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

Good morning, Welcome to the MindMed Conference Call and Webcast. [Operator Instructions] I would now like to turn the call over to Rob Barrow, CEO of MindMed.

Thank you all for being here today. We're very excited to share several updates from our lead program MM-120, which is being developed for the treatment of generalized anxiety disorder or GAD. During today's call, we will be making certain forward-looking statements. Please take time to review the disclaimer on Slide 2, which includes important information about these forward-looking statements. I'll start off today by making some introductory remarks. Well, let me join by Dr. Rakesh Jain, who will be providing a perspective on the unmet need in GAD in our Phase IIb trial results. This will be followed by a presentation by our Chief Medical Officer, Dr. Dan Karlin, who will review a summary of the full top line results from our Phase IIb trial of MM-120 and GAD and our ODT pharmacokinetics bridging study. Dr. Francois Lilienthal, our Chief Commercial Officer, will then provide comments on the commercial opportunity for MM-120 and we will conclude with summary remarks about the MM-120 development plan going forward. As we have advanced the organization over the past several years, we have embraced an unwavering commitment to bold, disciplined and science-driven leadership, putting patients and their loved ones in the center of everything we do. We aim to rethink the treatment of brain health disorders for the millions of patients in need by executing thoughtful rigorous science to deliver scalable treatments in areas of major unmet need. The past 12 months have been transformative for MindMed as we have delivered best-in-class execution and outcomes. Building on our progress, this is a year that we aim to move lysergide back to the front and center of the brain health pipeline, something that patients in the field at large have been waiting for, for over 50 years. Behind this critical mission is a team of experienced leadership and drug developers with a proven track record in developing and launching novel products in brain health and other high-impact areas of medicine. Our team has repeatedly set the standard for the field with respect to speed, quality and efficiency with which we have executed our programs and we could not be more excited about the path ahead of us. The need and opportunity for MM-120 to potentially provide a new best-in-class treatment option for GAD patients could not be greater. GAD is an indication that has been severely overlooked for the past several decades, resulting in a current prevalence of approximately 10% in U.S. adults, a number that has tripled in the last 2 decades. Of those suffering from GAD, roughly 3/4 have moderate to severe symptoms and only a fraction respond to first-line treatment. Given the poor efficacy and limited tolerability of these current therapies, new options are desperately needed. Aiming to meet this and other unmet needs in brain health, our R&D pipeline is comprised of 2 lead assets and MM-120 which we are developing for GAD and MM-402 or R(-)-MDMA, which we are developing to treat core symptoms of autism spectrum disorder. We're excited to be sharing several updates from our MM-120 program today. This includes positive 12-week durability data from our Phase IIb trial of MM-120 and GAD and data validating the enhanced product profile for our intended go-to-market formulation of MM-120, which utilizes Zydis ODT formulation. Additionally, we were pleased to announce that FDA has granted breakthrough Therapy designation to our MM-120 program in GAD, a recognition of both the seriousness of GAD and the potential of MM-120 to provide a substantial improvement over currently available therapies. Finally, today, our Chief Commercial Officer, Dr. Francois Lilienthal, will be providing an update on our planned commercial model and strategy for an efficient and scalable launch, should we ultimately obtain FDA approval for MM-120. Results from our Phase IIb study at MM-120 in GAD delivered and even exceeded our target product profile, demonstrating a significant improvement in all analyzed endpoints for up to 12 weeks after just a single dose. These results support the fast-acting and durable clinical activity at MM-120 and its favorable tolerability profile. Uniquely, the results we achieved were reached with no additional psychotherapeutic intervention beyond study drug. This strong clinical response, especially stands out in the context of current standard of care, which is dominated by serotonin reuptake inhibitors and benzodiazepines These standards of care are characterized by only modest efficacy with an average Cohen's D effect size of under 0.4, whereas in our Phase IIb study, MM-120 demonstrated in the size of 0.81, 12 weeks after a single dose, 100 micrograms. As I previously mentioned, we are excited and grateful for FDA's recognition of MM-120 as a breakthrough therapy in GAD. The benefits of the breakthrough therapy designation are many and are intended to expedite the developed review of breakthrough drugs such as MM-120. Additionally, today, we are excited to share results from our PK bridging study at the MM-120 Zydis ODT. As we embarked on our development program for MM-120, we sought to identify and advance a formulation that is innovative, differentiated, protectable and has an enhanced pharmaceutical and clinical profile. The results from this PK bridging study delivered on that goal demonstrating that MM-120 Zydis ODTs result in 50% faster onset of action and meaningful improvements in both the overall area under the curve and the area under the curve above target or therapeutic concentrations. We're also excited to be sharing further details of our views, model and strategy for the commercial opportunity of MM-120. In our view, all of the ingredients are in place to enable a successful launch and adoption of MM-120 should ultimately be approved by FDA. There seems a large market of millions of patients suffering from GAD, a best-in-class profile with strong value proposition and a commercial model that leverages proven pathways and a large infrastructure for interventional pediatric care. And with that, I'm pleased to introduce Dr. Rakesh Jain. Dr. Jain is a practicing psychiatrist in Austin, Texas, a Clinical Professor of Psychiatry and Behavioral Sciences at Texas Tech University and is Co-Chair of Site Congress, the largest mental health education conference in the U.S. Rakesh, thank you so much for being here with us today.

Thanks so much, Rob, for the very kind introduction and hello dear colleagues. You heard from Rob, I am an academic as well as practicing psychiatrist, and it's my pleasure to offer you my impressions on GAD because this is one disorder that we simply do not pay enough attention to. And as I will show you in a second, that really is a mistake that is worthy of rectification. So the first thing to be for all of us to keep in mind is GAD, generalized anxiety disorder is actually one of the more chronic disorders that afflicts as human being. And anxiety, particularly anxiety, that's focused on multiple issues and challenges that are long-lasting really create a profound negative impact in our patients and their families' lives. The title here says impact, but the truth is its impact and unmet needs. While we have had some innovation in the world of GAD treatment, the last one was all the way in February of 2007, that's simply too long for a disorder that is so prevalent. There is, of course, decades of research on LSD and psychiatric disorders that really does support its unique potential and as you will see in a minute to why I am so very excited about it. In terms of generalized anxiety disorder, it actually is a very high prevalence disorder. These individuals know they're anxious, their brain, their mind, everything is negatively affected. There's simply no doubt, it's a disorder that affects both the mind and the body, irritability, muscle tension, sleep difficulties, restlessness, fatigue, difficulty concentrating. Oh my goodness, it's quite a laundry list. It's, in fact, the second most common mental disorder amongst adults in the age group of 18 to 65. And here is another major challenge regarding anxiety disorders in that the prevalence has gone up. It's actually tripled in the past 2 decades. I'm also a child and adolescent psychiatrist and I'm unhappy to report to you, we are seeing very large numbers of young individuals with this condition. And it is, of course, very often comorbid with other anxiety disorders and major depressive disorder. Oh, gosh, in terms of the negative impact on many aspects of patients' lives, the more severe that generalized anxiety disorder is greater the negative impact on almost every measure of help. So it's not just that they suffer from an anxiety disorder. They actually have an acute deficit of wellbeing, a deficit in physical functioning, a deficit in quality of life and sadly, the presence of significant disability. Those of us who are wise, be it in the world of psychiatry or just the lay world would do well by respect in Generalized Anxiety Disorder because it's so impairing at so many different levels. I had mentioned before that it's a chronic condition. It really is a chronic condition. Once GAD takes hold of, it rarely on its own leaves. In fact, it often worsens with time and often precedes additional psychiatric disorders. So GAD often then becomes the cause of someone developing major depressive disorder. And the psychiatric profession often only looks at the end result and doesn't often think about what precipitated the challenge. This is perhaps one more reason why I am particularly excited about this interest in GAD because I have found that if I go after GAD well, then I help the patient in the long run. So as the mainstream focus on anxiety disorders returns, thank goodness, patients, however, are quite underserved by current medications, and I should know that. I know that because of my background in research psychiatry, I have actually helped develop benzodiazepines, buspirone, SSRIs, SNRIs and anxiety disorders. And I must report to you that the actual output from them, in other words, effect size of these treatments are not very good. The government -- the U.S. government has also taken a deep interest in it and they offer a grade B recommendation in terms of screening for anxiety in adults, including pregnancy and post-partum people. And by the way, this recommendation also applies to children and adolescents. Look, I do think that 21st century in America and the world is the century of anxiety. We are an anxious species it behooves us to be aware of that and to offer our patients the very best treatment we can. And in terms of what patients with GAD really want and how they're not being served, this slide should highlight for you some of the major shortcomings in the field. And it gives me great pain to have to report this publicly to you that we have not made significant progress in terms of GAD treatment. Our current treatments are very slow. They're not durable. They fade out. You have to take them on a daily basis, limited response, even if patients are willing to put up with side effects and the slog of taking daily medications, they really don't do well. The side effects are enormous, sexual dysfunction, sedation, weight gain, et cetera, and as you can see from these quotes from patients who suffered from GAD, they are telling us an important story that there is need for a new treatment paradigm, a new treatment approach. And current treatments aren't not only not very effective. They really have a pretty standard course. The patient after sometimes many years of waiting shows up to primary care, sometimes they refer to specialty care. But I'm afraid all they get is oral daily treatment with medications that are not only very effective, the side effects are considerable. You don't have to just take my word on what I just said. Just look around you, the odds are very high in your family and friends circle. There are people with GAD who are sadly tied down by these daily medications with all the side effects and it's not a good bargain because they end up not getting the very best of help that we can offer. So LSD. It's been around for a while as you well know, and it's been out in the research world for a long time too. Sure, psychiatry took its eyes off the ball, maybe 25, 30 years ago, but this is changing. There are actually 21 studies prior to 1974. They were actually quite good. I have looked at many of them, they may not meet the standards of today's research acumen, but it is important to know that this is not just a new interest of psychiatry, we've been actually looking at it for a while. But some of the modern day studies, the Glass study from 2014, the whole studies from 2022 and '23, both of them are asking psychiatry and the community at large to have psychedelics, particularly LSD, a very close look. So with that, I thank you very much for letting me describe to you in just a few words that I, as a practicing psychiatrists, who deals with patients does my very best to help my patients with this condition, I need better treatment options. I truly do. The unmet needs are huge. The patient suffering is tremendous, the current treatment approaches we're offering our patients truly are suboptimum. With that, I thank you very much for your kind attention and I'm going to pass the baton on to Dr. Daniel Karlin to continue the conversation. Thank you.

Thanks so much, Rakesh. To reiterate what Rob said, we are extraordinarily pleased to report positive 12-week top line results from our Phase IIb study in GAD that demonstrate a strong and durable effect of MM-120, 12 weeks after a single dose of the drug without any additional therapeutic intervention. The study met all top line primary and secondary endpoints with statistical significance and the results establish a clear dose response relationship for MM-120 in GAD and give us confidence in a go-forward dose. As Rob previously stated, the effect size of a Cohen's D equal to 0.81 at 12 weeks is more than double the estimated effect size of the current standard of care for GAD and was achieved after a single dose of MM-120. The statistically and clinically significant 21.9 point improvement on the HAM-A score at week 12 which represents an improvement over placebo that generates a p-value of 0.0025 represents further improvement from our 4-week top line data and is in part driven by a 48% clinical remission rate at week 12. MM-120 was well tolerated with no drug-related serious adverse events. The observed AEs were mild to moderate and transient, largely occurring on dosing day and are consistent with expected effects from the drug class and observations from previous studies. Importantly, there was no suicide-associated safety signal. The 12-week results provide strong evidence of the durability of a single administration of MM-120 and we believe it provides additional support for advancing a dose of 100 micrograms of MM-120 into Phase III development for GAD. In our Phase IIb study, we employed a standard design consistent with prior studies of approved GAD therapies and included the primary endpoint that supported registration for approved GAD drugs. This study was a randomized, double-blind, placebo-controlled 12-week study of a single administration of MM-120 or placebo monotherapy. Participants who enrolled in the study on background pharmacotherapy for GAD were clinically tapered and washed out of all anxiolytic therapies for at least 5 half lives after their last dose. This study enrolled 198 patients with GAD who were randomized to one of 5 treatment arms with a one-to-one allocation across the arms. The primary endpoint was the change in HAM-A from baseline to week 4 with secondary outcomes at weeks 8 and 12, which, in line with the FDA guidance, were assessed by remote central raters blinded to treatment assignment and visit number. Participants in the study were required to present with a primary GAD diagnosis and a HAM-A score of 20 or greater at screening and baseline. Eligible participants were randomly assigned to receive a single dose of either 25, 50, 100 or 200 micrograms of MM-120 or placebo. Participants were then followed for 12 weeks with outcome measures assessed on day 2 and weeks 1, 2, 4, 8 and 12. In addition to the HAM-A, the primary outcome measure, additional secondary outcome measures include the Montgomery Asberg Depression Rating Scale or MADRS and the Clinical Global Impression of Severity or CGI-S scale, among others. Our study was designed to demonstrate the drug-only effect of MM-120 with no other psychotherapeutic intervention. The importance of this approach was emphasized by FDA's 2023 draft guidance and uniquely in the field allows us to maintain the same delivery protocol between this Phase II study and our subsequent Phase III studies. More specifically, the participant journey in this study was consistent with other clinical trials in GAD. Before dosing, participants underwent a comprehensive informed consent process and eligibility evaluation. On the day of dosing, participants were continuously monitored for psychological and physiological safety by qualified site staff. An observation was completed when prespecified readiness criteria were met. To be clear, this study did not include any preparation sessions, assisted therapy or integration sessions. As a result, we believe this is the most valid assessment of a drug-only effect ever conducted for lysergide or any other molecule in this drug class. 198 patients were randomized into the study, resulting in approximately 40 patients per study arm, 74% of all randomized participants completed study activities through the end of the study at week 12 with a completion rate of 79% among participants in the 2 higher dose groups. These strong completion rates were achieved despite participants receiving only a single dose of the study drug and returning to the study sites for follow-up visits despite receiving no additional treatment. Participant demographics and baseline characteristics were generally well balanced across the treatment arms. Notably, the mean score of approximately 30 on the HAM-A scale indicates that participants in the study suffered from severe GAD, a level of illness supported by mean CGI-S scores of approximately 5, which corresponds to the scale category of markedly ill. Looking at the time course in clinical response as measured by the HAM-A, we observed rapid and durable reductions in HAM-A scores through week 12 with clinically and statistically significant reductions in both the 100- and 200-microgram dose groups. In the 100-microgram dose group, we observed a reduction of 21.9 points on the HAM-A at week 12, which represents a 7.7 point improvement over placebo and a p-value of 0.003. A clear clinical dose response was observed at post the doses tested with peak clinical effects plateauing at the 100-microgram dose and generally staying consistent at the 200-microgram dose. We were also especially encouraged that the study results demonstrated complete maintenance of clinical effect at week 12. Notably in this study, we observed a robust placebo response that also persisted to week 12 and is of a magnitude consistent with historical studies of GAD treatments, which have also employed in inner placebo. In inert, placebo has long been the goal standard in psychiatric studies despite the broad potential for functional and blinding across many classes of psychoactive drugs. We believe that the placebo response observed in our study reinforces the integrity of the study results. It also reinforces our long-held view that inert placebo is the correct choice of controlled condition in all studies of this economic drug class. The clinical activity of MM-120 and GAD is further supported by response and remission rates observed in this study. The clinical response rate, which is defined as a 50% or greater improvement in the HAM-A score with 65% in the 100-microgram group at week 12 and increased in a dose-dependent manner up to the 100-microgram dose level. The remission rate defined as a score of 7 or less on the HAM-A, which is indicative of not having clinically significant anxiety was 48% in the 100-microgram dose group at week 12, meaning that -- of the participants who received a single dose of 100 micrograms of MM-120 approximately one in 2 mission 12 weeks after treatment. The primary analysis of the HAM-A endpoint was conducted using the multiple comparison procedure modeling or MCP-mod, a sophisticated methodology developed by Novartis which is highly statistically efficient in establishing and characterizing dose-response relationships. Using this methodology, the primary endpoint was assessed at week 4, and the key secondary endpoint was assessed at week 8. These analyses achieved statistical significance with multiple dose response curves being statistically identified to inform future dose selection. As I mentioned, the CGI-S was used to assess the overall severity of GAD at multiple time points throughout the study because the CGI-S is a momentary assessment, it can be validly assessed as soon as the day following treatment, whereas the HAM-A is only valid with a 1-week recall period. In the 100-microgram group statistically and clinically significant improvements in the CIS were observed as early as day 2 and were maintained through week 12. On average, participants improved on the CGI-S from market deal to a level between borderline and mildly ill. In practical terms, this is a highly clinically meaningful improvement and aligns both the magnitude and direction with the rapidity and durability of the observed effects measured by the HAM-A. In addition to anxiety symptoms, participants were assessed on the Montgomery Asberg Depression Rating Scale, or MADRS, for the effect of MM-120 on comorbid depressive symptoms. GAD has a substantial diagnostic and symptomatic overlap with depressive illnesses and consistent with the general population of GAD patients, participants presented with comorbid depression symptoms with average baseline MADRS scores in the mid-20s. In both higher dose groups, a statistically significant and clinically meaningful separation from placebo at all time points with a p-value of less than 0.01 at week 12. MM-120 was safe and well tolerated in the study with 99% of adverse events rated mild or moderate. Only one serious adverse event in the study occurred in the 50-microgram dose group 98 days after dosing and was deemed unrelated to the treatment. Additionally, there were relatively few withdrawals from the study due to adverse events. Importantly, we saw no signal of increased suicidality from the treatment. There were no incidents of suicidal or self-injurious behavior. And there were no more than 2 participants per arm with suicidal ideation which, in all cases, was mild to moderate. Events coded as adverse effects on the day of dosing when the vast majority of AEs occurred as seen here indicated by DD were consistent with the pharmacodynamic effects of MM-120. These included illusion, hallucination and euphoric mood as well as nausea and headache, all of which were expected with our understanding of the drug's mechanism of action. These adverse effects were not dose limiting. I will now discuss our MM-120 PK bridging study that enables us to confidently bring our ODT formulation into Phase III development and as our intended go-to-market formulation if MM-120 should ultimately be approved. The transition to a Zydis ODT formulation offers numerous product performance, clinical and intellectual property benefits. Importantly, this formulation yields durable shelf life stability for an otherwise unstable molecule. We are also pleased to report that our PK bridging study or MM-120 Zydis ODT, also delivered on our clinical aspirations for the new formulation. Our goal with the MM-120 ODT formulation was to reduce the time between drug ingestion and reaching a target concentration of greater than 1 nanogram per milliliter, which is associated with acute perceptual effects, thought to produce the clinical improvements observed in the Phase IIb study that I just described. This PK bridging study was a standard crossover design in which each of the 29 healthy participants was randomized 1:1 to receive MM-120 100 micrograms in the capsule formulation used in MMED008 or the new Zydis ODT formulation. Following a 2-week washout period, each participant was administered the other emulation. A total of 24 participants completed dosing using both formulations. The overall PK curves generated from this study demonstrate a favorable profile of the MM-120 ODT formulation with a shorter TMAX, similar CMAX, higher overall AUC and most importantly, a higher AUC and target concentrations greater than 1 nanogram per milliliter. Zooming in on the early phase of the PK curve, we see that the absorption characteristics of the MM-120 ODT formulation allow us to reach the 1 nanogram per milliliter threshold approximately 50% faster. This is a key differentiator as the time spent between drug ingestion and reaching a clinically active concentration of the drug is minimized, making the most efficient use of patient's and clinician's valuable time. Looking at overall bioavailability. We see that the ODT formulation produced a 17% greater bioavailability and notably can drive a substantially higher area under the curve without markedly changing the CMAX. Perhaps most importantly, the ODT formulation shows a 23% increased AUC when the concentration of the drug is above the 1 nanogram per milliliter target. Even so, the MM-120 ODT formulation did not increase the duration of perceptual effects of MM-120. In summary, the characteristics of the ODT formulation demonstrated in this PK bridging study offer compelling evidence for its differentiated clinical profile and support its progression into Phase III development. I will now turn the call over to Dr. Francois Lilienthal, our Chief Commercial Officer, to discuss the commercial opportunity for MM-120 and GAD. Francois?

Thank you, Daniel. I'm honored to be here to be leading a talented team that together has launched multiple blockbuster drugs across many therapeutic areas. When our team considers the commercial potential of MM-120, we feel strongly that the key factors are in place to enable a scalable efficient launch and uptake to help the millions of patients in need of novel treatments in generalized anxiety disorder. Generalized anxiety disorder, or GAD, is a large and growing problem in the U.S. with millions of patients receiving inadequate efficacy, intolerable side effects or choosing not to remain on treatment. We are entering into a large mark with significant unmet need and establish reimbursement framework and a large and growing infrastructure. Our best-in-class profile with MM-120 creates a strong value proposition for all stakeholders, and we believe make for a compelling commercial opportunity. And importantly, in line with Dan's emphasis on the stand-alone effects of MM-120 that have been demonstrated in Phase II, we believe our care delivery model, which does not rely on psychotherapy, reiteration, integration or other intensive nondrug intervention could enable broader accessibility and a wider range of providers and delivery sites to potentially adopt MM-120 compared to others in our drug class. We recently conducted primary research with psychiatric health care practitioners to understand their enthusiasm and receptivity for the potential of the psychedelic drug class. What we found was staggering. The full 74% of health care practitioners indicated that the availability of FDA-approved psychedelic treatments will change how they approach anxiety and depression. And 62% indicated a belief that FDA-approved psychedelic treatments will radically transform the treatment of anxiety and depression. These effects were even more pronounced when focusing on health care practitioners that are providers of Johnson & Johnson's product. We also sought to understand this health care practitioner's impression of MM-120. When presented with the profile of MM-120 in GAD, the vast majority over 85%. We are impressed with the clinical activity of MM-120, including, in particular, its rapid onset and durability of activity. Based on these results, we believe that there is a clear desire for the future adoption of novel treatments such as MM-120 in psychiatry. Focusing on the commercial model that we believe can deliver on this desire, there is a large and rapidly expanding infrastructure of interventional psychiatry providers around the U.S. that are both well equipped and especially enthusiastic about the potential of MM-120. As we conceive our commercial model, it is likely to leverage a similar interventional psychiatry model that has been established by Johnson & Johnson for Spravato or intranasal esketamine over the last 5 years. U.S. net sales in 2023 for Spravato, which is approved for treatment-resistant depression and MDD with acute suicidal ideation or behavior, exceeded $600 million and are projected by Johnson & Johnson to surpass $1 billion in annual sales in coming years. Spravato treatment requires patients to come in for up to 56 sessions over the course of a year. In this session, the medication is self-administered by the patient who is required to be monitored for at least 2 hours before they are released to go on. With the rapidly advancing uptake of this model, there are now more than 3,500 clinics and offices that have been certified for the delivery of Spravato under the Spravato REMS. While we believe there is an even broader infrastructure for MM-120, the seamless transition for these clinics to 1 day provide MM-120 makes for a compelling and efficient initial target. Importantly, in this interventional secretory model, the pathways for patient care reimbursement, REMS documentation and logics are well established and could be leveraged for MM-120 if it is approved and marketed. Here is how this model works. Patients are evaluated by health care practitioner with prescribing rights of fun of psychiatrists and if appropriate, prescribe the treatment. The medicine is distributed by a specialty pharmacy and the treatment is then administered by the patient at the start of the treatment session that takes place in the clinic or office. The patient is monitored by licensed health care providers for the entire duration of the session before being safely released. We feel it is important to point out that in real-world practice, the health care practitioners who monitor treatment sessions are often quite different from the prescribing health care practitioners and monitors, most often have lesser surgeries, training or qualification than the prescriber. For each of these steps in the process, prescription, drug and monitoring, stakeholders are reimbursed by payers utilizing well-established processes and pathways. Digging into these dynamics further, each of the 3 stakeholders in this model received reimbursement from payers using established CPT codes. Notably, each step in the process is reimbursed differently with a unique economic driver. Evaluation in prescribing is commonly reimbursed on a per-visit basis. Drug costs are reimbursed as a pharmacy benefit based on established prices, rebates and discounts. And session delivery is reimbursed on an hourly basis to the clinics monitoring a patient. In this case -- in the case of Spravato, the list price of the drug is between $25,000 and $62,000 a year. In addition to the drug cost, payers reimbursed patient monitoring time on an hourly basis at a cost that can total up to $17,000 per year. We expect to be utilizing a similar model for care provision and reimbursement. And given the economic drivers and profile of MM-120, we believe the reimbursement and value proposition is compelling. While we look to the commercial model established by Spravato. There are a number of attributes of MM-120 that could make it even more attractive for providers and patients and ultimately more easily scalable. These differences are both clinical and logistical in nature. The 3 months durability results from our Phase IIb are ultimately supported in pivotal studies. This could enable 4 or fewer treatment sessions per year on average compared to up to 56 treatment sessions for Spravato. For patients, this means only a few visits to the clinic instead of having to be driven to and from the clinic and kept under observation every single week. For providers, this could also mean a lower administrative burden to submit documentation to insurance or REMS program. Also, given the potential duration of monitoring for MM-120, the care delivery model would only require providers to treat one patient per room per day to obtain reimbursement for that time while the same provider would have to see 4 patients back to back to back to back in order to achieve the same [indiscernible] of reimbursement for [ private ]. Well, conceptually, the potential advantages of MM-120 over a short -- over a shorter duration drug are clear to us. We wanted to test whether current Spravato providers would react. Here again, the response was overwhelming. 80% of current Spravato providers thought that MM-120 would be easier to arrange than Spravato. And over 75% of these providers believed that MM-120 would be more economically attractive for them compared to Spravato. These responses further support our view of the direct applicability of the Spravato infrastructure and commercial model to the pass forward for MM-120. And as we advance toward commercialization, leveraging this established infrastructure will be a priority for our potential launch. With a potentially advantageous delivery dynamics and profile of MM-120, it is perhaps no surprise that 92% of these Spravato providers indicated that they would be likely to refer a patient for MM-120. And 84% of these providers indicated that they would be likely to prescribe and administer MM-120 in their clinic if it becomes FDA approved and is marketed. Of course, an important element to enable scale, value and adoption is payer reimbursement. Generally, payer perspectives on the potential value of MM-120 are positive, and we believe there is a clear path to reimbursement. GAD patients represent a large burden on payers and the clinical profile of MM-120 could offer a predictable, compliant and efficient allocation of payer resources. Current treatment for GAD often take weeks to work, frequently fail and people stop taking them due to tolerability issues, which creates significant waste for payers. And their customers, larger employers are increasingly interested in better managing GAD and brain health. In this regard, it is important to understand that GAD has a major impact on employees by driving employee disengagement and work productivity loss even when employees affected by GAD are on currently available treatments. In fact, on average, an employee with severe GAD misses 46 work days per year and often drive significant incremental disability costs. Our hope is that by helping patients suffering from GAD, the benefit would be multitude and will extend far beyond the individual. As we continue advancing our commercial strategy, our approach will focus on these 3 key imperatives. First, we seek to engage and educate providers and patients about GAD and MM-120. Second, we will seek to continue accruing evidence and highlighting the value proposition to patients, health care practitioners, payers and employers who are frustrated with the state of GAD Care today. And third, we intend to engage and work with the current infrastructure to integrate MM-120 while pointing out its potential advantages versus competitors. While we understand that at the surface level, the commercial pathway for a novel treatment like MM-120 may seem unique, we believe that all the ingredients are in place to enable a scalable, accessible and valuable commercial opportunity. And most importantly, by doing so, we aim to reach the millions of individuals who are suffering from GAD and need new treatment options. I'll now turn the call back over to Rob for summary comments on the MM-120 development. Rob?

To conclude today, I would like to discuss the path forward for MM-120 in GAD. We've now achieved the goals of our Phase II development program, which included establishing the dose sponsor relationship for MM-120 and demonstrating rapid and durable clinical activity in GAD. We believe the data support dose selection and advancement of MM-120 into Phase III development and are excited to kick off our program later this year. In terms of our development pathway, we intend to conduct 2 Phase III pivotal clinical trials, which are in planning. This program is expected to include both 12-week randomized placebo-controlled primary efficacy study designs and long-term open-label extension studies to characterize retreatment parameters. In terms of our Phase III clinical design, we expect the design to be largely consistent with our Phase II study design which we believe may derisk our approach given the robust results already shown in Phase II. We intend to hold our end of Phase II meeting with FDA in the first half of this year, and we'll be initiating our Phase III program in the second half of the year. We anticipate presenting full data from our Phase IIb study in a peer-reviewed publication and at a scientific meeting later this year. We're also currently evaluating additional clinical indications for MM-120 and are excited to provide further updates in the future. I'd like to thank you all again for joining us here today. I'm thrilled by the progress we have made at MindMed over the past several years, and we're excited to share and all that is ahead as we seek to deliver on the therapeutic potential of our pipeline and provide new options to the millions of patients suffering from brain health disorders. And with that, I'd like to open it up to any questions.

[Operator Instructions] Our first question will come from Brian from RBC.

A lot to ask, but I'll keep it to one and hop back in the queue for any additional ones. Maybe just on the commercial side. You outlined some of the similarities and differences versus Spravato administration. I was -- if you could maybe elaborate a little bit more on what you think the center -- Spravato centers will need to do to accommodate the different needs and monitoring requirements for a drug like 120, including sort of fewer patients being monitored for longer sessions and whether reimbursement is strictly focused on monitoring hours or versus maybe to some degree on the number of patients coming through the rooms each day?

Yes. Thanks so much, Brian. I'll turn that one over to Dan to start there and maybe [indiscernible] I can expand.

So one of the things that's required for Spravato specifically is physiological monitoring and we actually don't anticipate that we're going to need to have a physiological monitoring requirement. It certainly reduces the burden on these clinics. The sorts of people who can be involved in the monitoring for MM-120 ought to have fewer medical requirements. And as we're working through plans for Phase III and beyond, coming to agreement with FDA on exactly what it is that we're monitoring for and what level of practitioners are required to do that. So in many ways, the setups that exist both in Spravato clinics, but also in the broader psychotherapeutic [ milieu ] are pretty appropriate as they are for what we anticipate to be the monitoring requirements for our product.

Our next question will come from Francois with Oppenheimer.

Just a quick one in terms of -- and I don't know if Rakesh is available to answer but I was wondering in the real world, here, obviously, in the trial, there's a washout period. But how do we think it's going to work out for patients in terms of getting totally off SSRI? Or is this something that you wouldn't expect that necessarily at first and then down the road could have been. I'm just wondering your thoughts on the real-world translatability of totally washing out patients.

Yes. Thanks so much, Frank. So I'll turn it over to Dr. Jain to catch up you there.

Yes. I'm certainly here. Francois, and a great question, my friend -- really is a good question because many of these patients are on medications, but not all of us, you'd be surprised how many aren't taking an SSRI, [ SNRI ] or benzodiazepines. Look, it is never easy to ask a patient to continue taking a medication that isn't effective. So asking a patient that, hey, here's a safe and effective way to taper down because we have a trial of a medication coming up. I don't think it's going to be challenging. I do that all day long. I would say 80%, 90% of the clinical visits I have with patients are transitioning patients from one to another medication. And deprescribing, which is what you're talking about, Francois is a skill set we in the psychiatry world have developed quite well over the last decade or so.

Thanks for that question. It's Dan. The other thing I think that's worth pointing out is that while for the sake of trial integrity, we're washing folks out of background therapy, there is emerging evidence in the field that background therapy doesn't interfere with the therapeutic action of drugs in the class. We haven't built that body of evidence yet but there's no reason to think that in the real world, we would necessarily have to insist on a pre-dose washout. And so in the real world, folks who respond well to treatment could then subsequently stop other medicines that they didn't need to be on any longer because they were in a state of [ stable ] remission.

Our next question will come from Charles with Cantor Fitzgerald.

Thank you for taking our questions and for hosting this very informative webcast. Congrats on the data. I did have a question for Dr. Jain and just to build some perspective, I'm wondering really if you think this is practice changing or incremental. And you see the durability at 3 months as sufficient? Or would you like to see 6-month durability? Or is that not really important at all? And then finally, which patients in your practice would you target? How would you incorporate this into your practice in terms of deciding the type of patients to administer the agent?

Thanks, Charles. Yes, Rakesh, please go ahead.

Charles asked 3 great questions, 3 great questions. Let me take them in order. First of all, is it game changing. Charles, this is my 31st year in psychiatry. And I [indiscernible] over the last 20, 30 years and seeing just incremental or sometimes side moving interventions, but this isn't one of them. This is a biggie. It's a biggie not just because it was a onetime administration of a medication. That in itself is quite remarkable, but it's an effect size. I've been doing clinical trials and clinical practice for decades, and we simply don't have interventions Charles that exceed 0.4, 0.5. And here, we have 0.8 but it is not just that about half the people were in remission. So if you look at numbers needed to treat, which is a very important proxy for drugs effective best, it's only 2. I had to treat 2 people in order to drive one person into full remission. I'll have to treat almost just 1.5 people to drive somebody into response with one of the most chronic diseases. So the immediate answer to your first question which is, is it a game changer? I actually think when I first saw this data. In my mind, I said psychiatry and anxiety disorder treatment will never be the same again. That's not hyperbole. I think it's going to be true. The second point you raised about was durability. Of course, the longer you can see durability, it is valuable, but let me share this with you. GAD is so refractory and so very prone to being present and recurring. If I can see data at 12 weeks, I can tell you with some confidence how things will be at month 4, month 6, month 9, month 12. So I'm actually quite satisfied with 3 months because someone who has a GAD at 3 months, if they're in remission or in response status, they are doing quite well. Your third question, which was which type of patients will I be selecting in, the obvious answer is not complete actually. It's not going to be just the GAD patient. It's going to be the GAD patient who is motivated, it's the GAD patient who has almost certainly a significant number of comorbidities. I hope you were paying very close attention to Dan's presentation when he showed it wasn't just anxiety that improved. It really was also be very often significant presence of depressive symptoms that also improved. By the way, don't miss out on the following point we're about to make, which is the clinical global impression severity, that is how we clinicians practice. The average person, I'm talking about the average person at week 12 was kissing [indiscernible] it is borderline illness. That doesn't happen in psychiatry very much. So the type of patient, I think, will be a pretty broad-based patient who is motivated, who is willing to accept the fact that these might be enduring changes and a clinician who is willing to engage with such a patient. So I hope I answered all 3 of your questions, Charles.

Absolutely, you did. I appreciate that. Do you have a perspective on the 20% noncompleters, is that more than or within line or less than you would have anticipated?

Yes. Yes. I also paid close attention to that number. When we think of GAD as a homogeneous condition, right? You've got a migraine, you got a migraine. But the truth is, with GAD, there's a huge variability in the kinds of people and the approaches they take. So that number actually was less than I had anticipated. Please also keep in mind, there was no psychotherapy component to this particular trial. Now while this study is a big deal, obviously, to MindMed, I cannot tell you how big a deal that is to my community, the 55,000 people I represent that psychiatry. Our major shortcoming in the world of psychiatry isn't just medication aren't affected. We don't have access to therapists. We don't have access to people who are trained in how to deliver cognitive behavior to therapy. So the fact that this worked, even without any significant therapy, Charles, that's a really, really big deal. And that 20% does not bother me. That's just the way it tends to be in real life.

Congrats to Rob and team on the results.

Our next question will come from Sumant with Canaccord Genuity.

Very nice to see this 12-week data. This question is for Dr. Jain and Karlin. If MM-120 were to eventually be approved from a practicing psychiatrist perspective, what do you think the key impediments, if any, might be to widespread patient use of a potentially game-changing products such as MM-120 in the GAD context?

Thanks so much, Sumant. Rakesh, maybe I'll point this one to you as well and then Dan can expand on this.

Sure, sure. Yes, there are challenges. Let's not be unrealistic about it. The first challenge is going to be my community which hasn't had a "real psychedelic" as a treatment option for the last, what, 70 years before that, we had lots of studies, as I showed you earlier, Sumant, but we didn't have an indication. But here is the good news. And I think we should give a lot of credit to the last 5 years of cultural change in thinking which is the accepted and [ set ] psychedelics and of course, MM-120 is a major class A psychedelic. Don't just change the mind but they change the brain that drives the mind, that is now fairly well established. And as a result, my community, if shown data like this is going to be quite persuaded and of course, this is a Phase II data, we will need 2 Phase III data sets. The other thing that I think we should appreciate as Spravato has really, really till the ground all of a sudden, psychiatry initially auction was just daily medications, and Spravato came in and showed us it is possible to give a medication intermittently though, of course, quite frequently, but still intermittently. And this provider centers have really learned the art of how to create time and space for patients and to allow for them without psychotherapy to improve. So Sumant, I actually think once we have the Phase III data with MM-120, my community is actually, for the most part, going to turn towards the medication and this therapy option rather than act as a barrier. But I would love to hear what you have to say Dan.

And it's a really excellent question because it gets us thinking about something that psychiatry has accepted in a world where we do have highly effective treatments, which is that when folks presented in distress, they're often relegated to the oldest and least effective medicines rather than getting early access to the most effective treatments. And with the advent of treatments that seem to be able to put people into true early rapid disease remission, psychiatry it will be incumbent on us to reorient psychiatry towards alleviating distress as effectively and early as possible. Before the pathways, the neural pathways that get activated by being in distress get [ overcrowded ] and patterns of life emerge from that distress. So while I agree entirely with everything Rakesh said, and the enthusiasm for these treatments in psychiatry amongst psychiatrists of all generations, new residents entering the field in part because they see these things coming down the pipeline. But the larger reorientation towards early, highly efficacious treatment. And a lot of that will have to be based on the recognition that in fact, health care savings and productivity increases from early treatment offset the potential higher initial cost.

Our next question will come from Patrick with H.C. Wainwright.

Congrats on the data updates today and the progress on MM-120. Just during the presentation, it was mentioned that there are more than 3,500 certified delivery clinics for Spravato. I'm wondering if you can tell us what it would take to have MM-120 certified for delivery at all of these clinics? And how soon would you anticipate that MM-120 could be certified at these clinics for GAD following a potential FDA approval?

Yes. Thanks so much, Patrick. It's a bit premature to say definitively the timeline is going to be a function of ultimately what the labeling and REMS and the requirements agreed to with FDA in terms ultimately improve. So a little bit premature to say exactly. But certainly, from a logistical standpoint and from a sort of infrastructure standpoint, we see very little standing in the way. I mean largely Spravato connects that we know well in the broad visit many of which conduct clinical research in our field have very minimal differences between the rooms that are used to treat patients with Spravato and rooms that are used in research for a broad drug class for our drug and ultimately, we see a very direct path to sort of transitioning and being ready for the adoption, and we're not talking about a significant capital investment at a site level, if all you have to do is buy a nice lamp in a rug really is -- a really practical implementation here that should be quite scalable quite efficiently. But again, the specific requirements are going to be subject to all those on [indiscernible] rooms.

Rob, if I may just operate a quick thought entirely agree with you my friend. This process is going to be quite straightforward. I think our [ things ] online should appreciate to become a REMS certified center first Spravato is actually one of the easier things psychiatry has ever encountered. It's a straightforward process. And every Spravato center by default already has the space or already has the equipment. And by the way, equipment really means a bed or it means the reclining bed. And [indiscernible] and music, and they're already quite used to that delivery methodology. So you're right. We don't know what the FDA will say ultimately. But from my community's perspective, the 55,000 that I represent were not going to have logistics challenges.

Our next question will come from Brian with RBC.

Just a couple of questions on the data I wanted to follow up on. First, can you remind us of the way you imputed for non-completers in both the response and remission calculations and then the mean HAM-A change curves. And then secondly, on the ODT, can you talk a little bit more about the implication of the steeper exposure curve, why you don't see differences in duration of hallucinogenic experience given the longer AUC above the target concentrations maybe a little bit more granularity on the AEs, it sounds like lower GI AEs or any more detail versus the capsule would be helpful. And then the degree of subject to subject consistency of exposure for the ODT versus the capsule, how similar or different was that?

Perfect. Yes. Thanks so much, Brian. So -- why don't we start with the second question first. So as we dug into the data from the ODT bridging study, really where what we do see, as you noted, is quite stark difference in the rate of absorption time to get to the onset of action of the drug. And that ultimately is what is driving the difference in AUC, right? We don't see after the absorption pace, you don't see a dramatic difference in any meaningful way. In fact, those codes are almost -- and statistically are quite overlapping from the time we get to CMAX and beyond. In the absorption phase, because of the more rapid absorption, we do get patients to CMAX faster. And that's, again, what's driving the vast majority, if not all of the difference in an AUC. So from an overall AUC standpoint, again, it is getting patients to that peak faster in terms of exposure. And then effectively, they stay at that peak for longer. So when we actually look at all the qualitative feedback we had from the study as well, there was really positive feedback about the overall nature of the ODT formulation compared to the capsule formulation. In terms of adverse events aside from that same potentially some to reduce GI burden, what we didn't see or we didn't really see any [ massive ] differences in terms of perceptional effects and really everything else was really consistent, which is represented by the fact even in the Phase IIb study, where we reported the specific AEs today, most of those are just pharmacodynamics of the drug, the action of the drug during the treatment session is really the best number and all of the AEs that are during the study. Last part of that in terms of subject variability. There certainly is a good degree of variability. A number of factors between individuals. What we see definitely is a difference in terms of elimination in terms of the clearance of the drug and we're still of course, and the development program starting on continuing to explore exactly what may be driving those enter individual differences in terms of metabolism and things of that nature. But I don't -- they'll have a definitive answer to the case yet, but there certainly is a degree of variability, which importantly sets the ODT apart because it makes it quite difficult to reliably get patients to have [ bioequivalence ] from a competitive standpoint, we think about [indiscernible] down the road, it creates an additional hurdle just pragmatically for a potential generic opposite to try to replicate formulation and demonstrate bioequivalence. As to your first question about imputation, that varied by the type of analysis that was being conducted, the primary analysis of the [indiscernible] with imputation based on current events such as patients failing treatment and we're aiming to return to their standard of care. In those instances, patients were imputed regardless of their treatment design what they were imputed based on -- as they have been in the placebo arm and if they were missing and they were imputed based on as if they were -- that in a group they were assigned to and treated. So as in mix imputation being on an [ RM ] that ultimately drive responses. What I can say, and again, varied by the different types of analysis we conducted. We did do extensive sensitivity analyses. And regardless of the methods of imputation or ultimately the statistical approach we took, we end up with the same conclusion. We didn't see any sensitivity due to the statistical methodology that would have changed the outcomes of the study.

We have time for one more question. Our question comes from Sumant with Canaccord Genuity.

Follow-up question. Clearly, these data suggest solid durability in the trial, but do you have any initial thoughts on whether retreatment might work as well once initial treatment wears off and whether the same dose might be optimal for retreatment as well?

Thanks, Sumant. It's a great question and something that we -- as we advance in the Phase III development, we'll certainly be exploring our intention, as we described earlier, as to following a 12-week randomized controlled phase of the Phase III studies to all patients [ already ] with open-label extension study to explore exactly that question to characterize the interval between retreatments and also the response upon retreatment. That's a question of real interest to us. And the exact timing of how that answer, of course, will be driven by Phase III programs and in relation to regulatory timelines, something we'll be discussed with FDA in Phase II.

This concludes our Q&A session. Thank you for joining, and have a great day. You may now disconnect.