Definium Therapeutics, Inc. Q4 FY2025 Earnings Call

Good afternoon, and welcome to the Definium Therapeutics Full Year 2025 Financial Results and Business Update Webcast. 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 and 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 the 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 details 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.

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?

Thank you for the question, Andrew. This was a blinded sample size re-estimation, and a key aspect of that analysis is that we never unblind the study or engage in inferential testing. Consequently, we don't gain insights about the performance of the two groups either separately or in comparison to each other. You can think of it as examining the right side of the plus or minus in the 95% confidence interval to evaluate the standard error and confirm that our initial assumptions for the study still hold, ensuring we don't lose power due to incorrect assumptions. Therefore, there are no implications or conclusions that can be drawn from this analysis for any outcomes. However, we are pleased to see that our assumptions appear to be sound. As Dan mentioned during the call, we are confident we have sufficient power at 99% or higher, assuming the current variables and nuisance parameters remain consistent. We look forward to the study results and performing the inferential test to compare the performance of 120 against 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 about the interim look. Have you conducted the interim look for Panorama yet, or are you planning to do so once you reach 80% enrollment like you did with Voyage? Also, regarding the MDD, when do you plan to conduct the interim look for the Emerge trial? Our second question is about the GAD readout. What are your expectations for the remission rate? What would you consider a good and differentiated rate compared to the standard of care? That's it for us.

Yes. Thank you, Basma. We announced the interim analysis for Voyage today. For Panorama, our second pivotal study in GAD, we will provide more details and enrollment updates at our Analyst Day in April. Emerge is now fully enrolled, and we will share the final top line data from that study. Currently, we are not conducting any interim looks on the MDD studies. Regarding GAD and the remission rate, I will turn it over to Dan to discuss our thoughts on response patterns and what ultimately impacts 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 rates 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 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 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 Q3? 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 timelines versus prior expectations in both directions. And I guess I'm curious about 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 drives 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, regarding your second question about the clinical significance, it's a crucial topic. It's important to contextualize the differences and the overall magnitude of change. There are indeed many approaches to these concepts. As Dan noted in the prepared remarks, in real life, patients don't receive a placebo. While we aim to show a strong placebo-adjusted response, it's essential to observe a noticeable magnitude of change in comparison to other available options, despite the inherent challenges in cross-study comparisons. We believe this is a key area to focus on. In terms of the placebo-adjusted change, when discussing drugs we think have transformative potential, we believe it should also reflect the consistency with which patients experience benefits and the extent of those benefits over placebo. We're encouraged by a low clinical threshold compared to our starting point and the study's power, but we want to see a standout change that persists as we noticed in Phase II. In the case of GAD, none of the currently approved therapies consistently achieve or exceed a 4-point improvement over placebo in their studies. Therefore, if we observe a magnitude of change that is equal to or greater than these and a placebo-adjusted change exceeding 4 points, it's hard not to feel excited about that. While we don't impose rigid criteria on these matters, we are certainly looking for impressive data that generates enthusiasm among payers, providers, and everyone involved, as we believe strongly in the potential and hope the data will support that belief.

Our next question coming from the line of François Brisebois with LifeSci Capital.

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.

Thank you for the question, Frank. When we examine the landscape of approved products and those in development, we're encouraged by our research findings so far. Dan pointed out our observations in the GAD population with milder illness. We're particularly focused on the severity of both MDD and GAD, as these metrics reflect the impact on patients and contribute significantly to their burden and perceived value. In assessing the response, we consider both the severity and the overall magnitude of change. We observed notable results for both anxiety and depression symptoms. Specifically, we noted a 6.4-point difference between the 120 mg group and the placebo in MADRS scores, starting from a lower baseline than expected in a dedicated MDD population experiencing a major depressive episode. We'll provide a more detailed overview at our Analyst Day in April, and as we approach the readouts, we aim to provide full context for expectations and the realities of the landscape. Currently, we see that a placebo-adjusted effect greater than 4 points is significant, and an absolute magnitude of change in the double digits is equally important to us, particularly in the MDD population, where moving patients from severe depression to high, moderate, or low severe does not signify a major change in our estimation. Thus, for this readout, we are looking for a large absolute magnitude of change along with the most significant placebo-adjusted change the drug can achieve.

Okay. If I could add one more thing, when you work on this, you often hear comments about transitioning from Phase II to Phase III, where it's typical to observe a smaller difference with the placebo. Does that resonate with people? Is there a rationale for that, or is it just a way of managing expectations?

Yes. The reality is that in historical studies of psychiatry, there are times when this occurs. We've observed it in schizophrenia and several other indications, where some of the best-performing drugs do not experience the anticipated compression as they move through development. Design changes and operational adjustments can influence this, which is why we are optimistic about our Phase III approach. We designed our Phase II program to mirror a Phase III study closely, placing significant importance on establishing a dose response and selecting the right dose for pivotal studies, which is why we executed Phase II as we did. This also meant we made minimal operational changes between Phase II and Phase III, allowing us to repeat almost the same process, just with 2 or 3 arms instead of 5 as in Phase II. This gives us substantial confidence. Additionally, there are several aspects of the study design that we believe will enhance patient retention through the primary outcome. Dan pointed out that the non-evaluable rate in the interim analysis of Voyage was 10%, compared to over 25% in our Phase II data. We think this is primarily due to the nine-month extension period in Part B, which allows patients to access open-label 120 if they complete the full 12-week blinded control period. All these factors contribute to our confidence in the operational execution of these studies as we move towards data collection.

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. Regarding your earlier stage asset, 402, could you provide some insight into which scales are important for assessing clinical effect? Additionally, your presentation and today's press release mention functional biomarkers. Could you 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. Thank you for the question. We are considering measurement from the beginning and carefully thinking about techniques that can track the drug throughout its development phases and ultimately through regulatory submission, if we reach that point, and possibly even measures that could accompany the drug once it is approved.

Congrats once again.

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

Congratulations on the progress. I have a question about MDD. One concern we hear about SPRAVATO is that while it effectively reduces symptoms of TRD, it may not enhance daily life productivity, such as work performance. I understand you're assessing various quality of life metrics in Emerge, but I'm particularly interested in the WPAI. Could you elaborate on your expectations regarding that? Additionally, can you share any general insights on how these patients are faring beyond just relief from MDD symptoms? I have one more question after this.

Thanks, Chris. I'll hand it over to Dan to discuss WPAI. First, I want to highlight that the dosing schedule for the treatment, which requires patients to spend multiple hours in a clinic at least once a week over an extended period, can significantly impact productivity. A treatment that reduces the need for frequent clinic visits, assuming we can maintain the durability observed in trials so far, would really set 120 apart from current options available. The burden of having to visit the doctor's office frequently can be quite challenging. In addition to the measurable increase in productivity, being able to work more regularly will likely be a key factor and will probably enhance patient satisfaction and overall utilization of the drug. Now, I'll let Dan elaborate further on 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.

That's very helpful. I have a quick question. Are you collecting data on patient time to discharge in these trials? If so, are you noticing any changes from the 6- to 8-hour monitoring period?

Yes, that's a great question. We are indeed collecting detailed data, which we believe is essential for making informed, data-driven arguments about what's happening on a dosing day and for aiding regulatory discussions. We begin our assessments with a structured set of evaluations measured on an hourly basis starting at hour 5. Additionally, we monitor all patients, regardless of their dose or whether they receive a placebo, up to hour 8 during the study. Ultimately, we expect to have a comprehensive assessment of various domains, particularly focusing on the time it takes for patients to be safely discharged after treatment. Given that we have several open-label treatment sessions, we have gathered some insights that we are not yet able to share in detail. We want to compile enough data to confidently disclose our findings. However, as we move forward and approach a top line readout, we believe it is crucial to start characterizing this information—an effort we've been undertaking with a careful approach that started in our Phase II study and has been refined, boosting our confidence throughout the 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.

Congratulations on the progress. I have two questions. Firstly, regarding the MDD program, you mentioned that the study is 80% powered to demonstrate a 5-point change. In your GAD study, you've observed a 6.4-point change on the MADRS. From a commercial standpoint, what type of profile would you aim to achieve in order to access a significant portion of the MDD market, beyond just treatment-resistant patients? Secondly, as you consider the evolving regulatory landscape and the recent FDA position on psychedelic therapeutics, how do you plan to demonstrate safety and efficacy?

Yes, thank you for the questions. In terms of the first question about profiles, I think it's a little early to make those definitions, but we are excited in the conversation around MDD and what that landscape looks like. And we believe that the profiles we can generate in our research can be compelling for a broader set of patients than just those who are treatment-resistant. I think as you noted, we are hopeful that our clinical data can establish a robust position in the treatment paradigm for MDD regardless of treatment resistance. But we will provide more insight into our thinking as we get closer to the data. Regarding your second point on safety and efficacy, we are conscious of these dynamics and the growing interest from regulators in ensuring that patients have access to safe and effective treatment options. We are working closely with the FDA and have designed our studies to meet the highest regulatory standards. We believe that demonstrating both safety and efficacy through rigorous clinical trials will be the cornerstone of our submission strategy going forward.

I will now turn the call back to Mr. Rob Barrow for any closing remarks.

Thank you 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.