Conference Transcript - ANRO 2026-05-13

Amit Etkin, CEO

Hi, I'm Amit Atkin. I'm the founder and CEO of Alto Neuroscience. Thank you for having us at the B of A conference. I want to take you through the story, focusing really on Alto 207, one of the most important programs in our pipeline. Those are the forward-looking statements, just to kind of orient how to think about Our goal is really to establish, to create highly effective new treatments for psychiatric disorders using tools like biomarkers to identify patients with distinct biology that map onto distinct mechanisms of actions of drugs, and to understand the biology to drive to new approaches that really have evidence of unique or outsized efficacy. We address broad populations, depression, treatment-resistant depression, adjunct abuse and depression, bipolar depression, schizophrenia, areas of tremendous need, where we've now systematically gathered data with our clinical trials, with our biomarkers on many, many patients at scale. So thinking about the impact of these trials as they ultimately get to reading out and coming into the clinic, we're currently looking at multiple major readouts, three different drugs in late stage, phase 2B, and hopefully soon phase 3, with cash taking us through all of those and through 2029, really exciting period of execution. This is our pipeline. Anchoring this pipeline is ULTO-207, which is a fixed-dose combination of pramipexol and undansetron. It's a direct dopamine agonist treatment that has shown outsized efficacy signals in treatment-resistant depression. I'll show you that data in a second. as well as Alto 100. 300-100 is a novel mechanism of action that enhances neuroplasticity in patients with bipolar depression identified by a deficit in neuroplasticity. Alto 300 is a drug agomelatine that's actually approved in Europe and Australia as a monotherapy. Here we're bringing it as an adjunctive therapy in depression using an EEG biomarker, and I'll take you through that. But let's first focus on Alto 207. The idea of dopamine and depression is, of course, something that we all inherently understand but what our biomarker work has pointed us to using a biomarker of dopamine in humans is that the more resistant end of the spectrum is even more enriched in a low dopamine phenotype and so the question is how to best get at dopamine one way to do that is with antipsychotic medications which have been approved for the treatment of adjunctive treatment of depression which increase the level of dopamine our view has been and backed up by clinical data that direct stimulation of dopamine receptors with a full agonist gives you a really differentiated clinical efficacy, more so than just generally increasing dopamine levels. The problem with doing so, and this is true for every dopamine agonist, is it causes nausea and vomiting. That is inherently dose limiting and limiting the speed with which you can titrate. And the more you give, the more you get. And if that's a limitation, you have to find a way around it. In this case, it's a co-formulation with ondansetron, which is an anti-medic shown to be safe and effective in mitigating the nausea and vomiting that comes with pramapexole. This is really the anchoring study behind the motivation here. There are actually quite a lot of trials out there historically on pramapexole, but this is the one that is sort of the nail in the coffin. It's a 150-patient TRD study at nine sites in the UK, a study called PaxD published in Lancet Psychiatry in July of last year that not only looked at the efficacy of prampexol, in this case up to two and a half milligrams, but kept people randomized for 48 weeks, which is something we never do in this field. By looking at that kind of long-term efficacy, you're able to show not only how effective the drug is, but how well sustained that is. What are the side effect profile that you see over time in those people? Really, what would it look like in the clinic? And what you see at the primary endpoint here at 12 weeks, you see a Cohen's D of 0.87 translates to 7.4 points on the madras as the delta between drug and placebo, which is a massive effect. You're talking about something two to three times the typical antidepressant effect. And this is in the most resistant patients out there. But the thing is, when you cast your eye across the rest of the timeline, you can see that that effect never waned across 48 weeks. And placebo, even though they're able to change their underlying antidepressant, never caught So clear evidence of efficacy, but also clear evidence of that tolerability issue with primal pexol, which is nausea and vomiting. That drove 20% dropouts due to AEs in drug, 5% in placebo. That's clearly then the bogey to solve in order to really get the benefit of pramifexil in the clinic. You can see that same limitation in prior studies, which have tried to dose in the left. You can see to different levels of pramifexil leading to very high rates of AEs, of adverse events, very high rates of dropout. And the consequences, when people try to use Prampexil, either for its approved utility in Parkinson's or off-label in depression in the real world, judging by medical record data, they go really, really slowly, with the vast majority of patients' dose more slowly than the label, and still experiencing adverse events. So the opportunity here is solving that in order to deliver the efficacy of Prampexil. Chase Therapeutics, from which we acquired this asset, did that. They showed the safety of giving the two together. That was critical. They showed that that improved tolerability at least two and a half fold for pramapexole. And we're able to deliver pramapexole at a five times faster rate than the label. So it's a non-subtle difference here. When you do that in depression, they ran a 32-patient phase 2A randomized proof of concept They saw a massive efficacy signal, even larger than the PAX-D study. This is 8.2 points on the delta, CONS-D of 1.1. You already see that separation begin quite impressively at two weeks, but perhaps even more strikingly, you see the CGI, which is a measure of global severity of illness, much less sensitive to drug placebo differences, nonetheless show these same effects. That got us really excited about this program and was a motivator for bringing it in-house to ALTO. Where we are now is we've now launched a phase 2b trial. This is a trial launched in Q2 this year, guided to second half next year reading out. Very well powered. It's a trial of 178 patients, randomized one-to-one drug versus placebo, targeting 3.2 milligrams of pramipexole with a fixed dose of 15 milligrams of ondansetron, all split BID, with a modified release formulation we developed that matches the kinetics, the PK of these two drugs that have two different half-lives. So we can better counter the nausea and vomiting that comes with Primapexole. All of these patients are on a stable antidepressant that they failed. This is added on top. So it's an adjunctive TRD program, just like the PaxD study. So following closely, given those results, and very well-powered, 80 percent power at a Cohen's D of 0.45, which is much smaller than the historical effect sizes. So we think puts us in a good spot here with the expectation that we then would be able to get in front of FDA, discuss with them a phase three program that we hope to launch by early 2027 to then fully develop this for the clinic. And within that clinic the context, you can also see, very importantly, the precedents that drive enthusiasm here. It's not just the efficacy signal. It's this whole approach of solving a problem through a combination strategy, co-benfi in schizophrenia, ovality in depression, even spravato is a drug device combination. And all of those have paid off really, really well because they've solved those problems in a unique way. These are massive markets with tremendous, tremendous need. I mentioned ALTO-100 and ALTO-300 briefly. Both of those are Phase IIb studies. All of that is funded through our current cache runway, which takes us through the Phase IIb and the Phase III as well for ALTO-207. And we'll then develop them based on the data that they show. But the opportunity here for both of them is really, really exciting. So Alto 300, a well-tolerated melatonergic 5-HT2C antagonist antidepressant with efficacy potentially enhanced through the biomarker here, which is based on EEG. And we've tied it then to what the drug does mechanistically. But that positioning takes a drug that's really well-tolerated in an adjunctive use context where it's just antipsychotic medication. And so as a doctor, you think about balancing those two. Well, as a psychiatrist, I'd rather prescribe the thing that is well-tolerated, even at the same efficacy, over something that carries metabolic effects, movement disorder, TD, and so forth, effects over time. All to 100 in bipolar depression, well, in bipolar depression, all we have is antipsychotics. Here we're selecting patients for this first-in-class novel neuroplasticity mechanism based on a deficit in neuroplasticity as evident by a deficit in a verbal memory task. So you have both the ability to guide patients, the right patients to this treatment, but also a drug that's well-tolerated that is not, again, metabolic effects, movement disorder effects, and so forth, who knows, could even become first line in that context. That's a tremendous, tremendous need out there, much less development, frankly, going on in bipolar than there is in MDD or TRD. as we're looking forward now there's a number of major clinical trial catalysts that's really what's what's noted here but there'll be a lot of other things that will come as we evolve across these programs discussions with the FDA and so forth we're really really excited this is a period of like tremendous heads down execution with a lot of programs going on but positioning us as a company well but I think even more importantly the opportunity to really move the needle clinically in the near term for patients in tremendous need. So with that, I thank you very much for your attention.