not that's an actual risk or not, early in treatment with SRIs, people tend to be activated and anxious, and even in some cases, a little bit agitated. That precedes improving mood. So the sort of the least comfortable condition for someone with in a depressive episode to be in is still anhedonic, still feeling depressed, but now energetic. That kind of agitated depression is actually a pretty high-risk state. So because SRIs are not effective against anxiety in many cases, the residual symptoms of treatment-resistant depression look a lot like GAD, and people between depressive episodes often have symptoms consistent with GAD, they've just been diagnosed with depression. There was a purposeful market shaping by many companies to notably Pfizer with Zoloft, who created the PHQ-9 to get people diagnosed with depression, to shift the focus of the market from anxiety to depression. And, you know, I remember TV commercials that said, "Everybody worries," but major depression means you have, you know, a chemical imbalance in your brain. Turns out it's like a Zoloft deficiency. And so the pendulum is swinging back toward the direction of recognizing that GAD is a really important, really debilitating, more constitutive, less episodic disorder. And so that sort of a focus on GAD, we think, recognizes where things are headed. And that's consistent with the fact that USPSTF, in the last eighteen months, issued recommendations for screening all adolescents and adults for anxiety disorders in healthcare settings. Got it. I mean, thinking ahead to the potential commercial approach, how could your approach be similar or different to J&J's Spravato for depression? The Spravato story is an interesting one. The development program for esketamine, which became Spravato, which is just the left enantiomer of a cheap generic drug, ketamine, which has created a whole interesting other commercial thing. The development for Spravato took place in hospitals. It took place in ERs, it took place in inpatient units, and that suggests a kind of a clear direction that the initial thought around Spravato was going, which was people who present acutely with severe depression, high suicidality, treat them with Spravato. And this is kind of how ketamine had been used in the academic studies that led us up to Spravato. Treat people in acute care settings who are acutely sick, get them better enough to get out of there. Ultimately, that is a really difficult market, hospitals particularly, right? To get into a doctor's office, you just have to get a doctor to write a prescription. To get into a hospital setting, you've got to go system by system to formulary committees and get on formulary. It's a slog, and it's a place where a lot of promising drugs have ended up as kind of commercial flops because that was the plan. It took the J&J team, and it actually took a kind of a team turnover a few years to respond to the fact that this ultimately wasn't the best target for their drug. And so what we saw after the Spravato approval was this flourishing of ketamine clinics, ketamine infusion centers, sort of cash pay, you know, strip mall-esque, go in, get your ketamine infusion, go home. That market then was able to gradually convert to payer-supported, more legit clinics, where esketamine was administered, and today we have about 3,500 of these places. They're not J&J controlled around or anything like that. They're individual businesses or private equity roll-ups or, you know, small networks or in some cases, hospital-owned places where the predominant treatment is esketamine, and there may be some other interventional psychiatry offerings like TMS. That development has now allowed J&J to move toward what they're saying is gonna be a billion-dollar annualized run rate. Not seeing that opportunity earlier, not supporting the creation of that infrastructure is what took them so long to get there. What we're trying to do is both to see how we can get into that market, get into those places, and anticipate a future much larger opportunity that could be things like any therapist's office, right? There's no safety reason that any therapist, any place where psychotherapy can be given, isn't suitable for someone to spend doing an MM120 session. So we're trying to be very proactive about both converting existing market and opening up and creating novel markets for the drug. Could you discuss the size of the phase III trials? And one of the reasons I ask is the GAD studies, I think, are 200 and 240 patients, while the MDD study is a little bit smaller at 140. Yeah. So we were able to show in phase IIB a high degree of statistical significance with forty participants per arm. That was, that was great. It was everything we could have hoped for from the drug. Obviously, as we go into phase III, we recognize that many drugs show smaller effect size in phase III than they showed in phase II. In the history. This is just the history of psychiatric drug development. There are a bunch of reasons for that, that we probably don't need to get into with folks who would be listening to me talk now, but we have every reason to think that the drug will show, if not the same, even greater efficacy in phase III than it did in phase II. Because we're not changing the study population, you know, while there are some risks about moving into new places, new sites, new countries, we really think that that's well mitigated by both the breadth of the mechanism of the drug and the remarkable effect size that it was able to show in phase II. We also know that because we're gonna have this extension period in the phase III studies, with the opportunity for open label treatment, that we expect to have a higher retention, particularly in the placebo arm, which ought to make our observed placebo effect lower than it was in phase II, where we saw a remarkably high placebo effect. Despite that high placebo effect, we're able to show strong statistical significance. The two hundred and two forty-... In the GAD, are both predicated on a sample size re-estimation where we could, if this is a non-alpha costing assessment of nuisance variables, where if the nuisance variables track as we expect, we'll be able to cut at 200. If we're seeing a higher degree of dropout or higher variance in the data, we're able to go to 300. And then MDD, this is just predicated on the observed effect that we've seen, both in academic studies of depression with LSD and in our MM120 phase IIb, the effect that we had on comorbid depressive symptoms in patients with GAD. So the really, the only difference between the MDD program and the GAD program, 'cause again, we're trying to run these studies in a way that's really operationally not just feasible, but actually easy for sites. We're making these studies as similar as possible, and the difference is that in the MDD study, we'll have folks who are in a major depressive episode and have a threshold of a MADRS greater than 26. And in the GAD studies, people can't be in a major depressive episode, and they are included based on a HAM-A cutoff of 20. So really remarkably similar studies and all 90% powered to show an effect size that's about 30% lower than the one we observed in phase II. For the open-label extension, how frequently do you anticipate redosing patients? It's a wonderful question, and one that we hope to answer in phase III. You know, we have some background evidence that allows us to think about redosing frequency, and that's that in Switzerland, they've long had a compassionate use program that allows the use of a number of different psychedelics, but LSD is obviously one of the preferred ones. And what we've seen in that population, and again, these are people who are sick enough to, and have or treatment-resistant enough to be accepted into a compassionate use program, is that as we saw in our phase II, you know, about half of people get real good pickup off one dose. They go into remission. That remission is sustained for a while. As some of them start to fall off, they get a second dose, and then maybe a third dose sometime in the next year, and at that point, no longer need to be in the program. We think that what we'll see in phase III is about the same remission rate with one dose. For folks who don't remit with one dose, we will pick up some additional percentage with the second dose. Then what we don't know is folks who get put into remission with the first dose, what that looks like long term. You know, what we didn't see in our IIb data was any evidence of sort of flagging off of the effect. It looked like a state change. The same folks who were in remission at week one stayed in remission out to week 12. So what it looks like when people sort of come out of remission is something we just don't know yet, and are excited to be able to see the patterns that emerge in the phase III. Great, and so maybe to finish up, could you tell us a little bit about 402 for autism spectrum disorder? Yeah. So the right enantiomer of MDMA behaves at a sort of neuropharmacological level really differently than the S enantiomer. The right enantiomer seems to be the driver of a lot of the serotonergic effects of MDMA, and the left enantiomer seems to drive more amphetamine-like effects. The serotonergic effects are obviously desirable in this case because they drive the pro-social, pro-communication aspects of the MDMA experience. The left enantiomer is likely responsible for a fair bit of what could be called acute toxicity, where you see some of the hemodynamic effects in higher doses, hyperthermia, and some of the hyperactivity. We've seen this play out in preclinical research, that the right enantiomer drives pro-social behavior in rodent models and does not increase locomotor activity, where the left enantiomer does drive locomotor activity and doesn't seem to drive that same pro-social effect. There have been a couple human studies in ASD with racemic MDMA that have shown good efficacy, but ultimately, what we think we've got here is something that looks a lot more like normal psychiatric drug, right? With MM120, we've got a session-based therapy. People go in, they need to be observed, they get long-term efficacy from a single dose. With MM402, what we think we've got is a drug that people would pick up. You know, obviously, we've got a long way to go here, but that people would pick up at the drugstore. Someone with ASD would take a dose before they went to work or school. While they were on drug, they would have this pro-social benefit, increase their ability to interact with, communicate, understand, engage, and then at the end of the day, it tails off. The model, there is very similar to what you'd imagine with, say, psychostimulants in ADHD. Great. So with that, thank you very much for joining us today. Yeah, it's a pleasure. Thank you for having me.