Great. Thanks very much, everybody. It's my pleasure to be moderating this chat with Heather Turner, CEO of LB Pharmaceuticals. We'll keep this mostly conversational, but maybe Heather to start, you could give us a 2-3 minute overview of LB and just set the stage on, you know, what this year looks like for you guys, and then we can do Q&A. Thanks for attending.
Yeah, sounds good. Thank you so much for having me. LB Pharmaceuticals is very well situated at this point in time. With our most recent financing, we have a very nice steady stream of clinically meaningful value creating catalysts. We have Phase 3 schizophrenia data coming in second half of 2027. We've got Phase 2 bipolar depression data coming in the first quarter of 2028, and we've got now adjunctive MDD data coming in the first half of 2029, and this is all with our late stage asset, LB-102. In a Phase 2 schizophrenia trial, what we think is emerging for LB-102 is a therapeutic with a differentiated profile in what can be a very large branded antipsychotic market.
From a differentiation perspective, we believe we'll have competitive efficacy in all of the indications I just talked about. The potential for class leading safety and tolerability just based on the fact that we had a very low rate of adverse events, and also an opportunity to have a differentiated effect in many residual symptoms that persist across all of these indications. Those are cognitive impairment as well as anhedonia. These are symptoms that persist in all three of these indications. Based on the data from the Phase 2 trial, we think we have an opportunity to have a beneficial impact there.
Great. Yeah, the Phase 2 data is pretty clear cut, right? Obviously the molecule itself builds off of a lot of data with amisulpride. Maybe talk about the Phase 3 design and, you know, just in the context of psych where good drugs can fail in clinical trials, like what are you at LB doing from a risk mitigation perspective, understanding, right, that you're only doing one additional pivotal in schizophrenia?
In the Phase 2 trial, we designed that trial to be registrational in nature, so this was a large Phase 2 trial. We evaluated 359 patients at 25 sites in the U.S. The scope and scale of the Phase 3 trial isn't all that different from Phase 2. For Phase 3, we'll be taking two doses, 50 and 100 milligrams. It'll be a three-arm trial, whereas the Phase 2 trial was a four-arm trial, so we do think that should help with the placebo rate. In the Phase 2 trial, we implemented a number of measures to manage that placebo rate, which is obviously one of the risks in this space. We had a central rater that we utilized. It had a vendor that helped us to identify and exclude professional patients.
We were very judicious in the scales that we chose. We know that too many scales or too much time to complete scales can really increase that placebo rate due to both rater and patient fatigue. The plan would be to take all of those measures into the Phase 3 trial. In addition, in the Phase 3 trial, we'll be adding a vendor, so we'll use two vendors to help identify and exclude those professional patients. The other thing that we know to be very important is that frequent, consistent engagement with the sites, and to do so in a unified fashion with your CRO. This is not a space where you can just hand it off to your CRO. You have to be very engaged, you have to be monitoring, you have to be asking questions and providing that oversight.
All of that we'll continue to do in the Phase 3. There's also a lot of overlap between the sites.
Yeah
... Phase 2 and Phase 3, so we actually know a lot of these sites. We have a history with these sites. The vendors are the same vendors from Phase 2 to Phase 3, a lot of the same people. We're trying to minimize, you know, the variables as much as we can, moving into this Phase 3 trial.
Yep. Okay. Makes sense. Maybe talk about the effect size you saw in Phase 2 and the degree to which you've powered it with some buffer in Phase 3.
Yeah. The effect size that we saw in Phase 2 was robust. Whether you calculate it with completers or with MMRM, we had an effect size that ranged anywhere from like 0.5 to you know upwards of 0.6. We feel that demonstrates the clinical robustness of the Phase 2 data and gives us quite a bit of confidence heading into Phase 3. We also are adding 2 weeks of duration to this Phase 3 trial. The Phase 2 was 4 weeks in duration. The Phase 3 is going to be 6 weeks in duration. We do think that'll give us a couple extra points reduction in the PANSS total. We think that we're well situated to have a successful Phase 3 trial.
Yeah. Okay. Then from a commercial perspective, like I definitely appreciate the strength of the efficacy data you have and talking about things like cognition and anhedonia. I think on the investor side, I think there's been, right or wrong, this kind of just rerate in how big the branded schizophrenia market for any new drug can be, given that the Uzedy launch is fine and maybe better than most, but still lagging consensus and honestly lagging what a lot of the physicians said ahead of the launch, right? I almost feel like this drug really surveyed a lot better than it sold. I think in the backdrop of that, like what is your view on kind of where this could be best positioned in schizophrenia?
Like, I'm not asking you to give guidance, but like how do you help people size that TAM?
Yeah. You know, I think what has been observed for Uzedy could very well be Uzedy specific. That molecule does have a couple of liabilities that LB 102 won't have. You know, it's twice daily dosing with a pretty significant food effect, which I think makes it challenging for adherence. It also has anticholinergic side effects, which, you know, make it difficult for some patients to get to that full dose 'cause there is some titration involved. For LB 102, we have rapid onset of action. We saw a statistically significant separation from placebo at the very first week of evaluation, and we don't have any sort of titration, so patients will start at a therapeutic dose.
In addition to that, I think you're right in that the launch itself was probably a bit overstated and the expectations were probably a bit too high for Uzedy, and that disappointment may be stemming more from that, frankly.
Yeah
than the performance.
Yeah
of the drug. I would say, though, in terms of LB 102, I fundamentally believe we're gonna offer a therapeutic that's going to be efficacious in treating the acute exacerbation of schizophrenia and offer a favorable tolerability profile as well as this opportunity to treat these residual symptoms. I think that puts us into a place where we could be the branded antipsychotic of choice offering something different. This would be the first benzamide available in the United States. It would be a new chemical class available for treatment. Physicians do have a an awareness of amisulpride, and some lament the fact that it hasn't been available in the United States. I do think there's a significant opportunity for it to be used among the branded antipsychotics.
Yeah. Okay. Fair enough. We'll get that data second half 2027, and then, you know, I think the indications that have you know I think created a lot of enthusiasm in the investor community have been bipolar and MDD. Bipolar comes first, and, you know, I feel like from my perspective on the one hand, I think of it as an easier indication for antipsychotics because it has MDD components but schizophrenia components. It's like more of a mixed feature kinda thing. You know, on the other hand, for amisulpride, we have really robust data in MDD, but less robust data in bipolar.
Just maybe talk about, like, LB-102, and we've got evidence on the two ends of the poles, but, like, what's the risk going into bipolar without really any true robust proof of concept?
Yeah, you're correct that we don't have specific data with amisulpride in bipolar in depression clinical data. It is used quite widely in mood disorders. Of the scripts that were written in 2023 in a subset of the EU, 20% of those scripts were in mood disorders. It continues to be used pretty widely in that space, but it's true that we don't have specific data. What I would say is that the biological underpinning of depression is the same, whether it's major depression or bipolar depression. It's the same, you know, biological functioning that's creating that depression. You would expect that if it works in major depression, that it would also work in bipolar depression. In bipolar depression, you also have to make sure that you don't or that you prevent the emergence of mania.
This is, you know, one aspect of this.
Right
Disease, and this is where having data in schizophrenia, I think, helps to provide some confidence that because we control psychosis and because we demonstrated that we can, you know, treat the psychosis in schizophrenia, that we would have an effect on mania or preventing mania in bipolar depression. While we don't have specific data in bipolar depression, I think we have quite a bit of clinical evidence to suggest that we would be efficacious in bipolar depression. In addition to that, we also have a very nice trial design planned for bipolar depression. This is a fixed flexible dose design where patients start at 25, and then at the end of three weeks, they would escalate to 50 in a protocol blinded fashion.
This will allow us to evaluate two doses in this disease while still maintaining a two-arm trial. We know in depression trials it's very important to try to limit the arms. Each arm that you add can increase that placebo rate. It's important to try to limit that. We think we have a nice trial design to really evaluate this.
Yeah. Okay. I think from my perspective, like, it feels like there's so much mechanistic and clinical evidence why this should work. The only thing that we've kind of struggled with was just kind of like how do we think about the right dose? And specifically the right dose to hit, I guess, what we think is the contributing part of this mechanism to bipolar, which in CNS is always really hard to know.
Yeah.
How would you answer that question? You know, you dropped down in dose, right? What was the thought process there?
Yeah. When you look at bipolar depression and antipsychotics, there is two dosing regimens that you tend to see. Some antipsychotics cut the dose in half when they go into bipolar depression. This is what Vraylar did. They did it, I think, predominantly because they have a very high rate of EPS at their schizophrenia dose, and so in this population, they really needed to lower the rate of EPS. They still have a pretty high rate of EPS in this, even with half the dose. You also have a drug like Caplyta, which kept the same dose, as in schizophrenia as it did for bipolar depression. They really don't have the same safety concern that, say, Vraylar did, so they can keep it at the same dose.
Because of this fixed flexible dose design, we're able to actually test two doses. We test the schizophrenia dose, the lowest schizophrenia dose, which is 50, and then we're also testing half of that dose, which is 25. We think that this will set us up well to kind of hit that sweet spot for the treatment of the symptoms of this disease. The other thing that I'll note is when you look at amisulpride and you look at the D2 receptor occupancy across its uses, you know, between major depression where it's dosed at 50 to negative symptoms, which, remember, with negative symptoms you really need to make sure that you prevent the emergence of psychosis in that patient population.
Right.
It's between 100 and 300 milligrams. Then when you move up to schizophrenia, it's 400-800. With amisulpride you do see this stepwise reduction in-
Right
dose.
You can kind of just follow that paradigm basically.
You can look at the receptor occupancies, and we think where we land with both bipolar depression and the MDD dose is right in the same receptor occupancy range, as amisulpride.
Yeah.
We think that we're in that kind of range where we need to be.
Yeah. Okay. From an execution perspective, is it fair to say you're doing all the same things in bipolar as you are in schizophrenia, like SAFER criteria, other stuff like that?
We are using SAFER in both bipolar and in MDD.
For people who don't know what that is on this panel, can you just like explain it for 60 seconds?
Sure. SAFER is something that comes out of Mass Gen and it's an opportunity where you have a patient that's met the inclusion criteria of your trial, and it's another layer of review that's conducted by this third party in order to ensure that the patient that you're enrolling does in fact have major depression or does in fact have bipolar depression one. It's a way to just triple check that this patient has met the inclusion criteria of the trial. You can imagine that not all patients come with pristine medical records of their history, right? If you were to require all patients to have, you know, very specific medical records, you'd never enroll the patients that you need. This is an opportunity where you can just pressure test, you know, the inclusion criteria for these patients.
What it does mean is you might have a higher screen failure rate.
Yeah
which is why the trials take a little bit longer to enroll.
Yeah. Okay. Makes sense. For bipolar, is it as simple as showing, you know, a favorable safety profile and hitting a P value, or is a win in that indication more than that?
I think for all of these indications, the competitive efficacy is table stakes. You have to have competitive efficacy, meaning you're in the range of the previously approved therapeutics.
Right.
Whether PANSS delta or MADRS delta, you're in the range of competitive efficacy. It then becomes what is the safety and tolerability profile? Can this patient stay on this drug and avoid relapse? I think importantly, if you can treat some of these residual symptoms even better, right? If not only are these patients able to stay on the drug, but you can actually treat some of these residual symptoms of anhedonia or cognitive impairment or in the case of schizophrenia, negative symptoms, then that I think would be viewed as even more attractive.
Yeah.
I think you have to have competitive efficacy and then it becomes what's your safety and tolerability profile and do you offer something differentiating?
Yeah. Okay. To that point, do you wanna like drill down a little bit more into your tolerability profile? You know, I think if I can think about the questions I get from investors or some of like the presuppositions out there are a contingent of people who think Caplyta really raised the bar on safety, and is super clean. I, you know, even heard one KOL say, "Hey, you know, I wasn't a prescriber of atypicals for mood disorders and now I am because of this drug." Maybe talk about your AE profile and just like-
Yeah
How does it compare in the key events to something like a Caplyta or like a Vraylar or these other drugs that are, you know, gonna be blockbusters if not already in the mood disorder space?
Yeah. I think one of the big AEs that is present with antipsychotics is extrapyramidal symptoms or EPS. This is a broad range of adverse events that are associated with Parkinsonian-like movement disorders.
Right.
The rate of EPS that we observed in our Phase 2 trial was actually quite low. For 50 milligrams we only had one case of EPS, and that rate was actually lower than that of placebo. At the highest dose, 100 milligrams, we only had two cases of EPS. This EPS rate is actually on par with that observed with both Uzedy and Caplyta. Given the receptor occupancy, the dopamine receptor occupancy we observed, this is quite interesting and differentiating. Caplyta does have a sedative effect, right? That's its liability is that patients you know it does cause sedation in a number of patients, which can be very challenging in you know bipolar depression or MDD where these patients are much more functional.
We had negligible sedation in our Phase 2 trial. We only had one case at the 75 milligram dose of sedation. We think we'll be differentiating in that regard with respect to Caplyta. Vraylar, and it's a very large antipsychotic, right, it's approaching $4 billion in sales, still has a very high rate of EPS in both bipolar depression and MDD. Even though it cut its dose in half, right, it still has 10%-15% EPS rates. Having that lower rate of EPS we think would be differentiating in this space.
Yep.
From a tolerability perspective, we think we stack up pretty well.
Yep.
Just from what we observed in the Phase 2 trial.
Okay. I think I've asked you this before, but for EPS specifically, like is four weeks long enough to de-risk differentiation there? I always think of tardive dyskinesia. I know that's not only what EPS is. It's something that is like a more of a lifelong cumulative exposure issue.
Yeah, tardive dyskinesia definitely does come later, so you're right in that you wouldn't expect to see that in the four weeks. Although the rate of EPS does tend to track to whether you see TD at, you know, later in time. Yes, that does tend to take more time. There isn't a whole lot of TD with amisulpride.
Right.
You don't tend to see it there either. I wouldn't expect to see it with our compound.
Yeah.
Just the low rate of what we observed.
Right. Okay. Maybe lastly on MDD, you recently did a financing to support MDD specifically. You know, what was the rationale of, I guess, pulling MDD forward? Like, the history of a lot of the development of these drugs is companies are conservative, they do schizophrenia, then they do bipolar, and then they wait. Maybe that has the benefit, right, of like really understanding your drug by the time you get to bipolar MDD, but sounds like you feel like you're ready to go for it now. Where's your? What's the team's perspective there?
Yeah. We think we have a pretty good gauge on dose for adjunctive MDD. Like I mentioned before, when you look at the dopamine receptor occupancy for the use of amisulpride, we think where we landed with dose for MDD, which is 15 and 25, and then for bipolar depression, which is 25 and 50, is in the range of the dopamine receptor occupancy that you see with amisulpride when it's used in MDD. We think it's important with MDD to look at that because you don't want too much dopamine receptor occupancy because you can actually blunt efficacy and create some anhedonia-like symptoms. We think it's important to go lower in MDD than we did in bipolar depression. Also, with the IRA, we do think there's a lot of strategic value in-
Yeah
Pulling forward this indication when you only have seven years before you actually have to negotiate that price. We think pulling that in makes a lot of sense strategically as well. Then for major depression, we're also doing a fixed flexible dose design, so we will be able to evaluate two doses here, 15 and 25, which we think will also be, you know, helpful in planning for the later stage development.
Right. Okay. Makes sense.
Yeah.
Yeah, maybe the only question I have left, and then Heather, anything else you'd like to highlight I think would be good, is just in going back to timelines, right? I mean, I think when I've covered companies doing schizophrenia like Karuna and Cerevel and depression and bipolar, there seems to be like a wide range actually company to company in how long it takes to do these studies. Your estimates for completion, so 2027, 2028, 2029, like maybe just talk about what you're assuming there and your level of confidence that you're gonna hit those timelines.
Yeah. We looked at a number of different things in planning on that enrollment rate. We of course looked at our historical experience with these sites and how they did against their projections for the Phase II schizophrenia trial. We looked at the competitive landscape, how many different trials are going to be going, how competitive might they be. We talked to the sites about that as well. We of course talked at length with our CRO about our CRO's experience, and its perspectives on the enrollment timelines. We also looked at the quality of the sites. It's really important that you have very high quality sites and your ability to contract with these high quality sites. It's for this reason that for the adjunctive MDD trial we're gonna go into Europe.
This will be a Europe and U.S. trial, and that's because we think we need to go into Europe to continue to make sure we use high quality sites for that trial. It was a combination of all of those factors that we looked at in order to think about the enrollment rates that we're using in order to project when we think these trials will come to fruition. I would say that these are, you know, base case at this point, right? We'll of course continue to monitor this and but we think for now these are really good estimates.
Yeah. Okay. What's your updated cash runway at this point?
With the PIPE, we have cash into the second quarter of 2029.
Okay.
That now what that means is that all of these programs that we just talked about today are now fully funded. We have capital to take us through those trials. We have capital that allows us to conduct all of the NDA enabling studies as well as the safety study for schizophrenia so that we're in a position to seek approval if we have a successful Phase III trial. The company is very well situated at this point in time, fully capitalized, ready to go, and really now the focus on executing against these trials.
Yeah. Okay. Awesome. All right.
Yeah.
Well, thank you, Heather. Appreciate it. Always a pleasure to see you.
Yeah, thank you so much.
Okay. Thanks everybody for joining.