Neumora Therapeutics Inc R&D Day Transcript

The following is excerpted from the question-and-answer section of the transcript.

Question: Anton Porsteinsson - - Analyst : Good morning, Bill and good morning, everyone, who's on the call.

Question: Anton Porsteinsson - - Analyst : Absolutely. My pleasure. Again, good morning, everyone. My name is Dr. Anton Porsteinsson. I'm trained as a geriatric neuro psychiatrist, and I completed my training back in the mid-1990s. Since that time, I've singly focused on the CARE study of people with Alzheimer's disease and related dementias I spent about 25% of my time in an academic based, the specialized memory disorders clinic and 75% of my time I spend on doing clinical research. I've done somewhere north of 350 clinical trials in my career. And the work I focus on ranges from biomarkers and imaging to prevention studies in Alzheimer's disease, intervention studies for early symptomatic Alzheimer's disease, MCI, mild, moderate disease. And with my background coming out of psychiatry, I've always been particularly interested in it as well in neuropsychiatric symptoms in Alzheimer's disease such as agitation and aggression, psychosis, depression, apathy, et cetera. And within that space, I've helped with defining diagnostic guidelines, refine clinical trials and their operations as well as kind of the regulatory process. So glad to be here.

Question: Anton Porsteinsson - - Analyst : Yeah. Thanks, Bill. You highlighted some of it, but agitation and degression is almost ubiquitous for patients with Alzheimer's disease as well as related dementias and that is that at some time during the course of their disease, 70% of people will experience agitation and degression. And that can be enduring that can be short-lived. It tends to increase as the disease wears on, becomes most frequent in the moderate stage and as well into the severe stage. But you can see agitation in particular and sometimes aggressiveness as early as the mild cognitive impairment stage. So no stage is kind of immune to it. REFINITIV STREETEVENTS | www.refinitiv.com | Contact Us consent of Refinitiv. 'Refinitiv' and the Refinitiv logo are registered trademarks of Refinitiv and its affiliated companies. OCTOBER 27, 2025 / 12:00PM, NMRA.OQ - Neumora Therapeutics Inc R&D Day When you talk to patients, they experience the agitation and the distress that comes with it. And caregivers identify this as probably the most disruptive component of the disease. There's one thing being kind of happily confused and working with your care partner, be that family or a professional caregiver, but if you are agitated, oppositional, angry let alone physically or verbally aggressive, it increases the burden monumentally. And this, along with incontinence, relentless incontinence are the main reasons why patients get the move to higher level of care. And higher level of care is emergency rooms, urgent care, hospitalizations and admissions to memory care units as well as skilled nursing facilities. And there's nothing about going into any of these institutions that somehow minimizes the behavior. In fact, it may make the behavior even more intense because it's a new environment unfamiliar to them. So the treatment needs are not only in the outpatient setting, but they extend to these institutional settings as well.

Question: Anton Porsteinsson - - Analyst : Yeah. Let me quickly step back, and there was one thing that I want to highlight, and that is that agitation and degression at this point is a well-defined condition. We have a solid diagnostic criteria that have been exported and refined over a decade that are now accepted by regulatory bodies. So that means that we have a regulatory process here as well. Despite that, we have very limited options in terms of anything that is FDA approved. There is only one medication that is FDA approved for agitation and aggression in Alzheimer's disease. We have a number of medications that are used off label. I should point out that the standard of treatment is to use nonpharmacological interventions first. And that sounds easy, but it isn't. First of all, there is no set of nonpharmacological interventions or behavioral dimensions that work for everyone. Number two, they mostly work when there is mild disease, not if there is moderate or acute disease. Doesn't mean that we don't try them, but you have to offer them very frequently with medications. And they're not easy to do. You need the people to do the interventions. They need to have training. They need to have understanding. And in most places, these resources aren't available. So we resort to medications. And the medications that are used are in some degree dictated by the treatment necessity here that you cannot treat this even if, for the longest term, no medications were available. And it's important to understand that the treatments we use have very limited evidence of efficacy, maybe more evidence that they're not that efficacious, but they have solid evidence that they are associated with complications. And let me highlight a few of them. So conventionalist antipsychotics like Haldol, that was, to some degree, replaced by atypical antipsychotics like risperidone and quetiapine, medications that then showed very variable benefit, but clear problems in terms of increased all cause mortality in terms of cerebrovascular events, in terms of worsening of disease progression, in terms of falls, increase sedation, acute kidney injury, et cetera. You mentioned that those are conventionally typical antipsychotics have boxed warnings to kind of highlight that. I also want to point that other medications. I've done a lot of work with SSRI antidepressants, and it was disappointing that. Last year, we showed that treatment with citalopram did not separate from placebo and retain some of the problems that we saw with citalopram such as QTC prolongation and falls. So even medications that are in wide use are associated with different kinds of risks in this population. And let me not start with people that are still using benzodiazepines, moved stabilizing as the conversions, et cetera, that have their own clear set of limitations. So we need more medications that are safe and well tolerated and have a differentiated type of action from the ones we have currently because there is so much pathophysiological variance in terms of what leads to agitation and degression in the brain. REFINITIV STREETEVENTS | www.refinitiv.com | Contact Us consent of Refinitiv. 'Refinitiv' and the Refinitiv logo are registered trademarks of Refinitiv and its affiliated companies. OCTOBER 27, 2025 / 12:00PM, NMRA.OQ - Neumora Therapeutics Inc R&D Day

Question: Anton Porsteinsson - - Analyst : Well, Bill, for those that know me, and I'm sure that a few of the people in the audience know me and have spoken with me before. I'm kind of a pharmacology a nerd and pathway. I really am intrigued by that. And I'm particularly intrigued by us discovering more and more pathways that may have a high relevance in terms of memory disease in general as well as the emotional control that is so often lost with the disease. And I highlighted the kind of parapsychological logical variance before. And that parapsychological variants actually translates into the agitation of depression is rarely alone, it often travels with anxiety depressive features, psychotic features, but it's the agitation that brings the kind of care needs in. So we need other options. And what I like about the vasopressin pathway and the V1a receptor potential is that the these are so strategically located. We have such a density of these receptors in the amygdala the hippocampi, areas that really have a major role in emotional control. It's kind of where the strategic sectors of that. We have the animal studies that you mentioned before in both mice and marmosets. We have the human studies that if you stimulate the AVP process, basically, you get this increased behavioral and pathological reactivity to threaten a stimuli and stressful situations. So the pathway has face validity. Now the the pathway is relatively clear. But AVP has a number of different areas of impact, for example, the kidneys. And that's why the drug that you're using has to be very specific, have high affinity for the receptor of interest. So we want to target the V1a receptor. And one of the things that interested me about the NMRA-511, and I'll probably call it 511 from now on is the high specificity for that receptor and the lack of engagement of the other receptors and particularly some of the receptors in the kidneys. So that's what interests me. And we also have just a medication that seems to be -- or a molecule that behaves well. We have the data from kind of normal humans, we're getting the elderly PD data. And soon, some of the first data about the target of interest patients with Alzheimer's disease and meaningful agitation of depression.

Question: Anton Porsteinsson - - Analyst : Yeah. So Part B of our Phase Ib study has clearly the group of interest to me, that is patients with Alzheimer's disease and agitation and degression. You have done a good job in designing this because you need to design the study so that it's going to provide the information that you want. So you'll have the right population. You'll have a good number for a Phase Ib study. So 44 in each group. And you have multiple outcomes that all are very informative. You have the CMAI, which is an outcome that gives you granular information about the type of behaviors, the type of agitation and aggression that might be responding. And you can look at different domains to see which domain might respond to the best and also confirm, is this a scale that is optimal moving forward. But then, in addition to that, because the CMAI is a caregiver only-based scale, you have a secondary outcome measures basically the CIS, which is a clinician global impression for severity. So an expert clinician will evaluate the patients, get history from the patient as well as the caregiver REFINITIV STREETEVENTS | www.refinitiv.com | Contact Us consent of Refinitiv. 'Refinitiv' and the Refinitiv logo are registered trademarks of Refinitiv and its affiliated companies. OCTOBER 27, 2025 / 12:00PM, NMRA.OQ - Neumora Therapeutics Inc R&D Day and establish specifically the severity of the agitation and aggression. You have the CTIC, or the Clinician Global Impression of Change. Now this is the modified ADCS version targets or centers on agitation and depression. So you have an expert clinician also saying, I think this person is improved, same or worsened. And you furthermore, have a broad-based behavioral scale, the NPI, which gives you information about other behavioral domains. Like I said before, agitation and aggression is rarely alone. We haven't talked about different types of agitation and degression. Some fall into the effective domain, often alongside the anxiety and depression some fall in the disexecutive domain that is dyscontrol because people can't make sense of what's happening around them and can't control their emotions and then a domain that has a psychotic element, et cetera, et cetera. So you want to know, are we only having an impact on agitation or aggression or does it kind of spread to these other areas that are incredibly important as well to the well-being of patients and the comfort of caregivers. So you will get a broad set of information that will give you the -- what you need to basically take it to the next stage of development. And that's exactly and more what I would expect and hope for from a Phase Ib study. So I'm excited to see the results hopefully in the near term.

Question: Anton Porsteinsson - - Analyst : Absolutely. I want to be thoughtful about the fact that the CMAI is definitely not the alpha and the omega. It's one tool of many. And particularly at the early stage as we understand what targeting this pathway does, we need to look at this from multiple different viewpoints and have a well-informed foundation so that we can design the Phase II, Phase III studies that hopefully will follow. And we will also understand a lot more. We are doing a Phase Ib study. We want to understand a lot more about safety and tolerability. So far, that looks good. And if you think about the pathway, it ought to look good as the selectivity of the drug. But we want to see that in the healthy elderly population and in this population, if basically the occasional headache is the most common side effect or is the one that we kind of see emerging that overall it's a fairly benign safety and tolerability profile because it's such a vulnerable population.

Question: Myles Minter - William Blair Capital Partners - Analyst : Congrats on the updates. Just two questions for me, if I may, one for the company and one for Dr. Porsteinsson. First one is just you mentioned your confidence in the correlation between the DO and mouse models, correlating to what you would potentially see clinically on weight loss for 215. Can you just sort of like give us an update on where that confidence stands specifically for the NLP 3 inhibitor class, obviously, considering one of your peers last week did report a Phase II study that didn't show weight loss seen in monotherapy or in a combo setting. So that's the first one. And then the second one, Dr. Porsteinsson, would love your opinion on if there's any sort of overlap between Alzheimer's disease, agitation and psychosis? It's a question that we get a lot from investors considering some pretty heavy news flow on the psychosis side with the upcoming Adept study for Geny. So just wondering how you treat patients between agitation and psychosis? And whether they're individual indications or you would treat them together?

Question: Anton Porsteinsson - - Analyst : Absolutely, Myles. Good question. So yeah, I mean, agitation and degression really coexist with other behaviors very frequently. That can be anxiety, irritability, move disorders as well as psychosis. So if we think about the overlap between agitation and degression and psychosis, then let's start by looking at psychosis. If there is psychotic beliefs, but there is no emotional reactivity to it, no distress, no kind of upset with the participant not getting in the way of caregiving. We call those kind of quiet or silent psychosis. And it very often exists, but goes unnoticed. And people are loath to intervene with treatment because of the trouble that the current medications that are available bring. So it is really when you see psychotic features come and go with agitation and depression that the urgency to treat emerges. How do I deal with that? It depends on what's the stronger flavor. If someone is more nonspecifically agitated, aggressive with some mild suspiciousness, mild hesitancy about others intentions, I would focus on the agitation and the aggression alone. If this is clearly driven by a high level of paranoia or visual hallucinations or auditory hallucination's, which aren't all that common in Alzheimer's disease more maybe in dementia with levy bodies, I would lean more towards the psychosis spectrum. So that's kind of how I look at it. You see a lot of overlap between this, agitation and aggression as a whole kind of universe that doesn't have much of psychotic features to them. But when we look at the overlap then it depends on which type of behavior predominates and seems to maybe drive the other one.

Question: Anton Porsteinsson - - Analyst : Yeah, Douglas, thank you. Astute question. So because of the heterogeneity, both within just a simple domain of agitation and depression as well as the overlap with multiple other types of behaviors. And I rattled off a few anxiety depressive features, irritability, psychosis -- these all layer on top of each other. And then you want to see actually a broad-based benefit, what is driving that is always a little unclear. REFINITIV STREETEVENTS | www.refinitiv.com | Contact Us consent of Refinitiv. 'Refinitiv' and the Refinitiv logo are registered trademarks of Refinitiv and its affiliated companies. OCTOBER 27, 2025 / 12:00PM, NMRA.OQ - Neumora Therapeutics Inc R&D Day Is it just the reduction in the agitation and depression. But I think that if we have a kind of a medication with the potential for a broader impact so that we will see some benefit in mood symptoms benefit in agency, some benefit in irritability fearfulness, alongside the agitation of depression, that is something that clinicians truly appreciate. They want a broad-based benefit that decreases the distress across the system. And by that, I mean not only for the patient, but also the burden for the family or professional caregivers depending on the setting.

Question: Anton Porsteinsson - - Analyst : Yeah. Let me just address that quickly. So obviously, Rexulti is atypical antipsychotic. We can probably call it a third-generation atypical antipsychotic. So it has some of the basically category burden associated with that. So the box warning for use in patients with Alzheimer's disease and psychosis. From a use perspective, maybe one of the challenge is that this drug was first approved for use in conditions where there are already 30, 40, 50 drugs available. So the coverage for this medication was not very generous, which was unfortunate because it is the first medication that is approved for agitation and depression, but it carries over the tight coverage from insurance companies. So one of the main challenges has been basically the high cost and co-pay and the hoops that you need to go through with that. And also patients kind of therefore asking to have something, kind of something similar that maybe is a little bit cheaper. So that has been in the clinic a challenge. For what's been my experience with it, in patients that have more kind of psychosis overtones or more aggressiveness, particularly physical aggressiveness. That's the spot that it has shown particular efficacy maybe in both the clinical trials and the clinical practice, which kind of, again, leaves a lot of agitation and degression unmanaged.

Question: Anton Porsteinsson - - Analyst : Can I just comment on one thing. This is Anton Porsteinsson because Ami mentioned the magnitude of effect based on severity as part of your question as well. So I basically want to kind of highlight that you need to have a certain degree of severity so that you can see a treatment response. And I think that for the Phase Ib study, we have to understand that there -- it's a sizable Phase Ib study, but it's not the power that we expect to be able remotely to look at subgroups. But I would like to have people with moderate and maybe close to severe level of behavioral disruptions. And if the mean score on the CMAI at baseline is somewhere in the high 60s to high 70s, that will be very informative because it also allows us to kind of compare a little bit what we might see in someone that is kind of on the lower intensity of behavior versus higher intensity of behavior. And I know that the inclusion criteria allowed for that in the Phase Ib study.