Alto Neuroscience, Inc. (ANRO) September 14, 2026 Conference Transcript

Hello, everyone, and welcome back to H.C. Wainwright's 28th Annual Global Investment Conference held on September 14th to 16th, 2026. My name is Patrick Trucchio. I'm a senior health care analyst at H.C. Wainwright. It's my pleasure to introduce Amir Ekin, CEO of Alto Neuroscience. Alto is a clinical stage biopharmaceutical company that's pioneering a precision psychiatry 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 1, a Phase 2b adjunctive trial expected in the second half of 2027. PACE 2, a Phase 3 adjunctive trial is initiated by early 2027, and PACE 3, a Phase 3 monotherapy trial set to initiate in the second half of 2027. And behind this program, Phase 2b top-line data for ALTO 300 and MDD are expected in the first half of 2027, Alto 100, in bipolar depression in mid-2027. So I mean, 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. So 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. And 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, and 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. And so we have three programs right now in Phase IIb trials, as Patrick was mentioning, also one transitioning to Phase III soon. And those are Alto 207, which is a dopamine agonist, direct agonist strategy. Alto 300, which is a melatonergic and serotonergic strategy. strategy, and ALTO-100, which is a neuroplasticity-focused strategy.

Great. Maybe we'll jump right into ALTO-207. So this is a fixed-dose combination of Pranopexil and Onsintron. Why each of these two drugs? Maybe you could talk about the history of these drugs, and why does administering them together as a single fixed-dose product give you confidence that dosing them separately would not have?

Yeah. So let's start with why mechanistically even focus in this way on direct dopamine agonism, in this case, treatment-resistant depression. We've known, obviously, in general terms, dopamine is important for reward. It's important for depression. We've 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's what Primapexol does, focusing in particular on the D3-type dopamine receptor. And 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 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's three times the average successful drug in psychiatry. And then they carried it out for 48 weeks. So they showed it was very durable. But the problem is with pampexole, and it's 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 prampexole, 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. And so that becomes a really compelling opportunity. We then brought that in, and now it's in this Phase 2b PACE 1 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. Prampexol 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 the same, a lot of side effect burden that primepraxol has really not shown, things like metabolic effects, movement disorders, and so forth.

Can you talk about the primepraxol study and the PAX-D study in more detail? What were these studies, and how did they inform, you know, the PACE program?

So PAX-D is this Lancet psychiatry study I alluded to. that was an adjunctive program. In TRD, that's what our PACE program is modeled after. So they took patients from the national health system in the UK. It was nine sites, 150 patients with TRD. So run, frankly, as an academic study out of Oxford, but run like an industry study and had very robust results. Praxel is a single-site study out of Lund, published Nature Medicine earlier this year, they 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. And keep in mind, antidepressants don't generally move anhedonia different from placebo. So this is an area of tremendous need. And so across the two studies, you see large effects on depression and anhedonia with PAX-D, large effects on anhedonia that even reach a CONS-D of 1 in the MDD subset of that study. So really, really striking effects. And all of that is an adjunctive use of the drug. So in both cases, it was on top of standard of care. So that told us a lot about where to start, not necessarily where to end, but where to start. And that's why PACE 1 and PACE 2 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. But 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. And that led us to add PACE-3 as a second PACE-3 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.

So primepraxol's constraint has always been tauability. And nausea, I think, was even at 60% in primepraxol, even with that slow titration. So can you, how does the ondincentron component in Alto 207 change the achievable dose? Maybe you could talk about, you know, some of the other methods you're using to sort of improve tolerability.

Yeah, so what has been shown in the phase one study that Chase ran is that by pairing the two, you could not only go five times faster than the Prampexol label, but you can reach a dose that's at least two and a half times higher. So 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 kind of custom titration schedule that we've 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 effect will become a starter pack clinically. So it's a fixed titration pack. The doctor doesn't have to think about how they're going to titrate it. And so 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 2b includes 3.2 milligrams of pramapexole and 15 milligrams of ondansetron split twice a day. that 3.2 is higher than PaxD, which was at 2.3 milligrams. So we're able to achieve a higher dose faster, but the important part is we're 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's 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 design in the way it is?

So as I mentioned, it's based on the PAX-D design. And then the phase 2B is designed like a phase 3. So it's powered well, 178 people randomized one-to-one to drug versus placebo. And that's an 80% power at a Cohen's D of 0.45. 0.45 is actually lower than what has been seen historically for pramapexole studies, but is where we think a very differentiated profile exists relative to everything else that's out there, both on the efficacy picture and especially on the anhedonia picture. So comfortable with a conservative powering relative to prior data. And it's an eight-week treatment duration, so very much looks like a lot of acute registration-type studies. The phase three, we will have a discussion with the FDA in terms of the design and alignment on it being a phase three, aiming to start that study, PACE 2, 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 eight-week duration acute trials, and we'll guide more to the specifics, obviously, once we have that discussion with FDA.

So PACE-1, I believe, is powered at 80% for Cohen's D of 0.45. 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 3 program, and how would this de-risk the program overall?

So the way we've designed it, the intent is to use it as part of support for the registration package across the phase 2b and the phase 3 the phase 3 would be we presume more conservatively powered even still so put us in a very strong position for being able to to read out a consistent effect across these trials whether there'll 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 three.

And when do you anticipate you may have more details on phase two and phase three? And what exactly do you need from the FDA for phase three? Is this just sort of dependent on the data that you see from phase one, and how should we think about this?

Yeah. So that's an important question. We're not waiting for the readout of PACE 1 of the Phase 2b study to inform PACE 2, which is the Phase 3, for two reasons. One is that we know efficacy is already there from prior studies on Pramapexol. So that's often one reason for waiting for a Phase 2b. And then safety data will be submitted to FDA for the ongoing trial. Well, safety and efficacy are the two things that you need to know as you design your phase Because the design right now for PACE-1 is like a phase three design, we're anticipating mainly it's the addition of the lower-dose arm that then, you know, is what we need to get alignment on, and of course that the study is a phase three study with FDA.

PACE-3 would come with an FDA interaction after that.

We're focusing first on kind of completing the PACE 1 and 2 package. And 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.

Now moving on to Alto 300, this is the EEG biomarker selected, adjunctive antidepressant and 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?

So a little bit of background, Agomelatine Alto 300 is a drug that's actually approved as an antidepressant monotherapy in Europe and in Australia. We're developing it here as an adjunctive treatment. So again, the goal is displacing antipsychotics. It's a drug that's very, very well tolerated and has a distinct mechanism of action. So 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's how it was approved. But what we've also done is found a potential biomarker here through EEG. So we use the machine learning approach that we've 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's how we've stratified this study. So a positive result would tell us two things. One is, does the drug have efficacy in an adjunctive population? It's actually never been tried in a randomized trial in an adjunctive population, so it's a really critical question. That opens up a path for the drug in an area where it would be quite welcome clinically, and then can you further enrich using a biomarker for those patients with a larger clinical effect using EEG in this case? And 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, well, you know, as a psychiatrist, I'm 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. And ALTO 100, this is in bipolar depression. It targets neuroplasticity deficit and indication where only antipsychotics are approved. I think the top line is mid-2027. Evan, what would you view as positive data in this program?

Yeah, so you can kind of see the sort of go-against antipsychotic theme here. In bipolar depression, as you mentioned, all they have are antipsychotic. So 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. 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. So 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 three for bipolar disorder.

So 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 100 and 300 and 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 across the pipeline you know so this change was really in response to what we saw in the alto 100 phase 2b which is a risk of professional patients as a site-level activity risks, 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. So we've 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, or I'm sure broadly.

So beyond, you know, 207 and 300 and 100, there's 101 and several other pipeline programs. Would you, you know, have updates on any of those other programs?

Yeah, so mainly Alto-101 is a program, a PDE4 inhibitor that we've 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. and then in a trial in schizophrenia 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. And so there we've talked about really looking for partnering to take something, in this case that, you know, 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.

So we 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?

And 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 we'll read out next year that present important clinical opportunities and the ability to start phase three 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, you know, that's fine. We're happy to let that read out. Financially, we're in great shape right now. But 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. So, Amit, thank you so much. Thanks for joining us. Thanks for everyone for being in our conference. Have a great rest of your day and conference.