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

Good day, and welcome to the Definium Therapeutics Phase III Voyage Topline Results Call. [Operator Instructions] As a reminder, this conference is being recorded. If you have any objection, please disconnect at this time. I would now like to pass the call over to Rob Barrow, Chief Executive Officer. Please proceed.

Thank you, operator. Hello, everyone, and thank you for joining us this morning. I'm Rob Barrow, Chief Executive Officer of Definium Therapeutics, and I'm joined today by our Chief Medical Officer, Dr. Dan Karlin; and our Chief Financial Officer, Brandi Roberts. We cannot be more excited to be here with you this morning to share the unprecedented and top line results from VOYAGE, our first pivotal study of DT120-ODT and generalizing anxiety disorder or GAD. Before we get started, please note that on today's call, we'll be making certain forward-looking statements. We encourage you to review our SEC filings for a discussion of the risks and uncertainties associated with these statements, including the risks described in our most recent annual and quarterly reports. When we presented our emergency results in June, I noted how rare it is to have an opportunity to share truly transitional data. That is even more true today when we have the privilege of sharing such findings for a second time in a row. As with our MDD results, we believe the findings being presented today have the potential to redefine what patients can expect from the treatment of GAD and position DT120 as a potentially best-in-class product across 2 of the biggest and most impactful indications in psychiatry. I'd also like to take a moment to thank our study participants, investigators, partners and our incredible team at Definium for making all of this possible. We are deeply appreciative and humbled by your commitment, your trust and your belief in our vision. Your efforts have brought us to this remarkable moment and most importantly, have brought us 1 step closer to making our [indiscernible]. We have an ambitious vision at Definium and belief that profound change in psychiatry is truly possible. We set a high standard for DT120 to demonstrate that a single supervised dose to deliver rapid, robust and durable efficacy and offer new hope to the tens of millions of people living with depression, anxiety and other mental health disorders. We believe there's a particular need for innovation in anxiety and remains steadfast in prioritizing GAD as a lead indication for DT120. GDA plays an enormous burden on patients, families and society impairing daily function, productivity and quality of life, and that burden has grown dramatically, prevalence has increased from roughly 3% in the early 2000s to approximately 10% today. At the same time, we've been on an era of far greater awareness on openness surrounding anxiety and its impact on people's lives, but our ability to treat it simply hasn't kept pace. There hasn't been a new drug approved for GAD since 2007, and that's not a selective time. Over that period, roughly a dozen drug candidates spanning numerous mechanisms of advancing the late-stage development. Nearly all has sales was most unable to demonstrate any meaningful improvement over placebo. That long period without success is also left the field without a modern benchmark for what truly compelling efficacy in GAD looks like. We believe the unprecedented voyage results we're sharing today change that. They represent the promise of real progress for patients with GAD and further reinforce the potential of DT120 to help usher a new era of psychiatric care. Voyage marked our second pivotal readout for DT120 this year and our first pivotal readout in GAD. As with our emerged readout, Voyage the primary and all key secondary endpoints with a high degree of statistical significance. Seeing consistent positive outcomes across 2 large Phase III studies in 2 adjacent comorbid and highly prevalent psychiatric disorders further strengthens our confidence in the potential of DT120 and a broader opportunity ahead of us. To briefly summarize some of the key points. The primary endpoint demonstrated a 5.4 point placebo-adjusted improvement on the hand at week 12 corresponding with an effect size of 0.81 and a p-value of less than 0.0001. To our knowledge, this is both the largest nominal change and largest standardized effect size ever observed in a pivotal study in GAD. This was also rapid with a 7.7 point placebo-adjusted improvement on the [indiscernible] week 1 and a 0.8 point placebo-adjusted improvement on the CGI at day 2. DT120 was well tolerated with no new safety signals identified including no suicidality signal. We continue to observe an efficient and predictable dynamic of treatment session with an average time appearing the structured in discussion checklist of 6.4 hours and over 90% of participants [indiscernible]. The strength of the DT120 program as a whole is anchored in consistency. DT120 has demonstrated a large and consistent effect size with the cohen's D of over 0.8 in each study. Using the standardized effect size is especially useful in looking across studies as changes in study design, population, [indiscernible] characteristics and other signed dynamics can impact nominal scores and make comparisons of nominal scores difficult. The fact that this extraordinary effect size has now been shown across 3 studies in 2 indications, gives us a high degree of confidence in the robustness of the efficacy and continues to build the case for a potential multi-indication practice-changing profile. Then finally, to put all of this in context of the broader treatment landscape, DT120 has now shown in 2 studies in GAD an effect size of 0.81 and that is more than double the standard of care. To reiterate that in a disorder with high prevalence, high burden, high unmet need and no innovation in decades, a single dose of DT120 has shown a rapid and durable effect with a magnitude that is more than twice as large as the drugs approved today. With that, I'll turn the call over to Dan, who will walk through the study results in greater detail.

Thanks, Rob. Today is a special day, as a psychiatrist who has treated many patients with GAD, I have seen firsthand how difficult it is to help these folks find relief from the complex interplay among the emotional, cognitive and somatic experiences of the illness. In our studies, these are measured using standardized assessments like the HAM-A. But in people's lives, they produce a nearly constant onslaught of distressing internal experiences. Medications available today may tamp down 1 aspect of someone's experience of anxiety, but often leave the others untouched. What we've seen in Phase II and now in Voyage is that DT120 provides a different kind of relief in those who benefit from it, a release that isn't bound to 1 domain of the illness. I'm excited to share further specifics of the buoyant results with you. As Rob highlighted, the study demonstrated rapid, robust and durable improvements in anxiety along with a favorable tolerability profile and efficient treatment session dynamics. So let me begin with the study design. Voyage is comprised of 2 parts. Part A, which is a 12-week randomized, double-blind, placebo-controlled period. And Part B, which is a 40-week extension period with opportunities for open-label treatment. Participants were tapered off background antidepressant and anxiolytic medications prior to enrollment and no psychotherapeutic intervention was provided as a part of the study. In Part A, participants received a single dose of DT120 100 micrograms or placebo and were followed for 12 weeks. The primary endpoint in the study was changed from baseline in HAM-A total score at week 12, assessed by independent central raters who are blinded to treatment assignment and visit number. In Part B, participants continue to be followed for an additional 40 weeks and completed regular blinded, centrally rated efficacy assessments for a total of 52 weeks of blinded efficacy assessments. Each time a participant meets the study's prespecified criteria for retreatment, they become eligible for an open-label dose of DT120 for a total of up to 4 open-label doses. The retreatment threshold in Part B is a HAM-A total score of 16 or greater, which corresponds to the cutoff for moderate illness and is characterized by a meaningful increase in disease burden, functional impairment and disability. From the outset, we picked this cutoff as the target for treatment because we thought it was both achievable and meaningful to patients. A total of 214 participants were randomized in the study with 107 participants in each arm. Approximately 90% of randomized participants completed Part A. The demographics of participants enrolled in Voyage were generally balanced between treatment groups and representative of GAD patients commonly encountered in clinical practice. Participants entered the study with a high degree of disease severity as reflected by baseline HAM-A and CGI-S scores of 27.9% and 4.6% across the groups. These values place participants firmly within the severe range of anxiety. We also observed past psychedelic exposure consistent with the background range of use in the population we would expect based on epidemiological estimates with 21% reporting any prior psychedelics use and 9% reporting prior LSD use. Another way to understand the enrolled population is to look at the distribution of disease characteristics at baseline. 3/4 of participants were characterized as severe on the HAM-A with a score of 24 or higher, and the remaining 1 quarter categories is moderate with a HAM-A of 20, the minimum for study enrollment to 23. Despite a limited number of treatment options, we observed a population with characteristic prior treatment experience. 36% of participants reported receiving 2 or more prior GAD pharmacotherapies. One particularly notable aspect of the experience of GAD for these participants is the time since diagnosis and time since symptom onset. On average, participants in the study reported experiencing GAD symptoms for approximately 24 years at the time of enrollment and on average, received their GAD diagnosis about 12 years prior to enrollment. This speaks to both the long delays in diagnosing GAD and the reality that GAD is a chronic lifelong condition that leads the folks who suffer from it to do so without diagnosis or explanation for many years. And in cases like our enrolled population to continue to not find relief even long after diagnosis. Between our MDD program and our GAD program, we have endeavored to recruit populations that are maximally representative, so that we can make reliable and reproducible assessments of DT120's ability to treat the disease of interest, both with and without comorbidity. On the HAM-A, which was the study's primary outcome measure, DT120 demonstrated rapid, robust and durable efficacy. At every measured time point, DT120 statistically and clinically exceeded placebo on the HAM-A total score, demonstrating a consistent treatment effect throughout the study. In fact, at each time point, the p-value was less than 0.0001. There are several dimensions we consider when evaluating a treatment profile. First is robustness. At the primary endpoint measured at week 12, DT120 demonstrated a mean improvement of 11.6 points and a placebo-adjusted change of 5.4 points. Rapidity is particularly important for patients with GAD. By week 1, the first HAM-A efficacy assessment after treatment, patients receiving DT120 showed a mean improvement of 11.9 points from baseline corresponding to a placebo-adjusted change of 7.7 points. This early separation from placebo was maintained across subsequent assessments. Taken together, the rapid onset of action, robust magnitude of improvement and durable benefit observed over 12 weeks provide strong evidence of a meaningful and sustained treatment effect after a single administration of DT120 in patients with GAD. A secondary measure of disease severity is the CGIS and here we see that the CGIS tells essentially the same story as the HAM-A. Key secondary endpoints shown here are change from baseline in CGIS score at week 12 and early improvement measured at day 2. Notably, these instruments, the CGIS and the HAM-A use different mechanisms to assess the underlying illness and are conducted by different raters. The HAM-A is assessed by independent centralized rater while the CGIS is a local site-based clinician-rated measure. The consistency across these independent measures gives us tremendous confidence that the treatment effect that we are able to measure represents real meaningful clinical improvement in the study participants. Another way of looking at the HAM-A data is based on fixed thresholds, remission and mild. We can also look at relative response rates. At week 12, 14% of participants receiving DT120 were in clinical remission compared with only 4% of those receiving placebo with a p-value of less than 0.05. 51% of participants in DT120 group reached mild or better status compared with just 23% of those receiving placebo with a p-value of less than 0.0001 and 43% of participants receiving DT120 met the response criteria compared with 16% of those receiving placebo with a p-value of less than 0.0001. The response and remission outcomes further support the clinical relevance and robustness of the treatment effect observed with DT120. We also conducted subgroup analyses to better understand whether the treatment effect was consistent across different patient populations and baseline characteristics. Reevaluated factors such as time since diagnosis, prior GAD medication exposure and [ SES ], along with a number of other baseline measures. Across each of these analyses, the treatment effect was reliably similar. Importantly, this included patients who have been failed by 2 or more prior GAD treatments, a population with substantial unmet need and often more limited treatment options. The consistency of these results across the subgroups strengthens our confidence that the benefits observed in voyage are broadly applicable across the GAD population and are not being driven by any single patient group. Turning to safety. DT120 was generally well tolerated, and the adverse event profile was consistent with the known pharmacology of DT120 and with prior clinical experience. DT120 showed a favorable tolerability profile with all adverse events mild to moderate in severity at most treatment-emergent adverse events occurring and resolving on dosing days. There were no serious adverse events in the DT120 arm, no suicidal or self-injurious behavior and no indication of drug-related suicide signal or suicide-related risk based on CSSRS assessments. In the DT120 arm, 61% of AEs were mild and 38% were moderate. 1 severe AE of diverticulitis was reported in the placebo arm. There were 3 treatment-emergent serious adverse events in the placebo arm, 1 adverse event leading to discontinuation in the drug arm and no adverse events leading to death. The discontinuation was related to a new onset depressed episode approximately 6 weeks after dosing in a patient with comorbid recurring MDD. Taking a look at the most common treatment emergent adverse events, those with an incidence of at least 10%. The most frequently reported events were the expected transient perceptual effect of cognitive and behavioral changes occurring primarily on dosing day. These events were mild to moderate, occurred on dosing day and resolved by the conclusion of the dosing session. Rob mentioned this earlier, and we believe the treatment section dynamics remain one of the most important aspects of the overall profile of DT120 and the DT120 session is well matched to the needs of GAD patients with a combination of session duration and depth of experience that continues to produce efficacy outcomes like the ones we've been able to share with you today. We use a structured end of session checklist to assess readiness to safely leave the treatment setting. The average time for clearance on the checklist was 6.4 hours with more than half of participants clearing at hour 6 and 92% cleared by hour 8. When we look at all of the known Phase III DT120 dosing sessions, we see a remarkably predictable duration with the vast majority lasting between 5 and 8 hours. We believe this translates very cleanly in the clinical practice where the end of session checklist can be easily implemented to inform medical decision-making and the critical staff involved in supervising sessions. Now we turn to Part B, the 40-week extension phase. As a reminder, participants are eligible to receive up to 4 open-label treatments with DT120 based on disease severity of moderate or worse as assessed by the centrally related MAA. The purpose of this phase is to better understand long-term durability from Part A, subsequent treatment patterns, response to retreatment and their durability over the full year of observation and dosing opportunities. At the time of the interim analysis, the 87 participants assigned a DT120 and 90 participants assigned to placebo had entered Part B. Today's discussion focuses on data through week 28, where enough participants have been evaluated to provide a meaningful analysis. The demographics and baseline characteristics of participants entering Part B were generally consistent with the broader Part A population. As expected, symptom severity of Part B entry reflected the treatment effects observed during Part A. As anticipated, multiple treatment trajectories emerge with participants receiving intermittent open-label treatment based on symptom recurrence and retreatment eligibility. The data show a distribution of participants receiving 0 to 3 open-label treatment through week 28. These early patterns provide an encouraging first look at how DT120 may be used in a real-world treatment setting. Longitudinal HAM-A scores moving from Part A into Part B continue to show both the ongoing durability from the initial dose of DT120 in the active arm and the incremental benefit from open-label treatments. Participants originally assigned to placebo begin to converge toward those who received DT120 and Part A after receiving open-label treatment. These results increase our confidence in the durability and retreatment paradigm for DT120 and provide early support for how intermittent dosing could sustain improvement over time. As with Part A, we can look at response and remission over time in Part B. What we see is that across each of these measures, patients continue to benefit with subsequent treatment administration. Response and remission rates improved through week 28, demonstrating sustained disease control over time. The consistency of these findings across multiple clinically meaningful endpoints and safety measures gives us enormous confidence in the potential for DT120 to safely deliver durable efficacy with intermittent symptom triggered retreatment in a variety of real-world clinical settings. And with that, I'll turn the call back over to Rob.

Thanks so much, Dan. As I said at the outset, our goal at Definium is to enable a new treatment paradigm. You can profoundly reshape [indiscernible]. We believe the landmark results shared today are another important step in pursuing that goal. The unprecedented results we've delivered in MDD and GAD, we continue to believe -- to build [indiscernible] is one of the strongest clinical data packages in psychiatry. We are moving with a high degree of urgency to pursue a potential NDA submission for DC120-ODT, and we approach our final pivotal readout of 2026 with more momentum than ever. Looking ahead, we anticipate the top line readout from Panorama next month. We continue to advance Ascend and MDD toward a top line readout in 2027, we are progressing plans to initiate HAM-A in PTSD in 2027. The need across GAD and MDD remains enormous. Today, an estimated 50 million adults in the United States are affected by GAD or MDD with approximately 26 million diagnosed, 13 million receiving pharmacotherapy and more than 4 million having been sailed by 2 or more treatments. We believe this represents a significant opportunity to bring a differentiated treatment to patients who continue to need better solutions. Even modest uptake in the addressable population that has the potential to impact tens of thousands of patients and create substantial value. Importantly, we view that at initial scale as the starting point better than the ceiling with a long-term opportunity that could meaningfully expand as we continue to generate evidence, broaden access and reach additional patients across these large and underserved markets. We see 2 distinct value drivers ahead of us, our continued commitment to excellence in clinical and regulatory execution and setting the standard for commercial impact and execution to bring this clinical promise to patients is impactfully as possible. We're working tirelessly to build the Definium into a psychiatric powerhouse that can reset expectations for what patients and providers can expect from care. Before we go to Q&A, I will say special thanks again to our incredible team at Definium. We've built an organization of exceptional people who are deeply passionate about our mission and the patients we serve. None of this would be possible without your unwavering dedication and tireless effort. It is an honor and a privilege to work alongside each and every one of you every day, and I cannot wait to see what the future holds for all of us. With that, we will open up for Q&A. Thank you.

[Operator Instructions] Our first question comes from Andrew Tsai, Jefferies.

Congratulations again on another robust reassess. So my question is basically around -- now that you have 3 profound game-changing Phase II/III data sets in MDD and GAD. Can you maybe talk briefly about what your FDA interactions actually have been like after the MDD data set in June, whether there is any inclination the agency might be supportive to a combined filing in MDD and GAD actually. And then secondly, for MDD, could we expect you to seek a breakthrough designation. You already have one in GAD. I figure maybe a breakthrough can help the MDD time lines as well because I think you're waiting for the base case MDD second Phase III readout in 2027?

Yes. Thanks so much for the question, Andrew, for being here this morning. Yes. We've had an incredible dialogue. And I think if we're taking a minute to just acknowledge the divisions psychiatry at FDA. These drugs that we are working on and the entire fields working on have been sitting on the shelf for 60 years, almost 50 years. The willingness to look at science objectively and lean in and understand the complexities and navigate those complexities with us is something that isn't required of any agency. And FDA has really stepped up to meet that mark. It's really encouraging, I think, for all of us and for the field what lies ahead. In terms of interactions, we regularly are having formal and ongoing dialogue with FDA on a number of fronts on everything that goes to what's going to inform our NDA filing strategy. As we approach the EMERGE data in MDD, we obviously were very much focused on that potential, and we've been working very hard over the course of this year to prepare ourselves for an NDA filing and track a lot of the NDA, which we made incredible progress towards with data 3 sets and Phase III if Panorama is positive, we certainly believe there is a compelling opportunity and on reason to consider filing and consider a path to getting both of these indications on label. The expect sizes, we have now consistently shown across 3 studies are outstripping everything that is approved today and really from what we've seen in everything that's in development. And that puts us in a position where we can think broadly about the patient population that the need here. And with the strength of those results, we're still connecting if I can study in MDD, but the added value of additional research, we already have a high, high degree of statistical significance and belief in the effects across both of these indications. So we continue to dialogue with FDA. We're going to continue having those meetings. We've had meetings. Since the Emerge results, we'll continue to have meetings in the months ahead as we approach -- we get closer to the filing or potential filings for DT120 in these indications. And as far as the break-theapy designation goes, we have had, again, a great dialogue and a great opportunity to really interact with the agency frequently under the GAD program, we're always exploring every opportunity to bolster that alignment, that collaboration with FDA and to seek every way to expedite development and path to market. So we're going to continue exploring all those options. And certainly, as any of that unfolds, we'll continue to share updates then.

Our next question comes from Marc Goodman with Leerink.

Basma, on for Marc. I was just wondering if you could share some detail on what exactly is included in the end of session checklist. And if the FDA has given any feedback on how it may be used in clinical practice. Also, if it's evolved over time since it was used in the Phase II study.

I'll turn that 1 over to Dan here to comment.

Yes. It's an excellent question, and we obviously focus on this because we think it's incredibly important to provide tools to clinicians so that they can make informed medical decisions in the use of a product, if approved. The Phase II study used a different instrument that we devised because we hadn't had clinical experience using 120 in treatment of people with GAD at that time. So in Phase II, we looked at the entirety of the DSM defined symptoms of hallucinogen intoxication to just try to understand what it looked like for both between hours 8 and 12 after treatment. We also used a 200-microgram dose in Phase II. So we just really wanted to understand and characterize what the end of that experience looks like. Beginning in Phase III and in our safety studies after the transition to the ODT product, we created the end of session checklist, which effectively looks at the domains required for capacity for decision-making. They look at people's alertness and orientation. They looks at the resolution of perceptual symptoms. It looks at their ability to safely navigate their environment and things like this. It's an 8 item scale. And throughout our use of it, it's been submitted alongside protocols for FDA review. So we've gotten an extensive FDA feedback. We've been back in court with them on even the details down to the item level and the phasing of those items as we've moved along. Because we use the checklist in our trials, despite having made our minimum, the requirement for end of session in the studies is 8 hours plus checkless completion. What we take this to mean is that check list is adequate for determining people's ability to safely in their sessions. And so while we have no reason to think that an 8 hour minimum persists in the real world because that's a trial artifact. We need to have long enough sessions to ensure that we're not letting half of patients in Part A lead at whatever that minimum is, and the others have to stay longer because they're not quite ready to live that would provide another source of unblinding and confounding in the study. But based on the check list results that are showing the sorts of numbers we're seeing in 5 and 6 hours ready to leave, we fully expect that it will translate very cleanly into real-world clinical practice.

Our next question comes from Gavin Clark-Gartner with Evercore ISI.

Great to see this data. Just for the second GAD Phase III study, could you remind us what your expectations or maybe lack of expectations are for the 50-microgram control arm that's included there?

Thanks so much, Gavin, and thanks for the question. I think this is one of those -- when we look at the field and research methodologies in the field, historically, there's been a lot of different ideas out there. And all of those have fallen by the wayside. The concept of adding on additional controls and studies is a reasonable one, depending on the motivation for it. With the inclusion of an intermediate or a lower dose of drug, particularly here in what it's intended to do is trying to mitigate the connective tissue, let's say, between tendoexpectancy and biasing outcomes after the drugs administered. We continue to see that patients who are administered 100 micrograms of DT120, can reliably get that they receive the active drug. I think is just somewhat comments here that people taking a high dose of any psychiatric drug, but a high dose of certainly profoundly drug that is profoundly alters aspect and perception and things of that is going to be tactical. And so what we're trying to do is to include the 50-microgram dose so that in the consent process. We can inform patients that just because they feel something on the day of dosing, they can't be sure that it's the active dose of drug. As we've also seen in our Phase II study that 50 micrograms produced no clinical separation activity over placebo. It was also very reliably detectable by the patients. So the logic is, just because you feel something, don't assume it's a real thing. The important part is that it doesn't have any impact on how we are assessing, analyzing or interpreting the results of the study. I always probably too much rely on analogy of eyeglasses. If we do a study of patients with eye glasses and gave some people have the prescription that they would see well with, and we gave other folks placebo, and we gave other folks, their correct prescription, it wouldn't negate anything. If we found that people who didn't have the prescriptions can feel a little bit better. The reality is that a drug that works regards of what other doses of that drug do. And so we're not at all focused on that retrospectively as the sort of analytical outcome. It is purely an operational control and something that is designed to have prospective utility in the study.

Our next question comes from Paul Matteis of Stifel.

This is Emily, on for Paul. Congratulations on the data. We were just wanting to think like as we look ahead to the commercial opportunity in GAD, what is the profile of the early adopters? And given that many of these patients are currently treated in primary care, what are kind of like the levers you guys can rely on to change referral code to that patient and to these more introduction centers?

Thanks so much, Emily. I think there's part of our belief in the opportunity to have a profound impact for these patients is a recognition that if we go all the way back, Society really started focus on anxiety set. I mean that is structurally where the focus was. It's where early pharmacotherapies, we're really focusing around things at [indiscernible]. Over time, the entire system shifted away from that, perhaps in part because it's so difficult to actually show any improvement on. And so when we look at that reality, and we think of what's possible, we don't look at the fact that a lot of anxiety patients are given SRI and primary care and say, "Oh, we inaccessible to us. It's just an artifact of reality that that's kind of all we have today. And without long-term [indiscernible] use, it's a class of drug that is really used or SRI, and there's only a few of them approved in anxiety disorders. And so when we -- certainly, we're not on a [indiscernible] when we talk to anyone the anxiety, we don't hear them saying, why I'd rather stay in primary care on the drugs that have been taking it. They haven't been working for them there's a real eagerness to have better options. And even for those patients who aren't currently in treatment, the availability of something that is really actively effective for them, could drive further seeking care, right? If a patient doesn't have hope they can get better by getting treatment, why go get treatment in the first place. And so that's really, I think, an opportunity initially to focus on those that are even [indiscernible], they're already showing up to have comorbidities that obviously, one of the things that's really how we've seen so far in the data is that we seem to have an even more pronounced effect when looking at anxious depression or depressed anxious populations. I mean either of these studies, either direction we look. And so there's an enormous initial opportunity with millions of patients. But over time, we think that it grows even further. Turn it over to Dan, maybe comment a little bit further just on patient profile.

Yes, for sure. And so I absolutely agree. And what we've observed repeatedly in the epidemiology that exists and in the epidemiological work that we've done is that there is this huge population of folks who are either undiagnosed or undertreated. And as you know, that absolutely happens in primary care settings our early patient profiles most likely to get the drug soon after launch or folks who are exactly that population. Well, as Rob says, we will work on the levers that allow folks to advance through the care system such that they ultimately have access to the drug. But early on, the post most likely to get our driver people who have had these multiple drug trials, each of which has been in some way unsatisfactory either in efficacious or excess side effect burden and usually it's a combination of the 2, right? The side effect where you've seen the benefits, and it's not worthy to stay on the drug for the patient or they stay on it despite that because they offer some little release. But the time folks have had these drug trials, they're almost always in the care of the psychiatric professional, either an advanced practice nurse or a psychiatrist because working with these late-line drugs is something that the primary care just generally doesn't do. So it's those patients, in particular, the ones with severe illness who progressed through the system, who have ended up in the care of psychiatrists and ARN and where those prescribers are the very same people we talk to who say that they don't have the tools in their toolbox to be able to adequately address the suffering of those patients. So at every level, those patients who are out in the world have never been diagnosed, the patients in primary care who have been and the patients who've been traveling through the system and are in late-stage use of drugs that even we prescribe off label. We think we have the ability to access each of them at various stages after we launch it approved.

Our next question comes from David Amsellem with Piper Sandler.

So I have another question about commercial -- sorry, clinical practice. So how do you think treatment in practice has been a shake out between monotherapy of DT120 versus adjunctive therapy. In other words, patients staying on their background antidepressant or anxiolytic therapy. And this is bearing mind, of course, it's not easy to taper off of reuptake inhibitors, particularly dual reuptake inhibitors. So how are you thinking about that? And do you expect that practitioners will lean more into keeping their patients on their background medications and just layering in DT120? Or do you see a paradigm where tapering is going to be more of the norm?

David. I'll turn that one over to Dan to answer.

It's an excellent question, David, and it's something we talk about a lot ourselves and with the clinical experts we engage with on a near-daily basis. And there's a larger structure to how we've done things through our development program, which is to say that we've designed our trials to attempt to demonstrate the minimum conditions necessary for safe and effective use. That is not to push into specific practice patterns to the extent we're able. So consistent with the history of drugs that have been developed and successfully developed for anxiety and depression, we tested the drug as a monotherapy without associated psychotherapy, right? We stripped everything back and tried to show to the extent we were able drug-only effect. It's not because we think that's the absolute most efficacious way or it's a perfectly safe way to use the drug, but we didn't necessarily push for the most efficacious thing we can do with combination therapies because of that desire to show the minimum necessary conditions to save an effect of use that included taking people off background mitigation. In the real world, we expect that clinical practice will evolve over time and that individual clinical practice will dominate the day. So while there will absolutely be clinicians and patients who decide together that they want to take whatever meds are in the background because they're not working adequately and stops them prior to treatment. We also intend to continue to provide information that will allow clinicians to also make the choice with their patients to keep background meds in the picture until relief is sustained from DT120. So that aspect of clinical practice is something which we'll be very interested in. We'll continue to design studies inform clinical practice, but we wouldn't we wouldn't consider our role to say whether an individual patient and provider diet to make 1 choice or the other.

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

Congratulations on the data. So with these data in hand, what do you think you need to show in Panorama to support filing and that approval? Do you think you need to hit statistical significance at 100 micrograms? And then I'm curious if you could just remind us the alignment you have with the FDA, specifically on their recent guidance and if you're maintaining some blind here for the full 12 months, at least for investigators and patients to fulfill that?

Yes. Thanks so much for the question, Brian. I mean, I think especially given the results today and the consistency of the large effect size that we've seen, we feel quite confident going into these Panorama data in September. Obviously, as always, we're going to have be in a dialogue with FDA with more data is going to inform those discussions. And so we feel very good about the path forward, but we feel that we've demonstrated time again that efficacy that has really been seen in these indications. And so we feel as a clear path forward for this drug. In terms of guidance alignment, I mean we -- over the course of the development program less a little under 5 years, you've had an incredible dialogue with FDA and that dialogue has move towards the line that we think in terms of the overall program, the methodologies we use in our trials and all of that. And a culmination, this is public-facing documents like the guidance, that guidance is reflective of an ongoing discussion that we've had over that entire development program. In terms of the specific commentary about a year of winded assessment is exactly what we have in the study. Patients -- the rating of symptoms in the study is blinded at all times. [indiscernible] who are unaware of treatment assignment or visit numbers. They don't know if it's a screening visit or someone who's at week 52 after assuming several doses of DT120. Obviously, with a year-long study and the sort of urgency that we have to move this program forward at different times in the studies. We now have launched Part A of the study and unblinded Voyage and Voyage and Emerge. And the reality there is that of the 4 arms of the quadruple blinding in these studies at various points in time, one of those can be removed. When a patient takes open-label drug, of course, from that point forward in the study, they are no longer blinded to subsequent treatment status, but they still remain blinded to their initial treatment service. So all of it to say, we feel very much aligned with FDA with FDA's guidance. And through that constructive dialogue have landed, what we think is a very reasonable and thoughtful approach to demonstrating to take effect in these programs.

Our next question comes from Ben Burnett with Wells Fargo.

Congratulations to the data. I want to ask just about the placebo response. I was just -- it looks pretty low. And it looks like kind of nominal values for both drug and placebo were maybe a bit lower than was anticipating from the Phase II. Just curious if you could comment on that and maybe also just contextualize some of the remission rates relative to say the care drugs and anxiety.

Thanks so much, Ben. You're absolutely right. I mean the thing that gets missed a lot of times when studies do not show significance, placebo gets claimed, which may be the case may not be the case. But the reality is placebo effect isn't placebo effect really. It's the effect of participating in study, right? Placebo doesn't actually do anything, whether it be a bad placebo. And so when we think of the placebo effect, it's really something that is going to accrue to both -- to all arms that are participating in the same trial in the same way. And that's the case here, right? So in our Phase II study, we obviously have a much larger placebo effect. There's reasons that to believe that a study with 5 arms with an 80% likelihood of getting a dose of drug could demonstrate that, but we still saw an effect size of 0.81 there. We've seen that excise 0.81 here. And so while placebo numbers certainly change and interestingly, we saw virtually flat line for the drug from week 1 to week 12 in terms of HAM-A scores in this study, placebo scores change over time. That's really what drove any of the changes in separation between the 2 arms over the course of the 12 weeks of today's data. So when we think of that, we don't look at placebo as a sort of isolated thing. It's just a fact that in a study where a single intervention is given where patients are then followed for 3 months with no subsequent intervention and patient with a 50% chance of getting [indiscernible] is likely that you're going to have somewhat of a lower placebo than we've seen in the past. Now compared to other studies in the field, we're seeing actually a much larger placebo some of the pivotal studies in our field have shown 3 or so point placebo effects. Now we have the study very soon around 5 in a study where we show a little over 6 years. So we think that we're actually seeing a pretty robust placebo effect, and we're still exceeding that by a wide margin, a very large back side. And I guess in terms of contextualizing the remission and response rates, that's something that's also dramatically affected by this exact dynamic, right? Adding 10 points of a placebo response to both arms is going to make any 6 numerical cutoff, whether it be a percentage or a nominal cutoff seem a lot larger. The fact is we're seeing much higher rates of remission of response [indiscernible] mild attainment of mile or better symptoms, which I think is really the most important real-world clinical target. We're seeing much more of that in the DT120 arm we have with placebo. And we're also seeing over the course of the 52 weeks that really subsequent treatment availability and subsequent treatments, patients continue to accrue and we get more and more pickup approaching well in excess of 50% in that mild or better category.

The next question comes from François Brisebois with LifeSci Capital.

Congrats on the data here. I was just wondering, is there -- in terms of the end of session criteria list, is there something where obviously the language has been worked on and discussed with the FDA, but is there something about specific patients that are ready to leave earlier? And maybe if you can compare and contrast with an MDD patient that although are pretty long episodes, but just the chronic nature of JD versus MDD, -- just trying to get a little more color on what would make someone be able to leave earlier than some of us?