Hello, everyone, and welcome to the 6th Annual HC Wainwright Neuroperspectives Conference. My name is Patrick Trukio, and I'm a Senior Healthcare Analyst at HC Wainwright. We have a robust agenda at the conference this year, with more than 30 companies presenting, with their sessions available on demand through the conference portal. In addition, we're expecting a full day of panels and fireside chats with world-class KOLs on June 16th for the in-person portion of the conference, with a broad CNS drug development focus across multiple indications, from depression and epilepsy to Alzheimer's disease and ALS, and featuring novel methods of drug delivery to the CNS. This is by far our strongest agenda ever. With that, it's my pleasure to introduce our next presenter, Amit Etkin, CEO of Alto Neuroscience, a clinical stage biopharmaceutical company pioneering precision psychiatry through biomarker-guided drug development.
Alto is advancing a deep pipeline of CNS therapeutics, including five phase II programs in depression, bipolar disorder, and schizophrenia, using a proprietary platform that combines EEG, cognitive assessments, and wearable data to match the right patient with the right treatment. Maybe with that, we can begin with an overview of Alto's precision psychiatry platform and how it's designed to address the shortcomings of traditional trial-and-error drug development in psychiatry.
Yeah, first of all, thank you, Patrick, for having us on. You know, the problem that we're facing, that we've been facing for a long time in psychiatry, is really twofold and comes back to the same cause. When we have treatments in the clinic, I'm a psychiatrist as well as a neuroscientist, so I can directly attest to this, that, you know, we basically select based on no information whatsoever. The closest it gets is, did you or a family member respond to this particular medication in the past? That all comes, and the second kind of source of this is when we develop drugs, we also have very little visibility on what works for whom and why, and that just doesn't, at its base, make sense. What we've tried to do over the years at Alto is systematically solve that.
The way we solve that is by measuring biology that's critical for a variety of brain functions important for psychiatric disorders, things like cognition, various aspects of emotional, you know, processing both positive and negative emotion, and looking at sleep and activity measures, things that characterize how a person functions or sources of dysfunction during the day. We use biomarkers in two important ways to get there. One is to understand what a drug does in the first place to the brain, because none of these drugs come with, you know, labels, use this as an antidepressant, or this is to improve cognition. You've got to figure that out. How do you dose it, for whom, and so forth? In later stage trials, find a biomarker that can predict who responds better for that drug, obviously different from placebo.
We're trying to predict specific response, but also is scalable. It is something that we can put into the clinic along with the drug that allows physicians to know how to describe it. In sum total, it'll hopefully de-risk the process of drug development as a whole.
Right, great. Alto now has five clinical stage programs, each guided by a mechanistic biomarker hypothesis. How do you approach program prioritization and risk management across the portfolio?
Hello, everyone, and welcome to the 6th Annual HC Wainwright Neuroperspectives Conference. My name is Patrick Trukio, and I'm a Senior Healthcare Analyst at HC Wainwright. We have a robust agenda at the conference this year with more than 30 companies presenting, with their sessions available on demand through the conference portal. In addition, we're expecting a full day of panels and fireside chats with world-class KOLs on June 16th for the in-person portion of the conference, with a broad CNS drug development focus across multiple indications, from depression and epilepsy to Alzheimer's disease and ALS, and featuring novel methods of drug delivery to the CNS. This is by far our strongest agenda ever.
With that, it's my pleasure to introduce our next presenter, Amit Etkin, CEO of Alto Neuroscience, a clinical-stage biopharmaceutical company pioneering precision psychiatry through biomarker-guided drug development. Alto is advancing a deep pipeline of CNS therapeutics, including five phase II programs in depression, bipolar disorder, and schizophrenia, using a proprietary platform that combines EEG, cognitive assessments, and wearable data to match the right patient with the right treatment. Maybe with that, we can begin with an overview of Alto's precision psychiatry platform and how it's designed to address the shortcomings of traditional trial-and-error drug development in psychiatry.
Yeah, first of all, thank you, Patrick, for having us on. You know, the problem that we're facing, that we've been facing for a long time in psychiatry is really twofold and comes back to the same cause. When we have treatments in the clinic, I'm a psychiatrist as well as a neuroscientist, so I can directly attest to this, that, you know, we basically select based on no information whatsoever. The closest it gets is, did you or a family member respond to this particular medication in the past? That all comes, and the second kind of source of this is when we develop drugs, we also have very little visibility on what works for whom and why, and that just does not, at its base, make sense. What we've tried to do over the years at Alto is systematically solve that.
The way we solve that is by measuring biology that's critical for a variety of brain functions important for psychiatric disorders, things like cognition, various aspects of emotional, you know, processing both positive and negative emotion, and looking at sleep and activity measures, things that characterize how a person functions or sources of dysfunction during the day. We use biomarkers in two important ways to get there. One is to understand what a drug does in the first place to the brain, because none of these drugs come with, you know, labels, use this as an antidepressant, or this is to improve cognition. You've got to figure that out. How do you dose it, for whom, and so forth? In later stage trials, find a biomarker that can predict who responds better for that drug, obviously different from placebo.
We're trying to predict specific response, but also is scalable. It is something that we can put into the clinic along with the drug that allows physicians to know how to describe it. In sum total, it'll hopefully de-risk the process of drug development as a whole.
Right, great. Alto now has five clinical stage programs, each guided by a mechanistic biomarker hypothesis. How do you approach program prioritization and risk management across the portfolio?
It's a complex question in probably a complex time for all of us as we try to navigate, you know, these kinds of decisions and understand the budgets we have and so forth. The way we think about it is a couple fold. The level of data that we have for a drug, like how solid is that biomarker? How much have we replicated it? How much do we know about that population? How clear is that mechanism and the outcomes to evaluate that mechanism? What is the impact of a positive trial? For us, that tends to weight things more towards our late stage trials. We now have three phase II Bs going on across our five programs, all within the next two or so years.
That means patient selection in some sort of way, a drug that we already know something about its clinical efficacy from prior studies, substantially sized studies, and really meant to be a clear test of efficacy. We also try to be pretty broad across our representation of psychopathology. We have, as you mentioned at the top, we have depression, within depression, its adjunctive use in MDD. We also have treatment-resistant depression, bipolar depression, and cognitive impairment and schizophrenia. That gives us many opportunities to learn and leverage the data that's coming in from one trial to even inform the next.
Right. How does your platform align with the evolving FDA guidance on enrichment strategies in psychiatry trials, particularly as it relates to the use of digital biomarkers?
Yeah, enrichment is obviously not a new idea for psychiatry. The FDA has worked with this for years, and we benefit from the advances in other areas in medicine. What the FDA has done, actually in 2019, is codify the different ways one can think about using a biomarker. We followed that. Essentially, that lays down a road that you can decide, and you can understand based on your data how you follow. It's actually relatively clear. We've interacted also with the agency around this, for example, in our Alto 100 program. We've learned a few things in that process. One is obviously, and this is core to our sort of approach, knowing that you have something and it's replicated and there's actual solid science behind it is critical.
Understanding the biology, the why of a biomarker is not required per se, but is very much helpful. That's the case for our Alto 100 biomarker and our Alto 300 biomarkers. We figured out and kind of, you know, understanding the mechanistic basis of that, and then developing the drug in a way that both allows you to understand what the efficacy in the enriched population is, as well as some information, and certainly in phase III, more information about people who don't have the biomarker. All of those are laid out. We've interacted with the agency around our interpretation of that, which is in line with guidance. It's really for the data to play out as opposed to being uncertain about what a regulatory path would look like.
Right, great. Now I'm moving on to Alto 207, a Dopamine agonist for treatment-resistant depression, recently brought into the pipeline, a very exciting program. You described Alto 207 as a next-generation dopamine agonist strategy for TRD. What differentiates the approach mechanistically and clinically?
There is right now no dopamine agonist approach that's being taken. In the field, there's been antagonists. Those are second-generation antipsychotics that have efficacy in TRD and depression, adjunctive depression populations, but come with a lot of their own baggage in terms of side effects. What we're trying to do here is directly stimulate the dopamine system. Driving reward pathways that we have also separately shown using our biomarker tools are particularly reduced in TRD populations. In a sense, TRD is itself an enriched population in that way, even clinically defined. Driving more directly reward system restoration. The challenge there is when you stimulate the dopamine receptor, you get those beneficial effects. These are especially D3 type receptors. You also get side effects. Those side effects are nausea and vomiting. They're really tough, especially for psychiatric populations.
To deal with, they're not used to taking medications that cause nausea and vomiting. That is the part that we have to overcome. The goal is to be able to dose enough of the agonist, fast enough, and high enough. To get there, you have to be able to deal with the nausea and vomiting, which we do by pairing in a co-formulation, pramipexole as a D3 preferring dopamine agonist with ondansetron as an antiemetic that works on a pathway that is actually synergistic with dopamine. That turns out to work quite well. We can dose five times faster to a higher target with that combination and get pretty exciting evidence of antidepressant efficacy of a magnitude that is not usually seen at all in depression, and certainly not in this incredibly high need TRD population.
All of that puts us right into a late stage phase IIB trial. As you asked about prioritization, this is a new program that we've brought in, acquiring it from Chase Therapeutics, but allows us to go right into a potentially registrational phase IIB trial that will begin next year.
Right. In the completed phase IIA trial, we saw large effect sizes on MADRS and CGI-S and rapid titration. What were the key learnings from that study, and how do you expect them to inform the upcoming phase IIB design?
It's actually not just that study, but also the PAXD study that Mike Browning presented, which together tell us a couple of important things. One is that mechanism driven by pramipexole is validated. It's very clear that it is highly effective. The data, for example, that PAXD that Mike presented was 150 TRD patients drawn from the NHS, dosed to a lower and slower level than what we're able to achieve with Alto 207, but was able to achieve a Cohen's D effect size of nearly 0.9 by 12 weeks. That's a massive, massive effect. We were able to get, interestingly, an even larger effect size and doing it faster to a higher dose tolerably in that combination.
The learnings are that this is an effective pramipexole is an effective agent within this combination, that we're able to safely and tolerably get to a higher dose faster, which should also lead to a more rapid response. Now with those pieces in place, following a 505(b)(2) path ultimately for registration, within the background, kind of commercial success precedents like Axsome and Karuna with Auvelity and Cobenfy respectively, that puts us in the right spot for understanding who our patients are, how to dose this drug, how to make sure that we're getting large effect sizes that are compelling, and then from there making it a hopefully more straightforward registrational and commercial path.
Right. How do you expect to leverage your EEG and behavior-based dopamine biomarker strategy as a pre-specified secondary analysis in the upcoming phase II B trial?
It's a good question. As I mentioned, already starting with TRD, that's already an enriched population because what we've shown is a dopamine response biomarker that we've developed is enriched in that population to begin with. We anticipate the label will be a broad TRD label, which means a biomarker won't be required. However, we'd like to have a biomarker there to help a clinician understand of all the different choices, is this the one I ought to make for my patient? Large effect sizes, as has been seen with a drug, are great. If you can get even larger, that's even better. We look at that as both biomarkers of response or biomarkers of tolerability. Those would be complementary enrichment markers.
In other words, not required for the prescription of the drug, but a useful adjunct to the clinician deciding, is this the right drug for this patient? It also helps in arguments with payers, making a pharmacoeconomic argument that much more compelling if you know who this works for. That directly fits into all of the biology we already know and have been developing at Alto around EEG. We have, I think, the first EEG markers for dopamine, both up and down. Then behavioral measures of dopaminergic function that we've also been using across our trials, any of which can be deployed as the enrichment marker here.
Right. You mentioned the 505(b)(2) pathway for Alto 207. I'm wondering what your expectations are for interactions with the FDA regarding pivotal design and regulatory alignment and this potential for, you know, accelerated pathway.
We're planning in the near term agency interactions to flesh out our understanding of how the phase II B could support registration. It'll be designed like a phase III study. If you look at precedent like what Axsome has done, they had a phase II B and a single phase III. We think that that's a reasonable assumption. That certainly is a faster and more cost-effective path to market. You can imagine just a handful of years that this drug is on the market. We're drawing upon substantial safety with pramipexole and ondansetron. Ondansetron is labeled only for three days of use around chemotherapy, but its tox package supports chronic use. We would add the human chronic exposure safety data as part of our development effort. That allows us to build on a lot of work that doesn't need replication because it's already there.
We can focus on the efficacy in delivering a new treatment for TRD patients who, you know, this is 3 million people in the U.S. alone annually. It's a massive, massive high need, high cause population.
Right. It's a huge unmet need for sure. I'm curious, I know we're looking a little bit further ahead here, but about the commercial vision for Alto 207, if it successfully reaches the market, how do you envision it being positioned relative to Spravato or adjunctive antipsychotics?
If you look at two factors, right, for any drug, one is efficacy, the other one is safety. Maybe adding a third that's specific here because we're considering Spravato as an intranasal in terms of ease of use, I would argue it puts it ahead of all that competition in a couple of ways. The effect sizes that have been seen in pramipexole studies, be it the Chase phase II A study on the combination drug here, the PAXD findings, or even older randomized trials with pramipexole, have all been well above what's been seen for esketamine and antipsychotics. A dopamine agonist here has a totally different safety profile from dopamine antagonists like second-generation antipsychotics. There's no weight gain, no movement disorders, no tardive dyskinesia. On both safety and efficacy, we think that there could be really clear differentiation.
But also just being a regular pill you pick up at the corner pharmacy as opposed to needing to go into a clinic for two hours a couple of times a week with an intranasal injection, I think, or administration is a world of difference in terms of just accessing patients and people being able to use the treatment with really no barriers, just like you would take any drug at home. We think all that positions it really well, but having those kinds of effect sizes, that becomes something we have not seen in psychiatry really ever within depression. That is incredibly exciting.
Right. Great. Just moving on to Alto 203 and Alto 101, just first, what's the mechanism of action and clinical rationale for Alto 203? What should we look for in the second quarter of 2025, the proof of concept data? Is that the implication that that data is expected any day now, any week now?
Yeah. So we just talked about 207, right? The 200 series are focused on different aspects of emotion. 203 is a different mechanism to try to get at that using an H3 inverse agonist strategy. It is, by contrast to everything we've just said, 207, a really early stage program. This is the first time this has gone in humans. It's mainly a pharmacodynamic study. So understanding what are the effects on subjective response, cognition, wearables, EEG, different ways to understand what the drug does, to understand how to use it. There we've started with a lens of an H3 inverse agonist affects a variety of important neurotransmitters important for emotion and cognition like dopamine, norepinephrine, acetylcholine, beyond the H3 effects themselves on histamine, which causes an increase in arousal and wakefulness.
We'll be quantifying all of those things in depression patients who, you know, are getting single doses of the drug. This is really a test of that biology. We'll also be doing a multi-dose treatment period that's really more about safety and PK because the drug's only ever been given for nine days to anybody, and this is giving it for four weeks. That's coming really any day now. It's on track for data second quarter, which is this month. From there, we'll see and we'll learn what the data show us and how to develop that drug further.
Great. For Alto 101, this is in cognitive impairment associated with schizophrenia or CIAS. What are your expectations for the second half 2025 data? How does the transdermal formulation support tolerability?
Yeah. So 101, by contrast to 203, is, while also a phase II proof of concept, a more advanced drug in that it is a longer treatment course in patients with CIAS or cognitive impairment associated with schizophrenia. The idea there is improving cognition by increasing cyclic AMP levels. We've already shown that single doses can in fact improve cognition in healthy people. They change EEG signals that we've linked to patients with schizophrenia in large replicated data sets as good markers of the pathophysiology. What we'll be looking for in that trial, which is 10 days of dosing with drug or placebo in a crossover design, so each person is their own control, is do we see improvements in that primary outcome, which is improvements in that EEG biomarker relevant to CIAS?
A great outcome on top of that would be improving cognition, which 10 days of treatment, you would not expect a ton, but if you get some, that is great. These are very, very chronic refractory patients. We are also doing patient selection there with a biomarker. We are using processing speed, which is an element of cognitive behavior, to select patients because those people have the biggest EEG abnormality in other data sets. It is a setup for what would then be a large-scale phase II B efficacy study on the other side.
The patch that you mentioned is our reformulation of this drug from oral to transdermal, which essentially did a very simple pharmacokinetic adjustment, which is going from a very fast absorbed oral drug to a very slowly titrating kind of nice coverage of steady state drug that just with that switch mitigated the usual side effects that you see with PDE4s in general. This is for all approved PDE4s an issue, nausea, vomiting, and diarrhea. It turned out that it's all driven by the pharmacokinetics of the drug. You can actually see that in the oral form, you get side effects when it hits its peak fairly immediately within half an hour or an hour in a dose-related way. With a patch, you virtually eliminate those side effects.
It allows you to dose more, so triple the level of exposure with the patch because it is on all day, but do it much, much more tolerably. You actually take a drug that is dosed twice a day orally to now once a day as a patch. All in all, it is a good setup for the form that a drug should take, given that we are expecting, if positive and ultimately if approved, that a patient is taking this potentially for years, right? There are no treatments for CIAS right now. The expectation is this is the only treatment they would have. They would take it every day for years and it has to be well tolerated as a consequence.
Right. Interesting. Maybe moving on then to Alto 300 for major depressive disorder, MDD. I guess first, just if you could tell us about the mechanism of action of Alto 300 and how does it differ from traditional antidepressants?
Yeah. Alto 300 is an approved antidepressant in Europe and Australia. We're already starting with the fact that we know that it works. Here, what we're doing is a US-only development strategy, harnessing a biomarker for understanding for whom it works so we can target development to those people. The way the drug works is unique, as you're alluding to, from other antidepressants. It stimulates melatonin receptors, so it has circadian and sleep effects. It blocks 5-HT2C receptors, which by doing so leads to an increase in dopamine and norepinephrine levels. It's a disinhibition of dopamine and norepinephrine. That combination of mechanisms means two things. One is that you can find a biomarker for that drug that's unique because you're looking after mechanisms that are not shared with other antidepressants.
That's what we were able to do with the EEG using our machine learning approach and then even take it down to a mechanistic basis for that biomarker. It is a very well-tolerated drug by virtue of not having, first of all, any of the kinds of things that you associate with adjunctive treatments like antipsychotics, but even all the side effects that can come with SSRIs and SNRIs are not seen there. We are developing this drug as an adjunctive treatment targeting a high-need population, not just kind of the typical way people do monotherapies, but looking at people who failed and will continue on a baseline antidepressant to which this is added on top. There are no safety issues with doing that. That has again been a very well-tolerated path. Enriching in our biomarker-defined patients, we also have chosen a dose, 25 milligrams.
It's approved to 25 and 50 in Europe that has no issues with LFT elevations. It's been shown to be safe in thousands and thousands of people in clinical trials in real-world practice. At higher doses, you get some reversible adaptive liver changes that have never been a functional issue, but at 25, it's been actually quite neutral for LFTs, which is great. Now looking to a readout mid-2026 in those biomarker-positive patients with some patients alongside being biomarker negative to start to look at the enrichment that you get from the biomarker.
Can you tell us what design changes were made to the phase II B trial after the interim analysis and what led to those decisions?
The interim analysis, which we did earlier this year, was motivated by learnings from the Alto 100 program in the fall, which pointed to site-level execution issues at certain sites that are part of everybody's trials that produce a lot of patients, but unfortunately produce a lot of non-compliant patients or professional patients. In wanting to weed out those kinds of patterns, we did a blinded case review for the Alto 300 study with pre-randomization data, identified risky sites, removed the data, that data is gone forever, analyzed the biomarker-positive patients in a formal interim analysis that said, yes, there is a drug-like signal there. To go from 150 biomarker-positive patients to 200, that was the recommendation from the statisticians, which we followed.
That pushed the readout because we had to replace the missing patients as well to mid-2026, but says that we are in line with expectations. There have been no changes in the design at all. It is really just finding the sources of risk that pervade studies across the field. We have seen a lot of talk of professional patients of late, and it is something we have taken very, very seriously and are trying to root out in every way possible.
Just regarding the mid-2026 top line readout, what endpoints or subgroups do you expect to be most informative? What would you consider to be a successful outcome?
This one is relatively straightforward. It's the biomarker-positive patients and then the entire population. Those are the main more powered outcomes. We'll describe the biomarker negative, but they're going to be a small subset. Only about a quarter of the patients thus far have been biomarker negative. Usual outcomes, moderate change, and certainly we'll need to see a significant moderate change delta between drug and placebo in order to advance the drug into phase III.
Great. Maybe one on Alto 100 for bipolar depression. The MDD trial of Alto 100 showed a signal in the adjunctive group despite it missing the primary endpoint. I'm wondering what changes that you've implemented in the bipolar depression design or trial protocols that would enable this increased signal detection.
Yeah. Already the bipolar program is an adjunctive program. The adjunctive population, when you looked at compliance in the Alto 100 MDD program, was 100% compliance in those sampled. That was by measuring blood levels of the drug. We know that that population at base is more likely to be real treatment-seeking patients. These bipolar patients just clinically are very much in that vein, but we further strengthened by looking at PK on a running basis throughout the trial to make sure that we're able to pick up site execution issues as they come.
We've implemented the measurement of the mood stabilizer already being measured now, but adding on antipsychotic measurement at baseline to make sure that what they're saying they're taking, they're actually seeing in their blood, requiring medical and pharmacy records, basically as much belt and suspenders as we can, plus bringing in a lot of AI tools to better understand the patient profiles, analyze recorded interview data, and so forth to make sure that each and every patient is as good of a candidate for this trial as possible and that there aren't people just trying to game the system getting into trials, which is what we've seen in the monotherapy group within the Alto 100 MDD study.
That signal that we saw for the adjunctive trial, which is a 0.47 effect size, which would be great to see in a population like bipolar depression where the only treatments are antipsychotic treatments, that would be fantastic. The biological rationale, the clinical rationale is very similar in bipolar depression as it is in major depression. We just have to make sure that the trial is executed at the highest level, and then we'll let the data speak for themselves.
All right. Terrific. I think we're going to have to end the presentation there. Thank you so much to Amit and to Alto Neuroscience for attending the conference. Always a pleasure to catch up. This is such an exciting pipeline, and we are very much looking forward to these next data readouts as we further validate this precision psychiatry platform. Thank you very much to everyone for attending the conference. Have a great rest of your day in conference.
Great.