Good day. Welcome to the top-line results from phase II IRIS study for ML-004 in autism spectrum disorder. At this time, all participants are on listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question, you will need to press star one one on your touch-tone phone. Please note this call is being recorded. I would like to turn the call over to Chris Kroeger, Co-founder and Chief Executive Officer at MapLight Therapeutics. Please go ahead. Good morning, everyone. Welcome. I'm Chris Kroeger, Co-founder and Chief Executive Officer of MapLight Therapeutics. Thank you for joining us today. With me is Erin Foff, our Chief Medical Officer, who will be walking you through the phase II data. Before we begin, I'd like to remind you that today's webcast contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements represent management's judgment as of today and may involve risks and uncertainties that could cause actual results to differ materially from those expressed and/or implied by those statements. For more information on such risks and uncertainties, please refer to our filings with the Securities and Exchange Commission, which are available from the SEC or on our corporate website. Any forward-looking statements represent our views as of today, June 22nd, 2026. This presentation only speaks of the date hereof. We don't undertake any duty to update. For today's call, I'll begin with high-level overview. Erin will take us through the phase II IRIS study results in detail. I'll follow that with some discussion of the unmet medical need and commercial opportunity and close with brief summary remarks before we open to Q&A. Let's start with a high-level summary of the ML-004 program and the efficacy and safety top-line results from the IRIS study. ML-004 is an immediate release, extended release reformulation of zolmitriptan, a 5-HT1B/1D agonist. We originally developed this approach based on optogenetic data demonstrating that activation of 5-HT1B receptors in the nucleus accumbens reproduced the prosocial effects of MDMA. As we evaluated zolmitriptan in animals, we found that it showed robust activity in preclinical models of both sociability and aggression. The effects on aggression are hypothesized to be the result of suppression of striatal D1 medium spiny neurons. Based on these findings, we designed the IRIS trial as an exploratory signal finding phase II study. That framing matters when interpreting these results. It was not a pivotal registrational trial, but rather was designed to generate clinically coherent, biologically plausible signals to guide the next stage of development. We designed the trial knowing we had strong preclinical data on both sociability and irritability. We wanted to explore both in IRIS. IRIS did not meet its primary endpoint, a caregiver-reported measure of social communication deficits in autism spectrum disorder. Social communication in autism is an indication with no approved pharmacologic therapies and no established treatment-sensitive outcome measures, nor a successful regulatory track record. The study did, however, demonstrate a compelling effect on irritability in ASD, and we believe the data supports a path forward in that indication. In the pre-specified, pre-planned adolescent subgroup with moderate to severe baseline irritability, defined as an ABI-C score of 16 or greater, ML-004 demonstrated clinically meaningful improvements on both the caregiver-reported ABC-I with an effect size of 1.33 and a nominal P-value of 0.013, and the clinician-rated CGI-I irritability scale with an effect size of 1.08 and a nominal P-value of 0.036. Those are two separate measures assessed by different raters showing consistent results. Treatment effects were greater among adolescents with higher levels of baseline irritability, an important pattern that Erin will elaborate on in more detail in a few slides. On safety, ML-004 was generally well-tolerated. There were no severe or serious adverse events in the active treatment arm. All of the serious and severe adverse events were in the placebo arm. There were no extrapyramidal events, and the rates of somnolence in adolescents were low. Mean weight gain was lower with ML-004 than with placebo. All of these are important elements of potential differentiation from the standard of care, atypical antipsychotics. Based on this data, we believe there is a clear development opportunity with ML-004 for the treatment of irritability in autism. Current standard of care for the treatment of irritability in ASD are aripiprazole and risperidone, two atypical antipsychotics, and these are the only two approved therapies for this indication. The effect sizes we have demonstrated are at or above those shown in clinical trials for these medications, and the tolerability of ML-004 suggests a potentially differentiated profile. No weight gain relative to placebo, no extrapyramidal events, and low rates of somnolence in adolescents. These are side effects that matter clinically, particularly for long-term use in this patient population. The regulatory pathway for irritability has been established with aripiprazole and risperidone approved using the ABC-I scale as their primary endpoint, a scale that we also used in IRIS. We have a clear understanding of the design requirements, the patient population, and the operational considerations for a subsequent study. Following our full data review, we expect to request an end-of-phase II meeting with the FDA to establish the subsequent development path. From a commercial perspective, we believe the total addressable market for irritability in autism is large, and the side effect profiles of the approved therapies create substantial challenges for patients and families, particularly in the adolescent population, resulting in a very high unmet medical need. Before Erin walks through the clinical data, I want to spend a moment on the preclinical science underlying the irritability signal we are reporting today. We knew before we designed the IRIS trial that improvement on irritability was a strong possibility based on what was demonstrated in animal models. Biological rationale begins with serotonin and the 5-HT1B receptor. Decreased serotonin or loss of 5-HT1B receptor function has been linked to aggression in both mice and humans across multiple studies. Conversely, increased serotonin or activation of 5-HT1B receptors inhibits the brain circuits associated with aggressive behavior. This slide shows the resident intruder aggression assay, a standard preclinical paradigm for measuring aggressive behavior in mice. The data show that zolmitriptan, the active pharmaceutical ingredient of ML-004, reduces aggression at clinically relevant exposures with an effect greater than that of risperidone, one of the two approved therapies to treat irritability in children with autism spectrum disorder. These findings establish the direct preclinical rationale for evaluating irritability-related behaviors in the IRIS study. The clinical results you will hear from Erin are consistent with what this preclinical data predicts. Now I'll turn it over to Erin to walk through the phase II results in detail. Thank you, Chris. I appreciate the opportunity to walk us through the study top line. IRIS was a multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy, safety, and tolerability of ML-004. 161 participants were randomized one to one to either ML-004 or placebo, resulting in 102 randomized adolescents aged 12 to 17 and 59 adults age 18 to 45. ML-004 was administered as a once-daily oral bilayer immediate release, extended release tablet with a flexible dosing paradigm. The target maintenance dose was 48 mg or 72 mg based on the weight and baseline contraceptive use. There was a 24 mg option that was permitted based on tolerability. The primary endpoint, as Chris mentioned, was change in the ABI-SC domain score from double-blind baseline to the end of maintenance dosing. Key secondary endpoints included the CGI-I global score, change from baseline in the ABI-C, and change in the ABC-I score from baseline to end of maintenance dosing in participants who entered the study with more than moderate irritability at baseline. I want to briefly underscore the design context, building on what Chris has already said. IRIS was explicitly an exploratory signal finding study. The primary outcome measure, the ABI-SC, had not demonstrated treatment response in prior clinical studies with other agents. The dosing regimen was untested. Importantly, success in this study was defined not by a single statistically significant result, but by whether the findings were internally consistent, independently corroborated, and grounded in a plausible biologic mechanism. That consideration is important as we go on to discuss the data. This slide summarizes the results across all primary and key secondary endpoints, starting with the primary endpoint. As noted, ML-004 did not achieve statistical separation from placebo on the ABI-SC social communication scale, either in the overall population nor across the by age subgroups. The CGI-I global score and the ABI-C clinician-rated scales measuring more global autism features also did not reach statistical separation. The results that really stand out are on the two irritability measures. On the care partner reported ABC-I in the total population with a baseline score greater than or equal to 16, which represents the key secondary endpoint, we observed a large effect size favoring treatment, although this didn't reach nominal statistical significance. The same impact was observed on the clinician-rated CGI-I irritability, also clinically meaningful, but again, not nominally statistically significant. However, in the pre-specified adolescent subgroup with significant baseline irritability, what we observed was more profound despite the small n. Both on the ABC-I and on the CGI-I irritability scale, this was observed, and I'll go into more detail on the numbers on the following slides. Importantly, across both of these measures, treatment effects were greater in participants with higher levels of baseline irritability, and I'll show you that pattern shortly. This slide shows the time course of the change from baseline in the pre-specified adolescent subgroup with clinically significant baseline irritability. A few things to note. Numerical improvement over placebo emerged early, and by visit seven, which represents approximately seven weeks of maintenance dosing and is roughly equivalent to the time point used in pivotal trials in this indication, there was a mean change from placebo of 7.2 points and an effect size of one. This effect was maintained, and by the end of the 12-week maintenance period, visit nine, the LS mean difference from placebo was 9.6 points with an effect size of 1.33 and a nominally statistically significant P-value. The increasing separation over time is biologically consistent. This isn't a flash separation seen early in treatment, but rather a signal that has grown across the maintenance period with increasing duration of treatment, and that pattern adds to the coherence of the finding. This slide is one of the most important in the deck. It shows the irritability results side by side across both measures. The ABC-I, which again is caregiver reported, and the CGI-I irritability, which is clinician rated in both the total population and the pre-specified adolescent subgroup. In the total population with an ABC-I greater than or equal to 16 at baseline, again, representing the key secondary endpoint. On the ABC-I scale, the effect size observed was 0.64, with a P-value of 0.131. The CGI-I irritability analysis resulted in an effect size of 0.61 and a P-value of 0.153. Neither of these results reach nominal statistical significance, but the effect sizes are meaningful in a sample of this size. In the pre-specified adolescent subgroup of 20 participants, the LS mean difference on the ABC-I scale is a substantial 9.6 points. The effect size now observed is 1.33, and there is a nominally statistically significant P-value of 0.013. Similarly, the CGI-I irritability showed an effect size of 1.08 with a nominally statistically significant P-value of 0.036. Two instruments, two rater types, one consistent conclusion. That internal consistency across these two assessments is a meaningful indicator of true drug effect. This slide shows the treatment effect stratified by increasing baseline irritability severity in the adolescent population. From an analysis of all adolescents who entered the study with a non-zero baseline ABC-I, to those with the most significant baseline irritability corresponding to a baseline score equal to or greater than 18. Importantly, the non-zero group includes 91 of the 102 enrolled adolescents. With this increased sample size, despite inclusion of some participants with minimal baseline symptoms, we still see a meaningful effect size of 0.4 and a near nominally statistically significant P. Importantly, the pattern we observe and which is shown here is consistent across both the ABC-I and the CGI-I irritability measures. As baseline severity increases, the treatment effect increases. This is evidenced by increasing effect size and thus a leftward shift of the forest plot, culminating in effect sizes on the ABC-I of greater than one. The CGI-I mirrors this pattern, reaching an effect size of 1.08 in the adolescents who entered the double-blind period with ABC-I scores indicating moderate to severe irritability. This kind of severity response is biologically plausible. Participants with the highest baseline burden have the most room to improve and may be the population where the drug's mechanism is most relevant. It also gives us clear pilot data that we can leverage in the design of future studies. Turning now to safety, the overall profile of ML-004 was generally favorable, particularly in adolescents. The majority of treatment-emergent adverse events were mild, transient, and resolved without need for dose reduction. There were no severe or serious adverse events in the ML-004 arm. All severe TEAEs and the single SAE occurred in the placebo arm. There were no deaths or life-threatening events. The most frequently reported adverse events overall were headache, nausea, somnolence, vomiting, fatigue, and dizziness. Adolescents experienced fewer TEAEs overall than adults, as shown here. Two adolescents, representing 3.9% of the enrolled population, discontinued secondary to a treatment-emergent adverse event, compared to zero in the placebo arm. Three specific observations are really worth highlighting here for the adolescent population. Regarding weight gain, the mean weight gain in the ML-004-treated adolescents was 1.1 kilograms versus 1.9 kilograms in the placebo arm. No adverse events related to weight gain were observed with ML-004. Regarding somnolence, the placebo-adjusted value was low at 11.8% in the adolescents. This is very relevant given the importance of school function and daily performance in this population. As expected, based on the mechanism of action, no extrapyramidal events were observed. These are the safety dimensions that are most clinically meaningful in the context of chronic treatment in adolescents. Notably, events that are classically associated and common with commercial zolmitriptan in the treatment of migraine, such as jaw or chest tightening and paresthesias, were rare, with only one case each, and there were no cardiovascular, cerebrovascular, or vasoactive safety signal. With that, I'm going to turn it back over to Chris to discuss the unmet medical need. Thanks, Erin. The unmet need in autism-associated irritability remains quite high. Irritability and aggression affects 20%-35% of the 830,000 adolescents with autism spectrum disorder in the United States. Roughly one in six adolescents with ASD is being treated with an antipsychotic. As we've mentioned, there are only two FDA-approved therapies for this indication, and both of these drugs are associated with significant side effects that impact adherence and compliance and carry warnings and precautions specific to the adolescent patient population. There are multiple challenges with the use of atypical antipsychotics to treat irritability. A significant proportion of autism patients with irritability don't respond to atypicals, so there's clearly a need for alternative therapeutics with non-dopaminergic mechanisms. Additionally, as we've mentioned already, the atypical antipsychotics are associated with very problematic side effects that often impede long-term use of the drugs. This, combined with the stigma of using an antipsychotic in patients without psychosis, leads to hesitancy to utilize this class amongst caregivers. The side effect profile for the two drugs approved for the treatment of irritability is substantial and is shown here in more detail with labeled warnings denoted. Both contain warnings for weight gain, with a significant proportion of patients with weight gain greater than 7% of total body weight. Both are associated with very high rates of sedation-related adverse events, which can profoundly impact school attendance and performance. Both have warnings for very concerning extrapyramidal symptoms and movement symptoms. Risperdal, the atypical with the most robust effect on irritability, is associated with hyperprolactinemia and gynecomastia. Both have warnings for orthostatic hypotension and both are associated with a spate of GI-related side effects. ML-004 has the potential to address the significant unmet need in this indication. The efficacy signal from the IRIS study was at or above that shown with Risperdal and aripiprazole on the ABC-I scale, while ML-004 avoids their multiple significant safety and tolerability liabilities. No meaningful weight gain, no EPS, and low rates of somnolence and sedation. As such, we believe that ML-004 represents a potentially attractive alternative to atypical antipsychotics for patients and caregivers. Importantly, the ABC-I scale on which ML-004 demonstrated meaningful benefit in our study has served as the primary efficacy endpoint supporting prior approvals for this indication. Additionally, clinical development in the space has historically been reasonably efficient, with approval and studies enrolling on the order of 100 patients. In closing, let me provide a brief summary before we move to Q&A. ML-004 demonstrated clinically meaningful improvements in irritability with effect sizes on par with current standard of care therapies across two independent scales, the ABC-I caregiver scale and the CGI-I clinician-rated scale of irritability. ML-004 was generally well-tolerated with no drug-related severe or serious adverse events, and importantly, was devoid of extrapyramidal symptoms and the significant weight gain associated with atypical antipsychotics and demonstrated meaningfully lower rates of fatigue and somnolence. Taken together, we believe these data support potential development of ML-004 for irritability associated with autism spectrum disorder, an indication with high unmet need and a clearly established regulatory path. IRIS would not have been possible without the participants and families who chose to be part of this research and the investigators who brought rigor and dedication to the study. We are grateful for their contributions and hopeful that those contributions will ultimately make a difference for the autism community. Before we open to Q&A, I want to briefly note that IRIS is one part of our broader pipeline. Our lead program, ML-007C-MA, an M1/M4 muscarinic agonist co-formulated with a peripherally acting anticholinergic, remains on track with top-line results from our phase II ZEPHYR trial in schizophrenia expected by mid-August 2026, while results for our phase II VISTA trial in Alzheimer's disease psychosis are expected in the second half of 2027. As mentioned previously, ML-004 will move toward an end of phase II FDA engagement. We will now open the call for questions. Thank you. As a reminder, if you'd like to ask a question, please press star one one. If your question has been answered and you'd like to remove yourself from the queue, press star one one again. Our first question comes from Paul Matteis with Stifel. Your line is open. Hey, thanks so much. This is Julian on for Paul. Appreciate you taking our questions. A few from us. Can you just talk a little bit about the threshold of 16 on the ABC-I and why that's important that you pre-specified for? Is that something that's common in the field for the approved drugs and thinking about how you plan on designing your phase III? One more question on this study. If there were other pre-specified analyses on secondary endpoints, can you just describe where this ranked, sort of the irritability score on the caregiver assessment among others? Did you have especially high hopes here? One really quick one on the schizophrenia program two. Can you just talk a little bit about previous comments as it relates to your ability to show less frequent or milder AEs versus Cobenfy in the phase II? Just curious if you've seen anything in the blinded data that's notable or if it's tracking as expected. Thank you. Erin, maybe you can address the first two questions, then I can address the ZEPHYR study. Erin, are you still on? Erin, you may be muted. I can jump in until Erin's able to join. With respect to 16 as the primary endpoint, 16, we pre-specified that 16 cutoff because that really is commonly perceived to be kind of the cutoff for moderate irritability in autism. That's why we chose the 16. We also showed the cut at 18. 18 is the cut for more severe irritability that was used in the approval studies for risperidone and aripiprazole. That's the reason why we showed both of those cuts of the data. I am not remembering what the second question was. Yeah. The second question was, I think you may have shown on the slide that there were some other pre-specified analyses on secondary endpoints. I'm just curious if this was one that you had specifically high hopes for or sort of where it ranked among your scientific hypotheses for this study. Yeah. Just the primary was social communication deficit. The two other secondaries were really kind of broad scales that holistically evaluate autism. Then irritability was a third. I think, we have been clear from the very beginning with this program that irritability was an important secondary. I think we've always couched this as a study to evaluate both sociability and irritability. We have very strong preclinical data as we walk through for irritability and aggression. I think our view is that this study didn't uncover an irritability signal. It really confirmed an irritability signal. This was always a very important secondary for us. I think we had always viewed the two potential outcomes here. One was an improvement in sociability. A large market really affects the entirety of the autism patient population. Bigger commercial opportunity, larger unmet need, no demonstrated regulatory path to approval. Nothing's been approved for social communication deficit. There is not a scale measure that has been definitively shown to demonstrate movement on social communication. Social communication's obviously also a much more complex kind of circuit biology than is aggression and irritability. On the irritability side, our sense was very large unmet medical need given the challenges with the existing therapies, a smaller opportunity than the broader social communication mark. It also has the benefit of a clear regulatory path since there are precedent-approved drugs with the ABC-I. Typically, kind of a more efficient development path going forward since the studies for approval, precedent studies have really typically been on the order of 100 patients. Very much a key secondary for us really as we design the study. Not something that we looked at retrospectively at all. Turning to the ZEPHYR study, we're still blinded to the data, we can't really say much there. I think what we can say is we had an attractive safety and tolerability profile in the phase I. We're not seeing anything that's inconsistent with that in the blinded data so far. If we look at all-cause early termination rates, those are at or below our expectations going into the study, again, blinded. Thanks so much, Chris. Sure. Thanks for the question. Thank you. Our next question comes from Andrew Tsai with Jefferies. Your line is open. Hey, guys. This is John on for Andrew. Thank you so much for taking our question. As far as next steps, you'll talk to the FDA soon. When could we possibly expect an outcome? Is your goal of running kind of like a phase II-B next similar to ZEPHYR or VISTA or possibly even running just pivotal phase III studies? Thanks. Yeah, thanks for the question. I think first things first, we need to complete the comprehensive dataset review. Again, this is just top-line data. We're still waiting for the full dataset, efficacy data, safety data, subgroup analysis, exposure response, et cetera. Once we have the totality of that data, we'll request an end-of-phase II meeting with the FDA, and really the outcome of that, we hope, will be kind of clear direction on population endpoints, ultimately study size and design and the evidentiary requirements. Once we have all those, we'll make a decision about next steps with respect to definitively sizing and powering a study which I think would likely be a registrational study, but again, will be dependent on the outcome of both the data and the regulatory interaction. Obviously once we know what the study will need to look like, we can assess the risk-adjusted probability of success of that study against the full potential commercial opportunity here and balance that against the opportunity costs of spend on the rest of the portfolio. Great. Thanks so much. Thank you. Our next question comes from Sean Laaman with Morgan Stanley. Your line is open. Good morning, Chris. Hope you're well, and thanks for taking my questions. How should we reconcile the failed primary endpoint social communication with the strong irritability signal? Is it your interpretation that ML-004 simply does not have meaningful activity on social communication, or that the ABI S ocial Communication endpoint was not sensitive enough in the phase II setting? Yeah. Thanks for the question, Sean. I don't know if Erin is back on. She could answer the endpoint question. Let me know if you are, Erin. I am. Okay. Why don't I address maybe the mechanistic side of things first, and then you can address the endpoint side of things. From a mechanistic perspective, we started out with the concept that modulating the dorsal raphe to nucleus accumbens circuitry would be important for modulating sociability. That was clearly true in animal models, but making the jump from animal models to humans is always complex, but particularly complex here given the numerous various circuits that interrelate to ultimately drive social reward and social interaction. The effects of 5-HT1B on aggression really are different, we think. We hypothesize that it's probably a subset of D1 medium spiny neurons that are affected, that drive that reduction in aggression. We do think there's a reason to believe that there are different circuits that are being affected, and that sociability is clearly a very complex set of interactions and maybe ultimately quite difficult to impact in humans. Maybe, Erin, you can speak to the endpoint. Sure. Yeah. Regarding the question as to whether or not this was a failed endpoint for the ABI-SC or failed effect on social communication, I think the jury is still a bit out on that. The ABI-SC is, in essence, although not novel, it's an unproven endpoint. There really is no gold standard in social communication and nothing that has shown treatment response in the past. It was developed as a scale with face validity and internal validation in concert with the FDA. We had high hopes for that, but it, of course, has not reported out positively in other trials that were started contemporaneously with ours. That being said, we had a number of other social communication endpoints in the trial, more traditional measures that include those outputs, such as the SRS, the Vineland. We are still analyzing that data. We did have an objective measure of a social preference in eye tracking that was an exploratory measure, and we are still sort of wading through that data as well, in addition to some concordance analyses that will help us understand if there is any underlying signal there. I think the sort of short then answer to what has been a long-winded explanation is just that we don't yet know whether or not this was a failed endpoint or whether there is some signal of effect. Got you. Thank you. Can I just squeeze in, what were the absolute ABC-I changes in each arm? Let me get that exact number for you. I might need to come back to you, Sean, on that. Yeah. No problem, Erin. shortly after another call. Yep. Thanks for answering my questions. Sure. Thank you. Our next question comes from Marc Goodman with Leerink. Your line is open. Hi. Good morning, everyone. This is Alyssa in for Marc. Thank you for taking my question. Just a few from us. Based on the results, how are you thinking about the optimal patient population for a future study? Specifically, do you think you'd consider restricting enrollment in adolescents with the higher baseline irritability, or do you still see the rationale for a broader patient population in either age or irritability baseline scores? Then secondly, on the flexible dosing design, can you provide more detail on the actual dose distribution in the study? And how many patients or how many participants escalated or remained on the 24 mg option versus the weight-based option? Thank you. Erin, do you want to address those? Yes. Regarding selecting the population I think the data is telling us that the signal is strongest in adolescents. I think, it's reasonable for us to be on a path to consider restricting the population to adolescents in the next study. Of course, we'll dig a bit deeper into the study data to ensure that that's the right path. In terms of what is the appropriate baseline severity, the registrational studies in this field have always used 18 as a cutoff to indicate that moderate to severe irritability. Of course, the approvals for the indication don't restrict to just moderate to severe. The indication approval is simply for the treatment of irritability in autism. We are seeing an effect even in the participants with less severe irritability, and there is a clinical acceptance that 13 and above represents clinically significant irritability. I think it'll involve a deeper dive of the exposure response analysis in the study for us to fully land on what the appropriate baseline irritability score is and consider some of the operational considerations of difficulty or ease of enrolling participants into the trial. The older antipsychotics came into a field in which there wasn't approved therapies, and so now restricting to a much more severe population could make it more difficult to enroll because those patients are exactly the ones that are potentially on baseline therapy, even if it comes with liabilities. I'm sorry, what was the second question again? Dose- Oh, dose response. Right. Okay, great. Thank you. We haven't released the specific numbers on that. What I can tell you is that the vast majority of participants were able to escalate to their target dose, and the target dose was based on their baseline weight and whether or not they were on oral contraceptives. Most of them were able to escalate to those doses and remain on those doses. We did have a small proportion of participants that did make use of drop-down doses, but the maintenance dose was the most commonly used dose, and most participants were able to tolerate that. Thank you. Thank you. Our next question comes from Ash Verma with UBS. Your line is open. Hi. This is Huayan for Ash. Our question is, I know there are different programs and molecules, but do you think there's any read-across to your other programs, such as the efficacy or safety in the ongoing ML-007 schizophrenia trial? I'm sorry. I think maybe could you repeat the question? Sure. Although there are different molecules, do you think there's any read-across from this result to your other programs, such as the ML-007 schizophrenia trial? No. I don't think there's any read-across. Different molecule, different mechanism, different trial. Thank you. Our next question comes from Joseph Thome with TD Cowen. Your line is open. Hi there. Good morning. Thank you for taking my questions. Maybe for a future study, how do you see the need to maybe show non-inferiority, or maybe even superiority against risperidone or aripiprazole? Do you just plan to do a placebo control? Just thinking about what the FDA might want or what you think might be helpful from a commercial perspective. Maybe second, why specifically do you believe that the impact is seen in the adolescent age group? Is it a time range where irritability is highest in autism, or are these symptoms maybe just easier to capture on scales at this age? Any thoughts around that would be helpful. Thank you. Yeah, I can tackle the non-inferiority and then the adolescents. Certainly there's no regulatory expectation and will not be for our comparative trial or non-inferiority trial. The FDA is well aware of the liabilities of the current study, just in terms of regulatory guidance for demonstration of efficacy and safety for a drug, it'll just be a simple placebo-controlled trial for registrational purposes. Whether or not we decide to pursue any sort of comparative work in phase IV or switch work, for example, we certainly can discuss the program development. In terms of why the adolescents, we actually came into the study assuming both on social communication and on irritability, that there may be a stronger signal in adolescents. There's actually some biological underpinning. There may be more impact of serotonergic modulation in adolescents. Beyond that, there's just a very practical consideration in a trial like this. Adolescents are surrounded by parents, by teachers. The ability to observe change in these participants is just heightened given the number of reporters and eyes on these patients. Adults with ASD, particularly in this trial, were largely living independently. Most were not in group homes. There is just a potential for less of an ability to get accurate reporting of symptom change particularly in people for whom the social burden and reporting might be impaired. Great. Thank you very much. Sure. Maybe I can just also just add on to that. The end was obviously small. There was a little bit of a bias in the adult patient population with patients with an ABC-I greater than 16, which is the cutoff. There was an imbalance with lower rates in the active arm than in placebo. That's number one. In terms of biologic rationale that Erin had mentioned, there is preclinical animal model data suggesting that younger adolescent mice respond to 5-HT1B reduction in aggression, whereas older mice don't. There is some preclinical suggestion underpinning the adolescent response rather than the adult response, in addition to the reporter bias and the baseline entry demographics. Thank you. Our next question comes from Sumaira Zamurrad with Canaccord. Your line is open. Hi, everyone. Thank you. This is Sumaira on for Sumant. Just a couple from us. The first one is when you look at the efficacy and safety comparison with other and current antipsychotics, what do you think about placement for ML-004 as first-line or second-line eventually? Sorry if you may have answered this already, but how do you mechanistically think about or explain a reduction in irritability, but it not translating as well into social communication? Will the core positioning be solely based on ASD irritability for ML-004? Thank you so much. Yeah. With respect to the first question, I think we still need to do a fair bit of work to fully understand that. Clearly, what we see so far from the data is a robust effect size at or above that shown with the atypical antipsychotic and a safety profile that appears to be dramatically better. I think clear differentiation and clear potential to be first-line therapy. Obviously, the existing therapies are generic, I think it'll take a little bit of time. Probably there'll be step edits required at entry into the market, assume over time, I think the obvious potential benefit of a drug like this would move it to first line. Sorry, what was the other question? If you could repeat it for me, please. Yeah, sure. We were just asking how do you mechanistically think or explain a reduction in irritability, but it not translating into improvement in social communication, considering that the neural networks for both processes are connected? Will the core positioning for ML-004 be solely based on ASD irritability? Yeah. I do think, obviously, we need to get the full data set and fully understand all the concordance of all the other measures that Erin had mentioned. I think once we have all that, we can make a decision. I think the primary thrust of our future clinical development will likely be in autism irritability. We may explore some sociability endpoints going forward. Clearly the strong signal here is in the irritability and the clear regulatory path and the size of the clinical trials make that a likely attractive development path going forward. With respect to hitting on irritability and not seeing an effect on sociability, again, I think it comes down to the complexity, right? We have a circuit rationale for social communication deficit, which is modulation of the dorsal raphe and nucleus accumbens circuit. That clearly was sufficient in multiple different animal models. Social interaction is a very complex behavior involving both social reward and feedback. The complexity of that may just be difficult to modulate in a meaningful way in a heterogeneous population in humans. We do think that the circuitry is different for aggression. It really is a subset of D1 medium spiny neurons within the striatum that respond to serotonin to reduce aggression. I think at least that's the hypothesis. I do think we think there's a different mechanistic rationale for the two effects. Okay. Thank you so much. Thank you. We will now take our last question from Ami Fadia with Needham & Company. Your line is open. Hi, this is Poorna on for Ami. Thank you for taking our question. Could you elaborate on what the response rate on the ABC-I and CGI-I for the adolescent subset population was? Could you provide additional color on the discontinuation seen in the adolescents? What were the AEs which resulted in those discontinuations? Thank you so much. Erin, do you want to take that? Sure. I'm sorry, the first part of the question was cut off for me. Could you repeat that first part? It was really responder analysis. Responder analysis. Yeah. We are still in the process of doing our full responder analysis and our exposure response analysis. Stay tuned for that. In terms of the age of the discontinuations of the two participants, I don't have that handy exactly at this moment. Sorry. I didn't ask the age. I was asking what the AEs were which resulted in those discontinuations. The AEs. Thank you. Sorry, the sound was a bit cut off. I believe one of them was secondary to a headache and one was secondary to somnolence. Got it. Thank you. Thank you. This concludes the question and answer session. I'd like to turn the call back over to Chris Kroeger for closing remarks. I just want to thank everybody for joining us today and appreciate everyone's questions. Thank you for your participation. You may now disconnect. Everyone, have a great day.