Founder and CEO of Alto Neuroscience. Thank you for having us at the BofA conference. I'm gonna take you through the story, focusing really on ALTO-207, one of the most important programs in our pipeline. Those were the forward-looking statements. Just to kind of orient how to think about Alto, 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, substance 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 patients at scale.
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 II-B and hopefully soon phase III, with cash taking us through all of those and through 2029. Really exciting period of execution. This is our pipeline. Anchoring this pipeline is ALTO-207, which is a fixed-dose combination of pramipexole and ondansetron. 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 and ALTO-300. ALTO-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, I'll take you through that. Let's first focus on ALTO-207. The idea of dopamine in depression is, of course, something that we all inherently understand. 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. 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 a 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. 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 antiemetic shown to be safe and effective in mitigating the nausea and vomiting that comes with pramipexole. This is really the anchoring study behind the motivation here. There are actually quite a lot of trials out there historically on pramipexole, 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 U.K., a study called PAX-D, published in The Lancet Psychiatry in July of last year, that not only looked at the efficacy of pramipexole, in this case up to 2.5 mg, 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? 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 MADRS 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. This is in the most resistant patients out there. 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. Placebo, even though they're able to change their underlying antidepressant, never caught up. Clear evidence of efficacy, but also clear evidence of that tolerability issue with pramipexole, 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 pramipexole 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 pramipexole, leading to very high rates of AEs, of adverse events, very high rates of dropout. The consequences when people try to use pramipexole, 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. The opportunity here is solving that in order to deliver the efficacy of pramipexole. 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 improved tolerability at least 2.5-fold for pramipexole, and were able to deliver pramipexole at a 5x faster rate than the label. It's a non-subtle difference here. When you do that in depression, they ran a 32-patient phase IIa randomized proof of concept trial. They saw a massive efficacy signal even larger than the PAX-D study. This is 8.2 points on a delta, Cohen's d of 1.1. You already see that separation begin quite impressively at two weeks. 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 II-B 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 mg of pramipexole with a fixed dose of 15 mg 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 pramipexole. 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 PAX-D study.
Following closely, given those results, and very well powered 40%, 80% power at a Cohen's d of 0.45, which is much smaller than the historical effect sizes. 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 III program that we hope to launch by early 2027 to then fully develop this for the clinic. Within that clinic 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, COBENFY in schizophrenia, Auvelity in depression, even SPRAVATO is a drug device combination.
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 need. I mentioned ALTO-100 and ALTO-300 briefly. Both of those are phase II-B studies. All of that is funded through our current cash runway, which takes us through the phase II-B and the phase III as well for ALTO-207, and we'll then develop them based on the data that they show. The opportunity here for both of them is really, really exciting. 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.
That positioning takes a drug that's really well-tolerated in an adjunctive use context where it's just antipsychotic medication. 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. ALTO-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. 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 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 noted here. 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 excited. This is a period of like tremendous heads down execution with a lot of programs going on. 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. With that, I thank you very much for your attention.