Neumora Therapeutics, Inc. Common Stock Price & Performance (NMRA)

With that, I'll now turn the call over to Paul.

Thanks, Helen. Good morning, everyone, and thank you for joining us to review our fourth quarter and full year 2024 financial results and business update.

As you may know, I've recently taken over as CEO and I'm pleased to be here with all of you today. I have been fortunate to have had multiple experiences leading teams to drive the successful development and approval of medicines and I believe Neumora has the potential to achieve this outcome as well. The first two months of 2025 have been productive for the company. And we believe that we are poised to make a difference for the millions of people living with brain diseases as we strive to improve on the limitations associated with current treatment options. We have built an industry leading pipeline of seven programs all targeting novel mechanisms of action with best in class pharmacology. We are in a strong financial position providing us the flexibility to advance several clinical and preclinical programs adapt and follow the science, and ultimately deliver medicines to patients who urgently need new treatment We are also fortunate to have assembled a deep roster of neuroscience drug developers and business leaders that we believe can drive our mission to deliver medicines to patients suffering from brain disease. I will now turn the call over to Josh Tinto, who has been newly appointed President of Numora after serving as our Chief Financial Officer for the last four years, to review the pipeline updates.

Josh? Thank you, Paul. It is an honor to work with our team as we strive to deliver transformative medicines in a number of prevalent brain disease I'm excited to take on this expanded role as President of Numora Neumora, as we make important updates to our pipeline and prepare for a productive year, Beginning with nivacaprant, which is a highly selective kappa opioid receptor antagonist, It's currently in Phase three development for the monotherapy treatment of MDD, which is the leading cause of disability worldwide, affecting more than two eighty million people. As we detailed in today's press release, we've made important changes based on the learnings from the COASTAL-one study to optimize the ongoing Phase three studies with nivacaprant in MDD. Which Phil will walk through shortly. We remain confident in the potential of nivacaprant as a novel treatment for MDD at Anhedonia.

Multiple positive clinical studies from independent sponsors including data from our own Phase two study with nivacaprant in MDD the NIH run FASTMAP study, and the aticaprant Phase II study validate the clinical potential for kappa opioid receptor antagonism. This body of evidence suggests that our Coastal One results may be an anomaly and there is an important role for this mechanism in the treatment of mood disorders. The strategy for the coastal program was to stagger the studies intentionally to allow the opportunity to fine tune the COASTAL-two and three studies based on learnings from Coastal One. We've now tested nivacaprant in nearly six hundred people with MDD to date which has allowed us to follow data driven insights that inform the changes we've deployed across the program. We are passionate about our mission of bringing novel treatment options to people living with MDD. I look forward to reporting top line data from COASTAL-three in the first quarter of twenty twenty six and Coastal II in the second quarter of twenty twenty six.

Additionally, this morning we announced that we discontinued the Phase two clinical trial investigating nivacaprant for the treatment of bipolar depression. While we still believe that nivacaprant may offer benefits for treating bipolar depression, we're focusing on rigorous prioritization to allocate our resources to the coastal program and other clinical programs for now. Therefore, we will evaluate opportunities to investigate printed bipolar depression and other indications beyond MDD in the future. Beyond nivacaprant, we are advancing NMRA which we are currently investigating in a Phase Ib signal seeking study in Alzheimer's disease agitation. Agitation is among the most disruptive symptoms of Alzheimer's disease. And is associated with increased morbidity and mortality earlier placement in long term care facilities, and greater caregiver stress. Approximately seventy percent of the estimated seven million people currently living with Alzheimer's disease experience agitation And as the number of people living with Alzheimer's increases, its devastating impact The only approved product carries a black box warning for mortality in elderly people. So it is clear that there is a substantial unmet need to treat Alzheimer's disease agitation. We look forward to reporting top line data from the Phase Ib signal seeking study by the end of the year.

We also expect to advance our M4 franchise by progressing our next compound into the clinic by mid-twenty twenty five. We are confident in the PAM mechanism for a number of reasons. First, we believe that agonist struggle for selectivity. It is clear that M4 is the driver of the antipsychotic activity seen with muscarinic drugs to date, We are also excited by the possibility of non titrated once daily dosing and the improved safety and tolerability profile, [indiscernible] 2025 is going to be an important year for Numoro Neumora. As we move forward we will be relentless in pursuing our mission to deliver new medicines to people living with brain disease.

Because they represent one of the greatest areas of unmet need. And patients deserve better. I look forward to updating you on our progress throughout the year I'll now turn the call over to Bill to provide additional details on our clinical programs. [indiscernible] Thanks, Josh. We are advancing studies across two clinical stage programs in our pipeline. Giving us the opportunity to deliver innovative medicines to people living with brain diseases. I'll start with nivacaprant. Our highly selective, novel once daily kappa opioid receptor antagonist being developed as a potential monotherapy treatment for MDD in the Phase III coastal program. Earlier this year, we announced that Novacopran did not demonstrate a statistically significant improvement on the primary or key secondary endpoint in the COASTOL-one study COASTAL-one is the first of three randomized placebo controlled double blind Phase three studies that comprise the pivotal COASTAL program Following the announcement of top line results from the COASTAL-one study, we paused recruitment for COASTAL-two and three and conducted extensive analyses to identify factors that might have contributed to the study outcome. With the benefit of data on nivacaprant in more than six hundred patients across Coastal One, and our Phase two study we are in a strong position to make meaningful changes to improve Coastal II and III.

First, we are enhancing engagement with sites around medical monitoring to confirm that the patients enrolled in the studies have an independently verified diagnosis of MDD that helps to ensure they are appropriately meeting the eligibility criteria for studies.

To do this, we are adding the clinician rated Massachusetts General Hospital Clinical Trials Network and Institute safer approach. SAFER is an independent review conducted by clinical psychiatrists to verify the diagnosis and appropriateness of the patient population. Our internal medical team will partner with the SAFER clinical team to help ensure patients appropriately meet eligibility criteria for the studies prior to randomization. Second, we're adding an additional tool called the Verified Clinical Trial Screening Database aimed at identifying patients who are participating in multiple clinical trials and excluding them from enrolling in the COASTAL-two and three studies, This is an additive approach to the clinical trial subject database we use in Postal-one we believe it will help to ensure the appropriate patients are enrolled in our ongoing studies.

Third, we've reduced the number of clinical sites and selected those sites that we believe have the greatest level of expertise in conducting MDD studies to include going forward.

We are taking these steps to help optimize the coast program because we believe in the potential of an evacomprint to make a real difference for patients. Historically, there have been many approved blockbuster medicines in MDD and psychiatry broadly that have build Phase III studies ultimately succeeded multiple studies became important treatments. We designed the coastal program with these historical challenges in mind knowing that we would need two of three trials to be successful order to file an NDA, Beyond Avacoprant, we are currently evaluating 11, our vasopressin 1a receptor antagonist in a Phase 1b signal seeking study in people with Alzheimer's disease agitation. Which is a large market opportunity with significant unmet need. Based on converging lines of clinical and preclinical evidence, V1a receptor antagonist have the potential to reduce symptoms of agitation. We are excited about NMRA-five eleven given its pharmacology strong preclinical data, well tolerated safety profile to date We look forward to sharing results from the study end of twenty twenty five. We also expect to advance our M4 franchise by progressing our next compound into the clinic by mid-twenty twenty five. Each of our M4PAM compounds is chemically differentiated strengthening our franchise of Muscranix that have the potential to deliver antipsychotic efficacy in multiple indications.

We believe that we are well positioned to become a leader in MuscularNyx important new class of medicines, and we look forward to providing an update on our M4, PM franchise by mid-twenty twenty five.

Lastly, we are advancing an exciting pipeline of four preclinical programs each of which has strong biologic rationale. These programs have a range of potential indications including Alzheimer's agitation, schizophrenia, Parkinson's and ALS. Giving us the opportunity to address unmet needs across several brain disorders. With these programs, I believe we are well on our way to achieve our mission of redefining the development of novel medicines for brain diseases.

With that overview, we I'll now turn the call over to Mike for a review of the financials. [indiscernible] Thanks, Bill, and good morning, everyone. Our financial results for the fourth quarter and full year 2024 are detailed in the press release that we issued this morning. Which I encourage you to read.

I'll take a moment to review these results. As we advance our pipeline, we are focused on disciplined capital allocation we believe will enable us to leverage our strong balance sheet to realize multiple catalysts across our program.

Total operating expenses for the fourth quarter were $58,800,000 compared to $108,700,000 for the same period in 2023. Total operating expenses for the full year ended December 31, 2024 were $243,800,000 compared to $235,900,000 for the same period in '20 The increase was driven primarily by activities related to the Phase three program for Novacacrypt ongoing studies across the rest of our portfolio, and investments to support the growth of our business. As of December thirty one, twenty twenty four, ended the year with $307,600,000 in cash and marketable securities which we expect to support operations into mid-twenty twenty six. We believe this runway places us in a very strong financial position to exit NMRA-five eleven our M4 franchise, and the rest of our pipeline. With that, I'll now hand the call over to Helen to manage Q and A with the op [indiscernible] Thanks, Mike. Before I turn it over to the operator, I'll ask you limit yourself to one question. Now I'll turn it over to the operator to handle Q and A. Operator?

Thank you. Our first question comes from Brian Abrahams with RBC Capital Markets.

Hey, good morning. Thanks for taking my question.

You elaborate a little bit more on some of the differences between the vendor that you utilized for Coastal One and SAFR and any changes in the site auditing and patient caps that you utilized in Coastal one that you'll apply for Coastal two and three? Thanks.

Good morning, Brian. This is Bill.

Bill Aurora. Thanks for your question. We take a look at the approach we are taking for coastal two and grade.

What we are looking to do is enhance the medical monitoring confirm the patients for being enrolled independently verified diagnosis for MDD and we have an opportunity to take a look at their prior history coming into the study. That being said, we're relying on Mass General Hospital So as you may be familiar, SAFR is an independent review conducted by clinical psychiatrists at MGH to verify the diagnosis and the appropriateness of the patient population Our internal medical team will partner with SAFER clinical team to confirm patient records and the appropriateness of the patients before they're randomized. And Brian, this is Josh here. I would just add this approach to ad safer is really above and beyond all of the measures that we had already instituted in the coastal program. And so we are not swapping anything out to replace it with SAFR. We are continuing to do the full approach we had doing up to this point and then adding SAFR on top of that to really help, as Bill highlighted, ensure that we're randomizing the most appropriate patients based on the eligibility criteria. Got it. Thanks, Josh. Thanks, Bill.

Thank you. Our next question comes from Douglas Tsao with H. C. Wainwright. Your line is open.

Hi, good morning. Thanks for taking the questions. I guess a couple from me. Maybe just as a starting point, I think it might be helpful if you could provide some perspective in terms of how far along inter enrollment Coastal II and III are right now And just broadly how impactful you think these changes could be And then I guess I was just curious if in the work you did, you were able to identify anything that might have led to the very distinct effect or differences in effect that we saw between male and female patients. In COASTAL-one? Thank you.

Great. Thanks, Doug. This is Josh. I'll answer second part of the question and turn it over to Bill to really hit on the first part. And so as we think about Novacabran and just the prospects of moving it forward, I think first we have to look at the target here.

And really the clinical validation of the capital opioid receptor antagonist class has produced to date We've seen important positive studies from a multitude of independent sponsors including our Phase two study with the Macfran MDD the NIMH run FASTMAST study as well as the aticaprant Phase II studies. And so we feel like the body of evidence out there really suggests that the COASTAL-one results might be an anomaly within this class And as we've talked about before, we truly believe that Novak's brand has best in class pharmacology here.

As we've unpacked Coastal One a bit more, beyond the gender differences that we had previously highlighted, we also looked at sites to see were there any factors that particularly impacted how sites performed And one thing that we're about to pull out is we saw that site experience and relation to their performance in other recent positive MDD monotherapy Phase three studies was another key driver of ultimately how how performance was measured. And so sites that have participated in other recent positive MDD Phase three studies tended to perform much better, not only in females, but the males in those sites actually quite well. And in the population that was not at sites that had recent experience as we've defined, You can see that the females still perform well, but the males in that particular subgroup had a large placebo effect upwards of 15 points And so we really feel like site experience is important as well And so this has all led to the modifications that we're making K2 and K3 to focus on site selection. We want to make sure we've got the best sites with a critical level of experience As well as the patient screening and medical monitoring in terms of adding SAFR in the BCT database so that we can ultimately optimize the patient population that's coming into the study.

And I think finally, we do have to remember that many of the approved medicines in MDD and psychiatry more broadly have failed a Phase three study. Ultimately succeeded to become blockbuster medicines. And so that was part of the reason why we designed the COASTAL study the way we did, where we are running three studies in parallel knowing that we only need two for a successful MDD study. So now I'll transition over to Bill to really highlight where we are with the K2K3 studies and the current moment.

Thanks, Josh. And Doug, I would just comment that the population that Josh referred to with respect to those sites that participated in recent positive MDD studies in the analysis that has to about a quarter of the population in K1 So we're not talking about a diminished number of folks. It gives us some added confidence as we're looking at the data. With respect to how many patients have been enrolled, it's just really been our perspective not to comment on patient numbers for ongoing clinical trial enrollment. But what I can say is that for K2 and K3, those studies were initiated at the end of or towards the end of twenty three before being paused in January of twenty five. We're now guiding to those studies resuming for another twelve to fifteen months This gives us confidence that the changes we are making along with the timelines and the patients yet to be enrolled in the study has the potential to make a meaningful difference on the outcome of the overall trials.

COGSAL-two and three are already different than K1 as an example. That both already enrolled a higher proportion of females relative to males that are more aligned to historical NDD studies.

Okay, great. Thank you so much. That's helpful.

Thank you. Our next question comes from Yatin Sinuha Hi. This is Selma for Yatin. Thanks for taking our questions.

So when you look retrospectively at patients with exaggerated placebo response in CohuSAL-one, What was their Madras' current baseline, if you can give any Q on that? Was it lower than average? And in terms of adjustment clinical sites now for CoStar two and three, you provide any granularity on the number of sites that will be removed? And what was the average number of patients per site in Cohassal-one? Thank you.

Dama, thanks for the question. At this time, we're not providing details in terms of the average baseline score Neumora patients in sites that had a high placebo response. But what we can say is that we do believe that the changes that we're making to Coastal two and three will help to improve on how we executed Postal One and ultimately support what we really want to. As we've looked at the data, what's clear to us is that site selection is absolutely critical. And we have removed some of the sites from coastal two and three and we'll be looking to potentially add some more and then patient screening as well as medical monitoring during that screening to randomization phase is absolutely critical to confirm patients appropriately meet the inclusionexclusion criteria. So as Bill highlighted, beyond all of the measures we already had in COASTAL-one, we have added the SAFER approach from MGH as well as the VCT database.

Got it. Thank you And do you expect the number of patients per site to increase now with Cohassar two and three?

In terms of the number of patients per site, we don't necessarily know that they'll increase. As you can recall, coastal two and three are sized the same way that coastal one is where the target number of patients enrolled in each is about three thirty two. We do want to make sure that for the remainder of Coastal II and III, we are focused on the highest quality sites. But ultimately, we can't comment in terms final number of sites at this point.

Got it. Thank you so much.

Thank you. Our next question comes from Paul Matteis with Stifel? Your line is open.

Hey, thanks for taking the question. I just I guess one thing I'm a little bit confused about is during Coastal One, the team was really confident that the study was going well, that it was well conducted. I remember talking to Henry about leveraging sites that were high performing sites from the Phase two study and using kind of your thought process six to nine months ago, what do you think you missed while the study was going on? What do you think led you to think the study was well conducted when ultimately now in hindsight it doesn't feel like it doesn't feel like it was? And then just secondarily, on cash runway, certainly pretty tight with these studies. I understand that you're extending that guidance, which is great to see. But what's your thought process there? And I guess how comfortable are you to go into these readouts with materially less than twelve months?

Good morning, Paul. This is Bill. Let me start out by talking about the placebo response and some of the things that we're doing to augment K2 and K3 You're absolutely right. We did see an outsized placebo response in K1. Particularly in males where we close to 14 placebo response and we realized we could do more with Coach K2 and K3 moving ahead. And one of those important steps is really to further enhance what we believe we had in place was the medical monitoring, strengthened medical monitoring that was already in place. And quite frankly, NPH and SAFER will help us do that to verify the baseline degree of severity, the diagnosis, which we know is critically important. So those steps should put us in a stronger position with both of the studies that still have substantial number of patients Hey, Paul. This is Mike. For the the cash flow side, we always aim to be strategic and disciplined with our approach to financing the company. We believe we're in a strong financial position that our label has achieved multiple catalysts not just win the back of print but across the pipeline. Our current balance sheet, as you noted and we noted, provides cash runway into mid-twenty six.

A company, we're always opportunistic and looking at ways that we fund the business. And that won't change in the upcoming year. There are a variety of funding mechanisms business development, our current ATM facility and equity that we can consider.

Yes. And Paul, this is Josh. I'll just summarize a few of the comments. We had obviously deployed a number of enhanced measures as we were thinking about executing Coastal One. Beyond what we had done in Phase two. And I think what we've seen through the Coastal One results is that we can do more beyond what we had done. And I think in addition to the measures that we're deploying, I think what you'll hear from the team around the table today is that we are very diligent in terms of the oversight and the detail oriented focus that we have to have. In terms of not only engaging with the sites, but engaging with them to ensure that we are getting the right patients randomized that fit the inclusionexclusion criteria. And then to Mike's point, we've always been very focused on maintaining a strong balance sheet. We've always been focused on on our ability to opportunistically finance the company. And so we're going to continue that path as we move 2025 and look forward to continuing to progress the business as we move through this year and into 2026.

Thank you. Great. Operator, I think we'll take our next question.

Our next question comes from Myles Mentor with William Blair. Your line is open. Hi, team. This is John on for Myles. Thanks so much for taking our questions.

Maybe two from us. So first, I was just wondering if you have any updates on the peak data from KOLSTOL-one and if there was anything you could glean from there on how the various sites performed or if there was any sex based differences And second, do you still have the opportunity to increase enrollment by 25% for Coastal II and III And if so, was that included in your timeline guidance?

Hi, John. This is Bill. Let me take the first question here with respect to the PK data. The exposures from Coastal One were consistent with the results [indiscernible] The Phase two study And so in that context, the exposures were as we expected consistent with Phase two where we did see the robust set of severe population believe that the eighty milligram dose is a potentially efficacious dose with a favorable tolerability and safety profile? We could have the potential to consider a higher dose in the future given the clean safety and tolerability profile that we've been seeing Yes. And then John, on the guidance and timing piece, I think we built in the flexibility in all three of the coastal studies. Coastal studies, coastal one, two and three to increase the sample size by up to 25%. And so we have that flexibility in coastal two and three as well.

In terms of our timelines, we have looked at a range of potential study. And that has been factored into our timing guidance. We're not going to comment this time in terms of the final number of patients that we expect to enroll in each of K2 and K3 We have factored that into ultimately the guidance that we've provided Thank you.

Thank you.

Our next question comes from Greg Savannava with Mizuho. Your line is open.

Hi, this is Sam on for Greg. Thank you for taking our question. You may have alluded to this a bit earlier, but as a result of the post clinical trial modifications, have there been any changes to the powering assumptions? Thank you.

Hi, Sam. This is Bill. With respect to the powering assumptions, We have not modified assumptions with respect to the overall design, the powering and of course, we will continue to keep keep you and the rest of the team prizew we're thinking about that, but nothing has changed.

Got it. Thank you.

Thank you.

Our next question comes from Ami Fadia with Needham and Company. Your line is open.

Hi, this is Puna on for Ami. Thank you for taking my question.

I'm sorry if you've already asked this before, but have you started any interim analysis [indiscernible] Sorry, we can't hear you. Are you able to speak a little bit?

Can you hear me now?

It's a little bit, but you're pretty muffled. So just wondering if you've built in any incremental for the other two coastal studies that could provide some insights this year? And has there been any further discussion [indiscernible] if you continue to see a gender based efficacy in the other coastal studies? [indiscernible] in terms of the this is Josh. In terms of the interim analysis, we have not built an interim analysis into the protocols.

As you're aware, these are fairly short duration studies, only six weeks. And so so as we have looked at it, putting an interim analysis into or a futility analysis, Ultimately, we didn't feel the yield any benefits Neumora the coastal II and III studies that is not planned for these. And I'll pass it over to Bill to just maybe talk about where we are in terms of discussions with the regulators around JEDRA Sure. We don't typically comment on our interactions with the FDA. Early the results in K1 were interesting and have us thinking a bit about some of the differences seen in females relative to males we'll of course look to evaluate those findings and see if they're replicated in K2 and K3 we've been thinking a bit more if those findings are replicated, how am I able to take those forward. We'll comment on those at a later time point, if appropriate.

Got it. Thank you.

Thank you. Our next question comes from Tessa Romero with JPMorgan. Your line is open.

Hi, good morning, team. Thanks so much for taking our question. So NMRA two sixty six has been on clinical hold for almost a year. Why has there not been an update And can you provide a little bit of color on your latest thinking on if the convulsions that were observed preclinically with the product or specific to the candidate itself? Thanks.

Hey, thanks, Hess. This is Josh. I'll address that that question. And so we've been working through two sixty six ultimately to determine if we can move it off of progressing the follow on franchise molecules for M4. And so we are excited to note today that we do plan to get one of the follow on compounds into the clinic by the middle of twenty twenty five. We do have a lot of confidence in the follow on franchise and in terms of the rabbit convulsions, we would agree it would be logical for us to look to derisk the follow on compounds within our M4 franchise before we progress them into the clinic. And so we'll be coming forward with a fulsome update on the m4 franchise when we move our next program into the clinic over the next couple of the coming months.

That will conclude Q and A portion of today's call. With that, I'll turn it back over to Mr. Burns for closing remarks. Great. Thank you, operator, and thanks to all of you for joining us this morning. Think it's pretty clear we believe Nemora Neumora poised to create significant value for patients and shareholders By bringing forward the next generation of novel therapies, we need to offer improved treatment outcomes and quality of life for people suffering from brain disease. We have a diverse set of programs And I would say most importantly, we are supported by a great team with a strong financial position that allows us to drive the programs forward with what we believe to be important value creation for patients and shareholders. Before I conclude, I actually wanted to just emphasize a great amount of thanks to the talented and dedicated to our team members for their steadfast dedication and commitment to patients that we serve. Thanks again. Great questions today. Have a wonderful day everybody.

Thank you for your participation. This does conclude the program. You may now disconnect.

Good day.