Alto Neuroscience Inc. H.C. Wainwright 28th Annual Global Investment Conference

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 2B trials, as Patrick was mentioning, also one transitioning to Phase 3 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.

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 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. 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.

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 9 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, 9-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 1 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 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. 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 3 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.