Good afternoon, everyone. Thanks for joining us for the final afternoon stretch of the Sixth Annual Novel Mechanisms in Neuropsychiatry Summit, hosted by TD Cowen, and welcome to the Fireside Chat with LB Pharmaceuticals. I'm senior analyst for Tuva Raul, and with us from LB, we have CEO Heather Turner. Heather, welcome. Very excited to have you at this conference for the first time and to discuss your phase III asset.
Thank you so much for having us. Really happy to be here.
Let's get right to it. LB-102, your lead asset currently in schizophrenia development and an amisulpride derivative. Can you talk a little bit to the drug's mechanism and how that supports a potential therapeutic profile in schizophrenia?
LB-102, as you mentioned, is a derivative of amisulpride. Amisulpride is a generic antipsychotic that has been approved around the world but was never approved in the United States. LB-102 is a very selective inhibitor of D2, D3, and 5-HT7, and really very little else. So it has very few off-target effects. Amisulpride is a drug that has very poor permeability into the brain, and so one of the improvements made with LB-102 was to improve the efficiency in crossing the brain. As a result, LB-102 is a much more potent molecule than amisulpride. It also is enabled for once-daily dosing. So it's a very selective inhibitor of D2, D3, 5-HT7, and it's once-daily dosing.
Got it. As you think about the different receptors, D2, D3, what is the understanding of the biology and its contribution to schizophrenia and maybe some of the other indications that you guys have talked about pursuing?
Yeah. D2 is obviously very important when it comes to suppressing dopamine release, which is really mechanistically what you need to do to treat psychosis-related indications like schizophrenia. D3 and 5-HT7 have been implicated as both pro-cognitive as well as antidepressant. So those two receptors are mechanistically part of the reason we believe that we'll be efficacious in the mood disorders like bipolar depression, and adjunctive MDD. There's another mechanistic reason for success in both psychosis and MDD, and that is that LB-102 is a benzamide, like amisulpride, and there's an interesting bimodal mechanistic activity with this molecule, and that is at high doses, it operates to suppress dopamine, and at low doses, it actually triggers the release of dopamine.
You see this in the way that amisulpride is used and the way that we intend to use LB-102, which is at the highest doses, you're treating schizophrenia and other psychosis type of indications, and then at the lowest dose, you're treating depression-related indications. So for LB-102, we're intending to treat schizophrenia at 50- 100 mg. That's what we're studying in our phase III trial. In the adjunctive MDD indication, we're actually looking to study it at 15- 25 mg.
At that sort of dopamine release-
That's right, a much lower.
portion of the curve. Got it. Can you tell us more about the developmental history of amisulpride? Why was it never approved in the U.S., and what have previous amisulpride schizophrenia studies shown, effect size, and power and safety?
Yeah. It was originally developed by a very small biotech company in France called Synthélabo, and it was first approved in France in the late 1980s. Sanofi bought Synthélabo in the late 1990s, and at that point, they tried to bring amisulpride to the United States. FDA asked for a full development program, and that just wasn't compatible with the patent life that remained in the U.S. Of course, this was at a time when antipsychotics weren't necessarily blockbusters at that point in time. So the decision was made to not bring it to the United States. Amisulpride is actually considered one of the most efficacious antipsychotics. It has a treatment effect of about 0.73, which is second only to clozapine.
It also is considered one of the more safe and efficacious antipsychotics with one of the lowest all-cause discontinuation rates among the antipsychotics. And it's one of the few that has been studied in patients with predominantly negative symptoms. In three separate placebo-controlled trials, it was demonstrated to be statistically significantly better than placebo in treating patients with predominantly negative symptoms. So it's viewed pretty widely as a very efficacious drug with a nice balance of safety and tolerability.
And that's without the improved blood-brain barrier.
That's right. We're able to accomplish what we hope, and what LB-102 is designed to do is to accomplish, and be as efficacious with a much lower dose. What we determined was that 50 milligrams of LB-102 is about the same as 400 milligrams of amisulpride. So it's a much more potent molecule.
Got it. And how is amisulpride used in clinical practice outside the U.S.? Is there a particular patient profile? Is it used beyond schizophrenia routinely in other geographies? Where does it fit in the algorithm?
It continues to be very widely used, even though it was first approved in the late 1980s. There were around 2 million prescriptions annually for amisulpride, and when you look at just the prescription data, it will give you a sense of how it is used. About 60% of those prescriptions are used for schizophrenia and schizophrenia-like indications, like schizoaffective disorder. Then about 20% of those prescriptions are used in mood disorders, so bipolar as well as MDD. In some jurisdictions, amisulpride has a labeled indication for dysthymia, which is a persistent form of depression. Then there is about 14% that are in anxiety, and then there is a smattering of other kinds of indications that amisulpride is used for. But predominantly, it is used in a number of different indications.
Is there an antianxiety signal in the historical data, or is that one of the mood disorders that is often.
It is separate from the mood disorders. It is hard to know exactly what is driving the use in those scripts because we do not get a lot of that data. But it is an interesting data point that there does tend to be a number of prescriptions for anxiety.
What are the main limitations of amisulpride that LB-102 seeks to address? Beyond the potency, I think I am focused more on safety, tolerability, and as long as we are talking about that, where does LB want to differentiate LB-102 from standard of care? Is it extrapyramidal? Is it metabolic?
Yeah.
And other standard side effects. Yep.
What we observed in our phase II clinical trial for schizophrenia, we think a very attractive profile is emerging. One in which we think we'll have competitive efficacy. In the world of antipsychotics, I don't believe that there's a whole lot of differentiation occurring in efficacy. And really where the differentiation starts to occur is within the safety, tolerability, dosing, as well as opportunities to treat residual symptoms. And so on the safety and tolerability side, we think what's emerging for LB-102 is a profile in which we could have best-in-class safety with respect to EPS. As you mentioned, extrapyramidal symptoms is a side effect that has been associated with antipsychotics since the very beginning, and it's a side effect that tends to really challenge a patient's ability to function. And so it is one that can lead to discontinuation.
What we observed in our phase II trial was a very low rate of EPS. At our highest dose, we had a rate of just 5.6%, and that's pretty low relative to other D2 antagonists and the partial agonists like VRAYLAR, for example. And is actually in the ballpark of what you see with, say, COBENFY and Keppra, which are two therapeutics that really tout the fact that they have next to no EPS. We also would expect to see a better profile with respect to prolactin increases relative to other D2 antagonists as well. And then when you look at the dosing and the parameters around dosing, we think that we actually compete pretty effectively, which is it's once daily dosing.
We don't intend or expect there to be a food effect, and we don't have or anticipate any sort of really challenging drug-drug interactions. That would make this a difficult drug to dose. When it comes to an opportunity to treat the residual symptoms, I think we saw in our phase II trial some real potential there. In our phase II trial, we saw a dose-dependent, robust effect on cognition.
This was an effect that was statistically significantly better than placebo. The treatment effect that was observed is one that would be considered clinically meaningful. So if that's something that we can continue to show in our future clinical trials, there's a real opportunity there for differentiation. The other is with respect to negative symptoms of schizophrenia. So 60% of patients with schizophrenia suffer from negative symptoms of schizophrenia. To date, there is no treatment approved in the United States. As I mentioned, amisulpride is one of the few antipsychotics that has shown in placebo-controlled trials to be statistically better than placebo at treating patients with predominantly negative symptoms. So we do think that there's an opportunity for LB-102 to differentiate in this area as well.
That improvement in the negative symptoms that was seen in the low dose. Is the hypothesis that it was driven by more dopamine release, or at least-
Exactly.
Okay.
Yeah. We saw the low dose, the 50 mg dose was statistically significantly better than placebo on the PANSS negative symptom subscale. M It is consistent with the mechanism that we've observed, this bimodal activity that at lower doses, it tends to trigger the release of dopamine. At higher doses, it tends to suppress dopamine. So that is consistent.
Does that suggest that maybe the drug overall has a U-shaped response curve on larger efficacy, or is this U-shaped response curve only for negative symptoms?
I don't know that it suggests that there's a U-shaped response curve mechanistically. I think with respect to treating those depression-like symptoms of which negative symptoms has aspects of that. I think that a lower dose is more likely to be used than a higher dose. And you see that in the script data for amisulpride as well.
Right.
That, for example, for negative symptoms, it tends to be dosed between 100 and 300 mg, which is lower than the schizophrenia dose.
How should investors contextualize the efficacy relative to? And you know what? Let's throw safety in there, too, because LB-102 is talked about from a commercial perspective in terms of how COBENFY is doing and how CAPLYTA is doing. And of course, COBENFY has underwhelmed compared to very high original expectations, where CAPLYTA has probably surpassed investor expectations, which at one point were quite modest. Is it something about either trial design or patient populations that sort of contribute to how those drugs are seen and where LB-102 will fit?
Yeah, I think just hitting on the launches real quickly. I think that with respect to COBENFY, I think that the challenges with respect to dosing and the food effect and the GI side effects were probably underestimated as part of that launch. I think it's proven to be a more challenging drug for patients to take and then for patients to stay on. I think that might be contributing to the disappointing launch. For CAPLYTA was never really considered to be a schizophrenia drug. It actually had a pretty low treatment effect. Where you've seen it exceed expectations is really with respect to the mood disorders.
The fact that it got the bipolar depression and then MDD, and now it looks like they just announced the positive bipolar mania data. I think the movement into the mood disorders has really broadened the opportunity for CAPLYTA. With respect to LB-102, we think we will have efficacy where physicians will use it for schizophrenia. We think what we saw in the phase II trial and the treatment effect that we observed in the phase II trial is one that is clinically meaningful and suggests robust efficacy in the treatment of patients with schizophrenia. We would anticipate it to be used there. We do have this opportunity, though, to broaden the revenue opportunity by moving into the mood disorders, right?
Because we've got this mechanistic reason to believe that we'll be successful in the mood disorders, we do have an opportunity to expand in much larger patient populations by moving into bipolar depression and adjunctive MDD. That's why we've started the bipolar depression trial. That data is expected to read out in the first quarter of 2028. We also have plans to initiate the adjunctive major depressive disorder trial in early 2027, and then we would have data in the first half of 2029. So we are moving into those indications.
As you finalize the strategy, CAPLYTA's success in mood disorders, do you feel that that was more driven by unexpected efficacy or just, again, as we discussed, the safety profile, the ease of use, in what is a less dire acute disease phase?
Yeah. They definitely saw efficacy. Which I think is helping to drive the usage. I do think there are some challenges with sedation with respect to CAPLYTA. In these populations where they are much more functional, meaning they have jobs, they have families.
Yeah.
the side effect of sedation can be challenging for patients. As often occurs, patients may be not getting to that top dose because physicians are managing that sedative side effect. I do think there is an opportunity to differentiate with respect to the safety and tolerability profile. LB-102 only had one case of sedation in the 251 patients that we evaluated in the phase II trial. I do think there's an opportunity to separate there.
Can you talk us through the regulatory strategy, particularly the FDA feedback that supported a single phase III study, for an NDA because your phase II had such an effect size it will be considered pivotal data. Why not have a backup plan and start another phase III like many neuropsych developers do for all the indications?
Well, as you mentioned, when we looked at the statistical analyses from the phase II trial. When you looked at, not just the treatment effect that we saw, but also all of the sensitivity analyses around that primary endpoint. When you think about the most conservative way to impute missing data, all of those were very supportive of the primary endpoint, which goes to the fact that we think that the phase II trial is a highly statistically robust trial. If we have similar outcome in our phase III trial, we think we have a really nice opportunity to seek approval. If it comes down to the fact that we are asked to do another trial, I think, at that point we'll have to see what the data from the phase III trial suggests and make a decision at that point in time.
But where we sit today is, we have a lot of confidence in the opportunity to seek approval with just one phase III trial. Of course, we will be ready to respond in the event that we have to.
Got it. As we approach this data, right, in the first half of next year, and you guys have pulled that timing forward, how are you setting expectations? How are you setting investor expectations for the data? Is it a certain range of PANSS based on the phase II? Is it an effect size? And do you know at this point what will be included with top line?
Yeah. In terms of what we are setting expectations for, as I mentioned before, I do not think differentiation comes from efficacy. I think we would love to continue to see competitive efficacy. Efficacy that would suggest that LB-102 would be used in schizophrenia. We'd love to continue to see the safety and tolerability profile that we think would allow for patients to stay on the drug. That's an important element here in this space, and we see that, as I mentioned before, in the COBENFY launch.
If we're able to show some sort of a benefit on some of these residual symptoms, that would be great. So at the end of the day, it really boils down to continuing to demonstrate a therapeutic that's got competitive efficacy and a safety and tolerability profile which would allow these patients to stay on the drug, since that's really important for this patient population. In terms of what we would anticipate announcing-
Yeah
at the data, I would expect it to be very consistent with what has been done before.
Got it.
based on our phase II, based on what we've seen with other data announcements.
Understood. By some miracle, I have left us time to talk about bipolar disorder and adjunctive MDD. Can you review for us, Heather, the expected timing to the top line phase II data again? I'm sorry, review the phase II study designs, and repeat the timeline to that top-line data.
Sure. For both the bipolar depression and the adjunctive MDD trial, we're employing a fixed flexible dose design. We think that this allows us to evaluate two doses of LB-102 and keep these trials as a two-arm trial. We know that every time you add an arm to these kinds of studies, you have the risk of increasing that placebo rate. In the bipolar depression trial, all patients will start at 25 mg. At the end of week three, if they have not seen a level of improvement on the CGI scale, they would then escalate to 50 mg in a blinded protocol, guided way. Then they will stay on that dose for the remainder three weeks of the trial. It's a six week trial.
We're intending to enroll about 320 patients. We anticipate the data from this trial being the first quarter of 2028. For the adjunctive MDD trial, here we're also using a fixed flexible dose design. Patients will start at 15 mg. At the end of week three, if they have not seen an improvement or reached the level of improved, based on the CGI, they would then escalate to 25 mg and then complete the trial at 25 mg. For both of these trials, the primary endpoint is MADRS 10 which is the regulatory accepted endpoint. For the MDD trial, we're targeting 380 patients. This is an adjunctive trial, so patients will be on an SSRI or SNRI. Then they'll either be given placebo or LB-102.
It's either of those. They're not allowed to be on, say, background or Abilify or-
Right. Exactly.
Okay.
Yeah. The trial is also six weeks in duration as well.
Got it.
That is a global trial. So that one is U.S. and Europe.
Got it.
The data we expect to read out in the first half of 2029.
2029. Got it.
Yeah.
In the last minute that we have, Heather, what other indications could be considered for LB-102 given the
Yeah. It's an interesting molecule because it can go into a number of different directions. We are looking very closely at pursuing negative symptoms of schizophrenia, as I mentioned. It makes a lot of
As a standalone.
Yeah. Given the heritage of the amisulpride data.
Yeah.
Given the mechanism of LB-102. That is something that we're intending to engage with FDA on, and hopefully define exactly what that clinical trial might look like, and then hopefully put ourselves in a position to start that trial. We're also looking at Alzheimer's disease, agitation, or psychosis. First step there is a healthy elderly volunteer study to demonstrate the safety. We are planning to get that trial started as soon as we can. Then once that trial completes, we can then move into a phase II trial in one of those indications.
Great. Heather, thank you so much. This was incredibly comprehensive and a compact conversation, which I never seem to manage, so thank you.
Yeah. Thank you.
For helping me with that. Any outstanding questions for folks on the line, please email me, and I will get them answered for you. Thanks for joining us.
Thank you. Have a good one. Bye-bye.