Conference Transcript - ANRO 2026-06-03

Andrew Tsai, Analyst — Jefferies

We're going to get started on our next session. I'm Andrew Tsai, Senior Biotech Analyst at Jeffries, and to my right is CEO Amit Amit Eken. Welcome. So maybe for those in the audience less familiar with the story, would you mind talking about the Alto thesis and then maybe talking about your pipeline and then milestones we can expect over the next six to 12 months?

Amit Etkin, Board Member

Yeah, so we are a late-stage psychiatry drug developer. We take a precision lens to things, in other words, really try to understand using different ways of measuring biology in people who are the right patients for any particular mechanism given the tremendous heterogeneity that we have in psychiatry as we define diseases now. we also use those kinds of biomarkers to understand what drugs do in terms of how to dose them and therefore also what kind of people benefit from that and have applied it across a number of indications including different aspects of depression treatment resistant depression adjunctive treatments and depression bipolar disorder focusing on bipolar depression and cognitive impairments and schizophrenia so it's really a very broad green field out there as far as I'm concerned in psychiatry while there are obviously treatments for some things there's many areas with either no treatments and even those areas with treatments often they are lacking on a number of different fronts so lots of opportunity we are leveraging multiple different assets That's multiple different drugs against those, and that includes Alto 207, which we're developing in treatment-resistant depression. That's in a Phase 2b, and we anticipate a Phase 3 program soon. That's a drug that has a very unique efficacy profile we can talk about in a little bit more depth. Alto 300 is in adjunctive treatment in depression. that uses an EEG biomarker to select patients based on an approach we developed out of machine learning and validated as a way to identify those patients that we then linked to the mechanism of the drug itself and that's a phase 2b readout next year and then Ulta 100 is in bipolar depression and that's a potential first in class mechanism enhancing neuroplasticity for patients with evidence of impaired neuroplasticity as evident by impaired learning and memory which requires neuroplasticity also a phase 2b readout next year so a lot of opportunities coming up really really meaningful clinical milestones and now it's just kind of heads down execution on all these programs right maybe we can

Andrew Tsai, Analyst — Jefferies

start with ALTO 207 phase 2b data in second half 2027 bigger picture when I I think TRD, it's really just Spravato out there, approved and used. I guess MVX isn't really used. And then maybe to start, you know, walk us through why you are highly differentiated compared to Spravato, but not only that, to other TRD drugs in the pipeline as well.

Amit Etkin, Board Member

So I think actually it's important to start by even understanding what TRD really means, because I actually think that the TRD definition that people have sort of moved to in their minds is actually perhaps more narrow than the real opportunity out there. So TRD means two or more treatment failures. Two or more treatment failures includes a lot of the people in clinical practice who would get an antipsychotic, an adjunctive antipsychotic. They're also the people, by the way, who will end up in clinical practice getting ovality they're also the people who will get as ketamine at the higher end of failures or should they be approved at some point psychedelics at the very extreme end of number of failures that range though is the range that we're going after and so what differentiates auto 207 here are a number of really critical factors number one this is a dopamine agonist direct agonist strategy that has multiple trials of the pramapexole component of this fixed-dose combination of pramapexole and ondansetron that has demonstrated outsized efficacy across these trials. For example, PAX-D, which was a 150-person TRD study out of Oxford that published last summer, found a Cohen's D effect size of almost 0.9, three times larger than the typical successful antidepressant drug. That kind of an efficacy signal is something that we've not seen and doesn't have all of the baggage and certainly none of the REMS programs that an antipsychotic would have or for that matter that esketamine would have. And it's a drug that's shown efficacy consistently. We've in fact meta-analyzed all of the data that have been published on Prampexil historically And even with low-dose studies included, the average effect size is 0.64. That's a very different profile than everything that's out there. Also, unlike partial agonists or antagonists of dopamine receptors, antipsychotics, there's no metabolic effects. There's no movement disorder effects. You can get tardives for years after a short course of an antipsychotic. Not the case here for a dopamine agonist, full agonist like Primapexole. So that positions a drug that is highly effective based on these investigator-initiated trials and by combination with ondansetron should be much better tolerated than prampexol alone as a fixed-dose combination with a novel modified release that further better matches these two components and for us opens up a commercial landscape that's not just differentiating, as you said from from esketamine and potential future psychedelics but really differentiating from all of the available options out there and in displacing a very large market around

Andrew Tsai, Analyst — Jefferies

anti-psychotic medication for example okay great and then so the phase 2b started a couple months ago or so maybe talk about the study design and then the powering of the study You've mentioned Cohen's D of 0.9. I mean, I'm assuming you're not assuming that kind of no, no, we're not powering Yeah, I know what you're assuming drug and placebo behavior. Yeah, so I mentioned Pax D

Amit Etkin, Board Member

Pax D was an adjunctive study. So you take people who failed they stay on their drugs and you add In that case per impact or placebo on top Obviously is a very successful study in this population that is also the theme that we are then following so it is designed as close to pax d as possible two to five treatment failures you stay on that drug that you failed you add prampexol on top we have an eight week treatment period that includes a two week titration part of the the challenge and opportunity with prampexol is how to get it to the right dose we know that we need to get to a higher dose. Because of a lot of data in the field, we've shown that there is a dose response relationship amongst randomized trials, and that's been argued also amongst case report data. So you want to get higher. Our target is 3.2 milligrams of prampexole together with 15 milligrams of ondansetron, and that's dosed BID. Patients go through a custom titration schedule we've established that would actually look very much like the commercial starter pack that they would end up getting as a way again to bridge the trial to clinical practice. It's 178 people in the trial, that means it's powered at 80 percent power for an effect size of 0.45, 50 percent power is around 0.3, in other words anything from standard of care on up we'd be in a position to detect statistically and to put a more kind of direct point on it, any effect size reported in prior trials of Primapexole would be significant in that sample size. So very well powered. If we end up getting the 0.9 effect size of PaxD or the 1.1 effect size, which is over an 8-point Madras Delta that Chase Therapeutics found in their Phase 2A study with this combination, we'll obviously be throwing a big party and everybody's invited here. That's a great outcome, but it's not our base case. We needed to power this conservatively, make sure that we're in a position to detect a strong effect, and get the drug into the clinic where I think it'll meet a tremendous need.

Andrew Tsai, Analyst — Jefferies

And then simultaneously, you're planning for phase three, kind of, quote, unquote, at risk, starting it up first half of next year before the phase 2B reads out. Why is that first? And then secondly, how many phase 3s are we talking about? Just one, because I believe the phase 2b is designed as a pivotal registrational quality study.

Amit Etkin, Board Member

That's right. So that was part of our design thinking for the phase 2b. We also have, it's a unique situation, right? That we're in a position where we already know a lot about the drug, the active drug here, primpexil. There's been a lot of studies. There's studies that are yet to come out that came out even in preprint this fall, further supporting, even since PaxD, the efficacy of Prampexol. So it's less a question of efficacy that usually you wait on your Phase 2b before starting the Phase 3. It's more a question of have we solved tolerability with this approach. We'll know that already as part of Phase 1 studies that we're doing as part of blinded data analyses on the Phase 2b. And that opens up the possibility of starting your Phase 3 earlier and therefore putting yourself into a earlier position to seek potential regulatory approval. And that's our strategy here. And so we'll expect to go to the FDA to seek alignment on a phase three design to start by early 2027. That'll be an important outcome, a 2026 outcome here as a regulatory catalyst event, if you And that then allows us to compress the timeline to then get to NDA and we're funded through 2029 so we're funded through all of these activities funded through the phase three and to your question it would just be a single phase three then given the design of the phase to be being potentially registration and supportive

Andrew Tsai, Analyst — Jefferies

yep and then yeah one component is trying to mitigate or offset the side effects of parameter pixel you're using or dance atron very carefully in a titration sketch so ultimately what kind of nausea vomiting rates you think Like we can expect what is, for instance, pramipaxil alone show in prior clinical studies.

Amit Etkin, Board Member

Yeah, so I think the rates of nausea and vomiting are perhaps less of the kind of operative rate as the rate of dropouts due to adverse events. You can get a little bit of nausea if you don't drop out. If you, you know, like the drug and you stay on it, it's fine, right? The dropout rates have been massive with pramipaxil alone. So, again, with the PAX-D as an anchor, 15% of patients dropped out due to AEs incrementally more than placebo in the prampexole arm, so 20% versus 5%. Most of that was nausea and vomiting. So if you can get that down, and an anchor point might be where an adjunctive antipsychotic For example, Kaplyta, very successful adjunctive antipsychotic, has about a 9% dropout due to AEs on average across its base three trials that gives you a very commercially competitive product and I think we'll you know be in a good place to get there with this combination with the modified release furthermore PK matching two drugs with very different half-lives so you have a long half-life on prampexil a short half-life on ondansetron on prampexil is what's driving the nausea and vomiting so now if you can better match them you can better counteract the nausea and vomiting all of that plus the titration schedule itself should lead to strong tolerability okay so something less than

Andrew Tsai, Analyst — Jefferies

15% placebo adjusted Delta for sure yep and so you know D let's just say hypothetically it was like a Cohen's effect size of I don't know 0.25 or something something lower than what you've you're 80% powered for like do you still commit the phase three studies the the root of question is at what point do you kind of discontinue the program entirely due to unfortunate results from the phase 2b or do you commit phase three regardless I mean we

Amit Etkin, Board Member

will have already started a phase three by the time we learn about the phase 2b but there's really nothing historically indicating that that's what you would see. In fact, the data historically indicate that maybe we're being too conservative in our estimates. If you take again that meta-analytic effect size of 0.64, including a lot of lower dose studies, and we would be the second highest dose study right under the chase 4.1 milligrams that got a 1.1 effect size, then maybe the 0.45 effect size powering here is going to turn out to be quite conservative and maybe that would have meant we could run a smaller study but obviously you don't know that until you run it and I think it's better to be conservative

Andrew Tsai, Analyst — Jefferies

than you know powering to perfection understood and phase 3 again starts first half 2027 what would the timeline be as we think about potential approval timeline because the phase 2b seems like it's only going to take a year or a year and a half will that same be well the same

Amit Etkin, Board Member

be for the phase three as well yeah so we'll guide obviously more on timing once we have the final phase three design once everything is signed off with with FDA for that study so I don't want to get ahead of things that aren't yet finalized however one of the things we have messaged again with FDA feedback is that we're expecting two drug arms two levels of prampexol so the FDA likes reasonably to look at dose response relationships so we'll have a lower dose in there as well that will certainly increase the overall sample part of our goal is also to try to maintain as close to 5050 drug and placebo even if you have multiple drug arms they all would go into that 50% or so drug component that helps maintain expectations for patients so that will lead to a larger study obviously that would mean you know either more sites or it takes longer will be more specific once we've finalized that but I do expect to be some dose response information in addition to the efficacy overall at the 3.2 milligram

Andrew Tsai, Analyst — Jefferies

dose yep very clear and you know notorious in depressions plus high placebo responses so how are you mitigating against a high placebo response or professional patients and so forth maybe talk about that yeah so we

Amit Etkin, Board Member

actually I haven't had an issue with high placebo response per se that comes from various other sources that you can control well in terms of how you do your assessments and how you structure your trial and how you message expectations to patients, but I think where the real risk is that's a systemic risk across our field is professional patients. We've seen it in multiple major pharma and biotech readouts over the past couple of years. It's always been an issue, but it's become more and more of an issue of late for a variety of structural reasons. What we've been doing is being very explicit, very directly messaging what our internal process has been to prevent as much as possible professional patients from coming in so things like requiring medical and pharmacy records all of our trials are adjunctive you should have a record for having the diagnosis and been prescribed the drug and then we need to be able to measure it in your drug or in your blood or in your your urine and we do that repeatedly throughout the course of treatment as well and that tells us that we're getting the right patients who are showing the right behavior and not just in a trial because they want compensation that's a huge risk especially for as it turns out monotherapy trials which are are still very common in this field we've seen in the data that we've reported even earlier last month interim updates on the compliance pattern in both Alto 100 and Alto 300 ongoing studies where we see a hundred percent compliance in Alto 300 with their underlying drug you You can't measure the drug itself because it's too short of a half-life, but you can measure their underlying drug, 100% compliance throughout double-blind and open-label. With ALTO 100, where we've been measuring the PK of the drug in kind of batches of patients rather than waiting all the way to the end of the trial, we've seen 97% compliance. These are really, really strong numbers and require you to have a very clear gate, which we run as a sponsor-led eligibility review that has to okay each and every patient as they come in. It's just a systemic issue with our field, and I think we all have to act differently to prevent it and change the incentives. Until that changes, I think each company has to be very responsible for its own trials, and we feel it needs to be clear in messaging how well that's worked.

Andrew Tsai, Analyst — Jefferies

Thanks. And then maybe last question and then we'll shift to your other program's life cycle management opportunities for 207. Let's just say TRD and second half 2027 was successful. Do you feel compelled to move to MDD or not? It sounds like no, you don't need to, but bipolar depression? Other indications?

Amit Etkin, Board Member

I mean, look, there's good data, even similar data, I would say, to major depression in bipolar depression. so that certainly could be a next step but I think again starting with where I started this discussion of like what what do we really mean when we say TRD there's ideas of like much much more resistant and that I think the field has in its narratives around things like psychedelics pushed to but TRD actually will cover the kinds of people who an insurance company would pay for getting a branded drug. So I think that really is a very wide spectrum even under that label. And by an adjunctive program as we are doing here, you don't have to come off of your existing drug. It fits much more the pattern that clinicians like myself use when you prescribe a new drug to a patient, especially one who's already failed a few drugs, which is let's not rock the boat with their underlying drug. Let's add the new drug on top See how it works and then make it a decision with the underlying drug great. Thank you

Andrew Tsai, Analyst — Jefferies

And so then shifting gears to alto 300 Agamela teen There's a data readout now in first half 2027 phase 2b Originally, it was guided to mid 2026 so maybe talk about why what happened exactly why the delay?

Amit Etkin, Board Member

Yeah, so so the delay is really Really coming out of that quality filter that I mentioned, making sure that we have the right patients and are preventing professional patients from getting in. When we initially estimated what the readout timing would be, it was without a clear understanding of exactly what that ultimate recruitment rate is with that filter in place. And then we saw progressive acceleration as we restarted the ALTO 300 trial with this new approach, now having a much better understanding of where that recruitment rate puts us, and that trial got pushed out a little bit, but obviously I think we would all appreciate making sure the right patients are in a trial and giving us the best chance of success is the most important factor here. But the other important thing to remember is that because we've now had that experience, The way we're projecting 207 has already accounted for the recruitment rate that imposing all these professional patient filters achieves. So that gives us even more confidence in the 207 timeline for second half 27 for that phase 2b.

Andrew Tsai, Analyst — Jefferies

Got it. And fundamentally, agamalitine is approved in the EU, was never approved in the U.S. Maybe you walk us through remind us what happened what and why you think you can get it approved this time around?

Amit Etkin, Board Member

so sagomelatin ultra 300 Followed frankly much the same pattern as every all-comer antidepressant Which is at some trials work and some trials don't and you need two positive ones at the same dose To be able to get it approved Novartis developed it in the United States Servier developed it in Europe and Novartis saw frankly very much what Servier saw which is they had excuse me they had studies at different doses 25 milligrams and 50 milligrams at separate arms one phase three hit for 25 another phase three hit for 50 but they didn't get two at the same dose they would have to then do a whole new phase three to be able to get that second study they They were running out of composition of matter timing, and so they didn't proceed further with the program. But that's exactly why the precision lens that we're taking is so important. Because if you can be much more consistent in the patients that you are identifying and that you think may have a better chance of success, then you can bend those odds. And you don't need to wait for two positives and have to do three or four or five studies to get there that you can be a lot more deliberate in terms of the population that you're targeting. So that's part of the perspective. The others, of course, we're studying this as an adjunctive treatment, adjunctive treatment in people, therefore, who have failed the treatment also means a lower placebo response and people who are more clearly patient-like, that is, have a clear record of being diagnosed and being treated, as opposed to a lot of monotherapy studies where patients have absolutely no history of MDV or treatment.

Andrew Tsai, Analyst — Jefferies

Got it, got it. And then earlier last year, not this year, I think you decided to, you did an interim analysis, and then I think you decided to continue the study and upsize it. So what can we infer what the placebo-adjusted efficacy delta might have shown for you to upsize rather than fully stop for futility, for instance?

Amit Etkin, Board Member

Yeah, so the reason we did an interim analysis was really, again, to address that professional patient risk, which we saw, you know, in sort of clear terms with the readout of the Ulta 100 MDD phase 2B where the adjunctive portion of that study had a really nice effect, 0.47 and were 100% compliant with drug amongst those people we sampled for PK whereas the monotherapy arm was 56% compliant amongst the people that we sampled for PK and didn't show any effect. And so that led us to then say well can we identify those site level execution risk factors markers amongst the baseline data for our ALTO 300 study to take out those sites that have the highest risk of bringing in professional patients. We did that in a blinded way then ran the interim analysis to basically make sure that we have drug signal in there and then as Andrew was saying the resizing which was a very slight resizing from 150 to 200 patients with the biomarker. We set boundaries on either end for futility and for early success, which is a very high bar, as you can imagine, and it didn't meet either of those boundaries. So the effect size is somewhere in between, very consistent with a drug signal, but now amongst patients who are more confirmed in terms of removing that professional patient risk, and then revised our approach going forward. the upsizing was very modest was just what was recommended by the statisticians to go from powering at 0.45 to powering at 0.4 Coenstein thanks and on the

Andrew Tsai, Analyst — Jefferies

safety side I think agameline team at higher doses do show liver toxicity maybe talk about what you expect for your compound yeah so at 50 milligrams

Amit Etkin, Board Member

There is a slight rate of LFT elevations are actually not toxicity per se in the sense that it doesn't lead to any long-term issues these are actually adaptive liver enzyme changes at lower rates by the way than you see for other antidepressants and certainly for something like cobenfee which doesn't even have LFTs in its label but at 25 milligrams you get placebo-like levels of LFT elevations and also at 25 milligrams you get the same level of efficacy as you get at 50 milligrams in other words we chose the 25 milligram level specifically because meta-analyses have demonstrated there is no dose response on efficacy but there is on LFT so you might as well stick with 25 get the efficacy at that dose and avoid the LFT elevations as per for For example, the Novartis U.S. studies. So that's where we are, and of course we'll let the data dictate how things look, but that was the strategy for getting there.

Andrew Tsai, Analyst — Jefferies

And then what patents are you relying on this asset? Because I think agamelitine ran out in terms of exclusivity.

Amit Etkin, Board Member

So we have granted a method of treatment in patient selection using the EEG biomarker. so it's very much directly matching what would be in the label that's an approach we feel very strongly about I also think it's important to sort of take a moment to reflect on the importance of method of treatment in psychiatry all of the successful programs luma teperon cap light of velity from axon cobenfy from Karuna esketamine from bravado from J&J all are based on method of treatment patent. So we've studied that landscape for all of our programs. We've reflected that in our IP position, which we believe is very strong, and in this case already granted IP around our patient definition. Great.

Andrew Tsai, Analyst — Jefferies

And the last couple minutes is you do have another program, ALTO 100, which we touched BDNF is the mechanism. Data mid-2027. so maybe speak to your confidence around the why you think this could succeed in bipolar depression and how'd you power this study so this is a novel mechanism

Amit Etkin, Board Member

of action it's a potential first-in-class drug that enhances neuroplasticity directly and that's a drug that was developed really out of a functional assay looking for neuroplastic mechanisms and it's being given to patients here who have an identified deficit in neuroplasticity as evident by deficits in learning and memory which requires neuroplasticity as its basis. So there's a good mechanistic match here in terms of what the drug does and how we define the patients. But also in bipolar depression more broadly which is where we're targeting it's been repeatedly shown just like in major depression that people with cognitive problems like memory problems tend to have a much worse course of their depression more chronic more disabled and all they have in bipolar depression right now is adjunctive antipsychotics with all of their side effect burden so the opportunity here is a really strong opportunity the confidence that comes for us comes for example from the adjunctive arm of that MDD phase 2b study that I mentioned which had an effect size of 0.47 and various other analyses we've done of the MDD data which give us good reason to think that we're in a good position here to deliver a potentially first-in-class novel mechanism which itself would be a super, super exciting outcome.

Andrew Tsai, Analyst — Jefferies

So, three major readouts in 2027. Well, thank you so much for the time and congrats on all the progress and thanks everyone for listening. Thank you.