Definium Therapeutics, Inc. (DFTX) Q4 2025 Earnings Report, Transcript and Summary

Good afternoon, and welcome to the Definium Therapeutics Full Year 2025 Financial Results and Business Update Webcast. [Operator Instructions] The webcast is live on the Investor and Media section of the Definium website at definiumtx.com, and a replay will be available after the webcast. I would now like to introduce Gita Jain, Head of Investor Relations of Definium. Please go ahead.

Thank you, operator, and good afternoon, everyone. Thank you for joining us today for a discussion of Definium's full year 2025 financial results and business update. Leading the call today will be Rob Barrow, our Chief Executive Officer, who is joined by Dr. Dan Karlin, our Chief Medical Officer; Brandi Roberts, our Chief Financial Officer; and Matt Wiley, our Chief Commercial Officer. An audio recording and webcast replay for today's conference call will also be available online as detailed in the press release announcement for this call. During today's call, we will be making certain forward-looking statements, including, without limitation, statements about the potential safety, efficacy and regulatory and clinical progress of our product candidates, our anticipated cash runway and our future expectations, plans, partnerships and prospects. These statements are subject to various risks such as changes in market conditions and difficulties associated with research and development and regulatory approval processes. These and other risk factors are described in the filings made with the SEC and applicable Canadian securities regulators, including our annual report on Form 10-K filed today. Forward-looking statements are based on the assumptions, opinions and estimates of management at the date the statements are made, including the nonoccurrence of the risks and uncertainties that are described in the filings made with the SEC and the applicable Canadian securities regulators or other significant events occurring outside of Definium's normal course of business. You are cautioned not to place undue reliance on these forward-looking statements, which are made as of today, February 26, 2026. Definium disclaims any obligation to update such statements even if management's views change, except as required by law. With that, let me turn the call over to Rob.

Thank you, Gita, and thank you, everyone, for joining our call today. We are incredibly excited to share today's updates as we rapidly approach our anticipated pivotal readouts for lysergide tartrate or DT120 ODT in generalized anxiety disorder and major depressive disorder in the months ahead. The momentum is palpable both across our development programs and in the world of psychiatry as we prepare for the adoption of psychedelics as potentially transformative new treatment options. We continue to believe in the potential of DT120 ODT as a best-in-class product candidate. And over the past year, our team has yet again set the standards for scientific rigor, efficiency and thoughtfulness and execution. As I reflect on 2025, I could not be prouder of our team and the progress we have made. Over the course of the last year, we rapidly progressed our late-stage pipeline, significantly strengthened our balance sheet and continued to expand our world-class leadership team and Board of Directors to drive our next phase of growth. Through ongoing engagement with the FDA under the breakthrough therapy designation program, we reached alignment on many key aspects of our development and submission strategy, positioning us to maximize the speed and efficiency of our NDA submission for DT120 ODT, subject to positive trial readouts later this year. Our commercial strategy and organizational readiness have mirrored these R&D successes with the addition of key commercial leadership led by Matt Wiley, who joined as our Chief Commercial Officer in March 2025. We've seen strong engagement across the spectrum, positioning us to deliver on our aim to yet again define the standard of excellence in the adoption of psychedelics. We began 2026 with the launch of Definium Therapeutics, a refreshed brand that reflects the evolution of our company and our leadership in psychiatry. Our differentiated strategy grounded in disciplined execution, scientific rigor and an ambitious view of the impact we can drive positions us to develop scalable, accessible treatments and drive long-term value for our shareholders. With 3 Phase III readouts expected in 2026, the first of which is just months away, we expect the year ahead to be a pivotal one, both for Definium and psychiatry at large. Our goal is clear: to address the urgent need for a new class of drugs that can offer meaningful relief to the millions of people who are living with GAD and MDD, disorders that have long been underserved by treatments with high burden, moderate efficacy and often poor tolerability. Building on our strong dose optimization Phase IIb study, which was published in JAMA last September, our clinical program for DT120 ODT consists of 4 pivotal Phase III studies, 2 in GAD, the Voyage and Panorama studies, and 2 in MDD, the Emerge and Ascend studies. I'm pleased to share today that Emerge, our first pivotal study in MDD, is fully enrolled, and we anticipate delivering top line data in late Q2. And while Emerge is the last of our 3 ongoing pivotal studies to be initiated, we could not be more excited to share this readout first across our Phase III programs. This sequencing both provides the opportunity to establish evidence in a second major market indication and enables us to engage with FDA with ample time to explore potential opportunities for accelerating our regulatory submission strategy for the MDD and GAD indications. We've also made significant progress in launching Ascend, our second pivotal study in MDD. Our first sites in Ascend have been activated, and we anticipate first participant dosing by early Q2. On to our GAD program, we continue to see strong enrollment across Voyage and Panorama. Enrollment in Voyage is approximately 80% complete. And based on the enrollment rate in current queue of patients, we expect to conclude enrollment in the coming weeks with top line data expected in early Q3. I'm also happy to share that with the preplanned blinded sample size re-estimation is complete with no required increase in sample size. Dan will be sharing further details on the sample size re-estimation in a few moments. Enrollment in Panorama, our second Phase III study in GAD is rapidly progressing, and we remain on track to deliver top line data in the second half of 2026. We plan to provide a further enrollment update and to disclose the outcome of the Panorama blinded sample size re-estimation at our Investor and Analyst Day in April. Our team remains focused on delivering high-quality data across our Phase III studies, targeting 2 of the largest and most impactful indications in psychiatry. We continue to believe in the best-in-class potential of DT120 ODT and are dedicated to the scientific rigor and disciplined execution that has defined our organization and successes to date. With that, I'll turn the call over to Dan to share additional details on our clinical programs.

Thanks, Rob. We remain highly encouraged by the enrollment trends we are seeing across our Phase III GAD and MDD studies. We've been spending a lot of time with our sites and investigators, and there is a high degree of excitement and engagement as we get closer to delivering top line data. As Rob mentioned, we are especially excited to deliver Emerge as our first pivotal readout in late Q2. While our Phase II Montgomery-Asberg Depression Rating Scale, or MADRS, results in GAD have given us great clinical confidence through the design and execution of Emerge, we have not previously had the opportunity to establish the efficacy of DT120 in a dedicated MDD population with patients in a major depressive episode. While GAD and MDD are substantially overlapping disorders, MDD is defined as an episodic illness with periods of euthymia or normal mood interrupted by major depressive episodes, which are characterized by dysthymia or depressed mood that must persist for at least 2 weeks and may last many months. GAD describes and is defined by a more continuous state of heightened anxiety. In our GAD program, starting with Phase IIb, we demonstrated DT120's remarkable ability to improve this continuous background condition, while our MDD program is intended to demonstrate the same effect on the course of major depressive episodes. Taken together, these data suggest that if approved, DT120 may represent a data-driven evidence-based clinical choice for providers and patients with the potential to improve patient outcomes, whether the patient is currently in a major depressive episode or not. Each of our 4 pivotal studies across GAD and MDD is comprised of 2 parts. Part A, a 12-week randomized, double-blind, placebo-controlled parallel group period, assessing the safety and efficacy of a single dose of DT120 ODT versus placebo, and Part B, a 40-week extension period with opportunities for open-label treatment. The primary endpoint in our MDD studies is the change from baseline in MADRS score at week 6 between DT120 ODT 100 micrograms and placebo. The MDD trials were designed with 80% powered to detect a 5-point improvement over placebo on this endpoint. The primary endpoint in our GAD studies is the change from baseline in the Hamilton Anxiety Scale, or HAM-A, at week 12 between DT120 ODT 100 micrograms and placebo. The GAD trials were designed to have 90% powered to detect a 5-point improvement over placebo on this endpoint. Our Phase III studies are modeled after our successful Phase IIb study in which we observed placebo-adjusted improvements of 7.7 points on the HAM-A and 6.4 points on the MADRS at week 12. In the context of other approved pharmacotherapies, which have typically shown a placebo-adjusted effect of less than 4 points on these endpoints, we believe DT120 has the potential to be not only a best-in-class product among psychedelics, but among anxiolytics and antidepressants broadly. And while placebo-adjusted changes are critically important for establishing efficacy, the absolute magnitude of improvement may be a more representative measure of the real-world patient experience. This is where DT120 even further stood out, having demonstrated a 21.9 point absolute reduction in HAM-A scores at week 12, corresponding with a 48% clinical remission rate and a 65% response rate. In addressing comorbid depressive symptoms, we saw an 18.7-point absolute reduction in MADRS scores at week 12. I'll now recap progress with our MDD studies. Enrollment is complete, and we expect to deliver top line data from Emerge in late Q2. Based on the progress in Emerge, we are moving forward with the execution of our second pivotal MDD study, Ascend. In Ascend, we are targeting enrollment of approximately 175 participants randomized 2:1:2 to receive DT120 ODT 100 micrograms, 50 micrograms or placebo. Our first sites in Ascend have been activated, and we expect to begin dosing by early Q2. We expect Ascend to continue to benefit from operational efficiencies that enabled the rapid enrollment of Emerge, including the ability to fast track select sites that participated in Emerge and those that are actively enrolling in our GAD program. Regarding our GAD program, we are in the final stages of enrollment in Voyage with completion anticipated in the coming weeks. In Voyage, we are targeting enrollment of approximately 200 participants randomized 1:1 to DT120 ODT 100 micrograms or placebo, while in Panorama, we are targeting enrollment of 250 participants randomized 2:1:2 to DT120 ODT 100 micrograms, 50 micrograms or placebo. Each GAD study includes a sample size re-estimation that allows for adjustment of the target enrollment based on a blinded evaluation of nuisance parameters. As Rob mentioned previously, we completed the sample size re-estimation for Voyage and determined that no increase in the trial sample size is required. In the initial study power calculation, we assumed a standard deviation of 10 points and a non-evaluable rate of 15% at week 12. Among the first 100 participants who completed week 12, we saw a model-based standard deviation of 6.7 points on the HAM-A and a non-evaluable rate of 10%. These observations suggest that the study's ability to detect a statistically significant drug effect substantially exceeds the planned power. In fact, if these nuisance parameters were to remain unchanged from the final analysis, this would imply that the study has over 99% power to detect a 5-point difference on the HAM-A and that the minimum difference required to achieve statistical significance would be less than 2 points. Beyond DT120, we are excited to have initiated our Phase II study of DT402 in autism spectrum disorder, or ASD, in late 2025. DT402, the R enantiomer of MDMA, has shown promising prosocial effects with a potentially favorable tolerability profile. We're developing DT402 to target the core symptoms of ASD, specifically addressing social communication that is central to the experience of the disorder. We believe this program represents another significant treatment opportunity given the high unmet need, the increasing prevalence of ASD and no FDA-approved therapies that specifically address these core symptoms. Having completed a Phase I single-ascending dose study that characterized the tolerability, pharmacokinetics and pharmacodynamics of DT402 in healthy adult volunteers, we dosed the first participant in our Phase IIa study and initial data is expected later this year. This study is a single-dose open-label design, assessing early signals of efficacy in up to 20 adult participants with ASD. The objectives and endpoints of the study are designed to characterize the pharmacodynamics and clinical effects of DT402 across multiple functional domains. Across our late-stage pipeline, we are making strong progress and rapidly approaching multiple pivotal readouts for our DT120 ODT program. We believe the remarkable profile of DT120 has the potential to be best-in-class among GAD and MDD pharmacotherapies, and we are confident in our strategy and execution to drive the broadest possible impact for the millions of patients in need. Now I'll turn it over to Matt for commercial comments on DT120.

Thanks, Dan. As an organization, we are deeply committed to and focused on impeccable commercial readiness for the potential launches in GAD and MDD. Over the past year, we've comprehensively mapped the provider landscape nationwide, and in close collaboration with our cross-functional internal teams, prioritized key states for launch. If approved, we are fully positioned to execute rapidly and with precision. Our vision for Definium commercialization is to deliver a genuinely high-touch white glove experience for our providers, one that extends the collaborative partnership-oriented approach that has distinguished us throughout our clinical development and with our trial sites. This philosophy has been a key differentiator for us, and we intend to make it a foundational element of our commercial model. We fully appreciate that providers will have multifaceted needs beyond just product information. They will seek clear guidance on REMS certification, regulatory requirements, operational integration and reimbursement pathways. Accordingly, we are building the robust infrastructure and cross-functional teams required to address these elements seamlessly and support providers from day 1. To strengthen our launch capabilities, we've assembled an exceptional commercial leadership team over the past year in marketing, market access and operations. This leadership team comes with deep experience in navigating complex launches, including experience with REMS and scheduled drugs. Their proven track record gives us tremendous confidence as we prepare for launch. We look forward to sharing more detail on our commercialization strategy at our upcoming Analyst Day on April 22. But stepping back, our message is simple. We are preparing to introduce something meaningfully different. Historically, when new classes of medicines have been introduced in psychiatry, they have generated significant value and delivered multibillion-dollar opportunities. We believe DT120 has the potential not only to participate in that kind of opportunity, but to improve on what has come before, most importantly, for patients who urgently need more than better. With that, I'll turn our call over to Brandi to discuss our full year 2025 results. Brandi?

Thanks, Matt. Research and development expenses were $117.7 million for the year ended December 31, 2025, compared to $65.3 million for the year ended December 31, 2024, representing an increase of $52.4 million. This increase was primarily driven by $44.7 million in higher DT120 program expenses, $9.3 million in internal personnel costs, reflecting expanded research and development capabilities, and $0.4 million in preclinical and other program expenses, partially offset by a $2 million reduction in DT402 program expenses. General and administrative expenses were $48.6 million for the year ended December 31, 2025, compared to $38.6 million for the year ended December 31, 2024, an increase of $10 million. The increase was primarily attributable to $6 million in professional services and pre-commercialization activities, $3.6 million in personnel-related expenses to support expanded operational activities, $0.7 million in directors' deferred share unit expense driven by our year-over-year stock price appreciation, and $0.5 million in other administrative expenses, partially offset by a $0.8 million reduction in legal and patent-related expenses. Overall, our R&D and G&A expenses for 2025 were in line with our internal expectations as we continue to make significant progress across the DT120 and DT402 programs. Net loss for the year ended December 31, 2025, was $183.8 million compared to $108.7 million for the year ended December 31, 2024. As a reminder, our net loss can be significantly impacted by changes in the fair value of our 2022 USD financing warrants. During 2025, the change in fair value was $22.8 million, reflecting an increase in our stock price from $6.96 at December 31, 2024, to $13.39 at December 31, 2025. We ended 2025 with cash, cash equivalents and investments of $411.6 million compared to $273.7 million at year-end 2024. Based on our current operating plan and anticipated milestones, we believe our cash, cash equivalents and investments as of December 31, 2025, will be sufficient to fund operations into 2028. We are pleased to enter 2026 with the financial flexibility to accelerate several key initiatives, including NDA preparation, market access priority activities, market research and KOL education. These investments are intended to support our path to market, and if DT120 ODT is approved, enable a well-prepared and robust commercial launch. We are also encouraged by the continued evolution of our investor base with strong engagement from existing shareholders and growing interest from new investors as we progress through 2025. As we look ahead to a very important year in 2026, our focus remains on disciplined execution, thoughtful capital allocation and advancing our programs in a way that supports long-term value creation. I'll now turn the call back to Rob for our closing remarks.

Thank you, Brandi. 2025 was a year of bold ambition and disciplined execution. In 2026, Definium is set to deliver some of psychiatry's most important data, highlighting our progress and ambition to bring novel scalable therapies to patients underserved by today's standard of care. With a strong balance sheet and a late-stage pipeline with multiple catalysts in the months ahead, we're excited to continue driving value for our shareholders and the millions of patients who deserve more than better. Of course, none of this progress will be possible without our exceptional team whose passion, commitment and unmatched execution continue to set the standard for our field. Thank you again for joining our call today. We will now open the line for questions.

[Operator Instructions] Our first question coming from the line of Andrew Tsai with Jefferies.

For this interim that you did, it's very interesting for Voyage. I'm curious in the hypothetical scenario where the DMC asked or recommended you to upsize the trial, what would have been effectively the placebo-adjusted delta for that to happen, give or take? And just to confirm, there were no other scenarios with this interim such as stopping for futility or even stopping for success?

Yes. Thanks so much for the question, Andrew. So this is -- first of all, it was a blinded sample size re-estimation. And so an important feature of that analysis is that we don't ever unblind the study. We don't do any inferential testing. And as a result, we don't actually learn anything about the performance of the 2 groups independently or in relation to one another. Effectively, you can think of it as looking at the right side, right of the plus or minus on the 95% confidence interval to assess the standard error and ensure that the assumptions we made at the beginning of the study are reflected or we don't lose power because we've made the wrong assumptions. And so there was no implication. There's no learnings or inference that can be derived either from this analysis or for any other outcome of the analysis. But we are certainly excited to see that we're good with the assumptions we made. And if anything, as Dan mentioned during the call, have certainly adequate power at 99% or greater if the current variables hold, nuisance parameters hold. And we're eager to get to the study results and ultimately do that inferential test and look at the performance of 120 versus placebo.

Wow. Okay. And then really quickly, by the time you top line the Voyage data now in early Q3, would you consider piecemealing some of the Part B open-label extension data just to further showcase how durable a single dose of 120 could be? Otherwise, when would you share the open-label portion?

Yes, absolutely. I think one of the things we've been really focused on is, of course, the durability and the response patterns over the course of an entire year. And of course, in all of the studies have been running for quite a while now. And so as we continue to accrue patients who have gone through certain milestones and either events of retreatment or have made it through a fixed interval of time, we'll have, of course, increasing data and increasing confidence in those data to be able to share some insights. So we haven't firmed up a commitment to exactly when we would present Part B data. So we certainly don't want to get ahead of ourselves, and we present data that we don't feel are representative or that we're not confident in at any time. So we'll certainly be taking a look at that. And as we accrue those data, be it at any of the readouts from the ongoing studies or at another time, we'll have an opportunity to share as much insights as we possibly can about the performance in Part A and Part B.

Our next question coming from the line of Mark Goodman with Leerink.

This is Basma on for Mark. Our first question is on the interim look. Again, have you conducted the interim look for Panorama as well or not yet? And -- or are you planning to do it once you hit 80% enrollment similar to Voyage? And also regarding the MDD, when are you going to plan to do the interim look exactly for the Emerge trial? Our second question is for the GAD readout. What are your expectations regarding the remission rate? What would you consider as a good and differentiated rate versus the standard of care? That's it for us.

Yes. Thanks so much, Basma. So in terms of the interim analysis for Voyage, we, of course, announced that today. For Panorama, our second pivotal study in GAD, we'll be sharing additional details and enrollment updates at our Analyst Day in April. For the 2 MDD studies, of course, Emerge is now fully enrolled and the data -- top line data that we'd be sharing would be the completed final top line analysis from that study. So we're not conducting an interim look on either of the MDD studies as currently. In terms of GAD and the remission rate, I'll turn it over to Dan to maybe comment about our thinking around response patterns and ultimately what drives patient experience and value in this population.

Yes. It's a great question about the remission rate because we've obviously talked about that from our Phase IIb outcomes. I think it's important to note that mostly what we know about pharmacotherapy-induced remission rate come from MDD studies. And in MDD, what we see in SRIs, the first-line treatment that's most commonly used, attributable remission rate in the real world is something in the 10% to 30% range. But of course, it's difficult to necessarily interpret those data because MDD is necessarily a cyclical illness so that when a major depressive episode is resolved, whether with meds or without, then that is a period of remission from those symptoms. We made some design choices in Phase III for both GAD and MDD, which was to target open-label treatment of the Part B treatments to the threshold between mild and moderate illness on the scales on the HAM-A and the MADRS. So in this case, what we are really looking at is given the availability of open-label treatment in the Part B, are we able to treat people down into that mild or better range reliably with the redosing. So while we're not priority specifying what we would hope for from an absolute remission rate, what we're intending here to do is to get people out of moderate or worse illness and see how well we can keep them in mild or better.

Our next question coming from the line of Evie [indiscernible] with Evercore ISI.

You have Evie on for Gavin. Congratulations on all the progress made this year. It's great to see that the SSRE is now complete. Any color you could provide on enrollment and how it is trending for the second GAD and MDD trial seeing as Voyage data is now expected by early 3Q? And our second question is in addition to the SSRE and variability, can you speak to anything else giving you incremental confidence? Could be something like baseline characteristics, OLE rollover, retention, screen failures or anything like that?

Yes. Thanks so much for the question. So in terms of enrollment updates, of course, with Emerge, our first MDD study now fully enrolled and with data expected in late Q2, we've just been overwhelmed by how fast we're able to enroll that study and how excited we think that represents the field and the researchers who are working on the study have been and are about the potential here. We certainly are, and our team has done an incredible job at executing on these studies. In terms of Voyage, we shared that approximately 80% enrollment, and we continue to see incredibly strong enrollment with our best months yet and we absolutely are seeing the continued growth and acceleration of enrollment across the program. So for our second study for Panorama, again, we'll be sharing further updates at our Analyst Day in April, but we've been encouraged across the board and really happy with where we are in enrollment in that study. Ascend, we're also, of course, will be starting in the coming weeks. We're really excited to get studies activated really faster than I think even we anticipated and the ability to get studies DEA activated and DEA approvals in place in a matter of just a few weeks has allowed us to really accelerate the start of that second study in MDD. So really across the board, we've been very encouraged by the enrollment trends and where that positions us for 3 pivotal readouts over the course of this year. In terms of incremental confidence, we won't be commenting on specific variables or what we're seeing in those variables. So we are extraordinarily confident in the profile of 120. And as Dan mentioned during his prepared remarks, with the observed parameters that we saw in the interim analysis for Voyage, that would imply a quite high, over 99% power to detect a 5-point difference and less than 2 points required in terms of the separation between the groups in order to achieve a statistically positive result if those nuisance variables are the same at the end of the study as they were at the interim analysis. So that gives us quite a bit of confidence if the study only has to show a couple of points difference to get a statistically positive outcome, of course, we would hope to see better than that. We think that a 4-point difference between the arms is something we'd really like to see that would really stand out as the best drug we've seen and the best results we've seen in GAD to date. And so we're certainly excited to deliver those data. But all that we're seeing across all of the studies gives us continued confidence in the program and positioning us really well for these readouts later in the year.

Our next question coming from the line of Brian Abrahams with RBC Capital Markets.

Congrats on all the progress and looking forward to a very exciting data rich year. Two for me. I guess, first, you've had some slight changes in the enrollment time lines versus prior expectations in both directions. And I guess I'm curious the impact that has on your views of the addressable populations of patients with these respective conditions who may be interested in a psychedelic. And then just with the interim passing and obviously, the low variability in dropouts, it sounds like a very narrow delta could still be statistically significant in Voyage. So can you maybe elaborate a little bit more on your latest views on clinically meaningful delta? And really how would hitting stat sig with a smaller delta potentially impact your plans in Panorama as well as how you'd see the drug positioned commercially?

Yes. Thanks so much, Brian. And both great questions. I'll turn it over to Dan to talk about the first one. And just Dan, maybe you can reflect on how we think about these populations and also how these patients, of course, show up in trials and show up for clinical attention.

Yes. It's an excellent question and a good observation. And while the time line changes don't necessarily change how we think about the patient population, certainly, what we know is that in the current environment of psychiatry with the drugs that are currently available, MDD has been a target of both drug development and clinical focus for really the last 30 years or so and left GAD a bit behind with no new drugs approved in GAD since 2007. The reality is that this is a massively overlapping patient population and that while GAD is a more continuous sort of background condition that people live with this experience day by day, and in many cases, for much of their life. And that both makes people not necessarily seek care. They're sort of used to being the way they are, even if it is quite disruptive to their lives. But it's not an acute change that people notice in their lives as they do when they enter a major depressive episode, which often drive people to seek care. So we're really excited about the opportunity to potentially provide a drug here that regardless of what induces someone to go seek care, whether it's this ongoing state of anxiety or newly developed anxiety or entering a major depressive episode, which represents a real state change for them. The way we think about this is that regardless of the driver of the presentation that we intend to provide a body of evidence that demonstrates that DT120 would be a good choice for the patient. So that gives us some temporal flexibility for people in the course of their lives and in the course of their illness.

Yes. Thanks, Dan. Brian, in terms of your second question about the clinical meaningfulness, it also is a great one. And I think really important contextually, both in terms of that difference and in terms of the overall magnitude of change. I think there is certainly a lot of different approaches out there to these concepts. In our minds, Dan mentioned this a little bit in the prepared remarks, but in the real world, patients, of course, don't get placebo. So while we definitely want to demonstrate as largely a placebo-adjusted response as we can, observing an absolute magnitude of change that stands out relative to the other options that are available, there are always limitations comparing across studies and such. But -- and we think that's an important variable to focus on as well. When it comes down to that placebo-adjusted change, again, when we're talking about drugs that we believe have the potential to be transformative, we think that should also be reflected in terms of the consistency with which patients are seeing the benefit and the magnitude of that benefit over placebo. And so while, yes, we're very encouraged when we have a low clinical bar relative to where we started and where we powered the study, we absolutely would like to see a change that stands out and continues to stand out as we saw in Phase II. And in GAD, when we look at the landscape of currently approved therapies, not one of them consistently delivers at or above a 4-point delta over placebo in those studies. And so if we're seeing a magnitude of change that's as large or larger than those and the placebo-adjusted change that's larger than 4 points, it's hard not to get incredibly excited about that in our mind. So while we don't set a sort of bright line on any of these kinds of concepts, we very much are looking for data that impress and data that get us and we think payers and providers and everyone excited about the potential because we certainly believe it's there and hope the data stands up to support that.

Our next question coming from the line of François Brisebois with LifeSci Capital. François Brisebois: A lot of interesting questions, a lot of interesting answers, too. And I was just wondering, so you touched on the 4-point kind of bar that is not a hard bar or anything, but something that you've been mentioning on the GAD side. Can you just remind us, now that MDD will be first, can you just kind of do the same exercise in terms of what you'd like to see and compare it to what's been seen for MDD? And maybe also remind everyone what you had seen previously on the MADRS side in the prior trial and maybe caveats around what you had seen because the trial wasn't necessarily for that originally.

Yes. Thanks so much for the question, Frank. I mean, again, when we look at the landscape of approved products and products that are in development, we continue to be encouraged qualitatively in the research we've done to date. Dan mentioned that we saw is in the GAD population with milder illness. I think we really focus a lot on the severity of both MDD and GAD because those severity are representative of impact on patients and drive a lot of the burden and the value. And so as we think about the response, we think about severity and that overall magnitude of change. And that's again where we saw really impressive results on both symptom sets, on anxiety symptoms and depression symptoms. So -- and we saw a 6.4-point difference between 120 and placebo in MADRS scores that was starting from a lower point than what we would expect in a dedicated MDD population of patients in a major depressive episode. We'll certainly be painting that picture, I think, more comprehensively as we get to the Analyst Day in April. And I think as we get closer and closer to the readouts, we want to set full context for those expectations and just the realities of that landscape. But when we look at -- roughly, when we look at that today, again, seeing an effect, a placebo-adjusted effect that is greater than 4 points seems quite important. And seeing a double-digit absolute magnitude of change also seems quite important in our minds. And that's true, especially in the MDD population where taking patients from severe depression symptoms to high, moderate or low severe wouldn't represent a major change in our minds. And so as we think about this readout, we again want to see a large absolute magnitude of change and as large of a placebo-adjusted change as the drug can deliver. François Brisebois: Okay. Maybe if I could sneak in just the last one there. In terms of -- when you do some work on it, you hear a lot of comments around, well, from going from the Phase II to Phase III, it's totally normal to get a smaller delta with placebo. Is that something that makes sense to people? Is there a reason behind that? Or is that just kind of protecting yourself a little bit?

Yes. No, I think the reality is that we certainly -- in historical studies in psychiatry, there are studies at times where that happens. I think where we see -- and we've seen this in schizophrenia, we've seen in a number of other indications as well, where some of the best-performing drugs continue to not see that sort of compression as they progress in development. And so the design changes, operational changes, those sorts of things can have an impact, and that's why we've been so encouraged with our approach in Phase III. And we designed our Phase II program to be exactly executed and designed like a Phase III study, although we thought it critically important to establish a dose response and select the appropriate dose to take into the pivotal studies, which is why we did the Phase II the way we did. That also means we made minuscule operational changes between the Phase II and Phase III study. So we're virtually doing the same thing over again is just with 2 or 3 arms instead of 5 arms as we did in Phase II. So that again gives us a lot of confidence. And then a number of dynamics in the study design that we think will drive better patient retention through the primary outcome in these studies. Dan mentioned that the non-evaluable rate that we saw in the interim analysis in Voyage was 10%. You compare that to over 25% in our Phase II data, which we think is largely driven by the fact that we're seeing with the Part B, the 9-month extension period, patients have an ability to access open-label 120 if they complete the full 12-week blinded control period. And so all of those dynamics give us a lot of confidence about the operationalization of these studies and give us a lot of confidence as we approach data.

Our next question coming from the line of Pete Stavropoulos with Cantor Fitzgerald.

Nice to see the progress. First one, just curious to hear how you're thinking about a potential filing strategy if the 2 GAD Phase IIIs are positive and if the first Phase III MDD study Emerge is positive, will you complete 2 MDD studies before filing an sNDA? Or is there a reason to wait for the second study?

Yes. Thanks so much for the question, Pete. It'd be premature to comment specifically on filing strategy given that we don't have data in hand. But certainly, we think that the stronger the data, the more compelling an argument that a sponsor can make, and that's true across the board. And so we'll be looking very closely at the data. And if we're seeing an impressive result, both placebo-adjusted and absolute magnitude of change, something that gets us quite excited, we will very much be engaging in those conversations to explore the most efficient pathway forward for both the indications.

Okay. And then just to touch on your earlier stage asset, 402. If you can give us a little bit of color in terms of assessing clinical effect, which scales are key for you? And in your deck and in the PR -- in today's PR, it mentions functional biomarkers. Can you just elaborate on that?

Yes, I'll turn that one over to Dan to comment on...

Yes. Happy to comment on that, and thanks for asking about 402. Obviously, with all the excitement around 120, sometimes we don't get a chance to comment on this as much as we'd like to because we're really excited about the program. We've gotten through a single-ascending dose safety study, which gives us good data for dosing in a single dose paradigm, which is exactly what we've said we've done, which is to bring the drug forward in a single dose open-label paradigm. And the question of measurement in ASD is always an interesting one. You're asking after the scales and the Vineland and other scales that have been used in attempts at approval before, of course, with no approved drugs for the core symptoms of the disorder, the right measure at the right time remains...

It sounds like a very narrow delta could still be statistically significant in Voyage. So can you maybe elaborate a little bit more on your latest views on clinically meaningful delta? And really how would hitting stat sig with a smaller delta potentially impact your plans in Panorama as well as how you'd see the drug positioned commercially?

Yes. Thanks so much, Brian. And both interaction, social communication and the other domains where we think that the drug will be effective. So considering measurement from the outset and very much thinking about measurement techniques that can track along with the drug through its phases of development and ultimately through to regulatory submission if we -- if and when we get there and potentially even measures that could travel with the drug out into the world if it's approved.

Congrats once again.

Our next question coming from the line of Christopher Chen with Baird.

Congrats on the progress. I had a question regarding MDD. So one of the things we hear about SPRAVATO is that it's good at alleviating symptoms of TRD, but not so good at increasing overall productivity of daily life, like just work -- productivity at work, one example. So I know you're measuring a number of quality of life metrics in Emerge, but I'm particularly interested in the WPAI. And so if you don't mind just expanding on your expectations there? And can you provide any high-level color on what you're hearing about how these patients are doing beyond just MDD symptom alleviation? And then I have one more after that.

Yes. Thanks, Chris. I'll turn it over to Dan to talk about WPAI. I guess I'd first say that with the dosing regimen that's required to go into a clinic for multiple hours, multiple or at least one time a week for a long time, being at work is certainly going to be a thing that drives productivity. So a treatment where you don't have to come in infrequently, which is if we're able to establish the same kind of durability as we've seen in trials so far, certainly something that we think would differentiate 120 from anything that's out there in the world today would be a pretty important impact, right? It's -- going to the doctor's office once or twice a week is quite a burden. And so even beyond the actual measurable productivity, the presence at work and being able to do that is going to be an important driver and certainly something that also shows up in patient satisfaction and overall utilization of the drug we would think. But I'll turn it over to Dan to elaborate maybe on the WPAI.

Yes. The domains that the WPAI look at absenteeism, not being able to make it work, presenteeism being impaired while at work and sort of tries to assess an overall percentage of impairment while at work. And of course, this isn't a primary outcome, and we're not looking to try to demonstrate efficacy overall based on a scale like this. But I think as you observed, this is really important, right, that just having a lower reported set of symptoms or suppressed symptoms doesn't necessarily mean that someone is back able to do the things that they need to do and want to do in their lives. And we very much are oriented toward the idea that just as we saw in Phase II that the experience of participants after treatment because, of course, unlike SPRAVATO, where the treatment is a continuous intermittent course, we anticipate having long periods of time between treatment if such retreatment is even always necessary. And the way that folks describe their experience post treatment in the Phase II was less about, as you're pointing out, sort of symptom suppression and more about having an outlook that was changed as it relates to the future of GAD, and obviously, as we hope to see in MDD as it relates to sort of the anhedonic or inability to take pleasure in activities that would generally give the person pleasure. So we are measuring WPAI and other scales of function and participation in life for exactly that reason because we remain optimistic and hopeful that the sort of change that we see with DT120 represents a more whole person change toward a state of what could be called recovery.

Great. That's very helpful. And then just a quick one. Are you collecting time to just -- patient time to discharge data in these trials? And if so, are you seeing anything that may suggest any shifts from that 6- to 8-hour monitoring period?

Yes, it's a great question. And we are absolutely collecting high granularity data. We think it's critically important to have data-driven arguments and a data-driven understanding of what's happening on a dosing day and to ultimately characterize that to inform regulatory discussions. We start assessing. We have a structured set of assessments that we measure on an hourly basis starting at hour 5. And we, of course, observe all patients regardless of the dose or whether they receive placebo through hour 8 in the study. And at the end of the day, we expect to have, again, a high granularity assessment of the different domains and ultimately, the time to which patients are able to be discharged safely, we think, from a treatment session. So we, of course -- given that we have a number of open-label treatment sessions, we have some insights there, which we can't share quite yet in great detail. We want to again aggregate enough data to feel confident in sharing that before we do so. But certainly, as we progress and as we get to a top line readout, we think it's really important given the nature of these drugs to start characterizing that, something we've been doing with a really thoughtful approach beginning with our Phase II study and certainly being refined and giving us increasing confidence as we've gotten through the conduct of a Phase III program.

Our next question coming from the line of Patrick Trucchio with H.C. Wainwright.

This is Arabella on for Patrick. Congrats on all the progress. We're looking forward to the upcoming readouts. Since Panorama also includes European sites, are there any meaningful differences in diagnostic practice, placebo behavior or standard of care that could introduce additional variability?

Yes, I'll turn that one over to Dan.

It's an excellent question and a good observation. The Panorama study does include European sites. And while there are, as you note, in the practice of psychiatry, regional variations even within the United States, different areas of the country have different practice patterns. And so the diagnostic criteria remain the same, the way they're applied can be different from place to place. We work our way through that by being very highly specified in our protocols. So diagnostic criteria that we use are standard from one country to the next and one site to the next, of course. And the way they're applied is standardized and that standardization is supervised and monitored from beyond the site level that all of our participants have really a 3-part confirmatory set of assessments, only one of which is based on the site assessment. We have central diagnostic confirmation and central severity confirmation so that it takes that kind of site variability out. Another advantage to the patient population is because we take both in the case of GAD, which as you know, as the European sites and MDD, which hasn't, because we aren't predicating enrollment in our studies on some set of past treatments or having been failed by some set of past treatments, local treatment pattern variation is not going to have an impact on who we bring into the trial. So we are incredibly confident that across sites here in the States and sites in Europe that we're getting the participants who we intend to get into the study. And because we're testing as a monotherapy, of course, we're getting participants independent of what might be local practice patterns for the treatment of these disorders.

Great. And then really quickly, I know we already touched on it, but specifically for GAD, and I know it's still early, if both Voyage and Panorama are positive, would that allow you to file? Or is there any additional long-term safety data or anything else that might gate submitting an NDA?

Of course, it's premature to talk finally about a filing strategy and filing dynamics until we had a final discussion with FDA at a pre-NDA meeting. But based on a really positive dialogue we've had with FDA throughout our pivotal programs, we feel highly encouraged that delivering Part A data, durability data out to 12 weeks is what we need for filing. And so as we get to top line data from these studies, we're already doing a ton of work to get ourselves ready to be in a position to file as quickly as possible and again, try to set that standard for how efficient and how quickly we can go to race across the finish line.

Our next question coming from the line of Ami Fadia with Needham & Company.

Congrats on all the progress. My question was on -- I have got 2. Firstly, just on the MDD program. You indicated that the study is 80% powered to show a 5-point change. And in your GAD study on MADRS, you've seen a 6.4-point change. What I want to understand is from a commercial perspective, in order to be able to tap into a meaningful portion of the MDD market, not just the really -- the patients that are treatment resistant, what type of a profile would you like to see? And then secondly, as you think about the regulatory landscape and how that's changing and the recent FDA stance on [Audio Gap]

[Audio Gap] and flexibility, although we are going to continue to hold ourselves to the highest standards of rigor. That all said, these are highly overlapping indications, and we are seeing, of course, and measuring symptoms of anxiety and symptoms of depression across all 4 of the studies. And so aggregating a large body of evidence if we're seeing consistent results across multiple studies across multiple domains with a high degree of both stand-alone and placebo-adjusted change. And the better the data are, the stronger the arguments are going to be whether it's 1, 2 or more studies for any program. And so we'll certainly take all of that into consideration and depending on the strength and the magnitude of responses that we're seeing across these studies, be in a position to chart a regulatory path forward there. To the first point, again, I think it's a little bit premature to talk overly precisely about segmentation about exactly where this would land in the commercial setting. I'll turn it over to Matt to maybe comment just how we think about that and the sort of expectations and hopes we would think about for both commercial adoption and for reimbursement as such.

Yes. Thanks, Rob, and thanks for the question. As it pertains to the patient profile in MDD, first of all, we take a step back and look at both of these indications. These are highly prevalent indications. There are over 50 million patients in the United States for both indications. And there's a still very significant unmet need. As we conduct market research with HCPs, we see that the unmet need is greater than 70% across both the indications. So even with the care that they have access to today, there's still something left significantly lacking in the treatment paradigm. So we know that payers do manage drugs and branded drugs that enter the market typically have a step or two. And so we believe that, that can narrow the overall addressable market slightly. But there are, for both GAD and MDD, a significant number of patients that are going to benefit if approved, from DT120.

Our next question coming from the line of Sumant Kulkarni with Canaccord.

As we eagerly await all the data you expect to announce this year. I have 2 questions, one on product development and the other on the commercial side. First, conceptually, we think investors are perhaps somewhat unfairly holding psychedelic therapeutics to a higher bar on point separations on scales in clinical trials. But our view for some time now has been that where the bar really should be different versus standard of care is on durability of effect. Is that a fair real-world characterization from your perspective? And I'm asking that because I don't think I heard an explicit callout for durability in your earlier answer on clinical relevance of a STAT6 on HAM-A and perhaps even more so on MADRS.

Yes. No, thanks so much for the question, Sumant. When we think about durability, there both the practical limitations of how long out in time you can look at single-dose durability in a placebo-controlled manner. There are certainly insights that we can gain beyond that. And in our conduct of the studies, we'll be looking the response patterns and the ultimate duration to events beyond just a 12-week period. But when we look at the landscape, 12 weeks is the outer bound of what most studies, particularly drugs that don't require a long time, for instance, SRIs can take many weeks to show any sort of activity. And so of course, sponsor in those studies would wait well beyond that to try to drive that separation. But when we think about the durability and our dialogue with regulators to date, the ability to show durability at 12 weeks past a single intervention is really at or close to the highest bar one could set for a drug. And so part of the decision-making in the design of our Phase III program was to have our primary endpoint be at that time, we would be showing if successful in these studies, really the longest durability of response that we could hope to or could hope to be established with -- in a parallel group phase of the study. And that stands out among all of the product candidates that we're seeing in late-stage development, certainly in our field. So we absolutely agree that durability is important and that durability well beyond a few weeks after a single treatment or the last treatment of drug is really meaningful and why we've designed our studies the way we have.

Got it. Yes, that's really why I was asking because you've shown really good durability so far. And on the commercial side, Matt, you mentioned a "high-touch white glove experience." So what are your latest thoughts on pricing in MDD and GAD, at least relative to SPRAVATO for TRD, if that's still a good benchmark? And what fraction of that high-touch white glove experience can be paid for by insurers?

Yes, thanks so much, Sumant. Yes, I'll just say briefly, I think -- and I'll turn it over to Matt. I think the -- when we think of pricing, it's really premature to talk specifically about pricing. But when we think about the dynamics, we continue to believe and sort of build conviction in our belief that the failure of currently available therapies to address a patient's depression or anything else is not a good proxy to define a population. And that what we see also in a lot of our HEOR work is that severity is a huge driver of disease burden. It shouldn't be surprising. The fact that drugs that don't work particularly well in a population haven't worked in the population doesn't mean that those who were underserved by those therapies are worse off necessarily. And so while we understand the dynamics of likely not being a first-line therapy for everyone, we do think that those distinctions are somewhat artificial and as a result, something that we both can look at within our subpopulation in our studies, but wouldn't sort of shy away from things like SPRAVATO as a comparator given the sort of artificiality of that distinction. But I'll turn it over to Matt to comment further on that.

Yes. So Sumant, as we think about the high-touch or white glove type of orientation we have for this launch is really to remove any friction that a patient or provider could experience. And so that will involve a hub service model, being really clear on the reimbursement pathway, how to bill and code, et cetera, ensuring that the patient out of pocket is not an obstacle, basically removing any of the obstacles to get to therapy as quickly as possible. That's our ambition. That's what we're building towards, whether it's through field team and high-touch field team exposure to either HCPs or otherwise in market access and ensuring that we have a seamless hub model that really helps coordinate all of the different touch points to ensure that the patient experience is positive.

And that's all the time we have for our question-and-answer session. I will now turn the call back over to Mr. Rob Barrow for any closing remarks.

I want to thank everyone again for joining us on the call today. We are incredibly excited to come to our top line readout for Emerge first in the months ahead. And with 3 pivotal readouts across the course of the year, we think this is really a defining year for us and are incredibly excited to get to those data readouts. So thank you again for joining us today, and I hope you'll join us at our upcoming events in April and thereafter.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation, and you may now disconnect.