Definium Therapeutics, Inc. (DFTX) Earnings Call Transcript & Summary

Hello, and welcome to the Definium Therapeutics Phase III Emerge Top line results call. [Operator Instructions] As a reminder, this conference is being recorded today. If you have any objections, please disconnect at this time. I would now like to pass the call over to Rob Barrow, Chief Executive Officer. Please proceed.

Hello, everyone, and thank you for joining us this morning. As the operator said, I'm Rob Barrow, CEO of Definium and joined today by our Chief Medical Officer, Dr. Dan Karlin, our Chief Financial Officer; Brandi Roberts; and our Chief Commercial Officer, Matt Wiley. We couldn't be more excited to be here with you this morning to share the landmark results for Emerge. Before we get started, please note that on today's call, we'll be making certain forward-looking statements. We'd encourage you to review our SEC filings for a discussion of the risks and uncertainties associated with these statements. Opportunities to share results like these today are exceedingly rare. We believe the findings being presented today has the potential to redefine what patients can expect in the treatment of major depressive disorder and position DT120 ODT [ as ] potentially best-in-class product. Major depressive disorder and generalized anxiety disorder and [ posed ] an enormous burden on patients, families and our society and despite decades of research, the need for transformative new therapies remains. Before going any further, I want to take a moment to thank study participants, investigators, study partners and our incredible team at Definium for making all of this possible. And deeply appreciative and honored to work together with you and for your trust, commitment and believe from what we're striving to achieve. Your efforts have brought us this remarkable moment and most importantly, have brought us one step closer to making our dream a reality. We have an ambitious vision at Definium and believe that profound change in psychiatry as a [ gel ]. We set a high standard for our program sequin to prove that a single dose supervised in a clinical setting of DT120 ODT can deliver rapid, robust and durable efficacy and can offer new hope to the tens of millions of individuals living with depression, anxiety and other mental health disorders. We're, of course, here today to discuss the top line results from our Phase III Emerge study of DT120 ODT, our first pivotal study for the program. It's my absolute pleasure to share highlights from the readout. Before turning the call over to Dan to discuss the results in greater detail. The Emerge study met all primary and key secondary endpoints and was highly statistically significant with a p-value of less than 0.0001. This was represented by an 8.1 [ point ] placebo-adjusted improvement on the [ MADRS ] at week 6, which was the primary endpoint of the study. This staggering [ effect ] was durable for the full duration of Part A with a 7.3-point placebo-adjusted improvement on the MADRS observed at week 12 and was further complemented by the rapid and significant improvements observed on the CGIS as early as day 2. DT120 ODT was generally well tolerated with no SAEs or suicidality signal in the study. And importantly, through our intentional granular approach to characterizing the dynamics of each dosing session. We're able to share further clarity on the efficient treatment session dynamics of DT120 ODT. The average time for participants to create [ the ] into study checklist was 5.8 hours with over 50% of participants clearing in hour 5 [ and ] all participants clearing the checklist by hour 8. At a recent Investor and Analyst Day, we shared our belief that a durable response to at least 4 points represent a potentially best-in-class profile in the context of both historical and moderate antidepressants under development. Today's results far exceeded those expectations with efficacy at week 6 [ we've ] more than doubled that bar and which stands out as one of the large placebo-adjusted effects ever observed in a pivotal study of depression. We could not be more excited by these results and what they need for the potential to deliver on our mission and for the millions of patients in need. And with that, I'll turn the call over to our CMO, Dr. Dan Karlin, to discuss the results in greater detail. Dan?

Thanks so much, Rob. Emerge is a Phase III study that consists of 2 parts. The initial part, Part A is a 12-week randomized, double-blind, placebo-controlled. This is a single-dose paradigm with DT120 ODT micrograms. This is a monotherapy [ participants ] were tapered off of any background antidepressant or [ antiolytic ]. And those medicines were washed out prior to participation. There was no psychotherapeutic intervention that went alongside the drug. So it's truly a single-dose study of drug versus placebo. The primary endpoint for the study was the MADRS at week 6 assessed by independent central raters who are blinded to treatment allocation and to visit number. The second part of the study, Part B was an extension phase where after that first 12-week double-blind period, participants remained in the study for 40 additional weeks and we're eligible to receive up to 4 open label doses over those 40 weeks, if they were eligible by having a MADRS score of 20 or higher, meaning that they were moderate or worse on that scale. 149 participants were randomized and all received a double-blind dose of DT120. Of the 149 participants, 84% completed Part A, which was completely aligned with our expectations for the study and consistent with historical studies in the field. The demographics of the participants who participated in the study were well balanced and representative of [ the ] MDD population. Notably, you see here that we enrolled participants with a high degree of severity as shown by a baseline MADRS of 34.5, which is consistent with a baseline [ CGI-S ] of [ 4.8% ]. This puts these participants well into the severe category on the MADRS. As anticipated, the extent of prior psychodelic use in the study is consistent with the general population, which is estimated to be about 15%. And prior LSD use is only 4%, which is also epidemiologically consistent with the general population and a small enough number, not to confound any outcomes of the study. Another look at disease severity here. We see that 34.5 MADRS along with the breakdown of the severity of the patients in the study with only 20 or so [ present ] at moderate and the remainder in the severe category. You also can note here the history of antidepressant use among these patients divides them nicely between people with zero or one episodes of prior antidepressant use and people who have been failed by two or more antidepressants. Clinically, we call that second category treatment-resistant depression. The length of the current depressive episode is consistent with the disease definition of MDD, with the majority of patients having a current depressive episode of less than 1 year and a fair number of the patients, approximately 25% having a current depressive episode length of 1 to 2 years. You'll note that none of these patients had an episode longer than 2 years at which point we start to look at diagnosis other than major depressive disorder. The number of lifetime depressive episodes is nicely distributed between people who are relatively early in their course of illness and people who have been dealing with major depressive disorder for a significantly longer time. At every measured time point, the treatment groups statistically and clinically exceeded the placebo group. That treatment group showed a difference at every time point with a p-value of less than 0.0001. There are a few categories that we look at when we describe the effect of the drug. Robustness. At the primary endpoint, we saw an 8.1 [ point ] separation from placebo. The primary endpoint was measured at week 6, which is the standard time point for showing antidepressant efficacy. We look at durability that single dose was effective out to week 12, where we saw a 7.3 point differentiation from placebo with that same level of statistical significance. Rapidity is an incredibly important feature for people suffering from major depressive disorder. And as soon as week 1, the first time point where we measured the measures, we saw a very strong 17.6 point total change from baseline and 14.2 point differentiation from placebo, which, of course, is also statistically significant with a [ p ] less than 0.001. This really remarkable rapid and robust response and tremendous separation from placebo give us enormous confidence in seeing this drug effect over time. Another way of measuring disease severity is the CGIS we see that the CGIS curve describes effectively the same response as the MADRS. What's most notable about this is that the CGIS is assessed by site-based raters, while the MADRS, as I said previously, is assessed by blinded centralized raters. These are two very different ways at looking at the same construct, which is how affected by MDD is the patient for the course of the study. These two different instruments assessed by raters with two different conditions describing effectively the same curve gives us tremendous confidence that the measured drug effect represents real change in these patients. Another way of looking at the MADRS is remission and response. Here, you see remission numbers for a MADRS of less than or equal to 12, which is generally thought to correspond to no clinically significant depression. Our remission numbers there are 24% of the population at week 6 versus 3% for placebo. We also look at mild or better. Mild and better will come up as we talk about Part B, where the trigger for treatment in the open-label opportunities for retreatment is moderate or worse. So effectively, Part B, we're treating to mild or better. At week 6, we see a rate of mild or better of 41% in the treatment group versus 13% in the placebo group. Another way of looking at the MADRS scores which rather than using absolute cutoffs, uses a relative cutoff to where a patient starts at their baseline score. And here, we see the conventional definition of response of more than 50% change in score. 35% of treated patients versus 7% of placebo patients reach that 50% cutoff. Each of these measures of remission and response is highly statistically significant. We looked at subgroup analyses to ensure that no subgroup was disproportionately responsible for the observed overall effect. Across each of these analyses, we did not identify any subgroup that could be independently responsible for that observed effect. This is particularly notable when we look at previous MDD medications. As I said before, we had a significant number of folks who had two or more prior medication failures. And in that case, we did not see a disproportionately high or low treatment response in that group relative to people who have been failed by one or no medicines. Overall, DT120 ODT was well tolerated, and the adverse event profile was consistent with what we've observed in prior [ side ]. 99% of adverse events were mild to moderate in severity. Most treatment-emergent adverse events, a [ con ] and resolved on dosing day, no treatment-emergent adverse events led to study withdrawal. There were no serious adverse events. There was no incidence of suicidal or self-injurious behavior. And there was no indication of increased suicide risk or suicide-related risk in the study. Here, we see a more detailed view of treatment-emergent adverse events. As I said previously, these treatment-emergent adverse events were mild to moderate in severity, with one exception for a severe adverse event, there was an episode of exacerbation of chronic back pain that occurred 6 weeks after dosing. One thing that's notable on the TEAE slide here is that we have a 99% rate of treatment-emergent adverse events in the treatment group. We have an expected profile with treatment-emergent adverse events. And the fact that we are picking these up in the study is suggestive of a high-quality clinical conduct at the study sites. There were no treatment-emergent adverse events that led to study discontinuation. These are the common treatment-emergent adverse events. And these, as I said before, completely consistent with what we expect from the study drug. These are perceptual, effective thought processing and behavioral changes that are expected during dosing day and generally resolved by the end of [ dosing ] day. Rob mentioned this before, but we think it's really important to reiterate the treatment session dynamics are remarkably constrained in the 5- to 8-hour window. We used a structured end of session checklist that assess participants to safely leave the treatment session. As Rob said, of participants cleared that end of session checklist at our 5 and 100% cleared by our we believe this translates very cleanly into clinical practice where the end of session checklist can be easily implemented under any subsequent REMS program. Now we get to talk about Part B. As I mentioned before, this is the 40-week extension phase where participants have the opportunity to receive up to 4 open-label treatments if they qualify by having a score of 20 or higher representing moderate or worse symptoms on the MADRS. At the time of our analysis, 94 participants had entered the extension population in Part B. Based on the way that these studies enroll with an increasing rate of enrollment over the course of the conduct of the study, we had a limited number of participants who had progressed beyond week 28 at the time of the data cut we're discussing today. Therefore, our ability to meaningfully discuss data beyond week 28 is somewhat limited. So what we'll focus on today are results through week 28 and the participants who reached that point. The demographics of Part B are obviously going to be similar to the demographics of Part A from which they are selected with lower MADRS scores representing both the treatment and placebo effect of the participants who completed Part A. This treatment pattern slide gives you a sense of how participants entering Part B have progressed through the first 3 months of Part B with those opportunities for open-label treatment. As we anticipated, multiple treatment patterns are emerging with most participants receiving only 1 or 2 open label doses across the first 6 months of the total study. Here, we see longitudinal efficacy moving from Part A to Part B. With the availability of open-label dosing, we see continued reduction in MADRS scores in both groups. Those receiving placebo and part A begin to converge with those who received DT120 ODT in Part A. The results from this Part B give us great confidence in the real-world treatment paradigm and give us our first sense of potential longer-term multi-dose efficacy and durability for DT120 ODT. As with Part A, we can look at response and remission over time in Part B. What we see here is that across each of those measures, the treatment groups converge at about 50% mild or better, MADRS less than equal to 12 remission and 50% response. This, again, gives us enormous confidence in our ability to ultimately show multi-dose drug efficacy and safety in the real world. Thank you very much, and I'll turn it back over to Rob.

Thanks so much, Dan. Our goal of Definium is to enable a new treatment paradigm that could profoundly reshape clinical practice in psychiatry. We believe the landmark results shared today are another important step in pursuit of that goal. With the incredible momentum heading into our upcoming Phase III readouts, beginning with the [ voyage ] and [ Panorama ] studies in the months ahead, cannot be more excited for the future of the DT120 ODT program and the patient [ game ] to serve. Given the enormous unmet need in these areas with over 4 million patients failed by these treatment options, the strong desire from patients and providers and the large and growing sites of care, we believe there is a unique opportunity to deliver significant impact on value in the years ahead. We see two distinct drivers of this value creation opportunity. Our continued commitment to excellence in clinical and regulatory execution as we continue to advance our pipeline and pursue regulatory approval for DT120 ODT and setting the standard for commercial impact and execution to bring this clinical promise to patients as impactfully as possible. We're working tirelessly to build Definium into a psychiatry powerhouse that can set a new standard for what patients and providers can hope to expect from care. Before we go to Q&A, I want to say again that special thanks to our team at Definium. We've built an organization of exceptional people who are deeply passionate about our mission and the patients we serve and none of this would be possible without your unwavering dedication and tireless effort. It is an honor and a privilege to work alongside each of you every day and I cannot wait to see what the future holds for us. And with that, we'll open up the Q&A [ law ]. Thank you.

[Operator Instructions] We'll take our first question from Andrew Tsai with Jefferies.

I really appreciate you taking the question. So in this study, can you remind us what percentage of MDD patients also had comorbid -- GAD or elevated anxiety. And what did you see on the HAM-A scores for that subgroup of patients? Just thought I'd ask. So we could have another or data point for your Phase III GAD readouts coming up very soon.

Yes. Thanks so much for the question, Andrew, I'll turn it over to Dan.

Yes. Thanks, Andrew. And it's a really good question. we had observed a GAD diagnosis rate of about [ 1/4 ]. So 25% of these patients had a GAD diagnosis, which is actually pretty high in an MDD population due to the features of the diagnosis. GAD is often not diagnosed. And so while many GAD patients will have received an MDD diagnosis along the way, that has more to do with epidemiological features related to making the diagnosis than actually having the experience of GAD. While we don't have the HAM-A data available in this top line readout, we do know there was a high level of background anxiety in part because MADRS also assesses for anxiety. What we see consistently is that in folks with higher symptomology, whether that's depressive symptomology or anxious symptomology, we are able to move [ these ] scales further. So we're really confident in our ability to move anxiety scores in the MDD population. And of course, based on our prior Phase II research, we know that we are able to move anxiety scores in folks with GAD not the major depressive episode.

We'll take our next question from Marc Goodman with Leerink.

Yes. I'm curious about this end of session data that you have, our 5, 6, 7, 8 to [ 1% ] of patients that lasted that long with respect to their experience and how you expected this to play out with respect to the label as well as the real world and how different you'd expect that to be and just your conversations with FDA about it right now.

Yes. Thanks so much for the question, Marc. At a high level, it be, of course, premature to talk about labeling and REMS as we have yet to submit an NDA for the program. But based on our dialogue with FDA and the sort of implicit realities of the fact that in these studies, while for research purposes, we kept everyone under observation for the full 8 hours, if any patients, we didn't know going to study, but if any patients had progressed beyond 8 hours, this checklist was what was going to be used to determine their safety to subsequently and monitoring during the dosing session. So there's some sort of implicit reality that this [ note ] list -- end of study -- or excuse me, in the session checklist is appropriate to inform the end of that monitoring. And as a result, we've had a very specific conversation with FDA over time, all in service of trying to reach a goal that appropriately monitors patients but doesn't place an undue burden on patients or providers. because we're talking about an extended intervention, of course, a patient who has a return to normality of perception. [ It's ] hard to see the value in holding that patient under observation for many more hours would be. So we think the approach and the very specific and intentional conversations we've had with FDA over the course of the development program, have charted a path to bringing this into the regulatory discussions at the NDA stage. And then, of course, as we see with products like [ Srivata ] out in the market today, using a similar framework to both setting a minimum standard for when patients need to be in the clinic under observation, but then using a checklist such as this to determine they can then safely leave observation.

We'll take our next question from David Amsellem with Piper Sandler.

Thanks. Can you hear me?

Yes.

Yes. Okay. Sorry about that. So I have a commercialization question here, which is -- as you think about the magnitude of effect, the rapidity of effect and the fact that this is a single treatment on a single day. Do you envision significant usage potentially as a frontline or second-line option. And I realize that might be putting the cart before the horse here. Obviously, you still got to get it approved. There's additional data readouts. But as you think about what you've shown this morning, how do you see the usage paradigm, particularly in patients that have not had significant antidepressant exposure playing out?

Yes. Thanks so much for the question, David. At a high level, and then I'll turn it over to Matt, [ may ] add some detail. But at a high level, of course, our expectation is that early adoption would be in patients who have been failed by two or more prior therapies. So we see this with virtually all new branded products in psychiatry in these indications. The intentional choice to go after the broad MDD and GAD labels, though, certainly opens up the possibility that over time, either as we build evidence or as the overall landscape changes and the recognition of the value that such a profound shift in patient expectations and improvement can lend not [ only ] those patients but to the overall system. We certainly think there are opportunities to broaden out where this treatment option could be available and try to have the broadest impact being siloed in a small corner of the market is certainly an early step, but to really drive the full potential of what we see with DT120 in this field and this -- the promise of these results, we do think quite expansively over time. But in the near term, our laser focused on getting the launch right, if we're able to get the product approved and to making sure that in the early adopters, we see a really good uptake and good results out in the clinical world. Matt, turn it over you to add any color there?

I agree with all of that. I mean the product profiles that we've tested market research, the data exceeds what has been tested to date. So there's more evidence to collect in market to understand how physicians and payers will react to it. But the data does open the opportunity for earlier line treatment downstream, as Rob said, and we're very excited about that.

We'll take our next question from Paul Matteis with Stifel.

As it relates to your guys' long-term retreatment data, I thought that was super interesting. Can you remind us how you're thinking about what constitutes a long-term exposure for your FDA retreatment database? Do patients need to be retreated a certain number of times per year to count as like an ICH guidelines, 1-year exposure? And maybe more broadly, talk about just like the filing scenarios here and your level of conviction that MDD study could be enough? Or is that still sort of an open question and all dependent on the GAD readouts?

Yes. Thanks so much for the questions, Paul. I'll take the second question first and then turn it over to Dan to talk about retreatment and safety. In our interactions with FDA, and just want to take a moment, we couldn't be here without the thoughtful partnership of FDA and the division of psychiatry. And they've really, over the course of the 8-plus years I've been working in this field, been great thoughtful partners in all of this and been really data-driven and thoughtful in their approach Of course, with drugs like this, the complexity of dynamics like retreatment and safety are somewhat unique from a regulatory standpoint. You need a regulator who is both thoughtful and exercises the good clinical judgment and discretion throughout. Yes. As -- going into this readout and over the course of the last several months, I think we've had some conversations with investors and the broader world about that potential. And certainly, even by long-established regulatory and evidentiary standards for approvals of products, there is a pathway that has existed for one study approvals when there's strongly compelling evidence. And so of course, our intent with such evidences to go have a conversation with FDA and they've, again, been very engaged with all of this dialogue over the course of both our JD and MDD program. So we absolutely intend to go have that conversation with FDA and certainly believe we'll have a receptive engaged audience and partner in those discussions. We absolutely hold ourselves to the highest standards of generating evidence, but when there is such a profound need and the results are so compelling, if today's results are compelling, I'm not sure what would be we certainly see and want to pursue every opportunity to accelerate access for patients because there is such an enormous need. And based on the data we have in hand to date, there seems to be a really unique opportunity to benefit those patients. And the same will apply in Dan's discussion, I'm sure of the ICH requirements, but I'll turn over to him to comment there.

Yes. Without reiterating too much of what Rob said about FDA as an incredibly collaborative regulator in this enterprise. I guess I can make a general comment about long-term exposure, which is that the designs of our study in this case in our other Phase III studies, and of course, our Phase II study are all very intentional and meant to meet multiple goals. One of those goals is thinking about what does a year of exposure mean when you have a drug that is fundamentally unique in psychiatry in that exposures are spaced out intermittent and likely triggered by need by clinical symptoms. And the reason that we have this year-long study with about as close to real-world opportunities for open-label treatment as you can get in a clinical study like that is because that gets to as close as you can get to what a year of exposure to the drug should look like and will look like in the real world. So in our discussions with FDA, we've obviously addressed exactly this question, what does a year of exposure to a drug that is intermittently dosed based on clinical need. And what we've come to is the studies that we've designed where folks get the opportunity for exposure should they need it over the course of the year. We're confident that these designs bring us toward a safety database that represents real-world likely exposures and generates great evidence for the safety of the drug in that paradigm.

Next question next question comes from [ Gavin Parkade ] with Evercore ISI.

I thought that the subset effect, the forest plot that you showed, showing a consistency of effect in various subgroups, especially the patients who had failed more prior antidepressants was really interesting. I was curious if that consistency of effect was maintained out to the 12-week time point. And I appreciate just the top line results. But curious if you had a chance to look at any other factors like length of depressive episode, patients with comorbid anxiety or anything else like that?

Yes. Thanks so much, Gavin. We are still early in digesting the full data sets, of course, so there will be, I think, some really interesting finding as we progress through that. The forest plots in our week 6 and at week 12 as we've been able to analyze them at this point. Really just speak to the consistency of effect. And as Dan alluded, the reality that we aren't seeing a particular group that is responsible for driving or not driving a treatment effect at this point. Certainly, the other features that we talked about, Dan alluded to the relative incidence of past exposure to psychidelic something that's come under a regulatory discussion historically. There too, we saw that those with past exposure to psychedelics didn't differ from those who had no past exposure to psychedelics and any sort of statistical way. And so what we're really finding is that where we have reliable subgroup analyses. And I say reliable because, of course, with small ends for a subgroup, such as that one, you can get statistical wobble, but we haven't seen anything yet that statistically rises to a level of explainability that would explain those results. And that's true at week 6 and at week 12.

I think to a larger point as well, when you have a magnitude of effect as large as what we've seen here in a study of this size, it's really unlikely that you're going to find any subgroup that was somehow the fundamental driver of that. I mean a magnitude of mean effect of this size kind of has to be a population effect. And so we're really confident that this outcome represents our ability to move this scale across the population of MDD patients that generalizes out into the MDD patients seeking care in the real world.

Next question comes from François Brisebois with LifeSci Capital, LLC.

Great. So I was just wondering about the 5- to 8-hour window to get out. Was there something there that you've seen with maybe the patients -- the stratification a little bit? Is it like the more severe patients take longer? And if you can touch on maybe the impact of the ODT formulation to fit in that window of 100% of patients getting out at 8 weeks. And then if you could just touch on also the bar going forward for GAD, does that impact anything? We see the powering going forward for 5, but any thoughts there for the GAD readouts and expectations on that side?

I'll turn the first question on sort of subgroups of in the session over to Dan.

Yes. I mean it's a great question, Frank, and something we're obviously very interested in because as we move through this process and towards submission and if successful, ultimately into the clinic, of course, we'd like to provide as much a priority guidance to treaters about what they can reasonably expect both in the session and after the session from an efficacy standpoint. A lot like the previous question where we look at subgroups and try to make predictions. At this point, nothing stands out that allow us for this sort of priority prediction of session length. But of course, as we speak, we're gathering more and more session data, and we'll continue to investigate every angle there to try to track down any features that might be [ to ] really anything out what happens with folks when they get the drug. We're thrilled with the performance of the ODT formulation. This oral disintegrating tablet has a predictable onset and clearly a predictable resolution of symptoms. And notably from the AE profile, and I didn't say this before, but I could have -- the gastrointestinal AEs are markedly reduced versus the powder and capsule formulation we used in Phase 2. So across the board, we're really excited about the ODT formulation. Of course, we're also using this new checklist that we devised for the Phase III studies after the Phase II so we've kind of got two variables that are changing session time from our previous experience. So attributing change to one or the other would always be a bit tricky. But again, like I said, we're going to keep looking at every feature we can that might offer predictive value to treaters who ultimately use this in the world that were successful.

And I'll just add briefly that the -- both of those changes were in service of what we have done from the beginning of this program, which is to start with the end in mind to really think about the impact we're going to have and how we can get product out to patients in the most impactful way and the ODT formulation, the steps, the incremental changes and the data-driven approach to inform both the dose selection, the dosage form, the way we monitor and the way we collect those data to really granularly assess and granularly describe exactly what's happening is incredibly important. And I think it's important for the entire field to be able to appropriately make arguments and make data-driven, data informed decisions and present those decisions and arguments to FDA so that we can have -- something that's grounded in science, something that's grounded in the data and what can be safely done because we absolutely are committed to patient safety while trying to maximize the opportunity out in the world. I think you asked about the bar in GAD too, Frank, thanks for that. I mean of course, we're just overwhelmed with excitement by the data today. We've seen quite exciting historical data from our Phase II study in GAD as well. And so we continue to have really strong conviction. The GAD studies, as we reported out from the sample size reestimation are quite highly powered and really our desire is to have positive studies that enable us to take to chart the path forward and to move forward with regulatory submission. So we need positive studies is really the bar. Of course, what we've said previously is that we think something that's 4 points or better really stands out. In GAD in the context of a disorder where there has not been an approval since 2007, almost 20 years. We think that compelling evidence really will stand out above that 4-point bar, and we're excited to get to those readouts for both VOYAGE and PANORAMA in Q3.

Our next question comes from Brian Abrahams with RBC Capital Markets.

Congratulations on the data. Just given the magnitude of effect you're seeing here, I'm curious, do you plan to apply for breakthrough status, what the implications of that might be in terms of regulatory interactions. And if you are able to get an expedited path across both indications, anything beyond the additional Phase III readouts in GAD that would potentially be gating for commercial launch and scale up here?

Yes. Thanks so much for the question, Brian. We tend to not talk about speculative things out in the future in terms of our regulatory engagements. As both Dan and I said, we have an incredible respect for in partnership with FDA and Dr. [ Pariani Division ] of Psychiatry and had such a constructive dialogue. We certainly always pursue every opportunity to chart an efficient path to bring this product to market as long as we're not introducing undue risk or lowering any sort of standard for the program. We're highly, highly committed to doing this the right way as efficiently and as quickly as possible. We're going to continue to have that dialogue in a number of venues in a number of ways, both through meetings and through the various submissions that are available to us with FDA. And as that progresses and as we have clarity on the outcomes of those discussions, we'll, of course, be sharing that more broadly. And in terms of what else comes after that, if we're in a fortunate position to get approval for this product. We have been building an incredible team led by Matt here a commercial organization that will stand our test of excellence, just like our clinical and regulatory and the full organization has over the past number of years. And so to bring in that leadership, to bring in those who have a ton of experience navigating complex launches, programs of REMS, controlled substances and psychiatry, we really think we're at the forefront of this field and are going to continue building in that direction and as always, try to set ourselves apart and set a new standard for what everyone should be expecting from this field and from psychiatry at large.

Next question comes from Sumant Kulkarni with Cannacord Genuity.

It's nice to see the data. Clearly, it's not typical to see the placebo-adjusted MADRS score change you saw with DT-120 in a Phase III for depression. When you combine that with the response and remission rates you saw and the longer-term Part B data, what might that mean for the number of doses of DT120 that might be required over the course of a year for depression and for potential pricing given the solid durability you see here, especially relative to the number of times a patient might have to go into the clinic for SPRAVATO as an example.

The staggering efficacy we saw in Part A of the study really is not normal. I think that something that really cannot be overstated is just how unique this is. And of course, while any sort of cross-study comparisons always have their limitations, right? Each study has different design and different sites and we will, of course, recruit different patients and have different things like placebo responses that can influence outcomes across the board, when we look at placebo-adjusted changes in this study, we see efficacy that stands out. And so that means things like a 9.8 point MADRS separation at week 4. You stack that up against 6.8 points for SPRAVATO at their week 4 time point in their monotherapy study for TRD that's the difference of 1 session with an average duration of 5.8 hours versus 32 hours in the clinic across 16 sessions for ketamine to get better efficacy more efficiently and a quite different and distinct, some more profound underlying change is what we hear qualitatively from the patients in these studies. Again, we have a very high bar for how we think not only of the standards of our data, but what we expect in this program and any context put up against any data that we have seen in depression this study and this drug continues to exceed those expectations and really stand apart. So we think that there is enormous degree of opportunity here and enormous degree of enthusiasm, of course, from us, but also broadly from the field of psychiatry and from the patients we want to treat.

Our next question comes from Jay Olson with Oppenheimer.

Congratulations on these landmark results. This is great news for patients and their families. Since you saw no increase in suicidal ideation, do you think that would be an important differentiator for DT120, especially for moving into earlier lines of treatment in terms of not requiring the patient to fail SSRI treatments to have box warnings for suicidality?

Yes. Thanks so much for the question, Jay. I mean what we see is that there tend to be a feature of depression, and that's true whether it be labels for MDD or TRD or bipolar depression, all tend to carry that box warning. And I think that it's a reasonable expectation that most products will continue to unless there -- even products like SPRAVATO that are approved to treat suicidal ideation and behavior in MDD carry that box warning. It is a feature of MDD and something that prescribers and patients should be made aware of. The really encouraging thing that we see, and we don't want to take a sort of deductive view of this from not seeing a suicidality signal. But what, of course, enters the risk for suicidality is when patients have an early activation but do not have the improvement in mood and to see such profound acute effect. As Dan described, category shifts on the CGI-S over the course of the first week, a 14-point placebo-adjusted change at week 1 on the MADRS to get such a rapid response. I mean that's the thing that's driving such enormous adoption of things like SPRAVATO out in the world is the fact that patients can come in and quickly thereafter leave better. The change here is that they also stay better, that we're able to show that they not only acutely improve on average, but that change is durable for at least 12 weeks thereafter. So we're going to be absolutely focused on continuing to craft that narrative and share those data and make sure that, that translates out into the world. But I don't know that we would point just to the lack of suicidality risk as a single differentiator.

Our next question comes from Christopher Chen with Baird.

Congrats on the data. Just kind of going ahead and looking ahead to ASCEND, just a quick question. If there was any kind of color on enrollment updates there and maybe thoughts on possibly how this data might spur enrollment for ASCEND.

Yes. Thanks so much, Chris. We don't have an update that we're going to be sharing today on ASCEND enrollment. We have seen a high degree of engagement from our sites, and that's true across the EMERGE and ASCEND studies and VOYAGE and the PANOAMA studies and every study we've conducted. What we hear, again, qualitatively quite often is that when sites are running studies of daily drugs and when they're running studies with DT-120, again, these are anecdotes. So take them with the appropriate grain of salt. But these sites tell us that patients really don't want to be taking daily drugs. They tend to have a preference for going into studies where they have an opportunity to take a drug to be in the clinic for a day and then potentially come out quite a bit better and impacted over the course of several months. So we expect that enrollment and the momentum we have across our clinical programs to just continue. And of course, we are incredibly excited to not only get to the ASCEND readout next year, but to get in very near term here to our two pivotal readouts in GAD.

That concludes a lot of time for the Q&A session. I will now hand back to management for closing remarks.

Yes. Thank you, everyone, for being here today. But before we close, I just want to say a brief thank you to everyone who's been involved in this process. To be on the cusp of delivering a new product like this is something that's really special to be a part of, and especially a part of no matter whether you're inside of the company or whether you're working with us in any capacity or supporting this in any capacity. And I think to zoom out for just a second, well, of course, we're here to discuss the study and our organization and the progress we've been making we have a real opportunity to actually change the landscape for these patients. We have been heading in the wrong direction for quite a while in the treatment of mental health disorders. And to have that opportunity to have an organization that can deliver on that vision is something that we certainly feel very proud to be a part of and a high degree of responsibility to do appropriately and to do well and again, whether you're sitting on the call here or involved with us directly in any day-to-day sort of operational role. I want to thank you for being a part of this and for making this possible and -- for believing in that future that we do, that we can really make a profound in psychiatry and profound change for these patients. So we're very excited about the months and years ahead of us and we look forward to sharing in those successes, hopefully, over the course. Thank you.

This concludes today's conference call. You may now disconnect.