Brian Abrahams, Senior Biotech Analyst at RBC Capital Markets. Our next presenting company is MindMed, featuring their CEO, Rob Barrow. Rob, thanks for joining us. Thanks, Brian. So maybe we could kick things off on some of the latest data we've seen for MM120 in Generalized Anxiety Disorder. You had some updated data at the APA conference earlier this month. Can you tell us a little bit more about what was most new or notable from that presentation? And then I guess I'm curious what the overall reaction was like. Are you getting a sense as to how the acceptance of a psychedelic for a treatment of psychiatric disorders has evolved amongst the physician community over time, as we've seen more and more data like yours roll out? Absolutely. So as you mentioned, we presented a poster at APA, and I have a publication forthcoming. It's an extension on the data we put out as a company in March of this year, which had 12-week durable effects after a single dose of MM120, which is LSD D-tartrate, in generalized anxiety disorder. We're fairly expansive with what we put out publicly in March, so there wasn't an overwhelming extension on what we presented at APA. One of the findings, though, that we've talked about quite a bit is, you know, the broader conversation about methodological challenges, and there was an ICER report for another company, called Lykos, and focusing on how do you, how one does research with drugs that have such a clear, sort of profound, psychological effect. We give patients the drug, they can feel the effects of the drug for the duration of a treatment session. And one of the things we found in our study that was really, really fascinating, we talked a lot about with colleagues at APA, was the fact... We tested, we asked patients whether they thought they were getting active drug or not, and we found that all of the patients, virtually 85% in the lowest dose group, in 25 micrograms, and 100% of patients at 50, 100, and 200 microgram dose levels, accurately guessed that they got a dose of the study drug. They didn't guess what dose of the drug, but they, they accurately guessed that they were on drug, not placebo. The interesting thing, though, is that across that same dose range, where everyone had functional effects, and guessed they were on drug, we saw a clear dose response in terms of the clinical effects, which can't happen if it's just a function of functional unblinding or these sorts of effects. So that was a large, you know, point of discussion and, and what we gave us even increasing confidence around the quality of our data and overcoming some of those, the methodological challenges that have been presented for companies that haven't looked at this. As far as providers, this is sort of twofold. One is, there is and has been, and this isn't so much a change, it's just an amplification of, of, an overwhelming enthusiasm for the promise of this drug class and, and our drug, MM120 in particular. Psychiatry has been wanting for good drugs for the last 30 years in, in mood and anxiety disorders, and the data so far are especially compelling that, that's what, that's what we're seeing here. The more, I don't know if it's surprising, but the more sort of vocal enthusiasm is for anxiety, and we've presented a lot about the epidemiology of anxiety and its growth in the past. Because it's such an unmet need, or? Such an unmet need and such as under-focused on- Yeah ... indication. I mean, the field has really focused on depression- Yeah ... as the predominant diagnosis in psychiatry for so long, and over that period of time, in 20 years, there have been no new drugs for generalized anxiety disorder, and the prevalence has tripled. And even since the pandemic started, the prevalence of GAD has grown by 40%, and I could go on and on. But the underdiagnosis is extremely costly to our healthcare system. So we know that patients who have GAD symptoms but are not diagnosed go to the ER much more frequently. They're diagnosed with other conditions, that the utilization and the work absenteeism and presenteeism that we see in this population is just astronomical. So it's one of the most costly patients in psychiatry, are patients who simply don't know that they have generalized anxiety disorder, and they're walking around the world with very severe symptoms. So that was the real enthusiasm we saw with providers at APA, is about the promise of both calling attention to this massive problem and then being able to actually have a major impact. Interesting. And can you maybe walk us through the dose-dependent anxiolytic effects that you have been seeing with this—with the study, and how the sustainability and durability of the effects compares to what's out there currently for GAD, as well as for MDD as well? Absolutely. So, you know, as I alluded to, we did a five-arm Phase II study with doses well below what we believe would be therapeutic doses. So 25 micrograms is really the threshold for any sort of perceptual activity of LSD. All the way up to 200 micrograms, which is higher than what we expected it to be therapeutic, and it ended up seeing sort of a plateau effect. So, in terms of the outcome measures, we saw on a standardized effect size of about 0.8, 12 weeks after a single administration. That is double the standard of care. So SRIs, benzodiazepines, all have effect sizes less than 0.4. These are Cohen's d's. And in terms of the magnitude of response, we typically see in low teens, at best, responses for the standard of care. We saw a 21-point improvement from baseline, 12 weeks after a single dose on anxiety symptoms. So, really, you know, more than double what we've seen with anything that is currently available in anxiety, and really the same held for depression. Of course, there's a huge overlap, both diagnostically and in the symptomatology of depression and anxiety, and we saw the same sort of pronounced durable effects. What is especially exciting when we talk to providers too is that the effects were observable within 24 hours of treatment. We can't measure this on the MADRS or the HAM-A, but we look at things like Clinical Global Impressions. Within 24 hours, we see a dramatic drop, and then as early as we can measure the symptoms of GAD or MDD, we see a near maximal effect that is then just sustained out to 12 weeks. So patients get better fast, something that is not available to us with current standards of care, and they stay better. We saw no deterioration of those effects out 12 weeks after that single dose. And so we certainly believe that that's going to persist much longer as we study patients for longer durations in Phase III. And then speaking of onset of action, your ODT formulation showed reasonably similar PK, but also had 17% better bioavailability, leading to 50% faster onset of action, and an AUC that was 23% greater. So what are the clinical implications of that and the potential advantages that this, I guess, the Phase III formulation could have for patients? And how does that impact how you think about ultimately delivering the drug and its benefits? Yeah, there are many, many implications, both clinically and from a market protectability standpoint. So, in terms of performance, when we conceive of patients come into a clinic, and they're in a clinic for a treatment session for a day, effectively. Every minute they're spending without the therapeutic benefits is effectively a minute wasted. It's just a person sitting in a room waiting for a drug to take effect. By getting faster absorption, by getting faster onset of activity, there's more time patients sitting in a clinic where they're actually getting the therapeutic benefits of the drug. We also saw a really interestingly that faster uptake didn't lead to a change in Cmax, but it led to a greater time at those sort of maximal therapeutic levels. So the AUC above in the therapeutic range, above about one nanogram per ml, was about 23% greater than our Phase II formulation. We did a bridging study. We looked at the differences, both from a PK and PD standpoint, and what we really found is that patients reported having kind of more pronounced and not more intense, but you know, prolonged and, again, more time in the sweet spot where we see therapeutic utility with this drug. So clinically, we think it's particularly meaningful. The ODT formulation is different, similar enough to not be a development risk, but different enough to be you know quite distinct in terms of protecting from potential generic entrants later on into the future. Because of the sophistication of the formulation and the limited number of manufacturers of this product, as you work with Catalent Zydis ODT technology, it really makes it very difficult, if not impossible, to replicate without infringing on the IP we've been able to generate. You feel confident that from a kind of a dose selection standpoint and an overall sort of safety, efficacy, safety balance, you'll see similar effects with the ODT as you saw with the original formulation from the Phase II? What we know is that the adverse event profile is largely a Cmax phenomenon. Okay. And so with no difference in Cmax, we don't expect any real change there. We also in our Phase II dose, patients up to 200 micrograms, which is a twofold increase in Cmax and AUC over the 100 microgram dose. So, by and large, what we expect is to see if anything, a maintained or even an enhanced or a therapeutic effect. And because of the mechanism of absorption too, we get much more pre-gastric absorption with the ODT formulation that allows us to get less serotonergic activity in the gut, which may reduce the AE profile, which was the GI effects we saw on Phase II. Interesting. Then, as you think about Phase III, what are your latest views on the Phase III requirements and the Phase III plan? I guess I'm also curious in particular how you might address potential for variability as you go into a larger population in sort of metabolism of the drug. Yeah, it's a great question. One of the FDA came out with guidance in the summer of 2023 on the development of psychedelics and clinical trials of the drug class. And one of the things in that guidance points to the need for complementary designs between Phase II and Phase III. So our Phase III program, of course, we're pursuing head-to-head studies. We're not going to have multi-arm, five-arm studies like we did in Phase II. But by having those answers we've already talked about a little bit already, you know, understood and being able to go to the agency and in Phase II, we're able to both replicate effectively all aspects of the core design of the Phase II study, operationalize it the same way. We've had to make virtually no changes, but just do head-to-head studies where we're looking at an active dose, 100 microgram ODT versus a placebo. In terms of the variability, there's definitely variability in metabolism. That doesn't hit so much on the absorption or the efficacy Phase. We haven't seen any real meaningful difference in terms of when the absorption of the drug or when patients are having those therapeutic effects. It does lead to variability in terms of elimination of the drug and when patients are cleared to leave the clinic. We've seen patients in some studies be able, you know, what we would consider free to leave the clinic, within 5 or 6 hours, and some patients, you know, take many hours longer. We keep patients under observation for a more prolonged period just to get high-quality data in our clinical studies. But, some of that variability in metabolism really is largely going to impact the duration of the psychological effects of the drug. How does having Breakthrough Therapy Designation potentially impact time to market and your regulatory processes? One of the greatest attributes... I've had the privilege now of working on two programs in this drug class with breakthrough designation, is you get early access. FDA always says, "Come early and often- Yeah When there's something novel," and we very much embrace that idea. So having breakthrough gives us the ability now to engage even more frequently and more often, and more constructively to make sure we get this right. We recognize that this is novel and that that's a good thing, that psychiatry needs novelty to really improve the utility of the drugs we have. So we embrace that with the agency. In terms of timelines, you know, certainly if we are able to get an accelerated review and shorten the timeline for review by four months, that would significantly speed things up when we come to review at the end of the road. But, for the time being, what it does is really help us de-risk and make sure that we're making the right decisions, and that we have full alignment with the agency before we kick off any of our pivotal studies. Good. We get asked a lot about scalability of psychedelic administration, so guess I'm curious your latest views on that, and just your level of confidence this can be delivered broadly. What's out there right now in terms of ketamine and/or Spravato administration centers that could be potentially leveraged? How quickly could those types of forums be pivoted to deliver MM120? Where else could you potentially see this being utilized? Yeah. So J&J's Spravato is a great, we think of it as sort of a floor of the opportunity for the uptake and the breadth of locations and providers that can deliver our drug. Primarily because of the strict requirements for physiological monitoring of patients with Spravato. Yeah. The you know, cardiovascular blood pressure effects are and vital effects are such that patients need to be under observation. They need those vitals measured, something we don't see with our product. So obviously, the psychological activity of the drug is something that we expect there to be some degree of monitoring required. But the number of settings and the types of providers that could then monitor patients grows vastly if it's not a physiological concern. It's just making sure someone is sort of psychologically under observation and contained. Spravato, now there's well over 3,500 centers around the country that are certified under the Spravato REMS. J&J is now guiding it to be a $1-$5 billion drug, and again, we look at that as very much of a floor for the infrastructure. I think there's a high degree of uptake beyond just those centers. That said, those centers are sort of turnkey opportunity to bring into the treatment infrastructure for MM120, if we get it approved ultimately. They have the capacity to monitor patients for, I guess, maybe with a little bit less closely, but for a much longer time period. Is that sort of an easy pivot that they can- Absolutely. Yeah. We actually went out and surveyed these centers and surveyed sites and asked them, "With the dynamics of delivering MM120 versus the dynamics of delivering Spravato, would it be easier or harder to deliver MM120? Would it be more financially attractive for the providers to administer MM120? Would they do it?" And on every point, around 80% of them said it would be easier and more profitable to administer MM120 because they don't have to turn over the rooms over and over. With Spravato, they have to have 5 patients in a room per day to keep the room occupied. It's much like airlines, right? Empty seats are a bad thing for site profitability, for airline profitability. And so, to have one patient who can occupy a room for a day and get reimbursement for that time is extremely attractive to them. And around 90% of them also said, "When the drug is approved, we will be prescribing and/or administering this drug in our clinic." And that just very much matches what we've seen qualitatively and, and at APA, where both Spravato-certified providers and generally in psychiatry, there is this overwhelming demand and, and a clear desire to administer these drugs when they become available. It's really driving a renewed enthusiasm, even down to the level of residents who want to enter psychiatry now because of the promise of this new drug class. What are your projections for the number of sessions on average that a patient would require per year? What are the implications for, I guess, how you think about pricing the drug and the impact to the healthcare system? And is that something that you plan to assess formally in studies? Absolutely, yeah. So, you know, this is a treatment paradigm that we think of as somewhat episodic in nature. That it's unlikely that there's going to be a prescribed interval where patients must be administered the drug. There's variable, both magnitude and durability and response. And we know this both from our studies, but also from... We have a research- Yeah ... collaboration with a group in Switzerland that has a large compassionate use program, and they're in the real world, treating patients with LSD and with other drugs in the class and characterizing exactly this. What we typically see is that in the first year of treatment, patients may need between one and four doses. By year two, that drops to between maybe one and two, and then by year three, there may be one dose, but the patients might come back not at all, or may come back once a year. That's either because they didn't respond, not everyone responds, and not everyone will respond, but over time, we see an increasing durability and increasing magnitude of response. I think we were particularly excited about that from a patient standpoint. The pricing and the reimbursement for that is, of course, something we can also be innovative around. I think we believe that there's going to be a likelihood that there's gonna be better effectiveness out in the real world than we'll be able to necessarily demonstrate in controlled clinical studies. That said, in our Phase III program, we're gonna have an open label period, where we'll follow patients and retreat them, if symptoms re-emerge. So we'll have a really fine-grained characterization of that recommended interval for retreatment and the kind of durability of response on average after a single dose. ... Good. I know you, you've talked about there not being so much focus on generalized anxiety disorder, which has really made MM120 stand out in a lot of ways. But you also saw a very substantial impact on depressive symptoms as well in the Phase II. So what are your plans? How do you think about strategically addressing MDD in parallel, just given that there are... It's maybe talked about more, but there are still unmet needs. This is a novel mechanism of, you know, essentially a one-time treatment or, you know, very, you know, very sporadic treatment. So there could certainly be a large opportunity there as well. How do you balance pursuing that versus, you know, the focus on GAD, which is kind of the core program? Yeah. So we're laser focused on getting the Phase III program right, getting it up and running, and getting to readouts for GAD. In parallel, though, we're actively, you know, assessing and making plans around other indications. Historically, there's evidence for the therapeutic potential in depression and use disorders. But depression is obviously one of the most focused on and costly mental health disorders, and one that really complements nicely with anxiety. When we go back to the advent of SSRIs, one of the real promises there was the ability, irrespective of diagnosis with depression or anxiety, to give patients the same treatment with a reasonable probability of success. Now that those drugs have shown not to be particularly effective in either. In many ways, we think anxiety is more difficult to treat. It's a chronic disease it's not episodic in- Yeah -in the disease itself. And in our Phase II study, we saw similarly pronounced. These weren't patients in a major depressive episode, but given just the measurement overlap and the construct overlap of measuring anxiety and depression, you know, we saw a really fairly high degree of depressive symptoms around a MADRS of about 25 in our studies. And we saw similarly pronounced clinical response that was dose-responsive, statistically significant, and durable, with no loss of activity out to 12 weeks after a single dose. So we're very excited by that. We're also building off of legacy studies from academia and the history of this drug with antidepressant effects. So we'll have a lot more to say, I think, about that as the months progress here. Good. Maybe one more question. In the development process, you made the decision to not incorporate extensive psychotherapy into the delivery of MM120? Right. What does that mean for, I guess, the Phase III conduct in terms of ease of running the study and potential reliability of the results, as well as the ultimate commercial scalability? Yeah. When we made that decision three years ago, we were somewhat of the odd ducks in the field. Yeah. When there was a lot more discussion about heavy engagement with psychotherapy, both during the session, prior to session, and after the sessions. Yeah, our view has always been, we develop drugs, and in the real world, you know, all manner of medical practice is carried out, and that should be left in the hands of physicians. It's not gonna, doesn't belong on drug labels, and FDA, you know, has said themselves, and we know legally, does not regulate the practice of medicine. So our view has been we're gonna study the drug as a standalone. And frankly, it was a risk that we took and, you know, fortunately paid off, and we saw some of the strongest data in the field. It also means we don't have to make any changes as we go, going forward into Phase III. So as the field has evolved, and now FDA has really put an emphasis on, you know, quantifying the drug effects in the absence of therapy, there's a lot of changes happening in the field. There's a lot of shifting that's had to happen in development programs. We've been in a fortunate position where we don't have to make any changes. Right. In the real world, it also means, again, that there's no prohibition on medical practice, including both drug and therapy, it just won't be required. And so when we think of, you know, it, it's easy, given the novelty of the drug class, it's easy to, for, I think, for, for observers and many even in the field, to, to feel overly constrained about the opportunity, you know, to, to feel like: well, this is new, and so it, it necessarily must be small. When we look at the magnitude, there's, there's 20 million people with, with anxiety, and closer to 30 million when you include depression. We are going to need to treat millions of people if we're going to have a, a significant impact on that. And while that may be sort of surprising to some, given the legacy of these drugs, if we can develop drugs in a manner where we just have to give someone a drug and keep them under observation in a room for a day, and there's months of durable effect, that's where we think there's significant upside and why we've aimed our development program to really enable that level of uptake once we get this on the market. Great. Well, with that, I think we're out of time. Rob, thanks so much. Really appreciate it. Congrats on all the progress- Thanks, Brian ... and, thanks for the updates. Appreciate it.