conference, Definium Therapeutics represented by their CFO, Brandi Roberts. Brandi, thanks so much for being here. Thanks so much for having us. Couldn't be more excited. Well, certainly exciting times at Definium these days, with a lot of key data points coming up. I was hoping we could maybe start with the next key data point that we're gonna see, which is the major depressive disorder data for DT-120. Yeah. I'm so used to MM. We're coming up on the phase III Emerge data any week now, and one of the questions we get most frequently is understanding the translatability from GAD and depressive symptoms in GAD, which in phase II DT-120 did a really good job. Sure. alleviating to true MDD or major depressive disorder, which is, I know a more can be more of a kind of a waxing and waning type of disease. Can you tell us a little bit more about how to think about the translatability between the endpoints, between these populations, and what your expectations are for what the placebo response might be in an MDD study? Yeah, absolutely. I mean, we are really excited to have Emerge anticipated to read out later this quarter. As you noted, we don't have a standalone phase II in MDD, so that's a question that we get quite a bit, and we had an Investor and Analyst Day a few weeks ago, and one of the things that we really tried to focus on was the overlaps between GAD and MDD and what gives us so much confidence there because so many of the symptoms are very similar between MDD and GAD. When you really look at the scales and you look at the MADRS scale and the HAM-A, there is so much overlap there, like so many of the actual scales overlap directly from the MADRS to the HAM-A. It gives us tremendous comfort for a standalone kind of MDD study. The other thing I would note is that in phase II, yes, we did take a look at MDD symptoms on patients with GAD, and we saw, you know, a 6.4% or a 6.4 placebo- adjusted change there. People from a baseline perspective on the MADRS scale, were coming in around the mid-20s. In a standalone MDD study, we would expect to see that be more in the mid-30s. We think in a phase III, we're gonna have more room to really show an impact because we're going to have patients coming in that are in a true major depressive episode. Would it be fair to expect that we might see a slightly higher placebo effect, but also a potentially slightly higher drug effect as well? Well, I mean, in general, in our phase II, we saw a very high placebo effect. We actually saw a 40% higher placebo than what has typically been seen in these historical studies. We've done a lot of things in the phase III to try to bring that down. You know, one of the key points of the phase II is that we saw a 25% dropout rate, and that was mostly on the placebo side because we were asking patients to come into the study for 12 weeks with nothing else to really offer them. Especially for those patients who got placebo and they were washed out of their background meds, it was hard to ask them to stay in for 12 weeks. Those patients that were doing particularly worse needed to go back on background meds. Yep. Therefore dropped out of the study. Right. One of the things that we wanted to do was really try to address that dropout rate and try to bring that number down. By having our open- label extension portion of the study, that has really helped. Now, you know, patients, if they get placebo and if they still have moderate or worse symptoms, can be able to get drug 12 weeks after that first dosing session, which has really shown a decrease in our dropout rates. We just put out our GAD dropout rates because we did our sample size re-estimations, and we saw numbers 10% and less. What can you tell us about the types of patients that are going into this MDD study in terms of the baseline characteristics, the degree of refractoriness, how rescue medications would be incorporated into the protocol? Yeah, I mean, just kind of expanding on what I said before. Yeah. I mean, these are patients that are in a major depressive episode. Again, we would expect to see baseline MADRS scores much more in that mid-30s range versus the mid-20s and what we saw in a phase II. Again, that MADRS scale is so sensitive. It's a much more sensitive scale than the HAM-A because so many things move together on that. For example, there's reported sadness and apparent sadness. It's hard to believe that those wouldn't move together. When you're really testing that in a true MDE situation, you do typically see higher scores there. We've seen some data recently emerge from pivotal studies of other psychedelics and treatment-resistant depression. What's your latest view on the bar that you'd like to show to be clinically and commercially meaningful and successful on the MADRS delta? How has that been maybe shaped by some of these other readouts that are emerging in the space? Yeah, I mean, obviously, this is a space that is still really ripe for new treatments. You know, patients are not really finding a lot of relief with what's out there today. As you noted, we have seen some results in TRD with placebo-adjusted changes that are, you know, in the 3.5 to high three ranges from a placebo-adjusted perspective. I think when we look at what we expect, we've obviously powered these studies to show a five -point difference. Really we put the bar out there, which is one of the things that we talked about at Investor and Analyst Day, put the bar out there at 4. We really think that if you saw a four-point placebo- adjusted change in addition to the durability that we expect, For MDD, our primary endpoint is six weeks, but we are looking at patients out to 12 weeks as well. You combine that with durability and the safety, really think a four plus would be dramatic. We really care about the drug effect and being able to show a meaningful drug effect because in general, that's what patients are gonna really see. Right. You know, once this gets further down the road. Maybe speaking of the overall landscape, how do you think that DT-120 differentiates most from some of the other psychedelics that are being developed to treat depression? Yeah. Big standout qualities? I mean, I think there's multiple. I think really in terms of the durability, you know, our phase II showing 12- week durability for, you know, 48% of the population was really key. This is on one dose, this is, you know, one dose in that 12- week period. A lot of the others need multiple doses in that period. Yeah. You kind of need a loading dose and then another dose. I think really thinking about this like a mental health day and saying, you know, you're gonna spend five to eight hours in the clinic, but you're going to potentially have relief for three months or even greater. This open- label portion of our studies is really gonna give us the ability to see how long that treatment is lasting. Going out to, you know, one year we're gonna be able to follow patients, and we're gonna be able to see if they needed, you know, two, three, four treatments during one year, but are really excited to get that open- label information as well. Let's shift gears to GAD. Sure. You showed rapid durable effects, anti-anxiolytic effects in the phase II in GAD. You recently provided some updates on the trial and the powering, based on what you were observing with regards to standard deviation. Yeah. Dropout rates, which you alluded to. Can you maybe talk a little bit more about, I guess, what some of those observations initially in those two studies and what the implications are? Yeah. When we did our phase II study, as I said, it was really the first time that we were studying this. We wanted to do a true dose- response study, really understand what was the appropriate go- forward dose, studied 25, 50, 100 and 200 micrograms, and felt very comfortable that we saw a dose response for the 100- micrograms. Felt very comfortable with that. Going into the phase III, again, we had put some parameters out there of what we expected in terms of powering. It was 90% powered to detect a five-point difference. We really wanted to put a bit of a belt and suspenders approach around this, and that's why we had that sample size re-estimation. Once we got half of the patients through the 12- week period, we said, "Let's take a look at those nuisance parameters. Let's take a look at the dropout rate and the standard deviation." Both of them were lower than what we had expected. For both Voyage and Panorama, we have 99% greater confidence in that five- point placebo- adjusted change now, feel really good about that. Also happy to announce today that we have completed enrollment in Panorama as well. We had said that that was coming soon and have now finished that, and that final patient number was 245 for Panorama. That's great. Yeah. Congratulations. Thank you. It's good to have all three enrolled. Then can you maybe remind us the different randomization approaches you're taking in Panorama, versus the Ascend study, and just how that would affect patient expectations, potential for functional unblinding, what you might see from placebo? Sure. Absolutely. I mean, we feel like we have really addressed functional unblinding with doing that true response, that dose- response study because we absolutely saw, you know, that the 25 and 50- microgram cohorts were perceivable but didn't have any clinical benefit, and the 100 and the 200 definitely did. We felt that we have addressed that there. One of the things that the FDA likes to see is really complementary designs when you're doing your clinical trials. One of the characteristics of Panorama was to include this 50- microgram dose, and it's really a confounding dose. We're not gonna do anything with it. This, the analysis is still on 100- micrograms versus placebo. What that lets us do is in the consent process tell patients that, you know, there is a 50- microgram dose as well as 100- microgram dose. Just because you feel the effects of drug doesn't mean that you got the clinical, the one that has clinical meaningfulness from the phase II. Just another way to tell people to try to be really. Right. Really truthful when they're going through these scales. We feel like with that we now have three different types of studies to go back to the FDA, and we, if we see positive results across those three, we've really done everything we can from a functional unblinding perspective. Got it. If 50 ends up looking as good as 100, does that matter? Maybe that's nice for a future, a future analysis. Okay. At 100 versus placebo for the analysis. Got it. PTSD, obviously a big unmet need, and an area where psychedelics have shown some promise historically. It hadn't really been on the top of your guys' focus list until very recently. What changed? Can you talk about this a little bit more, maybe the rationale for pursuing PTSD with DT-120 and maybe some of the learnings that you have from GAD that potentially? Yeah. The effort there? Absolutely. I mean, PTSD had always been on our list as another indication to take a look at. You know, we are a relatively small company and have three phase IIIs running and have Ascend kicked off now, four phase IIIs in process. There are a lot of overlapping characteristics of PTSD from an anxiety and depression standpoint. So it always made sense for us as something to take a look at. I think when we saw the executive order come out. Yep. Much more of an emphasis now on mental health, it made sense for us to really put that out there and say, "We are interested in PTSD, and we plan to kick that study off next year," and really look at that as rounding that out. That's another 13 million roughly, patients in the U.S. that are struggling with PTSD. Makes sense. Speaking of the executive order, I wanted to get into a little bit more around kind of regulatory next steps and policy. You know, with the president's executive order on psychedelics recently, it appears that the attorney general would be able to start the review of scheduling or rescheduling following a phase III readout in relatively short order. Is this something that you and your team are actively preparing for, and how much do you foresee this narrowing timelines post potential approval for a launch? Yeah, I mean, number one, we are excited to see much more emphasis on mental health. This is a ginormous problem in the U.S. We have 50 million patients in the U.S. with either anxiety and depression, and are really happy to see that. The scheduling component of this is something that we have been very focused on, and we have been working on that in the background for years now of really putting things in place so that when we get to the scheduling process, we can go as efficiently as possible. From a federal perspective, as it stands right now, the DEA has 90 days to get the drug scheduled, and then all of the states take a slightly different approach. We've really been working with the states to modernize their scheduling activities so that there are more that will accept the DEA's scheduling recommendation and so with that, we can go faster. What proportion have trigger laws now around? California and Massachusetts. Yeah. Have automatic trigger. We've recently worked with four additional states to get those to be automatic trigger, and we're continuing to work on more so that they're available when we get closer to NDA filing. The ability to potentially reduce that 90 days is dramatic, and so if the DEA could work in parallel while the NDA is being reviewed and we could reduce that 90-day timeline, that would be a dramatic approach for us. You know, obviously anything that we can do to get this drug to patients faster is really important. That's great. Speaking of getting the patient, the drug to patients more quickly, DT-120 has breakthrough status. Yeah. You know, some of the other psychedelic drugs with breakthrough status received the Commissioner's National Priority Voucher. Is this something that you guys have applied for or are considering applying for? I guess, have you had any interactions with the FDA around this yet? As you said, we have breakthrough therapy designation for GAD and have had a really good relationship with the FDA, feel very comfortable with those interactions to date. They have been very collaborative, and we have been very happy with responses that we get. They've been very timely in their response. We've had the same division director the entire time we've been working on this, are very happy with those. One of the interesting things for us is that if this MDD data is really compelling, we'd like to go to the agency and talk about filing both MDD and GAD at the same time. When you think about something like a CNPV, we have breakthrough therapy designation in GAD right now, but we don't have it in MDD. That is obviously something that we'd be interested in once we have our phase III data. Would we need two CNPVs? How would that kind of be in this new paradigm of kind of this new CNPV? You know, more to come there. I think for us, what's really important is continuing that dialogue with the FDA, getting to these data readouts, going and having a productive conversation with them. Okay. Maybe on the, along those lines, just given the FDA's evolving commentary around single trial registrational programs to the extent that, you know, with some of the changes in FDA leadership to the extent that's still going to hold, I guess, I mean, is there a possibility that positive Emerge data could support an MDD filing just on it, on its own concurrent with GAD? Right. Do you think you'll need two studies from both indications? That's something that's been on the regulations for a long time. Yeah. You know, the single study as a follow- on indication with significant overlap is something that the FDA has looked at before. We think that that absolutely warrants a conversation with the FDA once we have the Emerge data, and again, if it's compelling, really going and have that conversation. However, if we were to kinda go with the two GAD studies as our original plan and then submit the two MDD studies following, that is something that we could absolutely do too. You probably wouldn't have too much of a lag between having both out there because we do have Ascend, you know, in full force right now. The trials are moving quickly regardless. They are. Yeah. To really see, the interest and people, signing up for the clinical trials. We get a lot of questions on the scalability of psychedelics. Can you talk about maybe some of the latest work you're doing from a commercial standpoint ahead of a launch and just the size of a sales force that might be needed here, just given some of the nuances and distinctions of this space versus others? What other strategies are you gonna be utilizing to generate awareness, demand ahead of a potential launch? Absolutely. We have been building out our commercial team over the last year and a half, and it's been really great to bring on so many people with great experience in the background. You know, when we think about this, obviously we know that SPRAVATO's out there, and it's been great for us to kind of see their trajectory. You know, I think they're looking at $2 billion in sales and looking at $3 billion-$3.5 billion down the road. That's been a great place for us to look at as a starting point. There's about 7,000 centers that are signed up to do REMS for SPRAVATO right now. A majority of their sales are actually in a pretty concentrated, you know, let's call it 500-700 sites who have really learned how to do SPRAVATO day in, day out. That leaves a really big chunk who only do SPRAVATO on a, you know, semi-regular basis. What we would like to do is really do the same thing that we've done in clinical development. We've really taken the time to build relationships with our sites, and we think that that's how you do it from a commercial standpoint as well. It's not just about sales reps, but it's also about providing support for REMS and payer support, and making sure that their experience is as easy as possible. Once they have, you know, one patient do well, then they're gonna wanna do another patient. We think about that in terms of having, you know, 200 people on the ground, but it's not just doing sales support, it's doing kind of that whole gamut of making the experience great. What about from the payer reimbursement side? Some of the payer feedback we've gotten has been somewhat positive, but I guess I'm curious what specifically you've heard in your recent conversations with payers, how that guides your framework for how you might price DT-120 perhaps relative to the different price points or the price range of SPRAVATO. I'm curious what value proposition arguments do you think resonate most. Is it rapid onset, the durability, the reduced potential for hospitalizations? I guess, how are you framing this to payers, and what is their initial kind of pre-data feedback? Sure, sure. You know, the SPRAVATO pricing has quite a wide range right now. It's roughly $30,000-$70,000 a year depending on low dose or high dose and the frequency of taking it. You know, in general, SPRAVATO is taken 56 times a year. It's twice a week for the first month, and then once a week thereafter. From our perspective, we have used that SPRAVATO analog in talking to payers, and they are absolutely open to understanding that as an analog. Obviously, our data will inform that in terms of where in that range makes the most amount of sense. If we see the efficacy that we're hoping to see, along with the durability, I think that really is a game changer and can help us be on kind of that higher end of the range. Now, obviously, what we want to see too is what our retreatment patterns look like. Right now we talk about pricing from an annual perspective because that's really what payers care about. Once we get this retreatment information, which we will have some of that data at top line as well, will really inform us as to what that will look like on an treatment basis. When we think about what this really means to payers, when you think about a treatment that you have to take that often and you're going in, you know, once a week right now on SPRAVATO, unfortunately, a lot of people drop out after six months. From a payer perspective, they've kind of paid all of that money through the first six months, and now a patient's kind of back in the same spot, and they're gonna have to restart some type of new treatment. From our perspective, if we are able to show that treatment durability, that could make a big difference from a payer perspective if you're keeping people feeling better for a longer period of time. Maybe just speaking of retreatment and durability, what's your base case for how frequently this would need to be administered in an average patient? As you've seen sort of open- label experience kind of pan out between phase II, phase III, is there, you know, looking at other programs, is there anything that you're sort of centering around as, you know, maybe two treatments a year, three, one and a half? What's your best guess? You know, I think the hardest thing is there's probably not going to necessarily be an average patient. Yeah. Everybody's gonna have a little bit different of a case. You could see it where, you know, a patient is one and done. Yeah. You could see where a patient is, comes in once, and then in three months needs another treatment, and then is good for, you know, a considerable period after that. In our phase II, we had 12-week data. We didn't show it really reducing to baseline. Right. That line kind of stayed consistent. We'd really love to see something, you know, in that two to four realm, treatments per year. Again, we couldn't be more excited to see what we see in all of these phase IIIs. One last question. We often get asked about the intellectual property protection. Obviously LSD's been around a long time. You have some unique formulation. Can you maybe elaborate a little bit more on the overall IP strategy that you're using for DT-120 in terms of the protection offered by the formulation, as well as how other aspects like the REMS, the state drug scheduling might impact or might keep a generic off the market? Yeah, absolutely. I mean, really the strategy was to have a multi-layered approach. As you stated, we do have patents on salts and on polymorphs. We also have patents related to the ODT formulation of our drug, so that oral dissolving, the tablet does have IP strategy around that as well. Obviously, GAD and MDD methods of treatment, as well as you said, the REMS program and really what that will put around kind of barriers of protection around DT-120 to really protect that from generics as well. You know, you have to remember too that this is something where providers are gonna look at a buy-and-bill situation. Thinking about that spread that they get in terms of drug, having a higher priced drug is something that is really typically important in that buy-and-bill approach. Obviously the customer service that we're gonna bring too, and that white- glove approach that we want to have is something that would typically not be apparent with a generic if it was coming to the market. Operational considerations, for sure. Absolutely. A lot of layers there from an IP perspective. Good. Well, we're unfortunately out of time. Brandi, thank you so much. This was really insightful. Best of luck in the coming months. Thank you so much. A lot of luck. Couldn't be more excited. Thanks for being here. Thanks for having us. Appreciate it.