All right. Thanks very much, everybody. It's my pleasure to have Josh and Helen from Neumora up here with me to give us an update and an overview, and I'll ask maybe the two of you to just give a snapshot of the navacaprant phase III program, where things are with the pipeline, and then we'll do Q&A, so thank you.
Absolutely. And thanks, Paul, for inviting us to the conference today. We really appreciate it. And so, as we all know, brain disease is one of the largest medical challenges of our generation. It affects billions of patients globally, over 100 million patients in the U.S. collectively. And we all know someone that's impacted by neurodegenerative disorders or neuropsychiatric disease. And so at Neumora, we've really set the company up to innovate the next wave of novel therapeutics to come forward for both categories. We've built what we think is an industry's leading pipeline of seven programs, all targeting novel mechanisms of action. Our lead asset, navacaprant, is a highly selective, we believe, best-in-class kappa opioid receptor antagonist in phase III for the monotherapy treatment of MDD. And we're running three replicate phase III studies all in parallel.
KOASTAL I, which is the first of those studies, is expected to read out top-line data around year-end 2024. And KOASTAL II and III are expected to read out top-line data in the first half of 2025. Beyond MDD, we're also looking at navacaprant for the treatment of bipolar depression. It's currently in a phase II study in that population. We'll look to read that out in the second half of 2025. Our second clinical stage program, NMRA-511, is a V1a receptor vasopressin antagonist. And that's currently in a phase 1b study for patients suffering from agitation due to Alzheimer's disease. And we expect data from that program in the second half of 2025. And so, as you can see, a very rich 12 months coming up from a catalyst perspective. We also have a very strong balance sheet.
We just announced on our earnings call last week that we ended the third quarter of 2024 with about $342 million in cash, cash equivalents, and marketable securities, which provides cash runway into the middle of 2026, and so really hitting an exciting time for Neumora Therapeutics.
Great. So when you guys updated earnings and talked about data around the end of 2024, I think there was some confusion around what exactly that meant and whether that implies the data could be first quarter. Do you want to clarify that a bit? And I know you guys have been resistant to talk about enrollment and things like that, but anything you can say around exactly where you are with patients in the study would be helpful.
Yeah, no, absolutely. And so we are guiding towards top-line data coming around year-end. We did complete last patient early in the fourth quarter. And so we're well on our way to releasing top-line data. As we mentioned in our third quarter press release, we've built in the flexibility in all three of the KOASTAL protocols to increase the sample size by up to 20%-25%. We did take advantage in KOASTAL I of the ability to upsize the studies. We're not going to comment on final patient numbers until top-line data, but we are looking forward to releasing the top-line data around year-end.
So can you remind us of your original powering assumptions? And I don't know if you can get super specific, but what could an upsize imply for the degree to which you could actually have cushion on the lower end?
Absolutely. The three KOASTAL studies were all powered at 90% to detect a 3.2-point placebo-adjusted change on the MADRS at week six. The studies are very well powered in and of themselves. We just built in the flexibility around the upsizing to give ourselves additional cushion should we see fit. If you look at our phase II study with navacaprant, we initially targeted about 180 patients and ended up randomizing 204 patients. It upsized our prior study as well.
Okay. Makes sense. So maybe taking a step back, do you want to talk a little bit about some of the changes you made in phase III from phase II and kind of your view on the implications for each as it relates to probability of success?
Yeah, absolutely. So we've been laser-focused on really developing as well as executing what we believe are a set of very high-quality studies, mainly with the goal to mitigate placebo response so we can give navacaprant the best shot of showing a statistically significant separation. And so on the study design perspective, a couple of the changes we made is we shifted from using HAM-D17 as the primary measure in phase II to the MADRS as the primary measure in phase III. Both of the scales are registrational endpoints per the FDA for MDD. However, the HAM-D17 scale focuses on targeting more depressed mood as well as somatic measures such as sleep and GI elements. Those somatic measures are areas that the kappa opioid receptor antagonist pharmacology isn't necessarily suspected to improve.
And as we saw through our phase II data, most of the effect size on the HAM-D17 was driven through the HAM-D6, which is known to be the subset of the HAM-D17 focused on core depressive symptoms. If you contrast that to the MADRS, the MADRS is a 10-item scale. Five of the questions on the MADRS are known as the MADRS anhedonia factor. And so it's a scale that's really purpose-built to not only detect changes in depressed mood, but changes in anhedonia. From our phase II data, as well as prior studies such as the FAST-MAS study, which was run by the NIMH, it's clear that the pharmacology here is hypothesized to improve not only depressed mood, but also anhedonia. And that's what we've seen through the clinical scales.
And so we believe that switching to the MADRS scale can offer the potential to show potentially an even bigger effect size than we did in phase II and really give the drug its highest probability of success. We also moved the primary endpoint from eight weeks to six weeks. We know that the longer you follow patients, the higher the probability is for placebo response. Anywhere from that four to eight weeks from a primary endpoint perspective is consistent with the FDA's 2018 guidance on MDD clinical trials. And then from an execution perspective, the focus there is really ensuring we get a high-quality set of patients randomized that look as homogeneous as possible. And so the first step there is site selection. And we've been very diligent around site selection.
As we mentioned before, we ran a very robust phase II study where we enrolled at 40 sites in the US, and we've taken the best sites from that study and ported them over to the KOASTAL program, and we've supplemented that with sites that we have done diligence with our partners as well as outside vendors to ensure have experience in MDD clinical trials, not only enrolling, but showing separation from placebo, and we've added in a few additional measures such as central raters. That's really to protect the integrity of the baseline visits and ensure that we truly have a population of moderate to severe patients that have a baseline HAM-D score of 25 or greater, and then as the study executes, one of the things we wanted to be able to ensure is patient compliance. We've seen this be a challenge before in neuropsych studies.
The traditional way to ensure compliance is to look at PK samples after the study is run. We've employed an app on the smartphone called AiCure, which takes video capture of patients ingesting their drug. We as the company are flagged if a patient misses a couple doses, which gives us the ability to go engage with the site who can subsequently engage with the patient to ensure compliance is ongoing. Finally, we're using something called a placebo-controlled reminder script. Typically in these MDD studies, there can be patients and physicians experiencing expectation bias where the patients and the physicians want the patient to get better. We remind the patient and the rater before every efficacy assessment that they have a 50/50 shot of being on active and placebo, which has been published to lower ultimately the placebo response.
So Paul, in summary, we've taken a number of design and execution tactics to really be diligent around the study in addition to active oversight and monitoring of the studies.
Yep. Okay. And how are you thinking about what is the bar for a win? If you guys hit a p-value of 0.02, but the MADRS delta was 1.8 or 2.2, is that still good? Do we have a sense if there actually is a minimum hurdle for FDA or for clinicians in this space?
And so if you think about really where the unmet need sits within MDD, it's around agents that can offer a more palatable safety and tolerability profile as well as being able to treat some of the symptoms beyond just core depressed mood. And so as we think about the MADRS, really the bar for success is hitting statistical significance. Where we see the value proposition for the product coming into place that could really help to serve the unmet need is not only the safety profile, but the ability to potentially hit on anhedonia. And so we have SHAPS as a key secondary endpoint. But with both the MADRS and the SHAPS, we view statistical significance as the bar. And then we're going to look to couple that hopefully with a safety profile that looks similar to what we showed in phase II.
Yep. Okay. Do you have a view on what we know or what we don't know about aticaprant?
Sure. Well, I think that what we can say is there's been a lot of discussion about the recent initiation of a randomized withdrawal study for aticaprant. Of course, we can't know why they chose to initiate that study now, but what we do know is that these randomized withdrawal studies are typically post-marketing commitments for the FDA in the US, and they're big, expensive studies. So it's not something that a company likely chooses to do lightly. And so we think that it's a bullish signal.
Okay. Okay, but otherwise, we have no inclination of whether their data could come first, although it seems increasingly less likely. Is that fair?
Yeah. Based on their recent commentary, it seems like their data could come kind of any time now or in the first quarter.
Okay. Beyond the whole mono adjunctive piece, what are the kind of biggest differences between navacaprant and aticaprant? And I think one thing that sticks out to me is the lack of itch signal in your phase II study, but also that should theoretically be on target. So what can we realistically expect across phase III?
Yeah, absolutely. One of the biggest differences just within the pharmacology of the two compounds, navacaprant is much more selective for the kappa opioid receptor over the mu opioid receptor than other kappa opioid receptor antagonists in the market. Navacaprant is 300-fold selective. Aticaprant, as we know, is only 30-fold selective. In terms of side effect profiles and itch, the biology behind itch response is quite complex. There's thoughts that it could be driven by kappa, thoughts that it could be driven by mu. We really feel like it's the selectivity profile of navacaprant that enables us to dose at the 80 mg level and not see pruritus. As we look back at prior studies, we did see pruritus at 160 mg in the phase I SAD/MAD. We know J&J is seeing it at their 10 mg dose in phase II.
We think that that's due to their less selective profile where they're not only targeting kappa opioid receptors, but they're also hitting mu opioid receptors.
Yep. Okay. Okay. Makes sense. If KOASTAL I were to not succeed, are the things you could still change with KOASTAL II or KOASTAL III? The most obvious one to me would be trying to modify the primary analysis around patients either more severe or comorbid anhedonia and I don't know, maybe you don't want to get into those contingency plans, but just with three phase IIIs all well underway, right, one about to complete, what are the different we know the scenarios to the upside, right, as you have a really compelling drug, but what are the kind of risk mitigation scenarios on the downside?
Yeah, absolutely. And that was one of the reasons we built in the flexibility to adjust the sample size for each of the three studies. And so depending upon what we see out of KOASTAL I, that could cause us to look and think about what is the true effect size behind navacaprant and do we need to upsize KOASTAL II and/or III as well. In terms of other elements that we could make, we're not really commenting publicly on other changes. These are phase III studies, and so ultimately we're not going to be able to make wholesale changes, but we could think about different kind of analytical approaches. And ultimately, if that's the situation, we'll see what we choose to do going forward.
Yep. Okay. I think the only other safety question I had, I know you're doing ocular assessments in this phase III, also in the OLE. Do you want to talk about the back history of that and your level of comfort that there's no pun intended, nothing to see there?
Yeah. No, absolutely. And appreciate the pun there, Paul.
Thank you. That was actually spontaneous. I didn't write it down.
Great. So this signal originally came up in a rodent study. It's a standard preclinical toxicology study where you look at rodents' sensitivity to light. There was a signal in that study that there was sensitivity at the corneal level as well as the skin level. The margins were extremely high relative to the 80 mg dose, and so it hasn't posed really any concerns for us going on. Out of an abundance of caution, we did put ocular monitoring into the phase II study, and we did not see anything across the duration of that study in humans. And we have added it to the phase III studies, once again, out of an abundance of caution. But as I mentioned before, the margins to what we saw in the rodent are exceedingly high. We don't necessarily think this is something that translates from rodent species to humans.
So we're just going to continue to run the study and monitor it and hope that that'll clear up any ocular issues with the drug.
Anything else to add on navacaprant?
No. I don't think anything else to add on navacaprant other than we're about to head into a really exciting six-month timeframe where we're expecting to read out three phase III studies.
Yep. Yep. Okay. Well, let's talk about M4. Should we talk about the elephant in the room to start? What's the deal? Should we be as excited about M4 as we were two weeks ago?
Yeah. I think at Neumora, we're still really excited about M4. We're not really obviously going to comment on competitor data in detail, but we think that we have a really differentiated M4 franchise with multiple shots on goal. And so we're really looking forward to bringing our next M4 PAM into the clinic in the first half of next year.
I mean, I guess the question with the emraclidine studies is, did the drug fail or did the trials fail the drug? Do you guys have a view on that? I certainly do.
I think at this point, until we know more of the details about the study and the data, it's going to be very hard to decipher that. I don't think any of our view on selective M4 programs has shifted since before we saw that data. Some of the things we know is that you can see higher placebo responses based on the number of active arms you are running. And so one question is, was the heightened placebo response in that study driven by any design or execution elements? But at this point, as Helen mentioned, we really haven't wavered any of our excitement on selective M4 targeting and look forward to moving the follow-on compounds into the clinic in the first half of next year.
Okay. Is the underlying implication here that the lead compound at this point is probably going to be shelved?
That's not necessarily something that we've stated publicly. And so we are still working through a path forward with the FDA to see if we can resurrect and what a path forward for NMRA-266 would look like. What I will say is we are equally as excited about the follow-on compounds. They are chemically distinct and pharmacologically differentiated. And so as we think about how the M4 landscape is evolving, we actually think we're in quite a preferential state where we could, in the first part of next year, have three clinical stage M4 selective PAMs that'll give us the ability to truly charge hard towards this large market opportunity.
One of the bear cases on just the compound that you have, it's not even really compound specific. It's more that it came from Vanderbilt. Acadia also got a muscarinic from Vanderbilt. That one had a safety issue, and it's more this theoretical, can we be comfortable that, yes, this is an academic group that's done a lot of work with muscarinics, but do they have the same medicinal chemists as Pfizer? How should we be comfortable, right, that what you're getting there is competitive and not going to kind of run into some of these same idiosyncratic problems?
Yeah. And so I think I'll start by saying our partners at Vanderbilt have been fantastic this whole time. And we think they're world-class in terms of their drug discovery abilities. The leaders of that center there have long track records not only working in academia, but also within pharma. And so Paul, our view is, yes, we do think the Warren Center at Vanderbilt truly does bring pharma-level rigor to drug discovery. We've spent a lot of time partnering with Vanderbilt on not only NMRA-266, but the rest of the franchise and feel really good, really good about where we are. And we look forward to kind of continuing to progress the collaboration and bring the follow-on compounds into the clinic early next year.
Okay. Okay. I think one thing I forgot to ask about with navacaprant was bipolar depression. When we've looked historically at antipsychotics and the translatability of MDD to BPD, first of all, it usually goes in the other direction where drugs are studied in bipolar first and then MDD. But second, you see this kind of dynamic where with SSRIs, the efficacy in bipolar is a little murky. And the antipsychotics do work in bipolar, but antipsychotics have this kind of multimodality mechanism where they also probably help with the kind of whole mania cycling piece. So to that point, why do you think the KORA mechanism has got a good shot here?
Absolutely. So we are focused on bipolar depression, and so our initial study is in bipolar depression II patients. The rationale for studying bipolar depression is very similar to the rationale for studying MDD. Anhedonia is a very prevalent symptom within both disorders, and it's becoming more and more well captured that anhedonia is also problematic and not well treated within bipolar depression. And so the underlying biological rationale of why KORAs could work for anhedonia holds, and then ultimately the symptoms are prevalent in both of those indications. We have seen in transdiagnostic studies such as the FAST-MAS study that administration of a kappa opioid receptor antagonist does activate the ventral striatum. That's an area in the brain thought to really regulate and control anhedonia. And so not only in patients with MDD, but other mood disorders, that's been well established.
And so we feel like the biological rationale fits, the patient phenotype in terms of bipolar depression and level of anhedonia fits, which we've clearly seen is something that the KORAs can treat. And then finally, the registrational endpoint for bipolar depression is the MADRS scale, which is the same endpoint we are using for our MDD clinical studies. And as I mentioned before, five of the 10 questions are known as the MADRS anhedonia factor. And so it's a scale that really preferentially captures a benefit on anhedonia. So we feel quite good about that, and we'll have top-line data from the phase II study there in the second half of next year.
Okay. So maybe taking a step back, let's assume you get at least two out of three in KOASTAL. What does Neumora look like a year from now or two years from now? Do you envision yourselves raising the capital, going at this independently to compete with a powerhouse like J&J?
Yeah, absolutely. So we have always been a company that has been focused on building at scale from the start. And so from a capital perspective, our Series A was over $500 million. We've raised over $850 million over the last four years. We've started to build the foundations of a clinical group. And so we hired a chief commercial officer earlier this year. And so our plan is really to be able to bring these molecules forward and ultimately transition from development stage to commercial while also then having the next wave of our pipeline in terms of follow-on indications for navacaprant, NMRA-511, as well as the muscarinic compounds really slot into that next wave of innovation, as well as our preclinical compounds starting to rotate into the clinic. And so, Paul, we are ready, and we've got the team that we think can go at this alone.
Yep. Okay. Okay. Any questions from the group? Anything else we should cover here?
Maybe you want to talk about NMRA-511 briefly?
Yeah, please.
Yeah, absolutely. Our second clinical compound, as I mentioned before, is NMRA-511. That's a highly selective V1a receptor antagonist. The vasopressin system is really thought to control stress response, anxiety, as well as agitation. We initiated in the second quarter of this year a phase 1b study in patients with agitation associated with Alzheimer's disease, and that data will be coming out in the second half of 2025. We've run a number of preclinical models that have really shown not only in rodents, but in non-human primate species that the drug does have the ability to kind of reduce that anxiety agitation response. From a translational perspective, we've looked at brain signatures through EEG in non-human primates and correlated it with what we've seen from EEG in humans. We see very similar patterns of activity. We feel pretty good.
Obviously, Alzheimer's is a large, prevalent, and growing indication. Agitation is one of the most common symptoms within the disease. It affects upwards of 70% of patients. And it's a symptom that we know not only patients, but caregivers are looking for relief from. It is one of the symptoms that can result in patients moving from the at-home setting to the long-term care. And so we feel like bringing a new product forward that can potentially have an advantageous efficacy as well as safety profile could be quite compelling in that market.
It's obviously a super tough indication. What about the mechanistic rationale of this got you excited here, and is there anything you can do on the preclinical side or on the animal model side that got you thinking, "Wow, AD agitation is the right way to go"?
Yeah. So it really comes back to some of the biological rationales we've mentioned, Paul, where the vasopressin system is really known to regulate aggression as well as anxiety. There's not a lot of great preclinical models on AD agitation, and so nothing in particular there to be able to point to. What we can say is in some of the common models of aggression and anxiety run in rodents and non-human primates, we did see an effect that looked quite interesting.
Okay. And safety of this mechanism, I know that there was something preclinically related to the M4 in a different indication. You want to walk through some of that history?
Yeah. And so in terms of what we've seen thus far, we've completed our SAD/MAD study in the first half of last year. Didn't hit a DLT in those studies, dosed very high where we had expected modeled receptor occupancy coverage, north of 95%. And so molecule looks exceedingly safe in humans, and we're looking forward to seeing the 1B data second half of next year just to understand exactly how it's behaving in this population.
Okay. Okay. Anything else in the early pipeline side? I know when you guys went public, there were a lot of targets in the discovery stage you were working on, like GCase and things like that.
Absolutely. And so we continue to move forward the early pipeline. We're quite excited about it. A lot of the early pipeline is really focused on some neurodegenerative targets, including NLRP3, GCase, and CK1 delta. Some of those targets are ones that are being pursued by other companies. We feel like we've got very attractive molecules there. And as we move them forward and get them close to the clinic, we look forward to providing more details around those programs.
Okay. Maybe to finish up, you guys guided to cash into mid-2026. Does that assume a significant decrease in spending when these trials wrap up? I think I got some questions and trying to tie the math on that and your comfort that you really have that 12-plus month cushion even at KOASTAL III.
Yeah. No, absolutely. And so this guidance just came out last week, so we feel extremely confident in the guidance we've provided. The biggest spend within the company right now are the phase III KOASTAL programs, which we'll be wrapping up in the first half of next year. If you look at the rest of our pipeline, bipolar phase II is not going to read out until the second half of next year. NMRA-511 phase 1b is not going to read out until the second half of next year. And so we don't have a program that's necessarily going to immediately move into large registration studies. And so in terms of something that's going to replace that navacaprant KOASTAL spend, it'll take a bit of time as we think about getting into 2026 potentially.
Okay. Okay. Great. Well, best of luck. Thanks so much for joining. Appreciate it.
Thanks.
Thanks for having us.