Good morning, everyone. I'm Ami Fadia, biotech analyst here at Needham. Welcome to the next session with LB Pharmaceuticals. It's my pleasure to be hosting Heather Turner, CEO of the company. Heather, thank you so much for participating in our conference and taking the time for this session. I will turn it over to you for the presentation, and we'll have some time at the end for Q&A. Maybe this is a good time to remind our listeners that they can send me any questions that they'd like me to ask through the dashboard. With that, over to you, Heather.
Thank you, Ami Fadia, for including us in this conference today. We're really happy to be here in the Zoomiverse with you all. I will be making forward-looking statements today. The vision for LB Pharma is to build a fully integrated company focused on CNS-related diseases. This company would be ready, willing, and capable to successfully launch a therapeutic when we find ourselves with an approved asset. We have a late-stage asset, LB-102, in schizophrenia, bipolar depression, and adjunctive MDD. We presented phase II data from a schizophrenia trial last year, and from that, we think we have an opportunity for a very differentiated profile in what is a very large branded antipsychotic circuit. Coming out of that phase II trial, we engaged with the FDA, and with that engagement, we believe there's a streamlined path to approval in schizophrenia with just a single phase III clinical trial.
We have a significant opportunity to expand across psychosis and mood disorders, as well as developing a long-acting injectable formulation. We have a robust IP portfolio with composition of matter that takes us out to 2041, 2042, depending on the patent term extension. With the PIPE that we completed in February, we have a very strong balance sheet that takes us all the way through the clinical readouts and into the second quarter of 2029. The differentiated profile that we think is emerging for LB-102 is one where we think we'll have competitive clinical activity with a potential for rapid onset sustained response. We have an opportunity and potential for a class-leading safety and tolerability profile, and we saw robust effects on cognition and negative symptoms, which are two areas of significant unmet need. This is a validated mechanism, once daily, and a starting therapeutic dose.
There is no titration. This would be a new chemical class available in the United States. This would be the first benzamide antipsychotic in the U.S. As I mentioned, we do have an opportunity to develop a long-acting injectable. With the PIPE that we completed in February, we're really well set up for multiple clinical milestones over the course of the next couple of years, with cash runway into the second quarter of 2029. We're funded for a phase III schizophrenia trial. This data is expected to read out in the second half of 2027, and we recently announced the initiation of this trial. We're also fully funded for all of the NDA-enabling activities. This is the NDA-enabling studies, as well as the open label safety trial, so we can accrue the safety population that we need when we are in a position to submit for approval.
We also have fully funded a phase II bipolar depression trial. This trial has also initiated, and we're expecting data in the first quarter of 2028. An adjunctive MDD phase II trial. This trial we expect to start in early 2027, and we expect the data in the first half of 2029. We're really well set up for a number of clinically meaningful milestones. LB-102 is a derivative of amisulpride. Amisulpride is a generic antipsychotic that's been approved around the world. It was never approved in the United States, and it continues to be widely used, with more than 2 million prescriptions in 2023 in a small subset of Europe. It has approvals in schizophrenia, negative symptoms of schizophrenia, as well as dysthymia, which is a persistent form of depression, and it is extensively used in mood disorders as well.
It selectively inhibits D2, D3, and 5-HT7, and really very little else. It's very selective. It's got one of the highest effect sizes among the approved antipsychotics, and it has one of the lowest all-cause discontinuation rates. It's really viewed as an asset with a favorable safety efficacy profile. It does have a challenge, though. It's very poor at permeating the blood-brain barrier. This results in the need for high doses. For schizophrenia, it's dosed between 400-800 milligrams a day. It requires twice-daily dosing, which can be a challenge for many of these patients. The founders of LB set out to create a new chemical entity that could result in composition of matter IP and address this limitation of amisulpride. They did this through methylating amisulpride. You can see the methyl group that they added to the chemical structure.
This methylation improved the lipophilicity of the molecule, which enabled more efficient transport into the brain and a longer residence time in the CNS. This resulted in a number of advantages, improved potency, a lower dose, reduced systemic exposure, and once-daily dosing. This is LB-102 at 50 milligrams is about the same as 400 milligrams of amisulpride, and this is based on dopamine receptor occupancy data. At these doses, both of these are about 70% dopamine receptor occupancy. We also were able to maintain the receptor binding profile for LB-102. It is, like amisulpride, a very selective inhibitor of D2, D3, and 5-HT7. This is important. It's because these targets really enable the opportunity to develop in both psychosis and mood disorders. Of course, D2 is important for psychosis and mania, and D3 and 5-HT7 are important for depression and cognition.
In addition, both amisulpride and LB-102 have another shared attribute, and that is that they preferentially engage presynaptic autoreceptors that are implicated in mood, anhedonia, and cognition at lower doses. What does this mean? It means that in high doses, it's blocking dopamine, and at lower doses, it's actually triggering the release of dopamine. You can treat a number of diseases just by altering the dose. The path that we're pursuing for LB-102 is one that is very well established. You start in schizophrenia, you expand into bipolar depression, and then you expand into MDD. There's a method to this madness. Starting in schizophrenia is at the highest dose, and it allows you to utilize the safety population from this indication across these other indications. It allows for a very nice synergistic approach to development.
In addition, you can start with the antipsychotic pricing, and that then can get pulled through these other indications. This is the pathway that VRAYLAR has followed, which has resulted in almost $4 billion in sales. It's also the pathway that CAPLYTA followed, which resulted in the acquisition of Intra-Cellular Therapies. Schizophrenia continues to be a disease with significant unmet need. 74% of patients discontinue their medication within 18 months of treatment. Often, this is due to lack of efficacy or side effects. There continues to be a persistent challenge with negative symptoms. 60% of patients suffer from negative symptoms that are not adequately addressed by current treatments, and 80% of patients with schizophrenia experience some form of cognitive impairment, and this too continues to be a residual symptom that these patients suffer from. We announced early last year the successful results of a phase II trial in schizophrenia.
In this trial, we evaluated three doses, 50, 75, and 100. This was a 4-week inpatient trial. The primary endpoint was changed from baseline at day 28. We also evaluated cognition in this trial. This trial was designed to be registrational, 359 patients at 25 sites in the U.S. We had all of the statistical sensitivity analyses that you would anticipate for a registrational-type trial. During our end of phase II meeting with FDA, we asked if they considered this trial to be registrational in nature, and FDA responded that it did have the characteristics of an adequate and well-controlled trial. It's from this interaction that we have the belief that we can seek approval with just one successful phase III trial in schizophrenia. In this trial, we saw that each dose was highly statistically superior to placebo.
We saw a clinically meaningful reduction in the PANSS score. These patients were taken out of an acute schizophrenia state and into a more stabilized state, which would allow them to leave the hospital. We had a rapid onset of action with benefit appearing at the very first week of evaluation, and this was statistically significantly better than placebo, and it was sustained throughout the rest of the trial. We also had a very nice placebo rate. This was something that we had put a lot of thought and oversight into. We implemented a number of different measures to manage this placebo rate. We had a vendor to help identify professional patients. We used a central rater to provide quality control over the local raters.
In designing this trial, we were very judicious in the number of scales that we chose, as well as the time it would take to complete the scales. We know that both rater fatigue and patient fatigue is real. Importantly, we had very close oversight with the sites and the CRO. We had very frequent, consistent engagement with the site, which we think is also very important. We had a really robust treatment effect. Whether you look at this from a completers or an MMRM basis, this treatment effect is in the range of amisulpride, and importantly, at the 100 mg dose, it was greater than that observed for Cobenfy. This really speaks to the statistical robustness of this data, and it really gives us quite a bit of confidence heading into phase III. I mentioned that we also evaluated cognition. We utilized Cogstate.
We measured cognition at baseline and day 28. Here we saw a robust dose-dependent effect on cognition, one that was statistically significantly better than placebo at each of the doses. To see a treatment effect of 0.66 at 100 mg is actually quite unique in the realm of cognition. Importantly, the endpoint that's represented here is an endpoint that has not been enriched for patients who have severe cognitive impairment at baseline. To see this kind of effect in a broader patient population is, we think, quite interesting and encouraging, and something that we think we'll continue to look at in all of our upcoming clinical trials.
We were at a conference a couple of weeks ago, and at that conference, we announced in a poster another data point with respect to cognition, and that is, we evaluated whether cognition, the benefit that was observed in this trial, was really driven by the drug or by the fact that we treated the positive symptoms of schizophrenia. In that analysis, we did demonstrate that the effect that was observed was driven by the drug, which we, again, think is highly encouraging about this data. Of course, as important as efficacy is, it's equally important to have a drug that is both safe and tolerable. It's very important to physicians that their patients can stay on these drugs and avoid relapse. Every time a patient suffers from a relapse, it can cause irreversible harm to these patients.
To have a safety and tolerability profile which can enable these patients to stay on the drug is important. What we observed in our phase II trial is a really nice profile. It's one that is expected given we're a D2 antagonist. We had a very low rate of discontinuation due to adverse events. The overall discontinuation rate for this trial was 27%, which is on the lower side of schizophrenia trials. We also had very few serious adverse events in this trial. Overall, the safety profile that's emerging for LB-102 is one we think that is quite favorable. One of the things we observed in the phase II trial was a very low rate of EPS. EPS, or extrapyramidal symptoms, is an adverse effect that has been associated with antipsychotics since the very beginning.
These are often characterized as movement disorders and can be quite disruptive to patients and can often lead to discontinuation. We had a very low rate of EPS, and this is particularly true among the D2 antagonists and the partial agonist. This is potentially class-leading in terms of the rate of EPS. We saw a range of just 1%-5.6%. At the 100-mg dose, what was observed was lower than that of placebo. To put this into context, amisulpride has a rate of EPS in the teens, depending on the patient population. VRAYLAR, which is a partial agonist, at its schizophrenia dose, it has a rate of EPS of 24%-32%. This is quite low with respect to EPS, and one that we think is quite interesting and potentially class-leading among the D2 antagonists and the partial agonists.
We had very low rates of adverse events associated with increases in prolactin. Here it was just 1%-5.6%. One case of sedation among the 251 patients that were treated, and we had minimal QT prolongation. Importantly, no patient met the pre-specified stopping criteria. For phase III, which we just recently announced initiation, we're taking two doses, 50 and 100 milligrams. We'll be targeting 460 patients at 25 sites in the U.S. This trial will be six weeks in duration. It will be inpatient. The primary endpoint is, again, PANSS change from baseline, and this time at day 42. Cognition will be a secondary endpoint. In addition to this, we'll be in parallel opening an open-label safety trial.
Patients from our phase III trial will roll into this open-label extension, and we will also enroll new patients with the goal of having about 900 patients in this open-label extension. It'll last for 52 weeks, and the purpose of this is safety, and it will serve as the safety exposures that we need to have at the time that we submit for approval. In addition, in this open-label extension, we'll also be looking at two subsets. This is an outpatient setting, so this by definition is a group of patients who are stabilized, and we'll be looking at both cognition and negative symptoms in some subset analyses coming out of this open-label extension. We think this will be publishable and of course very informative as to how we might think about future development in these indications.
What's emerging for LB-102 coming out of this phase II trial is a therapeutic that we believe will be competitive with respect to efficacy and clinical activity. We also see a rapid onset of action that is sustained throughout the treatment. We have the potential for a class-leading safety profile with simple dosing once daily, no expected food effect or any challenging drug-drug interactions, and an opportunity for a differentiated effect in what are very challenging residual symptoms, cognition and negative symptoms. Altogether, we think we really have an opportunity to be the branded antipsychotic of choice in schizophrenia. Switching gears now to mood disorders. As I mentioned, we recently started the phase II bipolar depression trial, and we have plans to start the adjunctive MDD trial in early 2027. It is true that we are excited about schizophrenia.
We think there's lots of opportunity for schizophrenia, and most of the branded antipsychotics really reached blockbuster status when they expanded into the mood disorders, bipolar depression, and MDD. You can see here on the left, that the ones that have reached this blockbuster status have, in fact, had success in the mood disorders. We believe that bipolar disorder and MDD also aligns really well with the profile of LB-102. Similar to schizophrenia, there continues to be significant unmet efficacy needs with respect to anhedonia and cognitive deficits. This is true in both bipolar depression and MDD. There continues to be challenges with patients staying on these drugs due to safety or other adverse events. LB-102 has an opportunity to provide competitive efficacy, favorable safety and tolerability, and a unique opportunity to improve on these residual symptoms of anhedonia and cognitive deficits.
It's a very similar story as what I just described for schizophrenia. There's a number of reasons why we believe that the development of LB-102 in bipolar depression and adjunctive MDD have a very high probability of success. There's basically three pillars. There's the strong mechanistic rationale, validating clinical and real-world experience from amisulpride, and then supportive results from our phase II schizophrenia trial. With respect to the strong mechanistic rationale, I mentioned that LB-102 has this attribute where it selectively engages with the presynaptic autoreceptors at lower doses, and this then triggers dopamine signaling. In addition, I talked about the fact that it hits D3 and 5-HT7, both of which are implicated in cognition and depression. We also know that there's this opportunity in what we observed in our phase II trial for lower adverse events as a result of the improved dosing and tolerability.
There's also quite a bit of validating clinical and real-world experience with amisulpride. I mentioned that amisulpride has been approved in dysthymia, which is persistent depression, and it also has approvals in the negative symptoms of schizophrenia. It's been shown in randomized clinical trials to be as good or better than Paxil and Zoloft, and it's been shown to be significantly better than placebo with the MADRS delta of 4.8. It also has compelling antidepressant activity in bipolar depression. In addition, in the real-world experience, when you look at the prescriptions that are currently written for amisulpride, 20% are for mood disorders. It continues to have real-world validation for use in these mood disorders. Finally, with our phase II clinical trial results, we saw market competitive clinical activity, rapid onset of action. We saw effects on both cognition and negative symptoms.
A very nice tolerability profile, particularly in those adverse events that can really impact a patient's ability to function. We also saw an opportunity for efficacy in the emergence of bipolar mania, which is an important part of bipolar depression. This is just based on the positive symptom effect that we saw in the phase II trial. Let's talk a little bit about the trial designs that we have planned for bipolar depression and adjunctive MDD. Before I start, I want to just talk generally about this trial design. This is a fixed flexible dose trial design, which enables you to evaluate two doses in a two-arm trial. We know that in depression trials, every single time you add an arm, you have the risk of increasing that placebo rate. We're really excited about the opportunity to evaluate two doses in a two-arm design.
For bipolar depression, this is a monotherapy trial. Again, it's designed to be registrational. We expect the top-line data from this trial in the first quarter of 2028. We expect to enroll 320 patients at 30 sites in the U.S. This will be a six-week trial with MADRS-10 as the primary endpoint, and this is the regulatory accepted endpoint for bipolar depression. All patients will start at 25 mg. At the end of week three, if they have not seen an improvement based on the CGI score, they will be automatically escalated in a blinded fashion in a protocol-guided way to 50 mg, where they will stay on that dose for the remainder of the trial. The secondary endpoints will include cognition and anhedonia, and we have specified scales for those that are in this trial.
Again, we do believe this two-arm trial will be very helpful in mitigating that placebo effect. For adjunctive MDD, it's a very similar trial design. As I mentioned, this is adjunctive MDD, so this is a trial that is going to be used in conjunction with an SSRI or an SNRI. All patients in this trial will start at 15 mg. At the end of week three, if they have not seen an improvement in the CGI score, they will then be escalated in a protocol-guided, blinded way to 25 mg, where they would stay on the remainder of the trial. This also is a six-week trial, same endpoint, MADRS-10. Here again, we've included both anhedonia and cognition scales in a prospective way.
We're going to target 380 patients, and this is going to be a trial that will span across the U.S. and the EU. In summary, we have a really nice setup of a number of different compelling, clinically meaningful milestones that are on the horizon. We've got the phase III schizophrenia trial with data reading out in the second half of 2027. We've got the phase II bipolar depression trial reading out in the first quarter of 2028. We've got the adjunctive MDD trial reading out in the first half of 2029. Again, all of these are fully funded, and we have cash that takes us into the second quarter of 2029. We also have opportunities to pursue other indications for LB-102. We've got an opportunity to look at negative symptoms. There's also Alzheimer's disease, psychosis, and agitation.
LB-102 is a therapeutic that really has potential in a number of different indications. We think we're really well set up, and we're very excited about the opportunities that lie ahead. Thank you all.
Thanks, Heather. Thanks for that great presentation. I have a couple of questions that I wanted to just go back and talk about. There are some sort of differences in the mechanism for LB-102 and a typical antipsychotic. Can you sort of highlight for us what the differences in mechanism might be elucidated with the differences in the safety profile, and how does that translate into also the ability to demonstrate benefit in bipolar and MDD?
There are differences, and I appreciate you bringing that up. I would say in two important ways. The first is that LB-102 is a highly selective inhibitor of D2, D3, and 5-HT7, and that's it. It is not a promiscuous molecule. It doesn't hit a whole bunch of other receptors. There are a number of antipsychotics that hit a multitude of receptors, which we think can really contribute to a challenging safety and tolerability profile. So the fact that this is a very selective inhibitor, I think, is one big difference. The other is the fact that it's got this ability to preferentially engage with the presynaptic autoreceptors that are implicated in mood and cognition and anhedonia. What this means is that at low doses, it triggers dopamine signaling, right?
It triggers the release of dopamine, which does allow it to have a potential effect in depression, anhedonia, and cognition. There are a number of different mechanisms which support the ability to develop LB-102 in mood disorders. You've got D3, you've got 5-HT7, and you have this presynaptic, postsynaptic attribute, which I think makes it very different than many other mechanisms of antipsychotics, particularly the muscarinics. The muscarinics are really limited to pursuing psychosis-related indications because they really don't have a mechanism to move into the mood disorders. Then there are other antipsychotics which have a different mechanism when it comes to antidepressant, and then there are some that just don't work in mood disorders. I do think we have an opportunity here because of this unique mechanism of LB-102.
Maybe two follow-ups off of that. Maybe help us understand how you pick the dose for the bipolar and MDD studies based off of that, and how you're kind of getting to the right doses to be able to sort of activate the presynaptic autoreceptor activity. The other piece is maybe just with the muscarinic class also. Well, we have Cobenfy in the market, and we have a couple others that are in development. How do you see yourself sort of competing in a market where there is sort of a more differentiated mechanism that's emerging? I think you kind of just touched upon it in the last response, but maybe if you can elaborate on it.
Yeah. Get to your first question on dose. We think the best place to look when we think about dose is the amisulpride data. We have both clinical amisulpride data, and we have real-world prescription data for amisulpride. When you look at amisulpride, you can see that there is a reduction in dose as you move in towards adjunctive MDD. For schizophrenia, it's dosed between 400-800 milligrams a day, and it's got dopamine receptor occupancy of about 70%-80%. When you look at it for use in bipolar disorder and negative symptoms, it's really in the range of 100-300 milligrams. Then when you look at it for depression, it's used at 50 milligrams. You can see this progression down in dose as you move away from the need for dopamine blockade.
In schizophrenia, you need significant amount of dopamine blockade. These are psychotic patients. They really need to stabilize those acute symptoms. In bipolar disorder, particularly bipolar depression, these patients have a tendency for manic events. You do have to prevent mania in these patients. You do need a little bit more dopamine blockade so that you can prevent the emergence of manic events. When you get into adjunctive MDD, it's really all about depression. You don't really need any dopamine blockade, and in fact, if you have too much, you might actually trigger symptoms of depression. You do see this step-down in dose in the clinical trials. You also see this step-down in dose in the real-world prescription data. When you look at indications and at what dose they're being used, you do see that as well, so it mirrors the clinical data.
When we look at the doses that we're choosing for adjunctive MDD, bipolar depression, and then schizophrenia, you see this range of 15-100 milligrams, and if you look at the dopamine receptor occupancy across that range, we're in the ballpark of amisulpride, and that's what we were working towards doing. We also had the nice added benefit where because we had such a low rate of EPS, we actually didn't have to worry about that in both bipolar depression and adjunctive MDD. If you look at a drug like VRAYLAR, it had such a high rate of EPS in schizophrenia, it had to cut its dose in half for bipolar disorder because they had to reduce that EPS rate. This is a patient population that is more sensitive to it. They're more functional. It just wouldn't work very well.
They were forced to cut their dose in order to manage that side effect. We were fortunate enough that we didn't have to do that given the rates of EPS that we saw with the schizophrenia dose. To get to your second question about how do we think we will compete with the muscarinics? I think we'll compete very favorably. What we see with the muscarinics, and in particular Cobenfy, is that twice-daily dosing with the food effect is challenging. These patients have to take the drug on an empty stomach, which means they cannot eat one hour before or two hours after, which make it challenging. It also has pretty significant anticholinergic side effects, nausea, that sort of thing.
What you see in real-world is that patients often are suboptimally dosed because they're trying to manage this side effect, which means they're not seeing the efficacy that they saw in the phase III trial. While it is a new mechanism, it is harder for a conservative physician population to jump immediately to that new mechanism, particularly when there may be some challenges in how you switch patients. We saw from the ARISE trial, from Cobenfy, that there are some challenges with switching patients off of risperidone, for example. We know that the pines, like olanzapine, quetiapine, were actually excluded from that trial because of the anticholinergic effects. For two of the most prominently prescribed generics, olanzapine and risperidone, those are challenging for physicians to transfer patients or to switch patients to Cobenfy. We don't think we're going to have any of those challenges.
We're a once daily dose. We aren't anticipating any sort of a food effect. We don't have these GI side effects that go along with it. The other difference is that we have a pretty rapid onset of response, and we don't need to titrate. People are going to get a therapeutic dose right off the bat, and they'll see effect pretty quickly thereafter. We do believe we'll be competitive on efficacy. Really what it's then going to boil down to is, can these patients stay on the drug? I think having a simple dosing profile makes a big difference. I think not having to worry about a food effect makes a difference. If we do have this opportunity to really show a benefit in cognition and anhedonia, I think that's even further opportunity for differentiation.
Okay. Well, that was a good segue into my next question, which is about cognition, and anhedonia or negative symptoms. We've seen a lot of companies sort of measure that as a secondary endpoint. I wanted to better understand what is the path to getting it on label. Or is that, at this point, from a regulatory standpoint, is there a path?
Yeah
to be able to do that?
I think we need to draw a distinction between indications to completely answer that question. In the world of schizophrenia, it's very clear that to get it on label for negative symptoms and cognition, anyway, you really need to study it in a stabilized patient population where you don't have the confounding factor of having treated the positive symptoms. FDA has been very clear about this for these two indications. I think there's some question around the trial design for that and how you might do that. Generally speaking, FDA's been very clear. To get it in the label, you definitely need to be studying it in a stabilized patient population. With respect to the mood disorders, I think it's a little different. We've seen with Trintellix that you can get some cognition data into the clinical trials section of the label.
I do think there are opportunities within the world of mood disorders to get it into the label with the current way that if you have robust enough data, that there's an argument to get it into the label. That said, this is a pretty promotionally sensitive market, and we know that publications can be very helpful to physicians in thinking about how to choose therapeutics. I do think there's opportunities to generate data and publish data, in a compliant way of course, that can be impactful in this space.
Just going back to the trial design, so sounds like you need to do one study to seek an approval. Could you clarify, for BPD and MDD, that would be two studies each?
For BPD and MDD, you might actually be able to seek approval with just one successful phase III trial. Some companies decide, especially in bipolar, to do two, so they could get both a monotherapy and an adjunctive claim at that time. But I do think there's a strong argument to seek approval with just one successful phase III trial, given all the safety data that will already be accrued with the schizophrenia program. I do think there is an opportunity there.
Lastly, the two doses that you're testing in the schizophrenia study, the 50 and 100. Is the intention to bring both to market?
Yeah. We think there's a real benefit in having both of those doses available. When you look at how amisulpride is used, for example, it'll often be used at the highest dose to get these patients stabilized. It then gets used at a lower dose for maintenance, as well as even treating patients with predominantly negative symptoms. We think having that option for physicians is something that could be very valuable.
Right. Heather, those are the questions I had. Thank you so much for.
Thank you for the time and for participating in the conference.
Yeah. Thank you so much for having me.
Okay. Have a good day.
Thanks. You too.