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

Good morning, and welcome to the Mind Medicine Conference Call announcing top line preliminary results from the company's Phase IIb study of MM-120 and generalized anxiety this order. This call is being webcast live on Investors and Media section of MindMed's website at mindmed.co, and a recording will be available after the call. For opening remarks, I would like to introduce Schond Greenway, CFO of MindMed. Please go ahead.

Hello, and thank you for joining us on today's conference call to discuss top line results for our Phase IIb study of MM-120 in patients with generalized anxiety disorder. Our press release describing the results of this study was issued today and is available in the News & Events section in the Investors section of our website. Today's presentation will also be available in the Presentations section in the Investors section of our corporate website. During today's call, we will be making certain forward-looking statements, including, without limitations, statements about the potential safety, efficacy and regulatory and clinical progress of our product candidates and our future expectations, plans, partnerships and prospects. We believe our assumptions and expectations related to these forward-looking statements are reasonable, but these statements are subject to known and unknown risks and uncertainties. Such as changes in market conditions, difficulties associated with research and development and regulatory approval processes. Please read and consider the risk factors in our filings with the SEC, together with the content of this call. Forward-looking statements are based on the assumptions, opinions and estimates of management at the date of the statements are made, and we assume no obligation to update these statements in light of future events or new information except as required by law. You are cautioned not to place undue reliance on these forward-looking statements, which are made as of today. Joining me today are Robert Barrow, our Chief Executive Officer; Dr. Daniel Karlin, our Chief Medical Officer. Dr. Miriam Halperin Wernli, our Executive President; and Dr. Francois Lilienthal, our Chief Commercial Officer. I will now turn the call over to Rob.

Thank you, Schond, and thank you, everyone, for joining us. I'm very excited to be here with you today to share the positive top line results from our Phase IIb study of MM-120 in individuals with GAD. Before getting into the study results, it is important to set the stage for these clinical results by addressing the backdrop of significant unmet need in General Anxiety Disorder. GAD is a common debilitating brain health disorder associated with excessive anxiety and persistent worry, which can lead to significant impairment, including less accomplishment and work and reduced workforce participation, as well as significantly higher rates of comorbid conditions such as Major Depressive Disorder, Substance Use Disorders and Chronic Pain. GAD is also associated with significantly more health care resource utilization. GAD often preceded other psychiatric disorders and its chronic nature can lead to a lifetime of impact. Unfortunately, the problem has grown significantly over the past several years. A recent mental health study that was prepared for the Substance Abuse and Mental Health Services Administration, or SAMSA, on the 10% of U.S. adults report symptoms of General Anxiety Disorder, making it the second most common mental health disorder among adult. In comparison to historical studies in the prevalent of GAD, the condition appears to have tripled in the past two decades long. Despite all of this, GAD continues to be underserved by currently available therapy, which are dominated by serotonin reuptake inhibitors and benzodiazepine. These therapeutic classes are characterized by only modest efficacy and often involved side effects that are intolerable and dose or duration limited. Against this backdrop, we are developing MM-120 as a potential best-in-class therapy with a novel mechanism of action. It was a same administration conventually enable month clinical benefit. Before turning the call over to Dan to review the specifics of our trial design and data readout, I want to highlight some of the key findings from the Phase IIb study. The analysis presented today include both the study's primary endpoint analysis and top line results of additional secondary endpoints through 4 weeks. The trial met its primary endpoint with statistical and clinically meaningful reductions in HAM-A scores 4 weeks after single dose administration of MM-120. We observed the largest clinical activity in the 100-microgram dose group with an observed effect size of 0.88. On an absolute basis, this represents a 21.3 point improvement in HAM-A's work of baseline to week 4 and the 7.6 points better than placebo with an associated p-value of 0.0004. In both of the study's high dose groups that is dosing with either 100 micrograms or 200 micrograms, we also observed a 78% clinical response rate, meaning that 78% of participants achieved a 50% or greater reduction in HAM-A score from baseline to week 4. Additionally, we observed clinically and statistically significant improvements in all of the secondary endpoints at all time points analyzed as part of this top line analysis, which includes HAM- A, CGIS and MADRS results through week 4. MM-120 was well tolerated in the study with mostly transient mild to moderate adverse events, but predominantly occurred on a day of treatment. Overall, we believe these strong results support the advancement of MM-120 in the Phase III development for GAD. In the context of currently available therapies for GAD, these results represent a major step forward in the field that we suffered from little innovation in the past 20 years. In this study, we observed a large effect size of 0.88 in a 100-microgram dose group which is more than double the effect size of the standard of care treatments for GAD, which has been estimated to have effect sizes below 0.4 on average. We believe this result can wholly be attributed to the stand-alone of effect MM-120 as the study was conducted in the absence of any psychotherapeutic intervention or legacy like delivery protocols that have been common to other studies of psychedelics drug class. I will now turn the call over to our Chief Medical Officer, Dr. Dan Karlin, who will present key design elements and detailed results and analysis of the study. Dan?

Thank you, Rob. I'd like to start by summarizing key attributes of the study design. In this study, we employed a standard design that is consistent with prior studies of approved GAD therapies and included the primary endpoint that is supported registration for all approved GAD drugs. This was a randomized, double-blind, placebo-controlled 12-week study of a single administration of the MM-120 or placebo monotherapy. Patients who enrolled in the study on background pharmacotherapy for GAD were clinically tapered and washed out of all ambiolytic therapies for at least 5 half lives after the last dose. As Rob mentioned, the delivery protocol included no psychotherapeutic intervention, and we believe the overall design is closely aligned with the FDA 2023 draft guidance on the considerations for clinical investigations of psychedelic drugs. The study enrolled a total of 198 patients with GAD who were randomized to 1 of 5 treatment arms with a one-to-one allocation across the arms. The primary endpoint in the study was the change in HAM-A from baseline to week 4, which in line with FDA guidance, was assessed by remote central raters who are blinded to both treatment assignment and visit number. As a result, the primary and certain secondary outcomes were adjudicated independently by trained readers that had no knowledge of the acute perceptual effects experienced by a participant. 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 at day 2 in weeks 1, 4, 8 and 12. In addition to the HAM-A, which is the primary outcome measure, additional secondary outcome measures included 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 concomitant psychotherapeutic intervention. The importance of this approach was emphasized in the FDA's 2023 draft guidance, and we believe 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. Prior to 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 and observation was completed when prespecified readiness criteria were met. This study did not include any preparation assisted therapy or integration. As a result, we believe the results observed are directly attributable to MM-120 treatment. A total of 198 participants were randomized resulting in approximately 40 patients per study arm. Approximately 90% of all randomized participants completed study activity through week 4 with a completion rate of over 97% among participants in the two higher dose groups. These completion rates were achieved despite the fact that participants only received a single dose of study drug and returned to the study site 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 were suffering from severe GAD. The fact that is supported by mean CGIS scores of approximately 5, which corresponds to the category of markedly ill. Looking at the time course of clinical response as measured by the HAM-A, we observed rapid and durable reductions in HAM-A scores through week 4 with clinically and statistically significant reductions in both the 100 and 200-microgram dose groups at all time points. In the 100-microgram dose group, we observed a reduction of 21.3 points on the HAM-A at week 4, which corresponds to a 7.6 point improvement over placebo and a p-value of 0.0004. A clear clinical dose response was absorbed across the dose is tested with peak clinical effects plateauing at the 100-microgram dose and staying generally consistent at the 200-microgram dose. We were also especially encouraged that the study results demonstrated complete maintenance of clinical activity through week 4 with no loss of activity. This gives us a high degree of confidence that the anxiolytic effects of MM-120 will persist through the week 8 and 12 time points, consistent with findings of the multi-month durable effects of [indiscernible] virus studies. Notably, in this study, we observed a robust placebo response to these of a magnitude consistent with historical studies in GAD treatments, which also used inner placebo. Inner placebo has long been the gold standard in psychiatric studies despite the broad potential for functional unblinding across many classes of psychoactive drugs. We believe this outcome reinforces the integrity of the study results and supports our long-held understanding that inert placebo is the correct choice of controlled condition in all studies of the psychedelic drug class. The clinical activity of MM-120 in GAD was 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 HAM-A score, with 78% in both of the higher dose groups at week 4 and increased in a dose-dependent manner up to the 100-microgram dose level. The admission rate defined as a score of 7 or less on the HAM-A, which corresponds to not having clinically significant anxiety was 50% in the 100-microgram dose group at week 4, meaning that of the participants who received a single dose of 100 micrograms of MM-120, half of them were in remission 4 weeks after treatment. The primary analysis of the study endpoint was the multiple comparison procedure modeling or [indiscernible] a sophisticated methodology developed by Novartis, which is statistically efficient in establishing and characterizing dose response relationships. This statistical method, which has received qualification opinions from both the FDA and EMA allows for greater power from relatively smaller number of participants in a multi-arm trial by incorporating data collected from all of the participants in the study. The analytic process includes, first, establishing that a non-zero dose response exists, then testing observed study data against prespecified dose response curves. Using this analysis, the study achieved a dose response with three of the prespecified models proving statistically significant and being chosen to inform future dose selection. This statistical analysis aligns with the dose response relationship observed in the HAM-A, CGIS and MADRS. As I mentioned previously, the CGIS was used to assess overall severity of GAD at multiple time points throughout the study. Because the CGIS 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 both the high dose groups, there were statistically and clinically significant improvements as early as day 2 that were maintained through week 4. On average, participants approved on the CGIS from what would be considered an average approaching markedly ill to a level between borderline and mildly ill. In practical terms, this is a highly clinically meaningful improvement in alliance, both in magnitude and direction with the observed effects measured by the HAM-A. In addition to anxiety symptoms, participants were assessed on the MADRS for the effect of MM-120 and comorbid depressive symptoms. GAD has a substantial diagnostic and symptomatic overlap with depressive illness and consistent with the general population of GAD patients, participants presented with co-morbid depression symtoms and average baseline MADRS scores in the mid-20s. In both of the higher dose groups, a statistically significant and clinically meaningful separation from placebo at each measured time point in the two high-dose groups was observed. MM-120 was observed to be well tolerated in the study with more than 98% of adverse events rated as mild or moderate. There was only one serious adverse event in the study, which was in the 50-microgram dose group and which occurred 98 days after dosing and was deemed unrelated to the treatment. Additionally, there were relatively few withdrawals from the study due to adverse events with no such withdrawals in the high dose groups through week 4. Importantly, we saw no signal of increased suicidality from the treatment. There were no incidents of suicidal or self-injurious behavior. And there was no more than one participant for arm with suicidal ideation, which in all cases was mild to moderate and not related to the study drug. Events coded as adverse events on the day of dosing, which is when the vast majority of AEs occur were consistent with the pharmacodynamic effects of MM-120. These included hallucination and euphoric mood as well as nausea and headache, all of which are expected with our understanding of the drug candidates mechanism of action. These were not dose limiting. As we progress in development, we will be using a Zydis oral dissolving tablet formulation, which we expect could mitigate the mild to moderate and transient nausea that participants experienced in this study. Ongoing assessment of adverse events through the post dosing period, we reeled very few additional events. This emphasizes a key potential benefit of MM-120 that the side effect burden is restricted almost entirely to dosing day. I will now turn the call back over to Rob to discuss next steps for the MM-120 development program.

Thanks, Dan. We're excited by these study results and their implications for our MM-120 development program. With the results of this study, we've achieved all of our goals with Phase II development for MM-120. In particular, we have rigorously characterized the dose-response relationship with MM-120 and GAD achieved statistically significant and clinically meaningful results supporting its clinical activity, and has demonstrated the stand-alone impact of MM-120 to deliver rapid and durable therapeutic benefits by validated and regulatory accepted critical endpoint. . These results also build on over 20 legacy studies of [indiscernible] and anxiety, depression and other neurotic disorders, including our collaborators investigator-initiated trial that delivered statistically significant results in mid-2022. We believe the Phase IIb data presented today clearly support the selection for subsequent research and support advancement of MM-120 independent go clinical trials for GAD. In terms of our subsequent development pathway, key elements of the Phase III study design are expected to be highly consistent with this Phase IIb study, including the primary endpoint, minimal changes to key entry criteria and no plan change in dosing session protocol. We anticipate conducting two Phase III clinical trials to support a marketing application for MM-120 GAD. We expect these studies to include a 12-week randomized placebo-controlled primary efficacy design with an open-label extension stage to support durability and retreatment parameters. With these exciting next steps, we are entering a phase of many anticipated key development milestones in the quarters ahead. These include top line 12-week data readout from our Phase IIb study in Q1 of 2024 and along with PK bridging data on our Zydis ODT formulation of MM-120. We anticipate having an end of Phase II meeting with FDA in the first half of 2024 to align on the scope of our Phase III development program and to initiate our Phase III clinical program in the second half of 2024. We are planning to present full data from our Phase IIb study at a scientific meeting in 2024 and are excited to share the breadth of findings for this rich data set. Additionally, based on the promising data we have observed for MM-120 and indications beyond GAD, such as in depression, we are actively evaluating additional clinical indications and believe the overall development program for MM-120, may represent the best in class treatment for GAD [indiscernible]. Before concluding, I want to extend my sincere appreciation and gratitude for the critical work and unmatched execution that have brought MindMed ever closer to realizing its mission and to bringing this promising potential treatment to millions of patients in need. I would like to thank all of the patients and their families who participated in this study. In addition to our highly talented and deeply committed team, our research collaborators and clinical investigator teams, our investors and many other individuals who have been supported. We are working with tirelessly to deliver on the therapeutic potential of our pipeline and to transform the treatment landscape for many individuals living with brain health disorders. With that, I'd like to thank you all again for joining us today and I'm happy to take any questions.

Thank you. We will now conduct a question-and-answer session. [Operator Instructions] Our first question comes from Brian Abrams with RBC Capital Markets.

Congratulations on the data. A few questions for me, if I may. I guess, first off, maybe just on characteristics of responders. Did you find any commonalities amongst patients who seem to do the best in the trial? And to what degree do you think this lower touch approach without formal psychotherapy has helped reduce variability here and could reduce variability in the Phase III?

Yes. Thanks so much, Brian. Thanks for being here. In terms of commonalities, with a response rate that's approaching 80%, it's hard to drive a single group that would be responsible to that because it's really -- the vast majority of these patients were clinical responders and half of them were in clinical remission by week 4. We have not yet analyzed at a subject level, the responses and certainly are excited to dig into those analysis. But at this point, we don't have an answer on exactly what would put someone at a higher likelihood of being respond or not. In terms of the second part of your question about the reduction of the therapeutics around has been used in other studies. We certainly think that the consistency with which the drug can be delivered by taking out the variable? Is it the right way to conduct research? It ultimately resulted in a placebo response and the study outcome that was much more in line with historical studies in psychiatry, and we avoided any impact of potential functional unblinding or a potential nocebo effect, which we, of course, did not see in the study are robust with your response. So while it may or may not change the variability, I think we've seen variability in responses that is also in line with historical studies of GAD. What we do believe is that it's much more aligned with how research should be conducted with any psychiatric drugs, particularly in GAD and that it allows for much different scalability if we don't have to deliver hours and hours of therapy or press or integration sessions that we can just deliver the drug on a standalone basis. And of course, opens up the door to a much wider range of both delivery settings and what modes of delivery how the world [indiscernible] approved.

Got it. And then as you guys think about the Phase III plan, and I realize you still need to have the end of Phase II meeting with the FDA, but just sort of coming out of this data, knowing the recent FDA guidance, how are you thinking about, I guess, the number of doses you might test in Phase III and which dose or doses might be the go-forward ones? And are you thinking about in addition to a placebo-controlled study potentially having a high and low dose study, just given that the lowest doses here had modest effects on HAM-A and really no effect at all on MADRS?

Yes. So when we think about the number of doses, we like to look at precedent where forces advanced with FDA and one of those such approaches was [indiscernible] program, where a randomized controlled phase of the study was followed by a label extension, where patients were eligible for retreatment of thing that certain screening criteria. That concept seemingly would be perfectly applicable to this drug class. And when we think about characterizing the retreatment parameters and also the response over time, a design such as has been used with [indiscernible] development program, certainly seems to be a good price, it was something we would look to. In terms of using other doses or dose levels in this study, is that something or is there a final determinations of how we design the studies and the appropriate controls as we go in the Phase II meeting. But in our view, the data we have generated here really put to the side any arguments about whether placebo-controlled study is the right play designed for appropriate controls. The concept of using an alternate control with psychedelics is emblematic of this exceptionalism that happens with this drug class at times, where virtually every CNS drug has a degree of function on blinding, you only have to look as far as Spravato, to understand that the incidence of the associated effects are such that there was clear function on binding the thing would be true for psychostimulants for SRI or benzodiazepines for that matter that are approved in GAD, all of which have perceptual effects that could lead to functional and binding. Here, the biggest concern, of course, is -- and this is highlighted in FDA's guidance that an expectancy or performance bias could -- through being mediated by functional binding leads to a nocebo effect. And by stripping back any of that therapeutic surround and prep integration that has been done by versus all other programs in the drug class, our belief is that those activities serve to reinforce a performance or expectancy bias. And by eliminating those, we're able to get a true estimate of the drug effect. And ultimately, as we saw in the study to see a real typical and frankly, sizable placebo response, and we were still able to outperform in this study. So we certainly believe the goal standard for all research is placebo-controlled placebo-controlled head-to-head design. Certainly, we're constructive in all of our dialogue with FDA. We're science-driven and try to make data-driven arguments. We believe that we'll be able to support placebo controls in these studies. What I wouldn't want to get into is doing studies where we're comparing a low dose drug versus a high dose of drug because of them we were put in a position where we're trying to show superiority within what could ultimately be a therapeutic range. We even saw a slight statistically significant response in the 25-microgram dose group at 1 week. So we wouldn't do studies with any other drugs in psychiatry, where we compare a high dose and the low dose and trying to demonstrate superiority statistically. Nothing we should be doing with this drug class either. The only final comment I'll make there is that in the event we were in need of some additional aid and functional binding. There are opportunities to do that. And this is like we saw with 50 micrograms. There's a clear -- clear on the AE table that there was a higher incidence of allusion and the other [indiscernible] associated drug effects on dosing day at even 25 and 50 micrograms. If we needed to include a small cohort as supported aid in functional unblinding, we can consider doing something of that nature. But our view is that statistical testing and study design should compare a target therapeutic dose of a drug against the placebo, which is, again, the goal standard and being used to approve every single drug in psychiatry to our knowledge.

Got it, Rob. Now that makes a lot of sense. And if I could just squeeze one more quick one in. Can you just talk quickly about experience duration? Was that in the 8- to 10-hour predicted range, how that differed across the doses? And how does that affect? How you think about logistics and staffing for administration in the future?

Yes, absolutely. So in the study, we agreed with the agency that we would hold all patients for a fixed interval of 12 hours. And that was, in large part, driven by the highest dose we are testing, a 200-microgram dose, which has a longer duration of perceptual effects. At the 100-microgram dose group, which clearly based on the analysis, this would be supported both by the modeling, but also by just clinical observation where we saw the beginning of a plateau of drug effect and the overall maximum response of the study with the 100-microgram dose group. There, we did see the vast majority of patients were cleared between 8 and 10 hours to leave, although, again, we kept everyone for 12 hours, we started checking eligibility for release at 8 hours and believe that, that sort of time frame 8 to 10 at most hours would be appropriate with this formulation. As we have PK bridging study that's ongoing with our ODT formulation and certainly our hope with that formulation will be able to even further tighten up and perhaps you can shorten that duration of the perceptual effects by potentially driving faster absorption, better bioavailability and less variability in the elimination phase. So far, we're seeing some encouraging results in that study. And if we're able to deliver on that, we think we could even shorten or tighten up that duration even further.

Our next question comes from Charles Duncan with Cantor Fitzgerald.

Rob and team. I wanted to add my congratulations on the conduct of a really rigorous finding study, and the robust results. So, I appreciate all the detail. I have a couple of questions. First of all, with regard to the sample enrolled, can you give us some sense of any prior use in that patients may have had experience with LSD. And then in terms of the dose response, is it surprising to you? What does it say about the -- I guess, practice of micro dosing. Is that a nonissue going forward? And I imagine the agency would like to see that as well.

Thanks so much, Charles. I'll turn it over to Dan to initially address your questions. I have to add, if anything on to it, Dan?

So what we did in the study inclusion/exclusion criteria was to exclude -- have an excluding criteria and lifetime use of psychedelic substances, including LSD and then a recent exclusion as well. So what we don't have in this population is a group of folks who either have ever been regular heavy users or regular users at all for that matter or recent users of associated substances. So we believe that this is a population that is representative of the general population in terms of historical and recent use of substances. Rob, you want to take the second one do you have that one?

Yes, go ahead, please.

Charles, could you give me that one more time?

Yes. Yes. Regarding the dose, call it, use response. Yes.

Yes. So the point of the doses that were selected was to reach a plateau right, that we were -- we wanted to be sure that we dosed high enough that we answered the question, how we reached the maximum effective dose. And what we think we see here is, in essence, a plateau of positive drug response. And some of what may be not statistically significant differences between the groups, but some evidence that there is an underperformance in the 200-microgram dose group, may represent that, that level historically has been associated with perhaps some more challenging experiences during the experience that may mitigate some of the positive experience during the study. Now again, while that is directionally what we're seeing here, and of course, what we see in the data strongly points us toward the 100-microgram dose group as the appropriate go-forward dose, we'll have to look out to the 12-week data and get deeper into the data before finalizing any choices about go-forward dose.

Okay. That's helpful. And then regarding that next step, Phase III. Can you give us a sense of sizing? I mean you have really notable [indiscernible] effect size. So give us a sense of timing. And I assume that it's going to be one particular dose that you used, you mentioned 100, but any other changes with regard to endpoint or time to evaluate that endpoint? And then will the ODT be ready for that Phase III?

Yes. So in terms of phase III design, you're right, of course, we reserve the final determination of the study design and the size and everything for promoting having in the Phase II meeting and certainly look forward to sharing the specifics when it gets to that point in the first half of next year. Our initial thinking, of course, with an effect size, if one were to use an effect size of 0.88 to power subsequent research study that implies incredibly small studies in the scope of a Phase III development program. We also, of course, have an expectation we'll need to get to a number of overall exposures in the Phase III, an overall development program to support a marketing application to have an appropriate [indiscernible] safety database. So many factors will go into that. And in addition to other potential indications and studies that we can pursue, we're seeing some really promising results here in on the address that could have implications and read through to depression ultimately. So as we scoped out the overall development program, both in GAD and beyond, we'll have an opportunity to really refine those specific numbers. But certainly, we don't anticipate doing studies that are of a vastly different magnitude than what we've already been able to operationalize in the Phase II program and believe we'll continue to be able to execute these. We enrolled the majority of the study in just over 6 months and the entirety of the study just over 12 months. So we want to make sure there are millions of patients in need, and we have shown the ability to really execute efficiently and instead of pace, I think, for the field and the ability to get these studies operationalized and completed and now successfully completed. So we intend to continue doing that. We want to make sure that our scope of our program especially can be very efficient and quick to bring these patients a new treatment option.

That's helpful. Final question for you or Sean. Can you remind us of the intellectual property behind MM-120. And have you made any observations within this study that you would considered to be a surprise or not obvious observations that may even further strengthen or bolster that IP.

Yes, absolutely. I'll dovetail that with part of your last question that I didn't answer, the [indiscernible]. We absolutely will have the [indiscernible] formulation ready for our Phase III study. Virtually all of the preparations for the Phase III program are either completed or underway. And we've been working with Catalent over the past several years to develop this formulation and have everything in place that we'd be able to very efficiently transition into the Phase III program. We'll have the Phase I PK bridging study results for the first quarter of next year as well to inform the precise selection and progress in that formulation into the clinic in Phase III. But that also does sound nicely with your last question about intellectual property. We have certainly both through our PK bridging study and the Phase II study, I believe there are a number of observations and have filed additional intellectual property around those findings and those innovative steps that we've been able to deliver here, both in the clinic and then the performance of the ultimate commercial formulation [indiscernible] pursue. Our intellectual property portfolio is many layered. We believe we have a differentiated drug product and differentiated number of applications would be incredibly difficult to replicate. And unlike a very simple formulation that relies on a narrow API pattern, we're in a position where we have applications that are being prosecuted at every level of the process, both from a method and composition approach. So our view is that at a bare minimum, [indiscernible] has never been approved before, we expect that would be eligible for 5 years marketing exclusivity and I certainly believe we'll have a number of patents liftable in the orange book and a patent protection that if granted and successful would not start expiring until 2022. So this is a very strong position in our view, and really excited to share even more as we progress in the next couple of quarters.

The next question comes from François Brisebois with Oppenheimer.

Congrats, very strategic dose-ranging study, well done. So I was just wondering, in terms of the durability, you mentioned confidence in durability lasting to 8 weeks and then going to 12 weeks. Can you just help us understand a little bit why you're confident that this could last that long?

Yes. Thanks so much, Frank. As you mentioned, one of the things that really sets this study apart from some of the observations we've seen historically is that we're seeing this rapid reduction. First measurable in the CGI at day 2 and then measurable at the earliest possible time point, week 1 on Hamilton anxiety scale. With several other studies that initial response starts to revert back to the mean after the course of just 2 or 3 weeks, not so in the study. And when we talk to our key opinion leaders, their view is that the differential and the activity of LSD compared to really any other drug in the class, but also in its unique ability to deliver these robust and even more durable effects. We talked about the sort of critical period, the window for psychological processing and learning, and we know that, that spoke longer with LSD. And from a number of historical study, LSD has been the most research compound in the class for a reason, in our view, and there's a ton of reason to believe that we would see durable effects out to that duration. When we also look at things like find the data and look at the histograms of scores over time, we feel a high degree of confidence that we're going to be able to deliver continued performance of this molecule. And again, unlike what we've seen with some other [indiscernible], it appears that is something quite different about the durability and the magnitude of response. We lost no clinical response through 4 weeks of treatment. I certainly believe that flat lining of significantly reduced anxiety symptoms will persist for weeks longer. We also have an investing initiated study conducted by our colleagues over in Switzerland that demonstrated 6 months of activity. So we believe there's significant upside in terms of how much longer this drug can show and perform in terms of the [indiscernible].

The next question comes from Sumant Kulkami with Canaccord.

So in your Phase III trial protocol, do you expect to have a specific retreatment component? And what about potential use of background medication?

Yes. In terms of the retreatment component. Again, there is something we'll certainly be discussing with the agency as we go into Phase II. When we look at other drugs in Phase III in the sub class, we've seen a few different approaches to definition of retreatment parameters. But when we look more broadly, I mentioned the SAGE Biogen zuranolone program, where in that program, a 12-week randomized controlled study is followed by a variable duration ongoing screening, monitoring of patients. And then based on a relapse or an ability to hit screening threshold in patients with in eligible for retreatment. From what we know out in the real world, there's a large compassionate use program other than Switzerland, where patients are regularly administered LSD to treat anxiety and depression in other disorders. Our view is that this is not a drug that we expect to be delivered on a six interval basis. And that really leads to sort of an episodic intervention, which is in our view is the new wave of psychiatric treatments are more interventional unless a chronic daily or fixed interval treated regime. So when we think about the Phase III development program, certainly, we want to adequately define and characterize what occurs upon retreatment to define the interval between -- recommended interval to maintain effects between doses. But there are a number of approaches that can be pursued there. And because we're seeing such strong durability through 4 weeks and again, we anticipate that there's a good chance we'll see that continue out to 8 to 12 weeks. If we're seeing 3 months of effect after a single dose, it's very difficult to do placebo-controlled research, even beyond one month for highly anxious patients who are markedly ill and are tapered off of recommended medication. To ask those patients to stay off of any treatment for months on end is very difficult ethically tenuous at times. And so we're really going to be exploring ways that we can ensure patient safety that we can ensure good ethical conduct and design of these studies, but also I characterize all the parameters as the FDA is asking so we can inform prescribing intimation for this product if it's all approved.

And you've given a wealth of data here in all your slides, so thanks for that. What is the typical [ MEDA ] score for a patient with GAD? And how does that compare with the baseline level of [ MEDA ] scores you saw in the patients with GAD in this trial?

In terms of [ MEDA ] scores, the baseline [ MEDA ] scores were in the mid-20s in these patients. And this is typical. Both in [indiscernible] of anxiety is very common to see high levels of depression scores on things like the MADRS in part because both diagnostically and in terms of the scale, the MADRS and the HAM-A,are so significantly overlapping. We estimate there's something around 80% construct overlap in both the diagnostic criteria for GAD and MDD, but also in terms of the HAM-A and MADRS item 4 on the HAM-A is depressed mood. So it would be virtually impossible for patients in an anxiety study to not also score somewhere on the MADRS that would be clinically relevant in terms of depression symptoms. What we do require is that GAD is the primary diagnosis for the patient and that patients are not in a major depressive episode. But we did still -- like with depression studies, patients in depression scale of studies are higher in the high 20s or low 30s on the MADRS and have HAM-A scores that are around 20. Here, we saw HAM-A score of around 30 and HAM-A is a 0 to 56 scale, we saw MADRS score in the mid-20s. And of course, I saw almost 20 unit changes in both in the MADRS scale and over 20-point change in the HAM-A through week 4.

The next question comes from Patrick Trucchio with HC Wainwright.

And again, congrats on the data results this morning. I have a clarification on the baseline characteristics of the patients enrolled in the trial. Were these patients who failed standard of care became -- or became nonresponsive to standard of care? And then secondly, can you talk more about the improvement in global impression scores? Is this a score that we would expect to improve further for the 12-week readout? Or how should we think about that? And can you talk more about the significance of this endpoint in terms of approval or post-approval commercialization?

Thanks so much, Patrick. I'll turn it over to Dan to answer your questions about baseline characteristics and improvement of CGIS.

Yes. So these baseline CGIS scores are largely consistent with the severity of the illness we saw in the MA. So everything is sort of directionally in magnitude consistent across the CGIS scores. The rapid improvement in CGIS is, of course, quite promising. So the day 2 improvement. And what we see is a sustained improvement in CGI through week 4, with folks approaching borderline, which is really quite a great data, two category crossing from the original score. We would expect to see that persist. I'm not sure that we would necessarily expect that to necessarily improve dramatically through the end of the study. But at least we would expect persistence of that the -- for the same reasons, we expect persistence of the baseline MA, as Rob described. So we kind of expect those to track together throughout the study.

And then just in terms of the baseline characteristics for these patients, were these folks who did they fail standard of care? Or were they nonresponses?

Yes. So we had a mixture of patients that we think is representative of the real world of GAD patients between 60% and 70% of these folks had been on treatment between 30% to 40% had to be discontinued from a medication to enroll in the trial, which that means that we had a population of folks both coming in with moderate to severe anxiety on treatment at study start, mixed with people who had tried treatment in the past and discontinued for a variety of reasons, but almost invariably when someone discontinues standard of care treatment, generally SRI is these days, it's because their experience of the drug is that it either is inefficacious or has intolerable side effect burden. And usually, it's actually a combination of the two, of course, right? That whatever benefit someone is sustaining from the treatment is enough to warrant whatever side effect burden they're experiencing from the treatment. So what we think we've captured here is particularly based on the epidemiology of the illness, quite representative of a general population of folks who either have tried and not sustained adequate benefit from standard of care or for a variety of reasons, despite suffering from moderate and often severe anxiety haven't sought out treatment because of a perceived in efficacy or perceived side effect burden. So even psychiatry particularly, seeking treatment is often driven by a perception of the efficacy of the treatment, which is sought. And for anxiety, particularly, our sense, again, as we investigate the general population through epidemiological research is that there are plenty of people who just really think there isn't anything that's going to help them. So it was heartening to see, folks seeking out trial enrollment from both groups of people who were -- with all three groups, really, people who are on medication and not sustaining adequate benefit, who had been on medication in the past and not the same adequate benefit and people who hadn't sought out the current standard of care despite suffering from severe illness.

Right. Can you discuss more about the product profile that's emerging for MM-120 and GAD based on this data today? Do you see a scenario where MM-120 could be moved into a Spravato like paradigm? Or what changes, if any, to the existing infrastructure could be needed to accommodate MM-120 administration?

Yes. Thanks, Patrick. Go ahead, Dan. Yes, please.

Yes, happy to. So Patrick, I mean, absolutely right. There is this existing and growing infrastructure for the delivery of Spravato currently and certainly the increasing third-party payer reimbursement and the ease of getting that reimbursement has spurred the growth of these third-party payers supported interventional psychiatry centers, they may deliver Spravato and other interventional psychiatry treatments like TMS. So we very much see those as potential commercialization clinics for the delivery of MM-120. We also see that because there's such a low physiological burden from MM-120, Spravato in its REMS requires medically certified sites and a degree of physiological monitoring because of the perceived physiological risks of Spravato. We don't see that sort of physiological risk. So we actually can project out into a commercial world where not only are we able to enter interventional psychiatry centers, but we're able to be delivered -- if we're successful in this, in places where psychotherapy can be delivered that in reality that the requirements for monitoring someone undergoing MM-120 treatment aren't really different from what's required to deliver interpersonal one-to-one psychotherapy, Dyadic psychotherapy. So we see both the potential for the existing interventional psychiatry infrastructure and the potential for significant broadening into places that today are not able to provide interventional psychiatry.

The next question comes from Elemer Piros with StockBlock Securities.

What I'd like to maybe just touch upon is the observation that -- and this fits into the paradigm in psychedelic medicine that you're looking at response and remission rates that twice the control or even higher. How does that compare to standard of care? And I know that you talked about effect size, but I don't often see remission and response rates reported for anxiety medications. Can you please address that?

Yes. So you're right that this is less reported in the literature because the numbers aren't super promising with the existing standard of care. And just as we showed effect sizes of standard of care and our significant exceeding those effect sizes. The response rates that we show here, where we're significantly greater than placebo on response and remission rates compared to standard of care that -- where you see a difference from placebo and response? And again, this is sort of pooled data and again, numbers that are [indiscernible] you can think about maybe a 20% exceeding of response -- a placebo response rate with standard of care and a 10% to 20% exceeding a remission rate with standard of care. So substantially lower numbers than what we're seeing here.

Yes. I mean this is remarkable. And I just wanted to ask Dan or Rob that when you look at the depression scores, are you looking at the entire population? Or are you looking at only patients who came in with a baseline score above a certain level?

We didn't enrich the depression [indiscernible] MADRS scores in any way. So well, obviously, we had a 20 cutoff, 20 or higher on the HAM-A for enrollment and require GAD as both the primary diagnosis, the primary target of clinical interest and patients couldn't be in a major depressive episode on enrollment. What we effectively got from the MADRS as Rob described earlier, was the fact that folks with moderate to severe GAD, both because of diagnostic construct overlap, like you said, and because instrument construct overlap end up scoring in the mid-20s on the MADRS. But that was just an incident of the patient selection for GAD. We weren't seeking a specific MADRS score and didn't have a MADRS cutoff.

Yes. And the last question that I had is, how did you treat discontinuations across [indiscernible], please?

Yes. So the discontinuations in the primary analysis in remodel with a mixed invitation approach certainly as we progress, happy to provide some additional details there. In the secondary analysis, there were -- typically presented another slide of [indiscernible] was reported, that was an [indiscernible] model with baseline on a covariant depending on the endpoint where in many instances we're reporting the actual observed values. And as we progress, we'll also be doing sensitivity analysis of different approaches for data imputation. But given the high degree of completion through week 4. There's the expectation that any sort of sensitivity analysis would have very little if any impact on the outcomes we're observing here.

At this time, there are no further questions in queue. I would like to turn the call back over to Mr. Rob Barrow for closing comments.

I'd like to thank everyone again for being here today, and it's been the time and all the great questions. We're incredibly excited about these results. And I look forward to sharing much more data as we progress in the first quarter, both from the longer-term observation of patients in the study from our ODT formulation and certainly our regulatory and clinical progress as we move later into 2024. Thank you, everyone.

Thank you. This does conclude today's teleconference and webcast. You may disconnect your lines at this time, and thank you for your participation, and have a great day.