Hello, everyone, and welcome back to H.C. Wainwright's 28th Annual Global Investment Conference, held on September 14- 16, 2026. My name is Patrick Trucchio. I'm a Senior Healthcare Analyst at H.C. Wainwright. It's my pleasure to introduce Amit Etkin, CEO of Alto Neuroscience. Alto is a clinical-stage biopharmaceutical company that's pioneering a Precision Psychiatry Platform approach that uses electroencephalography and other objective biomarkers to match patients with the right treatment across major neuropsychiatric disorders. Alto's lead program, ALTO-207, is advancing through a three-trial PACE program in treatment-resistant depression with top-line data from Pace one, the phase II-B adjunctive trial expected in the second half of 2027. Pace two, a phase III adjunctive trial, is initiating by early 2027, and Pace three, a phase III monotherapy trial, is set to initiate in the second half of 2027. Behind this program, phase II-B top-line data for ALTO-300 in MDD are expected in the first half of 2027, ALTO-100 in bipolar depression in mid-2027. Amit, it's a very busy time for the company. Thank you so much for joining us. Maybe for those who are less familiar with the story, you can introduce them to Alto and the platform and the lead programs. Yeah. So pleasure to join you here. Alto Neuroscience is a late-stage psychiatric drug developer. We focus on areas like treatment-resistant depression, bipolar depression, and a range of related conditions. Everything that we've done centers around trying to understand in a much more biological and mechanistic way, what are the right targets in psychiatry? How do we show that our drugs engage those targets using biological tools? Ultimately, how do we find the right patients to be able to get larger effects? Because really, nothing has moved much in our field for decades across either the diversity of treatments or their efficacy. We have three programs right now in phase II-B trials, as Patrick was mentioning, also one transitioning to phase III soon. Those are ALTO-207, which is a dopamine agonist, direct agonist strategy, ALTO-300, which is a melatonergic and serotonergic strategy, and ALTO-100, which is a neuroplasticity-focused strategy. Great. Maybe we will jump right into ALTO-207. This is a fixed-dose combination of pramipexole and ondansetron. Why each of these two drugs? Maybe you could talk about the history of these drugs, and why administering them together as a single fixed dose product give you confidence that dosing them separately would not have? Yeah. Let us start with why mechanistically even focus in this way on direct dopamine agonism, in this case, treatment-resistant depression. We have known, obviously in general terms, dopamine is important for reward, and it is important for depression. We have actually found that the patients with treatment-resistant depression are even more enriched for a hypodopaminergic phenotype. In other words, would potentially benefit even more so from enhancing dopamine signaling. Well, that is what pramipexole does, focusing in particular on the D3 dopamine receptor. It has evidence going back to 2000 in randomized trials across multiple independent studies of consistent and outsized clinical efficacy, and that was really punctuated by a trial that was published in The Lancet Psychiatry last year, a trial called PAX-D, which used the drug adjunctively to standard of care in patients with treatment-resistant depression, showed an almost Cohen's d of 0.9 effect. That is three times the average successful drug in psychiatry. They carried it out for 48 weeks, so they showed it was very durable. But the problem is with pramipexole, and it is seen across all of these trials, is that frankly with any dopamine agonist, when you give more of it and you dose it faster, which is the kind of thing you need to do in depression as an acute treatment, you create nausea and vomiting in a substantial proportion of people that therefore becomes dose limiting. Chase Therapeutics, from who we acquired the fixed dose combination, showed that ondansetron, if given with pramipexole, greatly mitigates that nausea and vomiting, allowing you to dose much higher and much faster and be able to reach effect sizes in shorter periods of time that are even larger than what has been seen before. That becomes a really compelling opportunity. We then brought that in, and now it is in this phase II-B Pace one study designed like a pivotal trial. But on top of that, really fleshed out a lot more of the value proposition of ALTO-207. We developed a modified release formulation that better PK matches these two drugs. Pramipexole has a longer half-life, sticks around longer, so you want to make ondansetron come in and match that. We have a different titration approach. All of these things that really lead to what we think could be a very well-tolerated and effective drug, and the kind of thing that differentiates, therefore, from what is available right now, which the closest being an antipsychotic, which are partial agonists of the dopamine receptor, aren't that effective and carry a lot of side effect burden that pramipexole has really not shown things like metabolic effects, movement disorders, and so forth. Right. Can you talk about the PRIME-PRAXOL study and the PAX-D study in more detail? What were these studies, and how did they inform the PACE program? PAX-D is this The Lancet Psychiatry study I alluded to that was an adjunctive program in TRD. That's what our PACE program is modeled after. They took patients from the national health system in the U.K. It was nine sites, 150 patients with TRD. Run, frankly, as an academic study, but out of Oxford, but run like an industry study and had very robust results. PRIME-PRAXOL is a single-site study out of Lund, published Nature Medicine earlier this year, that took a little bit of a different approach. Rather than looking at patients with prominent depressive symptoms as a category, they looked at patients with specifically prominent anhedonia symptoms, so relatively less broad depression symptoms, much more focused on anhedonia. It was a shorter-term, nine week study, but showed the same thing, an effect size of over 0.6, Cohen's d of 0.6 on anhedonia. Keep in mind, antidepressants don't generally move anhedonia different from placebo. This is an area of tremendous need. Across the two studies, you see large effects on depression and anhedonia with PAX-D, large effects on anhedonia that even reach a Cohen's d of one in the MDD subset of that study. Really, really striking effects. All of that is an adjunctive use of the drug. In both cases, it was on top of standard of care. That told us a lot about where to start, not necessarily where to end, but where to start. That's why Pace one and Pace two are adjunctive programs in TRD, because as a psychiatrist, frankly, I'm not going to be taking a patient off a drug to put them on a new drug. I'm going to look for something that will treat their depression on top of their standard of care. We also recognize that as a primary care doctor or nurse, earlier stage prescriber, you'd be looking more for a monotherapy treatment, and maybe not as comfortable adding on to standard of care. That led us to add Pace three as a second phase III monotherapy study in treatment-resistant depression, so that now we can cover the entire spectrum of clinical use and frankly, the entire spectrum of prescribers out there with a drug that we think could have really a differentiated clinical profile. Pramipexole's constraint has always been tolerability, and nausea, I think, was even at 60% in PRIME-PRAXOL, even with that slow titration. That's right. How does the ondansetron component in ALTO-207 change the achievable dose? Maybe you could talk about some of the other methods you're using to improve tolerability. Yeah. So what has been shown in the phase I study that Chase ran is that by pairing the two, you could not only go five times faster than the pramipexole label, but you can reach a dose that is at least two and a half times higher. That combination of faster and higher gives you a lot to work with. What we have done across our modified release formulation and the particular custom titration schedule that we have developed is be able to guide patients essentially past the initial hump to a minimally effective dose and then quickly ramp up from there in order to maximize tolerability. We also do this with what will become a starter pack clinically. So it is a fixed titration pack. The doctor does not have to think about how they are going to titrate it. All of this was done thinking about the clinic in mind, that you want to get people to a higher target dose. Our current dose in the phase II-B includes 3.2 milligrams of pramipexole and 15 milligrams of ondansetron split twice a day. That 3.2 is higher than PAX-D, which was at 2.3 milligrams. So we are able to achieve a higher dose faster. The important part is we are thinking about how it will be used in the clinic and not creating burden for clinicians and figuring out how to titrate, how to avoid side effects, because all of that is already baked into our approach from the get-go. Right. Can you walk us through the PACE program and just sort of the reasoning for the design and the way it is? As I mentioned, it is based on the PAX-D design, and then the phase II-B is designed like a phase III, so it is powered well. 178 people randomized one-to-one to drug versus placebo, and that is an 80% power at a Cohen's d of 0.45. 0.45 is actually lower than what has been seen historically for pramipexole studies, but is where we think a very differentiated profile exists relative to everything else that is out there, both on the efficacy picture and especially on the anhedonia picture. So comfortable with a conservative powering relative to prior data. It is an eight week treatment duration, so very much looks like a lot of acute registration type studies. The phase III, we will have a discussion with the FDA in terms of the design and alignment on it being a phase III, aiming to start that study, PACE two, by early next year. There, we anticipate addition of a second drug arm, and that would be at a lower dose, so you get kind of a classic dose response assessment there, both on efficacy and tolerability, and then add an open label component to all of them. But those will all be 8-week duration acute trials, and we'll guide more to the specifics, obviously, once we have that discussion with FDA. Pace one, I believe, is powered 80% for Cohen's d of 0.45. That's right. You've already alluded to just sort of how you've come to this assumption, but how should we think about if the trial shows what you think it should show, how does this impact then, what would this mean for the phase III program, and how would this de-risk the program overall? The way we've designed it, the intent is to use it as part of support for the registration package across the phase II-B and the phase III. The phase III would be, we presume, more conservatively powered even still, so put us in a very strong position for being able to read out a consistent effect across these trials. Whether there will be opportunities with one trial to seek registration is, of course, impossible to know at this point. All of those policies keep evolving and changing, but at least it gives us the kind of study that can be used, certainly in support of registration together with a phase III. When do you anticipate you may have more details on Pace two and Pace three, and what exactly do you need from the FDA for Pace three? Is this just sort of dependent on the data that you see from Pace one, and how should we think about this? Yeah. That's an important question. We're not waiting for the readout of Pace one of the phase II-B study to inform Pace two, which is the phase III, for two reasons. One is that we know efficacy is already there from prior studies on pramipexole, so that's often one reason for waiting for a phase II-B. Then safety data will be submitted to FDA for the ongoing trial. Safety and efficacy are the two things that you need to know as you design your phase III. Because the design right now for Pace one is like a phase III design, we're anticipating mainly it's the addition of the lower dose arm that then is what we need to get alignment on, and of course, that the study is a phase III study with FDA. Pace three would come with an FDA interaction after that. We're focusing first on completing the Pace one and two package. That design we'll say more about, obviously, when we have that discussion, but could evolve further because at that point, you now have multiple different studies, somewhat different designs, informing different aspects of the registration questions around safety and efficacy at different doses. Right. Moving on to ALTO-300. This is the EEG biomarker selected, adjunctive antidepressant in Major Depressive Disorder. Top line data is first half of next year. What would a positive result establish for this asset and for the platform? A little bit of background. Agomelatine, ALTO-300, is a drug that is actually approved as an antidepressant monotherapy in Europe and in Australia. We are developing it here as an adjunctive treatment. Again, the goal is displacing antipsychotics. It is a drug that is very well tolerated and has a distinct mechanism of action. It stimulates melatonin receptors and blocks 5-HT2C receptors, which then secondarily leads to an increase in dopamine and norepinephrine. Has efficacy as an all-comer drug. That is how it was approved. What we have also done is found a potential biomarker here through EEG. We use the machine learning approach that we have developed and validated over the years to find EEG or other signals that tell us who are the most likely patients in terms of response, replicate that prospectively in an independent group of patients receiving the drug, and that is how we have stratified this study. A positive result would tell us two things. One is, does the drug have efficacy in an adjunctive population? It has actually never been tried in a randomized trial in an adjunctive population, so it is a really critical question. That opens up a path for the drug in an area where it would be quite welcome clinically. Can you further enrich using a biomarker for those patients with a larger clinical effect using EEG in this case? That could have benefit just in terms of the whole precision approach, but we think of it first and foremost in terms of the benefit of the drug for the patients who right now, as a psychiatrist, I am not eager to prescribe an antipsychotic for all of its side effects, and some very chronic side effects, would be a great option for them clinically. Great. ALTO-100, this is in bipolar depression. It targets neuroplasticity deficit, an indication where only antipsychotics are approved. I think the top line is mid-2027. What would you view as positive data in this program? Yeah, you can see the sort of go against antipsychotic theme here. In bipolar depression, as you mentioned, all they have are antipsychotics. Any treatment that's well-tolerated would be extremely welcome, let alone one that, in this case, is a potential first-in-class novel mechanism of action targeted specifically at enhancing neuroplasticity. So the ability of the brain to adapt and change, which we think is important for a subset of patients with major depression or bipolar depression. And here we're identifying that subset through a test of verbal memory. So learning and remembering lists of words, which relies on neuroplasticity as its basis. So a drug that enhances neuroplasticity for patients with impaired neuroplasticity, and there, a positive outcome would be phenomenal. These patients just do not have good options. The drug has historically been well-tolerated, and if, in fact, we see efficacy, especially in this population with impaired memory, which is quite prevalent in this population and predicts poor outcome itself, it gives us a great option to then move forward into phase III for bipolar disorder. Earlier this year, I think you introduced enhanced eligibility review and patient data quality procedures. This had the effect of pushing out the readouts for ALTO-100 and ALTO-300. It also, I think, removed 11% and 13% of patients from each of those programs. Can you talk about what the basis was for that change, and how should we think about it across the pipeline? Yeah. This change was really in response to what we saw in the ALTO-100 Phase II-B, which is a risk of professional patients as a site-level activity risk, that certain sites have a higher proclivity to let in patients who may not take your drug, may not have the disorder. And this is a risk that's frankly underappreciated across the field. And so we decided to do everything that we can, layering on top of what we were already doing, to do things like medical record, pharmacy checks, urine or blood tests for the underlying drug that these patients are taking in order to limit the potential for professional patients. The 11% and 13% that you cited are proportions of people who were removed during screening on those criteria, and that we've seen that then pay off. We have reported for ALTO-300 and ALTO-100 compliance rates at or close to 100%, really showing that this kind of approach now works and mitigates a risk in trial execution that is just pervasive across the field, certainly in psychiatry, and I am sure broadly. Beyond 207 and 300 and 100, there is 101 and several other pipeline programs. Do you have updates on any of those other programs? Yeah. Mainly ALTO-101 is a program, a PDE4 inhibitor, that we have reformulated and changed what usually is a very poorly tolerated mechanism, not just for our drug, but for all PDE4s, into a very well-tolerated extended release or modified release oral formulation. Then in a trial in schizophrenia, we used a transdermal formulation. We found evidence of engagement of brain targets that are important for cognitive disorders, schizophrenia, and disorders more broadly. Right now, our focus is primarily on 207, with focus additionally on 100 and 300. There we have talked about really looking for partnering to take something, in this case that takes a lot of work, a lot of time, especially in cognitive disorders, forward or other partnering opportunities there. But having a well-tolerated PDE4 is itself quite unique and really exciting to have within that pipeline. You covered a lot of ground in the pipeline. Is there anything about the pipeline that you think investors maybe are missing or need to be paying more attention to? Obviously, that differs by person. I think a lot of focus right now, reasonably so, is on ALTO-207, but that really means that there's two other studies that will read out next year that present important clinical opportunities and the ability to start phase III programs that may not be getting that much attention. That's ALTO-100 and 300. Even how we spend our time today speaks to that, and that's fine. We're happy to let that read out. Financially, we're in great shape right now. There's a lot of richness to this story that frankly, internally, has us really, really excited. Terrific. I think we have to leave it there. Amit, thank you so much. Thanks for joining us. My pleasure. Thanks for everyone for being at our conference. Have a great rest of your day and conference.