Good morning, and welcome to the MindMed conference call announcing top-line preliminary results from the company's phase IIb study of MM-120 in generalized anxiety disorder. Currently, all participants are in a listen-only mode. 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 the top-line results for our phase IIb study of MM120 in patients with generalized anxiety disorder. Our press release describing the results of this study was issued today and is available in the News and Events section in the Investors section of our website. Today's presentation will also be available in the Presentation section in the Investor 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 that 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. Miri Halperin Wernli, our Executive President; and Dr.
François Lilienthal, our Chief Commercial Officer. I will now turn the call over to Rob.
Thank you, Sean, 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 2b study of MM120 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 generalized 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 at 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 healthcare resource utilization. GAD often precedes 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 prevalence study that was prepared for the Substance Abuse and Mental Health Services Administration, or SAMHSA, found that 10% of U.S. adults report symptoms of generalized anxiety disorder, making it the second most common mental health disorder among adults. In comparison to historical studies of the prevalence of GAD, the condition appears to have tripled in the past two decades alone. Despite all of this, GAD continues to be underserved by currently available therapies, which are dominated by serotonin reuptake inhibitors and benzodiazepines. These therapeutic classes are characterized by only modest efficacy and often involve side effects that are intolerable and dose or duration limiting.
Against this backdrop, we are developing MM120 as a potential best-in-class therapy with a novel mechanism of action, in which a single administration could potentially enable months of 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 2b study. The analysis presented today includes both the study's primary endpoint analysis and top-line results of additional secondary endpoints through four weeks. The trial met its primary endpoint with statistical and clinically meaningful reductions in HAM-A scores four weeks after single-dose administration of MM120. 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 score from baseline to week four and with 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, doses of 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 four. 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, CGI-S, and MADRS results through week four. MM120 was well tolerated in the study, with mostly transient, mild to moderate adverse events that predominantly occurred on the day of treatment.
Overall, we believe these strong results support the advancement of MM120 into phase III development for GAD. In the context of currently available therapies for GAD, these results represent a major step forward in a field that has suffered from little innovation in the past 20 years. In this study, we observed a large effect size of 0.88 in the 100-microgram dose group, which is more than double the effect size of the standard of care treatments for GAD, which have been estimated to have effect sizes below 0.4 on average. We believe this result can wholly be attributed to the standalone drug effects of MM120, 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 the psychedelic drug class.
I will now turn the call over to our Chief Medical Officer, Dr. Daniel Karlin, who will present key design elements and a detailed results analysis of the study. Dan?
Thank you, Rob. I'd like to start by summarizing key attributes of this 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 has supported registration for all approved GAD drugs. This was a randomized, double-blind, placebo-controlled, 12-week study of a single administration of MM120 or placebo monotherapy. Patients who enrolled in this study on background pharmacotherapy for GAD were clinically tapered and washed out of all anxiolytic 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 was 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 one of five 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 were blinded to both treatment assignment and visit number. As a result, the primary and certain secondary outcomes were adjudicated independently by trained raters 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 MM120 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-Åsberg 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 MM120, 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 2 study and our subsequent phase 3 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 pre-specified 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 MM120 treatment. A total of 198 participants were randomized, resulting in approximately 40 patients per study arm. Approximately 90% of all randomized participants completed study activities through week four, 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, a fact that is supported by mean CGI-S 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 observed across the doses 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 MM120 will persist through the week 8 and 12 time points, consistent with findings of the multi-month durable effects of lysergide in prior studies. Notably, in this study, we observed a robust placebo response that is of a magnitude consistent with historical studies of GAD treatments, which also used inert placebo. Inert 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 control condition in all studies of the psychedelic drug class. The clinical activity of MM120 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, was 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 remission 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 MM120, half of them were in remission 4 weeks after treatment. The primary analysis of the study endpoint was the multiple comparison procedure modeling, or MCPMod, a sophisticated methodology developed by Novartis, which is statistically efficient in establishing and characterizing dose-response relationships. This statistical method, which has received qualification opinion 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 pre-specified dose response curves. Using this analysis, the study achieved a dose response with three of the pre-specified 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, CGI-S, and MADRS. As I mentioned previously, the CGI-S was used to assess 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 one-week recall period. In both the high-dose groups, there were statistically and clinically significant improvements as early as day two that were maintained through week four.
On average, participants improved on the CGI-S 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 and aligns 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 MM120 on 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 comorbid depression symptoms and average baseline MADRS scores in the mid-twenties. 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.
MM120 was observed to be well tolerated in the study, with more than 98% of adverse events rated as mild or moderate. There was only 1 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 1 participant per 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 occurred, were consistent with the pharmacodynamic effects of MM120. These included illusion, hallucination, and euphoric mood, as well as nausea and headache, all of which are expected with our understanding of the drug candidate's 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 revealed very few additional events. This emphasizes a key potential benefit of MM120, 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 MM120 development program.
Thanks, Dan. We're excited by these study results and their implications for our MM120 development program. With the results of this study, we've achieved all of our goals of phase 2 development for MM120. In particular, we have rigorously characterized the dose-response relationship with MM120 and GAD, achieved statistically significant and clinically meaningful results supporting its clinical activity, and have demonstrated the standalone impact of MM120 to deliver rapid and durable therapeutic benefits by a validated and regulatory accepted clinical endpoint. These results also build on over 20 legacy studies of lysergide or LSD in anxiety, depression, and other neurotic disorders, including our collaborator's investigator-initiated trial that delivered statistically significant results in mid-2022. We believe the phase 2b data presented today clearly support dose selection for subsequent research and support advancement of MM120 into pivotal clinical trials for GAD....
In terms of our subsequent development pathway, key elements of the Phase 3 study design are expected to be highly consistent with this Phase 2b study, including the primary endpoint, minimal changes to key entry criteria, and no planned change in dosing session protocol. We anticipate conducting two Phase 3 clinical trials to support a marketing application for MM120 in 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 a top-line 12-week data readout from our Phase 2b study in Q1 of 2024, along with PK bridging data on our Zydis ODT formulation of MM120.
We anticipate having an end of phase 2 meeting with FDA in the first half of 2024 to align on the scope of our phase 3 development program and to initiate our phase 3 clinical program in the second half of 2024. We're planning to present full data from our phase 2b study at a scientific meeting in 2024, and are excited to share the breadth of findings from this rich data set. Additionally, based on the promising data we've observed for MM120 in indications beyond GAD, such as in depression, we're actively evaluating additional clinical indications and believe the overall development program for MM120 may represent the best-in-class treatment for GAD and MDD.
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 the many other individuals who have been supportive. We are working 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. If you would like to ask a question, please press star one on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star two if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset. Once again, that's star one to ask a question at this time. One moment while we pull for our first question. Our first question comes from Brian Abrahams with RBC Capital Markets. Please proceed.
Hey, good morning, guys, and congratulations on the data. A few questions from me, if I may. I guess first off, maybe just on characteristics of responders. Did you find any commonalities amongst patients who seemed to do the best in the trial? And to what degree do you think this lower touch approach without formal psychotherapy could, you know, has helped reduce variability here and could reduce variability in the phase 3?
Yeah. Thanks, thanks so much, Brian. Thanks for being here. In terms of commonalities, with a response rate that's approaching 80%, it's hard to derive a single group that would be responsible for that because really, you know, 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 analyses. But at this point, we don't have an answer on exactly what would put someone at a higher likelihood of being a responder or not.
In terms of the second part of your question about the reduction of the therapeutics around what's been used in other studies, we certainly think that the consistency with which the drug can be delivered by taking out a variable is the right way to conduct research. It ultimately resulted in a placebo response and a study outcome that was much more in line with historical studies of psychiatry, and we avoided any, you know, real impact of a potential functional unblinding or a potential nocebo effect, which we, of course, did not see in the study because of our robust placebo response. So while it may or may not change the variability, I think we've seen a variability in the 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 psychiatry 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 prep or integration sessions, and we can just deliver the drug on a standalone basis, that, of course, opens up the door to a much wider range of both delivery settings and what modes of delivery out in the real world if we're able to get started or approved.
Got it. And then as you guys think about the phase 3 plan, and I realize you still need to, you know, have the end of phase 2 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 3, and which dose or doses might be the go-forward ones? And are you thinking about, in addition to an inert placebo-controlled study, potentially having a high and low dose study, just given that, you know, the lowest doses here had modest effects on HAM-A and really no effect at all on MADRS?
Yeah. So when we think about the number of doses, you know, we like to look at precedent where approaches have, you know, advanced with FDA, and one of those such approaches was Sage and Biogen's zuranolone program, where a randomized controlled phase of the study was followed by an open-label extension where patients were eligible for retreatment if they met certain screening criteria. That concept seemingly would be perfectly applicable to this drug class. And when we think about characterizing the retreatment parameters and ultimately the response over time, a design such as has been used within the development program certainly seems to be a good precedent and something we would look to.
In terms of using other doses or dose levels in the study, that's something, you know, we'll reserve final determinations of how we design the studies and the appropriate controls as we go to in the phase 2 meeting. But in our view, the data we have generated here really put to the side any arguments about whether a placebo-controlled study is the right study design or appropriate controls. The concept of using an alternate control with psychedelics is sort of emblematic of this exceptionalism that happens with this drug class at times, where virtually every CNS drug has a degree of functional unblinding. You only have to look as far as Spravato to understand that the incidence of dissociative effects are such that there was clear functional unblinding.
The same would be true for psychostimulants, for SRIs, for benzodiazepines, for that matter, that are approved in GAD, all of which have perceptual effects that could lead to functional unblinding. Here, the biggest concern, of course, is, and this is highlighted in FDA's guidance, that an expectancy and a performance bias could be mediated through, through being mediated by functional unblinding, lead to a nocebo effect. And by stripping back any of that therapeutic surround and prep and integration that has been done by virtually all other programs in the drug class, you know, our belief is that those activities serve to reinforce a performance or expectancy bias.
By eliminating those, we're able to get a truer estimate of the drug's 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 gold standard for all research is placebo-controlled head-to-head design. Certainly we're, you know, 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 of drug versus a high dose of drug, because then we're put in a position where we're trying to show superiority within what could ultimately be a therapeutic range. We even saw, you know, a slight statistically significant response in the 25 microgram dose group at one week. So we wouldn't do studies with any other drugs in psychiatry, where we compare a high dose with a low dose and try to demonstrate superiority statistically. Not something 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 in functional unblinding, there are opportunities to do that.
Doses like we saw with 50 micrograms, there's a clear in the AE table that there was a higher incidence of illusion and the other PD-associated drug effects on dosing day at even 25 and 50 micrograms. If we needed to include a small cohort, as a purported aid in functional unblinding, we could 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 a placebo, which is, again, the gold standard and been 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? You know, was that in the 8-10 hour predicted range? How that, how did that differ across the doses, and how does that affect how you think about logistics and staffing for administration in the future? Thanks.
Yeah, 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 were 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 maximal response to 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 timeframe, 8-10 hours at most, would be appropriate with this formulation. As we have a PK bridging study that is ongoing with our ODT formulation and certainly our hope with that formulation is that we'll be able to even further tighten up and perhaps even shorten that duration of the perceptual effects by potentially driving faster absorption, better bioavailability and less variability in the elimination phase. And 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.
Thanks again, and congrats again.
Great.
Thanks. Our next question comes from Charles Duncan with Cantor Fitzgerald. Please proceed.
Hey, good morning, Rob and team. Wanted to add my congratulations on the conduct of a really rigorous dose binding study and the robust results. So appreciate all the detail. Have a couple of questions. Thanks for taking them. 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, you know, I guess, practice of microdosing? Is that a non-issue going forward? And I imagine the agency will like to see that as well. Thanks.
Thanks so much, Charles. I'll turn it over to Dan to initially address your question, if you have to add anything on. Dan?
Hey, good morning. So what we did in the study inclusion/exclusion criteria was to exclude, you know, have an exclusion criteria around 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, you know, 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 me to take the second one, or do you want that one?
Yeah, go, go, go ahead, please.
Charles, can you give me that one one more time?
Yeah, yeah. Regarding the, you know, dose, call it the dose response. Yeah.
Yeah. So, you know, the point of the doses that were selected was to reach a plateau, right? We wanted to be sure that we dosed high enough, that we answered the question, have 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, you know, not statistically significant differences between the groups, but some evidence that there is an underperformance in the 200 microgram dose group, may represent that level historically has been associated with perhaps some more challenging experiences during the,
... during the experience, that may mitigate some of the positive experience during the study. Now, again, you know, 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 3, can you give us a sense of sizing? I mean, you have a really notable Cohen's d effect size. So give us a sense of timing, and I assume that it's going to be one particular dose that you use. You mentioned 100, but any other changes with regard to endpoint or, you know, time to evaluate that endpoint? And then will the ODT be ready for that phase 3?
Yeah. Thanks so much, Charles. So in terms of phase 3 design, you're right. Of course, we'll reserve the final determination of the study design and the size and everything for when we have an end-of-phase 2 meeting, and certainly look forward to sharing those specifics when we get to that point in the first half of next year. You know, 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, it implies incredibly small studies in the scope of a phase 3 development program. We also, of course, have an expectation we'll need to get to a number of overall exposures in the phase 3 and overall development program to support a marketing application, have an appropriately sized safety database.
So many factors will go into that, in addition to, like, other potential indications and studies that we can pursue. We've seen some really promising results here in anxiety that could have implications and read through to depression ultimately. So as we scope 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 2 program and believe we'll continue to be able to execute these. We enrolled the majority of this study in just over six months, and the entirety of the study in just over 12 months.
So, we want to make sure, you know, there are millions of patients in need, and we have shown the ability to really execute efficiently and set the 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 and want to make sure that our, the scope of our program and such can be very efficient and quick to bring these patients a new treatment option.
That's helpful. Final question for you or Schond. Can you remind us of the intellectual property behind MM120, and have you made any observations within this study that you would consider to be a surprise or not obvious observations that may even further strengthen or bolster that IP?
Yeah, absolutely, and I'll dovetail that with a part of your last question that I didn't answer about the Zydis ODT. We absolutely will have the Zydis ODT formulation ready for our phase 3 study. Virtually all of the preparations for the phase 3 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 3 program. We'll have the phase 1 PK bridging study results in the first quarter of next year as well, to inform the precise dose selection and progress in that formulation into the clinic in phase 3. But that also dovetails nicely with your last question about intellectual property.
We have certainly, both through our PK bridging study and the phase 2 study, 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 in the performance of the ultimate commercial formulation we intend to pursue. Our intellectual property portfolio, you know, is many layered. We believe we have a differentiated drug product, a differentiated number of applications that would be incredibly difficult to replicate. And unlike, you know, a very simple formulation that relies on a narrow API patent, 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, LSD has never been approved before. We expect that it would be eligible for 5 years marketing exclusivity, and certainly believe we'll have a number of patents listable in the Orange Book and a patent protection that, if granted and successful, would not start expiring until 2042. So puts us in a very strong position in our view, and we're really excited to share even more as we progress in the next couple of quarters.
Thanks, Rob. Very nicely presented results. Appreciate taking the questions.
Thanks, Charles.
The next question comes from François Brisebois with Oppenheimer. Please proceed.
Sorry, thanks for taking the questions, and congrats, you know, very, very strategic dose-ranging study. Well done. So I was just wondering, in terms of the durability, you mentioned confidence in durability lasting to, you know, to 8 weeks and then going to 12 weeks. Can you just help us understand a little bit why you, you're confident that this, this could last that long? Thank you.
Yeah, 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 two, and then measurable at the earliest possible time point, week one, on a Hamilton Anxiety Scale. With several other studies, that initial response starts to revert back to the mean after the course of just two or three weeks. Not so in this study. And when we talk to our key opinion leaders, you know, their view is that the differential in 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 set psychological processing and learning, and we know that that's both longer with LSD and from a number of historical studies, LSD has been the most researched compound in the class for a reason, in our view. And there's a ton of reason to believe that we'd see durable effects out to that duration. When we also look at things like, you know, blinded 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 molecules in the class, it appears that there is something quite different about the durability and the magnitude of response. We lost no clinical response through four weeks of treatment. Certainly believe that flatlining of significantly reduced anxiety symptoms will persist for weeks longer. We also have an investigator-initiated study conducted by our colleagues over in Switzerland that demonstrated six months of activity. So we believe there's significant upside in terms of how much longer this drug could show and perform in terms of anxiolytic effects.
That's great. Thank you very much, and congrats again.
Thanks, Frank.
The next question comes from Sumant Kulkarni with Canaccord. Please proceed.
Good morning. Nice to see this data set, and thanks for taking my questions. So in your phase three trial protocol, do you expect to have a specific retreatment component, and what about potential use of background medication?
Yeah, thanks so much, Sumant. In terms of the retreatment component, again, I think that's something we'll certainly be discussing with the agency as we go into phase two. When we look at other drugs in phase three, in this drug class, we've seen a few different approaches to definition of retreatment parameters. But when we look more broadly, I mentioned the Sage Biogen psilocybin program, where, in that program, a 12-week randomized controlled study followed by a variable duration ongoing screening, monitoring of patients, and then based on a relapse or the ability to hit screening a screening threshold, patients were then eligible for retreatment.
From what we know out in the real world, there's a large compassionate use program over in Switzerland where patients are regularly administered LSD to treat anxiety, depression, and other disorders. You know, our view is that this is not a drug that we expect to be delivered on a 6-interval basis. And that really leads to sort of an episodic intervention, which is what. In our view, this is the new wave of psychiatric treatments are more interventional and less as a chronic daily or fixed interval treatment regimen. So when we think about the phase 3 development program, certainly we want to adequately define and characterize what occurs upon retreatment to define the interval between the recommended interval to maintain effects and 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 8-12 weeks. If we're seeing 3 months of effect after a single dose, it's very difficult to do placebo-controlled research, even beyond 1 month for highly anxious patients who are markedly ill and are tapered off of concomitant medications. To ask those patients to stay off of any treatment for months on end is very difficult and ethically tenuous at times.
We're really going to be exploring ways that we can ensure patient safety, that we can ensure a good ethical conduct and design of these studies, but also characterize all the parameters that FDA is asking so we can inform prescribing information for this product if it's ultimately approved.
Thanks. You've given a wealth of data here in all your slides, so thanks for that. What is the typical MADRS score for a patient with GAD, and how does that compare with the baseline level of MADRS scores you saw in the patients with GAD in this trial?
In terms of MADRS scores? Yeah, the baseline MADRS scores were in the mid-20s in these patients, and this is typical. In both studies of anxiety, it 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 the MADRS. Item four on the HAM-A is depressed mood. So it would be virtually impossible for patients in an anxiety study to not also score so 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 the patients are not in a major depressive episode. But we did still, like, like with depression studies, patients in depression studies typically score 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 scores that are around 30, and the HAM-A is a 0 to 56 scale, and we saw MADRS scores that were in the mid-20s. And of course, saw almost 20 unit changes in both, in the MADRS scale and over 20-point change in the HAM-A after week 4.
Got it. Thank you.
Thanks, Mark.
The next question comes from Patrick Trucchio with H.C. Wainwright. Please proceed.
Thanks. Good morning, and again, congrats on the data result 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 not or became non-responsive 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, 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?
Yeah. Thanks so much, Patrick. I'll turn it over to Dan to answer your questions about baseline characteristics and improvement CGI-S.
Yeah, so these baseline CGI-S scores are largely consistent with the severity of illness we saw in the HAM-A. So, you know, everything is sort of directionally in magnitude, consistent across the CGI-S scores. The rapid improvement in CGI-S is, of course, quite promising, so the day 2 improvement. And what we see is a sustained improvement in CGI-S through week 4, you know, with folks approaching borderline ill, which is really quite a great deal. You know, it's a 2-category crossing from the original score. We would expect to see that persist. I'm not sure that we would necessarily, you know, expect that to necessarily, you know, improve dramatically through the end of the study.
But at least, you know, we would expect persistence of that, the same, and for the same reasons, we'd expect persistence of the baseline HAM-A, as Rob described. So we kind of expect those to track together throughout the study.
Then just in terms of the baseline characteristics for these patients, were these the folks who, you know, did they fail standard of care, or were they non-responsive?
Yeah. 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%-40% had to be discontinued from a medication to enroll in the trial, which, you know, 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 SRIs 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 isn't 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 inefficacy or perceived side effect burden. So you know, even in psychiatry, particularly, seeking treatment is often driven by a perception of the efficacy of the treatment which is sought.
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 on medication and not sustaining adequate benefit, who had been on medication in the past and not sustained adequate benefit, or all three groups, really, 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, is, you know, could be moved into a Spravato-like paradigm? Or what changes, if any, to the existing infrastructure could be needed to accommodate MM120 administration?
Yeah, so-
Thanks, Patrick. Go ahead, Dan. Yeah, please.
Yeah, 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 payer-supported interventional psychiatry centers that may deliver Spravato and other interventional psychiatry treatments like TMS. So we very much see those as potential commercialization clinics for the delivery of MM120. We also see that because there's such a low physiological burden from MM120, so, you know, 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, you know, if we're successful in this, in places where psychotherapy can be delivered. That in reality, the requirements for monitoring someone undergoing MM120 treatment aren't really different from what's required to deliver interpersonal, you know, 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.
Got it. Terrific. Thank you so much.
Patrick.
The next question comes from Elemer Piros, with Stock Block Securities. Please proceed.
Yes, good morning, Dan. Good morning, Rob. You know, what I'd like to maybe just touch upon is the observation that 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?
Rob, I'm happy. Go ahead, please. Yep.
Yeah. 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, you know, exceeding of those effect sizes, the response rates that we show here, where we're, you know, significantly greater than placebo on response and remission rates, compared to standard of care, that where you see a difference from placebo on response. And again, this is sort of pooled data and again, numbers that are defined, but you can think about maybe a 20% exceeding of response, of placebo response rate with standard of care and a 10%-20% exceeding of remission rate with standard of care.
Substantially lower numbers than what we're seeing here.
Yeah, I mean, this is remarkable. I just wanted to ask, Dan or Rob, that when you look at the depression scores, are you looking at the entire population, or you're looking at only patients who came in with a baseline score above a certain level?
We didn't enrich the depression score, the MADRS scores in any way. So what we-- well, obviously, we had a 20 cutoff, so 20 or higher on the HAM-A for enrollment and required 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 zero across all arms, please? How did you treat the data on some-
Yeah, so. Yeah, thanks so much, Elemer So, the discontinuations in the primary analysis, in our model, with a mixed imputation approach, certainly as we progress, have to provide some additional details there. In the secondary analyses, there were typically it presented another slide. The least squares mean was reported. That was an ANCOVA model, with baseline as a covariate. Depending on the endpoint, where in many instances we're reporting the actual observed values. And we'll, as we progress, we'll also be doing sensitivity analyses of different approaches for data imputation. But, given that the high degree of completion through week four, there's the expectation that any sort of sensitivity analyses would have very little, if any, impact on the ultimate outcomes we're observing here.
Yes. Thank you very much for confirming that. Thanks again.
Thank you. 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 spending 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. Have a great day.