Welcome to the first day of the B of A Healthcare Conference. I'm Geoff Meacham. I'm the Senior Biopharma Analyst. I have Charlie Yang on my team on stage with me as well. We're thrilled today to have Neumora Therapeutics with me on stage, Henry Gosebruch, President and CEO, and Robert Lenz, Executive Vice President, Head of Research and Development. So Robert, Henry, thanks, guys, for joining us.
Thank you. Great. Excited to be here.
Henry, you want to just give sort of the for those that may not be as familiar with the story, just kind of the high level, and then we'll get into some questions.
Sure. So we are a neuroscience-focused biotech company with seven programs in development, three of those in the clinic. Our lead program, navacaprant, is in phase 3 studies for MDD. It's going to be a very exciting year because we have the first of our three phase 3 studies reading out in Q4 of this year. So big year for us with a number of catalysts both this year and next year.
Give us a history, I guess, on Nava, Henry, kind of where it came from and your thoughts on the mechanism.
Yeah. So the kappa opioid receptor antagonist class has long been thought to be a very important class for neuropsychiatric indications. There's been various attempts over the years to drug that class appropriately, but it's really just been recent times that the field's been able to find the right chemistry to adequately drug it. And Bill, we'll talk about that a little bit more. So we're very, very pleased that we have, from a pharmacology point of view, the best agent in the class. It came originally out of the Scripps. It was licensed by a company called BlackThorn that we then acquired. And we're very, very pleased to have that now advanced all the way in phase 3.
I mean, as we look at that class, given the clinical validation with three independent studies, we really think the class will be kind of what the muscarinics are going to be for schizophrenia. We think the KOR class will be for MDD and a number of psychiatric indications following MDD.
Yeah. So maybe just to follow up now, right, I think MDD, it's pretty big implications. But obviously, there are a lot of drugs already in the space, generics or branded. And there are other new drugs potentially getting approval relatively soon. So how do you think the KOR antagonism kind of works in this space and where you will potentially fit in terms of the treatment paradigm?
Sure. Absolutely. So when we think about navacaprant and the kappa opioid receptor antagonist more broadly, what we know is there's different underlying neurocircuitry that's being targeted relative to the existing antidepressants that are currently approved. And in that context, we've got converging evidence preclinically, clinically that validates the target. To Henry's point, we now have three independent sponsors showing efficacy utilizing kappa opioid receptor antagonists, whether it be the NIH FAST-MAS study, whether it be the J&J phase II study, or our own phase II study. Despite the fact that there are existing agents that are approved, the unmet need that remains is quite high, specifically in treating symptoms like anhedonia, that we know are present in 70% of MDD patients. Anhedonia is associated and known to be a poor prognostic factor for response. It's associated with higher rates of suicide.
Quite frankly, it's a residual symptom after currently approved agents are often used. In that context, navacaprant really offers a step change relative to the currently approved therapies. Our phase II data demonstrated robust efficacy across a range of MDD symptoms, including anhedonia, which we think is highly relevant. When we think about the commercial opportunity that comes with this, efficacy is certainly a big part of this. But benefit-risk matters. Tolerability is also an important element when we think about this class of agents. It's really devoid of AEs like sexual dysfunction and weight gain. We didn't have those reported in our phase II.
We think these represent meaningful clinical differentiating opportunities upon replication in phase 3 for patients in their 20s, 30s, 40s to stay on product who often today are reluctant to both initiate and end up discontinuing prematurely due to weight gain and sexual dysfunction. A large commercial opportunity. We've been able to confirm this through independent market research on the back of our phase 2 data with L.E.K. We're really pleased with what we're seeing from the profile testing perspective.
Yeah. So again, I'd just add to that that there really hasn't been a novel mechanism in monotherapy in decades, right? So many of the new introductions have all been in the adjunctive setting. And so monotherapy is a far larger market. Again, as Bill talked about, these patients, unfortunately, cycle through a lot of older generics at this point. So we really hope to bring the first novel treatment to market and really change the paradigm and have a much better quality of life for these patients.
What would be your expectation in terms of the trials succeed and then in terms of kind of where you would fit into kind of treatment in terms of first line, second line, and how do you think that will evolve?
Sure. So in the work that we did on the back of our Phase II data becoming available with L.E.K., who independently did the work, the profile tested quite well. We're not anticipating or expecting a high degree of first-line use. We recognize that patients will typically have to go through an SSRI or a generic agent. And in fact, 90%+ of the use that's contemplated is second line, third line, fourth line, and beyond. Nonetheless, when we think about the epidemiology in the U.S., 21 million patients suffer from MDD. Half of those patients are treated with pharmacologic therapy. A small fraction of those patients that are currently treated being candidates for navacaprant really represents a sizable commercial multibillion-dollar opportunity, quite frankly, in the U.S. alone.
I guess the competitive landscape when you think about J&J versus Nava, just give us kind of your high-level thoughts about how you see the profiles, as we know now, in both monotherapy and the adjunctive setting. I know there's a lot of investor kind of uncertainty about which one is the more robust opportunity?
Well, again, it's important to understand that there's sort of two main differences. So one is development path. So again, we're in monotherapy. They're in the adjunctive setting. We just talked about the monotherapy setting is far larger and therefore far more commercially attractive. So the development plan is one area of differentiation. The two studies, by the way, will likely be right around the same time. I mean, it's sort of unclear exactly who's going to come first. But let's just say they will likely be on top of each other. But development plan path is one area of differentiation. And then pharmacology is the second part of differentiation. And I'll have Bill drill a little bit deeper on that.
Sure. So from a pharmacologic profile perspective, navacaprant's 300-fold more selective for kappa over mu opioid receptors. At the 80-milligram dose, which we've been able to push to 80 and attain 90% receptor occupancy, which we believe high degrees of receptor occupancy for G protein-coupled receptors in this indication are quite important, allow us to be able to have those high degrees of receptor occupancy while avoiding mu receptor AEs that could be present if we were less selective. In contrast, aticaprant is 30 times more selective for kappa over mu. That has meant that they've taken the 10-milligram dose forward in their MDD studies, not been able to push the dose a whole lot higher because of the mu-mediated AEs that can be observed. And at trough, over a 24-hour time period, end up in the low 70% range for receptor occupancy.
Clinically, in phase II, what we saw was a higher rate of mu-mediated AEs as a consequence with the aticaprant program at about 8% diarrhea, as an example, whereas we had no adverse event at a rate of 5% or higher in our phase II. A tolerability profile that was quite favorable and actually a higher rate of discontinuations on placebo versus active in the navacaprant phase II trial.
Makes sense. Let's talk a little bit about that. When you have the phase II data, help us with kind of how you would prioritize what you changed or what you tried to enhance in phase III to raise a probability of success, both tolerability as well as efficacy.
Yeah. Yeah. So we've done a number of important modifications. So one set of modifications is trial design. And then the second one is trial execution. So on trial design, we're focusing in phase III just on the moderate to severe population. That's the population that is typically studied in MDD that follows FDA guidelines. And that's where we saw the biggest effect in phase II, so study population. We changed the endpoint to a 6-week endpoint from an 8-week endpoint. Again, there's literature that the longer you follow these patients, placebo response can increase. So we think 6 weeks is the optimal time point to see the best effect without placebo rising up. And then we switched to the MADRS scale from the HAM-D17. So we inherited the HAM-D17 scale from the phase II, but we think the MADRS is much more suited to our pharmacology.
Those are the 3 major design changes. Then there are a number of clinical trial execution changes we've made that we didn't really do in phase II that should enhance the probability. One obvious one is we're running 3 studies. That's a big one. We only need 2 to succeed. But we are doing central raters as one example. We've paid a lot of attention to site selection and really tried to identify the highest quality sites. We are independently reviewing each patient's medical record as Neumora, so not just relying on the site or the CRO, but we've independently invested in colleagues that are reviewing each medical record.
We've also built a real-time data analytics capability where we can look at each assessment in real time and observe trends and make sure that we could intervene to the extent there are some irregularities seen on a real-time basis. Again, it's design changes from phase II to phase III. Then it's a number of trial execution steps that should really enhance the probability of success.
Maybe just kind of focusing on the phase II data, right? I think there are some kind of questions around the statistical analysis using MMRM versus LOCF based on kind of what change you presented and also kind of based on what you have presented before. Maybe just tell us a little bit about kind of how you think about that in terms of whether the difference in statistical analysis is impacting kind of the readout that you have and how that kind of and how you think about in terms of phase III analysis, which one to use, and how to think about that.
Sure. So for our phase II program, in our statistical analysis plan, we had pre-specified that in a scenario where we had more than 10% of patients with missing data, the LOCF would be the analysis that we would rely on. We were transparent in reporting the MMRM, which then pivoted to LOCF based on the SAP, the statistical analysis plan. We've reported the data accordingly. Importantly, when we think about the results for the phase II study, to be in the final efficacy population, patients had to have had a baseline HAMD. They had to have received one dose of medication. And they had to have had one post-baseline HAMD assessment, which in that phase II study, the only time points post-baseline were week four and week eight. And so in that context, the results that we've reported on the data are consistent with our SAP.
And with that is the underpinning.
Okay. Do you think that just using the if we were to do the mixed model method, would that have a negative effect on those data, or do you think we would actually still be comfortable in terms of what you've seen?
We were really comfortable with what we saw in our phase II study. We had, subsequent to those data, a very productive end-of-phase II meeting that really helped to align and give us confidence in moving forward with the phase III program. Importantly, in phase III, we have earlier time points for assessment. So we'll have, as we would anticipate, less missing data when you've got a week 1, a week 2, a week 4, and a week 6 endpoint. And you're not operating in a COVID environment, right? And so when you put these factors into play, we expect, certainly for phase III, a scenario where we would have less missing data than we did in phase II.
Got it. Then if we were to think about kind of the adjunctive setting versus the monotherapy setting, Janssen is obviously pursuing the adjunctive setting while you guys are doing the monotherapy. So maybe just tell us kind of why you're doing that and which one would you say is more difficult, per se, in terms of the bar of achieving a successful trial?
Sure. I'll start. And then Henry Gosebruch's chime in here, which is when we think about the overall market opportunity, whether it's published data, claims data, the vast majority of patients are treated in the monotherapy setting. We know clinicians are quite comfortable switching within class and outside of class within the antidepressant category. And as such, 60%-85% of the patients are treated in monotherapy. And often, there's switching that occurs multiple times before folks go to the adjunctive setting. As Henry pointed out, the adjunctive setting is much more crowded with a number of atypical antipsychotics that are moving in that realm, whereas the monotherapy setting, there's been less innovative approaches offered and really represents a large opportunity. What we know is that agents that have demonstrated robust efficacy in the monotherapy setting market research, published data, KOL feedback would all triangulate.
If you've demonstrated robust efficacy in monotherapy, clinicians are likely to utilize the product in later lines of therapy, including in the adjunctive setting. The converse isn't necessarily true. An agent demonstrating efficacy only in the adjunctive setting, there still remains a question if the agent possesses sufficient horsepower, if you will, to demonstrate efficacy in the monotherapy setting. And in the absence of data, that'll be a higher hurdle. So we started with monotherapy for those reasons. It doesn't preclude us from ultimately thinking about moving into the adjunctive setting through whether it be a company-sponsored or investigator-initiated set of studies that would allow us to further explore efficacy in that patient population.
I'd just add to that. I mean, keeping the patient first and foremost in mind, the premise here really is to bring a therapy forward that is much safer and the tolerability much improved over existing generics. So in the adjunctive setting, by definition, you're dialing in whatever those AEs are that come with the generic versus our idea is, again, in the monotherapy setting to, again, really change the treatment paradigm and hopefully avoid this constant cycling that these patients have, really keep somebody on an effective therapy that's well-tolerated and safe for an extended period of time. So that would really be a step change in quality of life and make a big impact. And I think that's another big reason we prefer monotherapy.
I know, Henry, a lot of investors tend to look at Neumora versus J&J versus Caplyta. There's lots of companies and drugs out there. It's not a zero-sum game, right? Maybe help us with kind of how you see the bigger picture from an access, reimbursement, unmet need perspective.
Yeah. Again, I think we hit on some of these themes already. I mean, first of all, we're really pleased to see these new approaches come in the market. It is a huge market. It is still very underserved. As Bill talked about, at least half, if not more, of available patients don't even seek therapy given some of the AEs that they're faced with. So we're pleased with those new approaches. We'd like them to succeed. I think more choice in the market generally has helped these type of markets in the past. From a reimbursement perspective, Bill talked a little bit about some of the market research we've done. I think our profile really tested really well. It's a novel pharmacology, right? So it's not another atypical. It's truly a novel mechanism of action.
It addresses anhedonia, which, again, the current agents and even the ones in development don't really adequately address. It's got the safety and tolerability that I've talked about. That tested quite well with payers. Obviously, we need to demonstrate that profile in phase III. Then we'll engage in those discussions once we have that package together. I think there's a big opportunity. There's a big opportunity also just to attract more patients into a category and then keep them on therapy much, much longer than the current medicines have the opportunity to do.
That's helpful. Well, let's switch gears to 266. So let's talk a little bit about maybe intro that. And we're getting to some questions.
Yeah. So 266 is our M4 program, our M4 PAM program that we advanced to the clinic late last year and started a SAD/MAD study. We were about 30 or we were exactly 30 healthy volunteers into that SAD/MAD study when we saw a tox signal in a non-clinical study that we've run at the same time. We reported that finding to FDA. We were put on clinical hold just about a month ago or so. So it was disappointing to us given that we didn't see any of the same safety issue with the 30 healthy volunteers. But we're working through with FDA that clinical hold. We think we have a good path in that dialogue. At the same time, also, we have a nice portfolio of earlier-stage M4 PAMs. We expect to advance one of those into the clinic next year as well.
So it's really a broader franchise approach. Again, we hope to be able to work with FDA to get 266 off of clinical hold. But we also have quite a nice play with the additional M4 PAMs that we are advancing to IND.
And I know that. Is there reasonable expectation that you think that could be done this year? Or you just don't know, I guess, given FDA dialogue? It can be unpredictable.
It's hard to speculate. I'd rather not speculate on this now. What we're confident in is that we will have one of the follow-on programs in the clinic next year so that I can be confident in how exactly the FDA timing works out on 266. It's hard to speculate.
Gotcha. Okay. And then on 511, when you think about the Alzheimer's and a lot of the foundational therapies today, agitation still ends up being a fairly actionable kind of outgrowth of the disease. Talk a little bit about 511 and give us some perspective on the mechanism and the profile.
Yeah. I'll start with the commercial opportunity. And Bill will cover the mechanism and how we're approaching that. So it's a very large area of unmet need. So agitation, frankly, is one of the key reasons patients get admitted to care. It is really underserved at this point. There's really only one agent in that area. And that agent carries a black box warning. So there's a big need to have a safer medicine for those patients in that setting. So we're quite excited about starting an efficacy study on that mechanism very, very soon. And I'll have Bill talk a little bit more about what gives us the confidence in that mechanism and how we're approaching that.
Yeah. Absolutely. So with V1a, it is a vasopressin 1a receptor antagonist with far greater selectivity for V1a over V1b versus V2 or oxytocin. So the profile in that regard is quite selective. What we know is from non-human primate studies, we've been able to show there's a reduction in anxiety, startle response, aggression. And in that context, those preclinical data have helped to support and underpin some of the confidence mechanistically around why we believe there may be an opportunity clinically with a profile that could be quite favorable from a benefit-risk point of view. To Henry's point, the existing agents that are available have quite a bit of baggage, if you will.
So being able to see a unique pharmacology, a differentiated mechanism of action with an underpinning towards aggression, anxiety, and some of the clinical data demonstrated with this target through other sponsors gives us confidence in moving this forward.
Yeah. So we're going to initiate that study here in the second quarter. And similar to what we did with bipolar, we're actually press-released that initiation today, which hopefully we'll talk about here in a minute. We'll provide more detail on what that study looks like and the timing and so forth when we've kicked off that study.
Maybe just to talk about the competitive landscape, right? I think you have KarXT. I believe that's also kind of looking into this as well because kind of thinking about the difference in kind of mechanism and why you think the 511 will be a better product, potentially a better product than.
Sure. So from a pharmacologic point of view, I've highlighted where we think V1a could fit in pharmacologically, the preclinical models, and the limited clinical data that give us confidence. We think this is a very large market. The unmet need is extraordinarily high. And I think the opportunity for multiple agents with differentiated mechanisms of action is quite real. Now, these agents, including the muscarinics, including V1a receptor antagonism, need to be able to generate that clinical evidence and data. But when we think about the profile of V1a receptor antagonism, it's not been associated with things like sedation, lethargy, things that could contribute to unsteady gait or be problematic in this population. It's early days. We need to replicate some of these elements. But it certainly represents an opportunity for multiple market participants with different mechanisms to be successful in this market.
Yeah. And look, we're really, really pleased to see some of the Alzheimer's disease-modifying agents really coming forward. That's a huge improvement for patients. But it'll actually increase the size of patients living with Alzheimer's and therefore facing the agitation much more than you had in the past. So there'll be an ever-increasing need for these type of treatments. And again, we hope to play an important role in that.
As you mentioned, I mean, with advancing the clinic, I mean, just maybe help us, Henry, with what you think success looks like in kind of the next phase?
I think success, similar to what we did on Bipolar today, is for us to see a clear signal that gives us confidence to advance to a much larger study. We're probably not looking for a large enough statistically significant type of impact. But we want to really, really test the hypothesis and do that in a capital-efficient way where we can see a signal within 12-18 months. And again, we'll be able to show more when we initiate the study.
Makes sense. Yeah. And Geoff, to amplify Henry's point, these are studies that are not designed to show a statistically significant difference from placebo but, in fact, intended to elucidate what the effect size is that will inform the next phase of development. So it's a really efficient way for us to be able to advance the program in a timely manner.
Gotcha. And from a BD perspective, when you think about the pipeline, how much of a priority is it to continue to bring in new assets and maybe just help us at a high level with kind of how Neumora, from the platform technology itself, can really differentiate itself among all the other companies out there?
So I'd say the history of Neumora is really through very creative business development to assemble this current portfolio where five of the assets that we have came ultimately through business development. Two were internally developed. So we can do both. We have a data sciences platform where we've onboarded a tremendous amount of data that gives us insights into the appropriate patient populations and maybe targeting some of these mechanisms in a much more sophisticated way than historically the field has done. That does give us an insight as we look at external opportunities.
So I would say, given what we have in our pipeline so some of the things we just talked about, obviously, navacaprant for MDD and Bipolar, the M4 PAM franchise, the V1a, our preclinical portfolio I mean, I'd highlight NLRP3 where we're actually getting a lot of questions where we just announced a really nice partnership with Parkinson's Virtual Biotech, one of the sort of big Parkinson's players. We have a GCase program. So frankly, I'm having a hard time looking at things on the outside that compete with the strength of our internal assets. So at this point, we're very, very pleased with the programs we have. Really, all of our effort is focused on advancing those. We'll keep our eyes and ears open for external opportunities. But I'd say the bar is very, very high to compete with our internal programs at this point.
From a BD perspective, the goal here is still to retain economics unpartnered as long as possible? Or what's the decision point for you guys?
No. No. Absolutely.
How does that change?
Absolutely. I mean, we're in a fortunate position that because all of our programs are novel assets, so we have actually intellectual property protection. And this is very important to understand. It's composition of matter protection. It's not method of use or other tricks in the book. It's composition of matter out to the 2040s. And so we have a really attractive commercial runway. And that gives us a chance to explore these other indications we've talked about. So our plan certainly is to execute against that plan, to bring additional indications forward. And we just brought on a chief commercial officer. We're pretty deep into commercial planning. And certainly, next year, as we unveil the phase three in Q4 this year and then second and third phase three in the first half of next year, we'll be investing more in the commercial infrastructure and prepare for launch.
I think this is a market where we can make a big impact. I'm quite excited to do that.
Awesome. Well, Henry, Bill, thank you so much, guys. Appreciate the dialogue.
Thank you. Yeah. Very good. Thank you.