Alto Neuroscience Inc. TD Cowen Novel Mechanisms in Neuropsychiatry & Epilepsy Summit

Yeah. First of all, thank you for having us, and as they say, save the best for last. Hopefully we'll come up to that billing. The question's a great one because pramipexole has actually been around and looked at in depression in different ways for over a quarter century, and the results have been very clear, both on the efficacy, which is outstanding, and the main issue, which is nausea and vomiting, preventing dosing high enough and fast enough, and that's really the motivation for this combination. Let me take a quick step back and just explain the context here. Of course, we broadly understand dopamine is important for depression, especially things like anhedonia. There's not been a direct dopamine stimulation or dopamine agonist strategy apart from pramipexole, which is a D3 preferring D3, D2 direct and full agonist.

Antipsychotics increase dopamine levels a little bit, but that's really not the same as directly stimulating dopamine. Pramipexole is approved for Parkinson's and restless leg syndrome, and usually it's dosed very slowly along with, in Parkinson's in particular, along with the disease. But trials in depression have consistently pointed out large effect sizes. Most recently, the trial PAX-D from the U.K., which is a 9-site, really well-done industry-like study in treatment-resistant depression, showed a Cohen's d of 0.87, so nearly 3 times the average drug placebo difference in depression, and this is in TRD, in 150 patients. The efficacy signal is very clear. Most of those studies have been limited in terms of the dose that they've used. Most are around 1 and a half.

Some of the more recent studies, a little bit higher in terms of milligrams of pramipexole, because the more you give of any dopamine agonist, pramipexole amongst those equally, the more nausea and vomiting you get, which precludes people from getting high enough, fast enough. You have clinical trial data, and you have case report data that all say that you need to actually go higher in treatment-resistant depression in order to get the efficacy signal really coming out. What motivated then the combination, originally developed by Chase Therapeutics, was this idea that if we can mitigate that effect, very much like the COBENFY concept of mitigating adverse events so you can get your full agonist effect clinically. If we can mitigate nausea and vomiting, then we can get to a much faster titration schedule. They used a titration schedule 5 times faster than the label.

Most prescribers go far, far slower than the label when they try to use pramipexole by itself, and we can get to a higher target. In their phase II trial, they got to 4.1 milligrams, which is the highest of any trial out there. With that, they were able to show both good tolerability and excellent efficacy, an 8-point delta on the MADRS, a Cohen's d of 1.1. That's really the motivation here, and then we can get into more of the specifics of the program itself, the way we look at TRD and the way we look at adjunctive and monotherapy use. But in terms of the groundwork, I think it's quite clear for the efficacy of pramipexole.

Yeah. When people use it in the real world, and we've actually looked at this data directly through the NIH All of Us dataset. The vast majority, so about 75%, go at least 1.5 times slower than the label. The average time to get to a milligram, which is the point at which you start to get efficacy in clinical trials, is over a year and a half on average in this dataset. So people go low and slow. The label is low and slow, but they go lower and slower. But often what you even see is at that next iteration when you're increasing the dose, and it's seen in that All of Us dataset equally, people immediately down titrate because they're not able to tolerate it. As a clinician, it's very hands-on.

Some people won't touch the stuff because you can't even get to 0.125. They'll just have a reaction in terms of not tolerating it. Then you go up a little bit, you wait, maybe the person has side effects, you go back down, you re-challenge. It's a very hands-on process. But once you get people to a good dose, clinicians tend to really like it because it works, because the efficacy has been very clear on a number of fronts, right? So one is it's being given right now because of what's involved in titrating it to very resistant patients, and yet they're responding well. You have an anhedonia effect that clinical trials point to as like 0.6 Cohen's d to 1.0 massive effects.

Nothing else has these anhedonic effects. It's clear clinically that that has an anti-anhedonic effect in just clinical practice. That target to be solved is how to get it to be tolerable, how to get titration to go faster. Remember, Chase used it 5 times faster than the label titration, which is probably an order of magnitude faster than a clinician would use in regular practice, and hit a higher target. And the important part here, and this is important in understanding what TRD really means to us and to this drug, is the very broad range of depression patients, if you now have a well-tolerated, unique, really first-in-class type mechanism, the broad range of the depression patient population should benefit from it. So when we talk about TRD, which is 2 to 5 treatment failures, it's really different populations at 2 than it is at 5.

In all cases, you need at least 2 failures to get insurance reimbursement. So you're really talking about at 2 failures, somebody who's failed like an SSRI and an SNRI, or 2 SSRIs, primary care populations. And that becomes a really important target where you can differentiate. General psychiatry, where they're comfortable using antipsychotics and various other kinds of drugs, but you're mainly still in all cases prescribing standard take-home drugs. That's another great population. And the much, much more severe end of the spectrum of TRD, where they're thinking about interventional psychiatry, and psychedelics, and esketamine, and what have you. Well, why do all those things with all the REMS program and needing to come in and so forth versus just taking a take-home- So much easier.

Right. So much easier, right?

It is about that differentiated clinical profile, the clear evidence of efficacy in prior pramipexole studies, and the tolerability that comes with the combination.