Hello everyone, welcome to the Seventh Annual H.C. Wainwright Neuro Perspectives Summit. My name is Patrick Trucchio. I am a Senior Healthcare Analyst at H.C. Wainwright. We have a robust agenda at the conference this year, with more than 25 companies presenting with their sessions available on demand through the conference portal. In addition, we are expecting a full day of panels and fireside chats with world-class KOLs on June 15th for the in-person portion of the conference, with a broad CNS development focus across multiple indications from depression, epilepsy to BBB delivery. With that, it is my pleasure to introduce our next speaker, Amit Etkin, CEO of Alto Neuroscience. Alto is a clinical stage biopharmaceutical company pioneering a precision psychiatry approach that uses electroencephalography, or EEG, and other objective biomarkers to match patients with the right treatment across major neuropsychiatric disorders. Today, our discussion will focus on Alto’s wholly-owned pipeline and biomarker platform. With that, maybe just to start, for those who are less familiar with the story, if you could give us a bit of background on the precision psychiatry platform and how you think about Alto today. Yeah. Look, take a big step back and ask just where psychiatry is, where psychiatry has been. Tremendous need in many, many areas. There is no doubt. There is areas with absolutely no treatments and areas with a lot of treatments, but they are really a lot of the same. Our problem has been that we have not known how to find the right mechanisms, how to target the right mechanisms for the right people, and ultimately how to go beyond what is basically phenomenology in describing disease, you have X, Y, and Z symptoms, to biology in describing disease. We use words like precision psychiatry to explain what we do, but ultimately I try to explain that what we are trying to do is essentially know what we are doing, is measure biology consistently in people that is informative for cognition, for mood, for whatever the disorder involves, understand how drugs change that, and then understand how to identify people based on that. Let me ground that in a little bit more granular terms. You mentioned EEG. EEG or brainwave recordings we get routinely across our trials. They tell us about brain activity. You can analyze the data in different ways, either ways that we already know or ways that are more data-driven, like a machine learning approach, to discover subgroups of people. For example, the ALTO-300 program targets a group of people where we use machine learning to discover an EEG signature that predicts response or as an outcome measure. We did that in the ALTO-101 program recently, which showed evidence of pro-cognitive signals across a number of EEG measures. We use other ways to characterize people. We characterize them based on cognitive measures. For example, with the ALTO-100 program, we have a characterization of neuroplasticity deficits in these patients for a pro neuroplasticity intervention. For ALTO-207, we're actually using clinical measures to enrich, to find that right target group because the clinical measures give you a proxy into the biology. For each program, we think of what the right way to understand what a drug does, understand who the people are to do that to, and then tailor the programs around that. Now in late clinical stage development, three drugs actively in the clinic right now in phase II-B and hopefully soon phase III studies. It's an extremely exciting time seeing what I hope will be a change in terms of efficacy, a change in terms of the kinds of mechanisms that we can bring to the clinic and bring to patients, and frankly, an exciting time in neuroscience as a whole. Right. That's a great overview. Maybe kind of digging deeper on ALTO-207, maybe you can give us the background on this program and how it fits into the Alto pipeline. ALTO-207 is our lead program. It's a fixed-dose co-formulation of a dopamine D3 preferring full agonist called pramipexole and ondansetron, which is a 5-HT3 blocking antiemetic. The logic here behind dopamine and depression is one, of course, people heuristically understand. You think of dopamine and reward and motivation. We actually have, through our EEG biomarkers, found that the patients who are on the more resistant end of the depression spectrum, so treatment-resistant versus less resistant patients versus healthy people even further along, are then enriched on that resistant end for a hypodopaminergic phenotype through this EEG biomarker. Others have also argued that things like anhedonia, lack of pleasure linked to reductions in dopamine, are associated with treatment resistance. A direct agonist approach, stimulating dopamine in ways that, for example, an antipsychotic, which just slightly increases dopamine release levels when given at a low dose, cannot achieve, that really becomes the strategy of choice, backed up by a lot of clinical data I'll discuss in a minute. The problem is with that approach is that every dopamine agonist causes nausea and vomiting, and often, and very much the case for pramipexole, that limits the dose you can achieve and limits the speed with which you can achieve it. If you can't dose somebody quickly, that's really not going to work as an acute treatment in depression. The co-formulation here delivers pramipexole and blunts the nausea and vomiting effects so that we can dose a lot faster and a lot higher because prior work in numerous clinical trials now of pramipexole alone has shown not only outsized efficacy signals across the board, an average of a Cohen's d of around 0.64 when you look across all these trials in a meta-analysis. The recent really seminal work doing this at a higher dose has pointed to even higher efficacy. Here I'll note the PAX-D study, which was published last year in The Lancet Psychiatry, nine-site study out of the U.K. in clearly treatment-resistant patients achieved almost Cohen's d of 0.9, so about 7.4 delta equivalent on the MADRS. That's a huge signal however you cut it. The fact that we can use a clinical measure to identify those people and now tailor our intervention solution to deal with the main thing holding back the ability to use a dopamine agonist makes this a really exciting program. It's a phase II-B. The program right now is in a phase II-B that launched in early Q2, and that's guided to read out second half of 2027. We anticipate starting, assuming we have regulatory alignment with FDA, a phase III program by early 2027. There's so much known about the efficacy signal, and it is such a large signal, it's really just a question of have we gotten the tolerability right, which we'll be able to understand even while the phase II-B is running, so that we can start a phase III earlier, get this thing on the market, and benefit patients as soon as we can. Yeah, that's really helpful. A bunch of follow-ups on that. The first is just on the PAX-D program. Maybe you could tell us more about that program and how it sort of created external validation for pramipexole in TRD, which parts of that data set are most related to the ALTO-207 program. Yeah. PAX-D, as I mentioned, 150 patients, it is actually not far from the size of our own phase II-B study at 178 patients. Very well-powered, diverse, well-documented depression population drawn out of the NHS in the U.K. They were treated with up to 2.5 mg of pramipexole. We are targeting a little bit higher than that, 3.2 mg. They were treated not only for an acute treatment period, which was for that study 12 weeks, and that achieved that almost 0.9 effect size, but they were continued on treatment randomized for 48 weeks, which is not something that we actually do almost ever in this field. People focus on do I do a six-week trial or eight-week trial, worried about effect sizes deteriorating. These guys went the whole way for almost a year, and the effect persisted the whole way. They saw massive effects across the board on anhedonia, which is a symptom that is not touched by other interventions out there. It is a huge unmet need. Suicidality decreased dramatically, work and functioning improved dramatically. This was actually seen across all the sites. Every single site had a numerical separation, which is, again, not something that you see across trials. Clear evidence of efficacy. Also clear evidence of the one limitation, which is nausea and vomiting. 20% of people dropped out due to AEs, predominantly nausea and vomiting in the drug arm, whereas 5% dropped out with placebo. That is the bogey that we are trying to hit in terms of tolerability to make this now a drug that is not its current form, as people try to use sometimes pramipexole off-label. There is a lot of hand-holding and titrating up and down slowly and challenging patients and backing down and so forth and make this something rather that a very wide prescriber base could use. Our study is like theirs, a TRD study. We follow exactly what they did in terms of the study design and the approach. We use an adjunctive treatment context, people come in on their antidepressant, and they continue that failed antidepressant, and ALTO-207 is added on top. That allows us to really be able to mimic as close as possible a very successful program. I should note that program is not an outlier. Chase Therapeutics, which developed this fixed-dose combination that we acquired the asset from, they did a small proof of concept trial, 32 patients, and they saw Cohen's d of 1.1, 8.2 points on the MADRS. There are consistent, very large signals. Given that base of evidence with PAX-D and the durability information, we felt that that was an important way to anchor our own development efforts. Yeah. That makes a lot of sense. Just on the phase II design choices for ALTO-207, just in terms of the TRD definition, I think it's two to five prior antidepressant failures. Just in terms of that decision as well as allowed background antidepressants, titration schedule, and just expectations around the primary endpoint, what are you looking to show there? Yeah. TRD is defined generally as two or more antidepressant failures. We capped it at five consistent with the esketamine program, just because once you are beyond that, they're quite variable in what they're actually getting, and you really run out of classes of interventions as well. There's something important I want to highlight there in that definition of TRD. I think when people have in their heads now what TRD means, it starts with esketamine and now increasingly things like psychedelics. Really on the far extreme of the failure spectrum, specialty, often interventional psychiatry clinics, maybe these folks are getting TMS or ECT. That is one end of the TRD spectrum. Actually, what we're trying to do here is capture a much broader range, labeled under TRD, but actually much more inclusive of the kinds of people, even in primary care, who are getting an adjunctive antipsychotic, for example. Generally speaking, insurance won't cover branded treatments unless they've failed at least one or two generic treatments, which already by two puts you into TRD, even though those patients may actually be seen in primary care or general adult psychiatry. Because the drug, unlike psychedelics, unlike esketamine, has no REMS program anticipated, has no dosing issues. It's something you take at home. It's a standard pill, get it from your corner pharmacy kind of intervention. We see the TRD landscape, if you translate it just back to the definition, as two or more treatment failures as representing a really broad range of patients aiming to displace adjunctive antipsychotics, not just drugs like esketamine, which themselves have been very successful. In terms of other aspects of the decision making, we power the study quite conservatively. It's 178 people, one-to-one randomization. The power here is at 80% power for Cohen's d effect size of 0.45. Maybe call it 4 points on the MADRS. The 50% power is close to 0.3. That puts us really at anywhere from standard of care on up, we'll be able to detect significance. The important thing is every single pramipexole study that's been reported in the past has an effect size that is large enough to yield statistical significance were we to see that effect size. That puts us in a really, really strong position. Of course, our goal is to show as high of an effect size as possible, but I think even if you think of where we're powered, that is a phenomenal outcome. That already puts you better than standard of care. As I mentioned earlier, the average effect in a meta-analysis across all doses, including many lower dose studies, was 0.64. If you see that's a home run scenario, let alone what PAX-D saw at almost 0.9 and what Chase saw at 1.1. Those are in the World Series kind of home run scenarios. A lot of outcomes that we could be really happy with. The way we're also delivering the drug is with a titration schedule that's already in essentially a blister pack form. Think of it as essentially in a trial doing what you would do commercially, which is a starter pack. That's important for two reasons. One is that it guides patients in sort of a custom pattern to the target dose to do it as tolerably as possible. That's important also for things like IP. Much more practically, that's the form that physicians will be giving to patients and not need to necessarily worry about how to titrate a somewhat complicated and custom titration. That makes it a lot easier for patients to get going on the drug to get to that right dose as quickly as possible, start seeing the benefit. Again, as you think of something that we're aiming will to span from primary care to specialty psych, makes it a lot easier for a lot of prescribers if there's a built-in starter pack there. Right. That's helpful. Maybe you can talk a little bit about the safety profile and tolerability. What would you consider win on that front? I think a great way to anchor tolerability is actually antipsychotic medication. If you look at lumateperone, the average discontinuation due to AEs is about 9% on average across the trials. Quetiapine's a little higher, Abilify is a little lower. Something in that range, I think is quite reasonable, obviously very commercially successful. I think that's a useful anchor point. I think less in terms of the rates of any particular adverse event and more in terms of do people drop out with the adverse events. That's important because one of the things that we're trying to manage is not just the nausea and vomiting early, right? That's what the co-formulation does and the titration schedule and so forth, but also later adverse events that can come up with pramipexole that are known over time. One of them, for example, somnolence, may be seen months thereafter, onset of that months thereafter. Can usually be readily managed with a dose titration down. That's in part why we settled on the dose target that we did, 3.2 mg with 15 mg of ondansetron. We have, by the way, a modified release formulation that PK matches these two components, again, further decreasing adverse events. By thinking about those long-term side effects, not just what you'd see in an acute treatment trial, and thinking about the target dose as one where you're going to optimize, maximize efficacy at that target dose, but still allow people to titrate down to deal with side effects and stay on the drug and still see its benefits, you want to make sure that you have enough range in your dose to still hit well into the therapeutic range or what we think is a therapeutic range while dealing with those adverse events. There's also pretty rare adverse events around what people have called impulse control disorders, which is essentially, look, if you're stimulating the reward system by stimulating dopamine, that's obviously a logical treatment for depression. In some people, that might be a little too much stimulation, and they may pursue rewarding activities more. Gambling, for example, being one that's been described in the past. It's not impulsivity like suicidality. That actually decreases dramatically. It seems that it's a lot less prevalent with depression than it is in Parkinson's, where the physiology of the dopamine system is very, very different. There was actually just recently a big nationwide registry study in Sweden published that showed that that rate was about 0.1% in depression. That's something that happens later, but PAX-D actually showed that there were two people who had that symptom essentially that could be managed also by dose titration down, and people continued the drug. Doctors will of course watch out for this. We're expecting it anyway to be in the label because it already is for pramipexole and aripiprazole and brexpiprazole. It's those kinds of things that by tuning where we are, I think we can optimize efficacy, long-term safety, and keep people on the drug that is delivering benefit in a unique way. That's the bottom line is do people like it and stay on it and continue to see benefit from it? I think all studies with pramipexole have really shown that that is the case, that even if you have a little bit of nausea or whatever in a person who's otherwise well-tolerating it, they will stay on the dose because they see benefit from it. That's helpful. I'd like to ask about some of the additional pipeline programs. First on ALTO-300. This program has a readout in the first half of 2027, I believe. Just want to confirm that. I guess maybe you can talk about the sort of the core pharmacologic and biomarker hypothesis and what are we looking for in that readout in the first half of next year? This is an antidepressant that is a unique mechanism. It's a melatonin agonist and a 5-HT2C antagonist. We know it's an antidepressant because it's actually approved as one, as a monotherapy in Europe and in Australia. We are doing is developing it here as an adjunctive treatment. Again, the comparison set here are antipsychotic medications, tons of side effects when you talk about antipsychotics, weight gain, metabolic effects, movement disorders. You can have tardives for years, maybe even your lifetime after taking even a short course of the drug. This drug doesn't have that. It's actually the single best tolerated based on meta-analysis, the single best tolerated antidepressant out there, but we're developing it as an adjunct. For us, there's a couple of important aspects of this program. One is the biomarker that we used. It was developed through machine learning applied to EEG, prospectively replicated, and though it was a data-driven signal, it turns out in understanding it that it actually relates directly to the drug mechanism. We actually showed that in both animals and humans. That selects people, and we'll also be looking at the whole population. The expectation here is because the drug has been approved in an all-comer context before in Europe, that probably it has efficacy in the all-comer population here, and then we'll see if whether it has additional efficacy in the biomarker-defined population. You can actually see across that and all the other programs how biomarkers differentially come into the mix. For ALTO-207, we're expecting large effects in the all-comer population because clinically it already enriches for that biomarker. With ALTO-300, we're expecting to see efficacy in the all-comer population and hopefully see additional efficacy in the biomarker-defined population, which would be an enrichment marker in that context on top of an all-comer approval. For ALTO-100, the expectation is probably efficacy is mostly or only within the biomarker-positive population, so that's more of like a companion diagnostic situation. Within our programs, you can even see an understanding of the regulatory strategy really laid out by FDA in their enrichment guidelines in 2019. What does the development path for ALTO-300 look like assuming a positive outcome next year? We would go to phase III. That obviously is a different timeline than the phase III program for 207. We are expecting 207 to be the commercial lead here, but it would come in alongside and give doctors another option. We actually get asked, if 207 is as successful in terms of efficacy as we hope to see it, what is the value of 300? Actually, there is quite a lot of value to 300 because of its tolerability, because of the profile in terms of potential unique effects on circadian rhythms through the melatonergic activation, effects on sleep that you actually don't see with other interventions writ large in the space. Really quite excited for the potentially new tool that a clinician would have in that now wide range of choices that they are looking at once the person has failed their first one or two antidepressants. ALTO-100 has moved into bipolar depression. What are the next steps for this program? That is just execution on the program and read it out. That, if successful, goes into a phase III program. Just briefly, ALTO-100 is a first-in-class mechanism. It stimulates neurotrophic pathways. We understand actually what its direct molecular target is. That has not been released beyond to say it is a G protein-coupled receptor. It has been of great interest to the field of plasticity for a long time, no clinical trials have targeted that target. The idea here is you are enhancing neuroplasticity for people with a deficit in neuroplasticity, and that is identified with a verbal memory test. Memory requires neuroplasticity as its basis. We have an easy, online, self-administered, validated test of memory that identifies these people who are then targeted. The option set for bipolar depression is very limited. It is just antipsychotic medications. That leaves a lot of room for opportunity, not only because they leave a lot of efficacy on the table, but also all the tolerability challenges, and this drug has been very well-tolerated historically. The prevalence of these kinds of impairments in bipolar disorder are around 40%-50% of the population, even higher, in fact, than in major depression, and associated with same kinds of things in both diagnoses, which is greater chronicity, greater impairment, and therefore become a really important, harder to treat population. Just briefly on ALTO-101, maybe tell us about this drug and next steps for the program. This is a brain-penetrant PDE4 inhibitor. We, of course, understand PDE4s elsewhere in the immune system where they've been quite successful. This one is aiming to improve a variety of brain circuit function relevant to cognition. There's two important things here. One is tolerability. All PDE4s have tremendous tolerability issues, nausea, vomiting, diarrhea being the most common, even when they're not brain-penetrant. What we did here is in two different ways, actually, modified the pharmacokinetic profile of the drug. We did that with a transdermal patch. That's what went into the proof of concept trial in cognition and schizophrenia just now, but also then developed later an oral modified release, in both cases, dramatically reducing these adverse events. We think we've actually solved, at least for this drug, this class-wide tolerability effect that creates a drug that could have uses across the body, not just in the brain. We saw signals on EEG, quite robust signals in areas of EEG measures relevant to neurocognitive disorders as a whole, relating to essentially brain excitability. Didn't really see so much in terms of robust signals on those much more specific for schizophrenia, and that points to probably utility across other aspects of the neurocognitive spectrum. Then we actually saw improvements in attention, even with only 10 days of dosing in this 83-patient study. Because of where things are with cost of capital right now, where we just raised funds not long ago for the ALTO-207, phase II-B, phase III, and ultimate NDA submission efforts to do the same thing, that cost of capital for a higher risk, long-term cognitive intervention, huge opportunity, but huge risks in that area, is not something we wanted to pursue at that time. We're looking for what the right way to advance a drug with clear signal. It is likely to be a drug, right? It's just a well-tolerated PDE4 alone, and that could be through partnering, that could be just through waiting. When our own cost of capital decreases, then we advance that program. Really excited for the results that we showed on both the brain and the tolerability fronts. Right. Just as a final question, we've talked about some of the big data updates that are expected over the next year or so, as we think about the key milestones that investors should look for to know that Alto is on the right track, whether it's trial starts, enrollments, maybe even presentations at academic conferences and so forth, what should we be looking for over the next 18- 24 months from Alto? Yeah. In that time, we'll have all of these trials read out. Those are obviously all going to be very major milestones. Even smaller milestones along the way, we've been talking about aiming to start the phase III study for 207 by early 2027. That means regulatory interactions to get alignment that we have a design and have it count as a phase III before then. We have data even before then that we'll be sending to regulators, looking at the role of different levels of ondansetron in blocking the adverse events with pramipexole and 207, and various other kinds of things. Then, of course, we take part in medical conferences on a routine basis, probably the next big one would be ACNP towards, well, early 2027. Some of these milestones that tell you you're on the path, as you were saying, we don't talk about exactly where we are in numbers in terms of recruitment, but certainly moving along, we generally report that we've finished enrollment for studies. That's an important marker along the way. All of that should be happening in the months to come. Exciting time. A lot of activity, a lot of late-stage activity that can give us really unique purview into what the clinic will look like in the next 5 - 10 years. Terrific. It's a really exciting time at Alto, so thank you so much to Amit and to Alto for attending the summit and the conference, and thanks for everyone else for being with us. Have a great rest of your day and conference. Thank you.