Definium Therapeutics Full Year 2025 Earnings Call - DT120 Phase 3 Readouts Imminent; Emerge (MDD) Late Q2, Voyage (GAD) Early Q3, Cash into 2028

Andrew Tsai, Analyst, Jefferies2: Good afternoon, welcome to the Definium Therapeutics full year 2025 financial results and business update webcast. Currently, all participants are in listen-only mode. 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 Gitanjali Jain, Head of Investor Relations of Definium. Please go ahead.

Andrew Tsai, Analyst, Jefferies0: 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 updates. Leading the call today will be Rob Barrow, our Chief Executive Officer, who is joined by Dr. Daniel 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 non-occurrence 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 twenty-sixth, two thousand and twenty-six.

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.

Andrew Tsai, Analyst, Jefferies4: Thank you, Geeta. Thank you everyone for joining our call today. We’re 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. Over the past year, our team has yet again set the standards for scientific rigor, efficiency, and thoughtfulness in 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 3 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 2b study, which was published in JAMA last September, our clinical program for DT120 ODT consists of 4 pivotal Phase 3 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 1st pivotal study in MDD, is fully enrolled, and we anticipate delivering top-line data in late Q2. 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 3 programs. This sequencing both provides the opportunity to establish evidence in a 2nd 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, we anticipate first participant dosing by early Q2. Onto our GAD program, we continue to see strong enrollment across Voyage and Panorama. Enrollment in Voyage is approximately 80% complete, based on the enrollment rate and 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 pre-planned 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 3 study in GAD, is rapidly progressing, 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 3 studies, targeting two 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.

Dr. Daniel Karlin, Chief Medical Officer, Definium Therapeutics: Thanks, Rob. We remain highly encouraged by the enrollment trends we are seeing across our Phase 3 GAD and MDD studies. We’ve been spending a lot of time with our sites and investigators. 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 2 Montgomery-Åsberg 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 dysthymia 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 2B, 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 two 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 and MADRS score at week 6 between DT120 ODT 100 micrograms and placebo. The MDD trials were designed with 80% power 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% power to detect a 5-point improvement over placebo on this endpoint. Our Phase 3 studies are modeled after our successful Phase 2b 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. 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 to 1 to 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 to 1 to DT120 ODT 100 micrograms or placebo, while in Panorama, we are targeting enrollment of 250 participants, randomized 2 to 1 to 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’s 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 in 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 2 study of DT-402 in autism spectrum disorder, or ASD, in late 2025. DT-402, the R-enantiomer of MDMA, has shown promising prosocial effects with a potentially favorable tolerability profile. We’re developing DT-402 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 1 single ascending dose study that characterized the tolerability, pharmacokinetics, and pharmacodynamics of DT-402 in healthy adult volunteers, we dosed the first participant in our phase 2a 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 DT-402 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. I’ll turn it over to Matt for commercial comments on DT120.

Andrew Tsai, Analyst, Jefferies1: 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 one. 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 22nd. 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’ve generated significant value and delivered multi-billion dollar opportunities.

We believe DT 120 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 Brandy to discuss our full year 2025 results. Brandy?

Dr. Daniel Karlin, Chief Medical Officer, Definium Therapeutics: Thanks, Matt. Research and development expenses were $117.7 million for the year ended December 31st, 2025, compared to $65.3 million for the year ended December 31st, 2024, representing an increase of $52.4 million. This increase was primarily driven by $44.7 million in higher DT120 program expenses.

Brandi Roberts, Chief Financial Officer, Definium Therapeutics: ... $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 DT-402 program expenses. General and administrative expenses were $48.6 million for the year ended December 31st, 2025, compared to $38.6 million for the year ended December 31st, 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 continued to make significant progress across the DT120 and DT-402 programs. Net loss for the year ended December 31st, 2025, was $183.8 million, compared to $108.7 million for the year ended December 31st, 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 31st, 2024, to $13.39 at December 31st, 2025.

We ended 2025 with 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 equivalents and investments as of December 31st, 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 NGA 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. 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.

Andrew Tsai, Analyst, Jefferies4: 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 would 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’ll now open the line for questions.

Andrew Tsai, Analyst, Jefferies2: Thank you. Ladies and gentlemen, to ask a question at this time, you will need to press star one one on your telephone and wait for your name to be announced. To withdraw your question, simply press star one one again. Please stand by while we compile the Q&A roster. First question coming from the line of Andrew Tsai with Jefferies. Your line is now open.

Andrew Tsai, Analyst, Jefferies: Hey, good afternoon. Thanks for the updates. Thanks for taking my question. 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? Just to confirm, there were no other scenarios, with this interim, such as stopping for futility or even stopping for success? Thanks.

Andrew Tsai, Analyst, Jefferies4: Yeah, thanks so much for the question, Andrew. This is, first of all, it was a blinded sample size re-estimation. 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 two 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 made the wrong assumptions.

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. We are certainly excited to see that we’re good with the assumptions we made. If anything, as Dan mentioned during the call, have certainly adequate power at 99% or greater if the current variables hold, at least those parameters hold. We’re eager to get to study results and ultimately do that inferential test and look at the performance of DT120 versus placebo.

Andrew Tsai, Analyst, Jefferies: Wow. Okay, thanks. 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?

Evie Tsai, Analyst, Evercore ISI: Otherwise, when would you share the open label portion? Thanks.

Andrew Tsai, Analyst, Jefferies4: Yeah, absolutely. you know, 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. Of course, in all of the studies have been running for quite a while now. 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. We haven’t firmed up a commitment to exactly when we would present Part B data.

We certainly don’t want to get ahead of ourselves when we present data that we don’t feel are representative or we’re not confident in at any time. 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 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.

Evie Tsai, Analyst, Evercore ISI: Great. Makes sense. Thanks again.

Andrew Tsai, Analyst, Jefferies2: Thank you. Our next question coming from the line of Marc Goodman with Leerink. Your line is now open.

Basma, Analyst, Leerink: Good afternoon. This is Basma on for Marc. Thank you for taking our question. Our first question is on the interim look. Again, have you conducted the interim look for Panorama as well, or not yet? Or are you planning to do it once you hit 80% enrollment, similar to Voyage? 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 readouts. What are your expectations regarding the remission rate? What would you consider as a good and differentiated rate versus the standard of care? Thank you. That’s it for us.

Andrew Tsai, Analyst, Jefferies4: Yes, thanks so much, Basma. 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 two MDD studies, of course, Emerge is now fully enrolled, and the data, the top-line data that we’d be sharing would be the completed final top-line analysis from that study. We’re not conducting an interim look on either of the MDD studies as planned 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 these populations.

Dr. Daniel Karlin, Chief Medical Officer, Definium Therapeutics: It’s a great question about the remission rate, because we’ve obviously talked about that from our Phase 2b outcomes. I think it’s important to note that mostly what we know about pharmacotherapy-induced remission rate come from MDD studies. In MDD, what we see an SRI, as, you know, the first-line treatment that’s most commonly used, attributable remission rate in the real world is something in the 10% to 30% range. Of course, it’s difficult to necessarily interpret those data because MDD is necessarily a cyclical illness, so that, you know, 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 3 for both GAD and MDD, which was to target open-label treatments, so the Part B treatments, to the threshold between mild and moderate illness on the scale, so these on the HAM-A and the MADRS. In this case, what we are really looking at is, given the availability of open-label treatment in the Part Bs, are we able to treat people down into that mild or better range reliably with the redosing? While we’re not a priori 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.

Basma, Analyst, Leerink: Thank you.

Andrew Tsai, Analyst, Jefferies2: Thank you. Our next question coming from the line of Evie Tsai with Evercore ISI. Your line is now open.

Evie Tsai, Analyst, Evercore ISI: Hi, 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? 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 or rollover retention, screen failures, or anything like that. Thank you.

Andrew Tsai, Analyst, Jefferies4: Yes, thanks so much for the question. 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 were able to enroll that study and how excited we think that represents the field and the researchers who are working on this 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. We absolutely are seeing the continued growth and acceleration enrollment across the program.

For our second study for Panorama, you know, again, we’ll be sharing further updates at our Analyst Day in April, we’ve been encouraged across the board and really happy with where we are in enrollment in that study. Ascend, we’ll be starting in the coming weeks. We’re really excited to get studies activated really faster than even we anticipated. 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. Really, across the board, we’ve been very encouraged by the enrollment trends and where that positions us for 3 critical readouts over the course of this year.

In terms of experimental confidence, we won’t be commenting on specific variables or what we’re seeing in those variables. We are extraordinarily confident in the profile of DT120. 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. That gives us quite a bit of confidence if, you know, if a study only has to show a couple 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, the best results we’ve seen in GAD to date. We’re certainly excited to deliver those data. 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.

Andrew Tsai, Analyst, Jefferies1: Thank you.

Andrew Tsai, Analyst, Jefferies2: Thank you. Our next question coming from the line of Brian Abrahams with RBC Capital Markets. Your line is now open.

Brian Abrahams, Analyst, RBC Capital Markets: Hey, good afternoon, guys. Thanks for taking my questions. Congrats on all the progress, 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. 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. Then just with the interim passing and obviously the low variability and dropouts, it sounds like a very narrow delta could still be statistically significant in Voyage. Can you maybe elaborate a little bit more on your latest views on clinically meaningful delta?

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? Thanks.

Andrew Tsai, Analyst, Jefferies4: Yeah. Thanks so much, Brian, and both great questions. I’ll turn over to Dan to talk about the first one. Just, Dan, maybe you can reflect on, you know, how we think about these populations and also how these patients, of course, show up in trials and show up for clinical attention.

Dr. Daniel Karlin, Chief Medical Officer, Definium Therapeutics: Yeah, it’s an excellent question and good observation. While the timeline changes don’t necessarily change how we think about the patient population, certainly what we know is that in the current environment of psychiatry and 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, 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. 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. 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. That gives us some temporal flexibility, for people in the course of their lives and in the course of their illness.

Andrew Tsai, Analyst, Jefferies4: Thanks, Dan. Brian, in terms of your second question about clinical meaningfulness, it also is a great one, and, you know, 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.

While we definitely want to demonstrate as large of a placebo-adjusted response as we can, observing an absolute magnitude of change that stands out relative to the other options that are available, you know, there are always limitations comparing across studies and such, but 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, you know, patients are seeing the benefit and the magnitude of that benefit over a placebo.

While, yes, we, you know, 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 2. You know, in GAD, when we look at the landscape of currently approved therapies, not one of them consistently delivers, you know, at or above a 4-point delta over placebo in those studies. If we’re seeing a magnitude of change that’s, you know, 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 minds.

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.

Francois Brisebois, Analyst, LifeSci Capital: Thank you.

Andrew Tsai, Analyst, Jefferies2: Thank you. Our next question coming from the line of Francois Brisebois with LifeSci Capital. Your line is now open.

Francois Brisebois, Analyst, LifeSci Capital: Hi, thanks for taking the questions. A lot of interesting questions, a lot of interesting answers, too. I was just wondering, you touched on the 4-point kind of bar that, you know, is not a hard bar or anything, but it’s 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? Maybe also remind everyone what you had seen previously on the MADRS side in the prior trial, and maybe caveats around, you know, what you had seen because the trial wasn’t necessarily for that originally.

Andrew Tsai, Analyst, Jefferies4: Yeah. Thanks so much for the question, Frank. 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, you know, 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 can drive a lot of the burden and the value. You know, 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 on depression symptoms.

We saw a 6.4 point difference between 120 and placebo in MADRS scores. I think that was starting from a lower point than what we would expect in a dedicated MDD population with 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. I think as we get closer and closer to the readouts, we wanna set full context for those expectations and just for the realities of that landscape.

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. That’s true, especially in the MDD population, where taking patients from severe depression symptoms to high, moderate, or more severe wouldn’t represent a major change in our minds. As we think about this readout, we again, wanna see a large absolute magnitude of change and as large of a placebo-adjusted change as the drug can deliver.

Francois Brisebois, Analyst, LifeSci Capital: 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 2 to phase 3, 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?

Andrew Tsai, Analyst, Jefferies4: Yeah, no. I think the reality is that we’ve 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 this in a number of other occasions as well, where some of the best-performing drugs continue to not see that sort of compression as they progress in development. 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 3.

We designed our phase two program to be exactly executed and designed like a phase three 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 two the way we did. That also means we made minuscule operational changes between the phase two and phase three studies. So we’re virtually doing the same thing over again, it’s just with two or three arms instead of five arms, as we did in phase two. So that again gives us a lot of confidence. Then a number of dynamics in the study design that we think will drive better patient retention and through the primary outcome of 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 2 data, you know, which we think is largely driven by the fact that we’re seeing with the Part B, the 9-month extension period, patients have a ability to access open label 120 if they complete the full 12-week blinded control period. All of those dynamics give us a lot of confidence about the operationalization of these studies and gives a lot of confidence as we approach data.

Andrew Tsai, Analyst, Jefferies3: Great stuff. Thank you.

Andrew Tsai, Analyst, Jefferies2: Thank you. Our next question coming from the line of Pete Stavropoulos with Cantor Fitzgerald. Your line is now open.

Andrew Tsai, Analyst, Jefferies3: Hi. Good afternoon. Nice to see the progress. Thank you for taking our questions. First one, you know, just curious to hear how you’re thinking about a potential filing strategy, if the two GAD Phase 3s are positive, and if the first, Phase 3 MDD study Emerge as positive. You know, will you complete two MDD studies before filing, an sNDA, or is there a reason to wait for the second study?

Andrew Tsai, Analyst, Jefferies4: Yeah. 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. Certainly, we think that the stronger the data, the more compelling an argument a sponsor can make and that’s true across the board. We’ll be looking, you know, 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, you know, we’ll very much be engaging in those conversations to explore the most efficient pathway forward for both the indications.

Andrew Tsai, Analyst, Jefferies3: Okay. Then just to touch on your earlier stage asset, 402. You know, if you can give us a little bit of color in terms of assessing clinical effect, which scales are key for you? In your deck and in the PR, in today’s PR, it mentions functional biomarkers. Can you just elaborate on that?

Andrew Tsai, Analyst, Jefferies4: Yeah. I’ll turn that one over to Dan Karlin to comment on.

Dr. Daniel Karlin, Chief Medical Officer, Definium Therapeutics: Yeah. Happy to comment on that, and thanks for asking about DT-402. Obviously, with all the excitement around DT120 sometimes, we don’t get a chance to comment on this as much as we’d like to ’cause 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. 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 a pretty open conversation both in the field with experts who treat folks with ASD, with regulators who are eager to be able to approve drugs for this condition that really doesn’t have treatments that target its core symptoms. What we’re looking at in the current early signal of efficacy study are measures that have high granularity. We want high sensitivity and high granularity measures so that we are able to repeatedly measure over the course of a dosing day to look at change that is consistent with the expected PK and PD of the drug.

We haven’t talked about exactly what measures we’re using, but we are using components of established measures along with some novel ways of looking at social interaction, social communication, and the other domains where we think that the drug will be effective. 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 and when we get there, and potentially even measures that could travel with the drug out into the world if it’s approved.

Andrew Tsai, Analyst, Jefferies3: Right. Thank you, and congrats once again.

Andrew Tsai, Analyst, Jefferies2: Thank you. Our next question coming from the line of Christopher Chen with Baird. Your line is now open.

Christopher Chen, Analyst, Baird: Good afternoon. Thanks for taking my question. And congrats on the progress. I had a question regarding MDD. You know, one of the things we hear about SPRAVATO is that it’s good at alleviating symptoms of PRD, but not so good at increasing overall productivity of daily life, like just work, your productivity at work, one example. I know you’re measuring a number of quality of life metrics in Emerge, but I’m particularly interested in the WPAI. 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? I have one more after that.

Andrew Tsai, Analyst, Jefferies4: Yeah. 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, you know, being at work is certainly gonna be a thing that drives productivity. A treatment where you only have to come 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 DT120 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.

Even beyond the actual measurable productivity, the presence at work and being able to do that is gonna be an important driver. It’s really something that also shows up in patient satisfaction and overall utilization of the drug, we would think. I’ll turn it to Dan to elaborate maybe on the WPAI.

Dr. Daniel Karlin, Chief Medical Officer, Definium Therapeutics: Yeah. You know, the domains that the WPAI look at, absenteeism, not being able to make it into work, presenteeism, being impaired while at work, and sort of tries to assess an overall percentage of impairment while at work. 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. 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.

We very much are oriented toward the idea that just as we saw in Phase 2, 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. The way that folks describe their experience post-treatment in the Phase 2 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 in GAD. 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.

We’re measuring the W-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.

Christopher Chen, Analyst, Baird: Great. That’s very helpful. Just a quick one. Are you collecting time to patient time to discharge data in these trials? If so, are you seeing, you know, anything that may suggest any shifts from that 6-8 hour monitoring period?

Andrew Tsai, Analyst, Jefferies4: Yeah, it’s a great question. 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 five. We of course observe all patients regardless of the dose or whether they receive placebo through hour eight in the study. At the end of the day, we expect to have, you know, 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.

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, again, aggregate enough data to feel confident in sharing that before we do so. 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 2 study and something being refined and giving us increasing confidence as we’ve gotten through the conduct of our phase 3 program.

Christopher Chen, Analyst, Baird: Thank you.

Andrew Tsai, Analyst, Jefferies2: Thank you. Our next question coming from the line of Patrick Trucchio with H.C. Wainwright. Your line is now open.

Arabella, Analyst, H.C. Wainwright: Hi, this is Arabella on for Patrick. Thank you so much for taking the question and 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?

Andrew Tsai, Analyst, Jefferies4: Yeah, I’ll turn that one over to Dan.

Dr. Daniel Karlin, Chief Medical Officer, Definium Therapeutics: It’s an excellent question and a good observation. The Panorama study does include European sites. 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. Though 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. Diagnostic criteria that we use are standard from, you know, from one country to the next and one site to the next, of course.

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 three-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, has the European sites and MDD which hasn’t

Andrew Tsai, Analyst, Jefferies1: because we aren’t dedicating 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. We are incredibly confident that across sites here in the States and sites in Europe, that we’re getting the participants who we intended to get into the study. 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.

Arabella, Analyst, H.C. Wainwright: Great. Thank you so much. 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?

Andrew Tsai, Analyst, Jefferies4: Of course, it’s premature to talk finally about filing strategy and filing dynamics until at a final discussion with FDA at a pre-NDA meeting. 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. 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 to again, try to set that standard for how efficient and how quickly we can go to race across the finish line.

Arabella, Analyst, H.C. Wainwright: Perfect. Thank you so much.

Andrew Tsai, Analyst, Jefferies2: Thank you. Our next question coming from the line of Ami Fadia with Needham & Company. Your line is now open.

Ami Fadia, Analyst, Needham & Company: Hi. Good afternoon. Thanks for taking my question. Congrats on all the progress. My question was on. I’ve got two. Firstly, just on the MDD program. You indicated that the study is 80% powered to show a 5-point change. 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, you know, the very, you know, the patients that are treatment resistant, what type of profile would you like to see?

Secondly, as you think about the regulatory landscape and how that’s changing and the recent FDA stance on wanting to move towards a one trial requirement, do you think you still need two studies in each of the two indications, or would there be opportunity to explore fewer studies should maybe the studies this year turn out to be positive? Thank you.

Andrew Tsai, Analyst, Jefferies4: Yeah, thanks so much, Ami. Perhaps I’ll take them in reverse order and ask Matt and or Dan to comment on your first question. In terms of regulatory stance, the statutory requirements for drug approvals have been in place for quite a while. We’re incredibly encouraged to see some of the dialogue around efficient pathways and regulatory understanding 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 four of the studies.

Aggregating a large body of evidence, if we’re seeing consistent results across multiple studies, across multiple domains, with a high degree of both standalone and placebo-adjusted change, and the better the data are, the stronger the arguments are going to be, whether it’s one, two, or more studies, for any program. 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 and about exactly where this would land in, you know, in a 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 for commercial adoption and for reimbursement and such.

Andrew Tsai, Analyst, Jefferies1: Thanks, Rob, and thanks for the question. You know, 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. 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. Even with the care that they have access to today, there’s still something left significantly lacking in the treatment paradigms.

You know, we know that payers do manage drugs, and branded drugs that enter the market typically have a step or two, we believe that that can narrow the overall addressable market slightly. There are for both GAD and MDD, a significant number of patients that are going to benefit if approved from DT120.

Andrew Tsai, Analyst, Jefferies5: Got it. I appreciate the response. Thank you.

Andrew Tsai, Analyst, Jefferies4: Thank you. Our next question coming from the line of Sumant Kulkarni with Canaccord. The line is now open.

Andrew Tsai, Analyst, Jefferies5: Good afternoon. Thanks for taking our questions as we eagerly await all the data I expect to announce this year. I have two 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. Our view for some time now has been that where the bar really should be different was the standard of care is on durability of effect. Is that a fair real-world characterization from your perspective? I’m asking that because I don’t think I heard an explicit call-out for durability in your earlier answer on clinical relevance of a statistic score on HAM-A and perhaps even more so on MADRS.

Andrew Tsai, Analyst, Jefferies4: Yeah. No. Thanks so much for the question, Sumant. when we think about durability, there are 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 in our conduct of the studies. We’ll be looking for response patterns and the ultimate duration to events beyond just a 12-week period. you know, 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. So, of course, sponsor in those studies would wait well beyond that to drive that separation.

When we think about the durability in our dialogue with regulators to date, an 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. Part of the decision-making in the design of our phase 3 program was to have our primary endpoint B at that time, which 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. That stands out among all of the product candidates that we’re seeing in late stage development, certainly in our field.

We absolutely agree that durability is important and that durability fall beyond a few weeks after a single treatment or, you know, the last treatment or drug is really meaningful and why we’ve designed our studies the way we have.

Andrew Tsai, Analyst, Jefferies5: Got it. Yeah, that’s really why I was asking, because you’ve shown really good durability so far. On the commercial side, Matt, you mentioned a, quote-unquote, "high touch white glove experience." 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? What fraction of that high touch white glove experience can be paid for by insurers?

Andrew Tsai, Analyst, Jefferies4: That’s a great question. Yeah. Thanks so much, Samant. Yeah. I’ll just say briefly, you know, and I’ll turn it over to Matt. I think the when we think of, you know, pricing, it’s really premature to talk specifically about pricing. When we think about the dynamics, you know, we continue to believe in this 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. That what we see also in a lot of our HEO or our work is that severity is a huge driver of disease burden. 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. While we understand the dynamics of likely not being a first line therapy for everyone, we do think that those distinctions and are somewhat artificial and as a result, something that we both can look at within our subpopulations 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. I’ll turn it over to Matt to comment further on that.

Andrew Tsai, Analyst, Jefferies1: Samant, 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. 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.

Andrew Tsai, Analyst, Jefferies5: Thank you.

Andrew Tsai, Analyst, Jefferies4: Thank you. 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 just thank everyone again for joining us on the call today. We’re incredibly excited to come to our top line readout for Emerge first in the months ahead. With three total 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. Thank you again for joining us today and 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.