NMRA - NASDAQ

Ladies and gentlemen, thank you for standing by. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to turn the conference over to Helen Rubinstein, Vice President of Investor Relations and Communications. Please go ahead.

Good morning, and thank you for joining Neumora Therapeutics Fourth Quarter and Full Year 2024 Financial Results Conference Call. Before we begin, I encourage everyone to go to the Investors & Media section of our website at neumoratx.com, where you can find the press release related to today's call. With me on the call are Neumora's Chief Executive Officer, Paul Berns; President, Josh Pinto; Chief Operating and Development Officer, Bill Aurora; and Chief Financial Officer, Michael Milligan. I would like to point out that we will be making forward-looking statements, which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. Please review the risk factors discussed in today's press release and in our SEC filings for additional detail. 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 2 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 7 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 options. 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 Pinto, who has been newly appointed President of Neumora after serving as our Chief Financial Officer for the last 4 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 diseases. I'm excited to take on this expanded role as President of Neumora as we make important updates to our pipeline and prepare for a productive year. Beginning with navacaprant, which is a highly selective kappa opioid receptor antagonist. It's currently in Phase 3 development for the monotherapy treatment of MDD, which is the leading cause of disability worldwide, affecting more than 280 million people. As we detailed in today's press release, we've made important changes based on the learnings from the KOASTAL-1 study to optimize the ongoing Phase 3 studies with navacaprant in MDD, which Bill will walk through shortly. We remain confident in the potential of navacaprant as a novel treatment for MDD in Anhedonia. Multiple positive clinical studies from independent sponsors, including data from our own Phase 2 study with navacaprant in MDD, the NIMH run FAST-MAS study and the aticaprant Phase 2 study validate the clinical potential for kappa opioid receptor antagonism. This body of evidence suggests that our KOASTAL-1 results may be an anomaly, and there is an important role for this mechanism in the treatment of mood disorders. The strategy for the KOASTAL program was to stagger the studies intentionally to allow the opportunity to fine-tune the KOASTAL-2 and KOASTAL-3 studies based on learnings from KOASTAL-1. We've now tested navacaprant in nearly 600 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 KOASTAL-3 in the first quarter of 2026 and KOASTAL-2 in the second quarter of 2026. Additionally, this morning, we announced that we discontinued the Phase 2 clinical trial investigating navacaprant for the treatment of bipolar depression. While we still believe that navacaprant may offer benefit for treating bipolar depression, we're focusing on rigorous prioritization to allocate our resources to the KOASTAL program and other clinical programs for now. Therefore, we will evaluate opportunities to investigate navacaprant in bipolar depression and other indications beyond MDD in the future. Beyond navacaprant, we are advancing NMRA-511, which we are currently investigating in a Phase 1b 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 70% of the estimated 7 million people currently living with Alzheimer's disease experience agitation. And as the number of people living with Alzheimer's increases, its devastating impact will only grow. The only approved product carries a black box warning for mortality and 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 1b 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-2025. We are confident in the PAM mechanism for a number of reasons. First, we believe that agonists 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 that M4 PAM may offer. 2025 is going to be an important year for Neumora. As we move forward, we'll 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. Bill?

Thanks, Josh. We are advancing studies across 2 clinical stage programs in our pipeline, giving us the opportunity to deliver innovative medicines to people living with brain diseases. I'll start with navacaprant, our highly selective, novel, once-daily kappa opioid receptor antagonist being developed as a potential monotherapy treatment for MDD in the Phase 3 KOASTAL program. Earlier this year, we announced that navacaprant did not demonstrate a statistically significant improvement on the primary or key secondary endpoint in the KOASTAL-1 study. KOASTAL-1 is the first of 3 randomized, placebo-controlled, double-blind Phase 3 studies that comprise the pivotal KOASTAL program. Following the announcement of top line results from the KOASTAL-1 study, we paused recruitment for KOASTAL-2 and 3 and conducted extensive analyses to identify factors that might have contributed to the study outcome. With the benefit of data on navacaprant in more than 600 patients across KOASTAL-1 and our Phase 2 study. We are in a strong position to make meaningful changes to improve KOASTAL-2 and 3. 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 the 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 KOASTAL-2 and 3 studies. This is an additive approach to the clinical trial subject database we use in KOASTAL-1, and 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 KOASTAL program because we believe in the potential of navacaprant to make a real difference for patients. Historically, there have been many approved blockbuster medicines in MDD and psychiatry broadly, that have failed Phase 3 studies, but ultimately succeeded in multiple studies and became important treatments. We designed the KOASTAL program with these historical challenges in mind, knowing that we would need 2 or 3 trials to be successful in order to file an NDA. Beyond navacaprant, we are currently evaluating NMRA-511, 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 antagonists have the potential to reduce symptoms of agitation. We are excited about NMRA-511 given its pharmacology, strong preclinical data and well-tolerated safety profile to date. We look forward to sharing results from the -- study end of 2025. We also expect to advance our M4 franchise by progressing our next compound into the clinic by mid-2025. Each of our M4 PAM compounds is chemically differentiated, strengthening our franchise of muscarinic that have the potential to deliver antipsychotic efficacy in multiple indications. We believe that we are well positioned to become a leader in muscarinic, an important new class of medicines, and we look forward to providing an update on our M4 PAM franchise by mid-2025. Lastly, we are advancing an exciting pipeline of four preclinical programs, each of which has a 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, I'll now turn the call over to Mike for a review of the financials. Mike?

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 that we believe will enable us to leverage our strong balance sheet to realize multiple catalysts across our programs. Total operating expenses for the fourth quarter were $58.8 million compared to $108.7 million for the same period in 2023. Total operating expenses for the full year ended December 31, 2024, were $243.8 million compared to $235.9 million for the same period in 2023. The increase was driven primarily by activities related to the Phase 3 program for navacaprant, ongoing studies across the rest of our portfolio and investments to support the growth of our business. As of December 31, 2024, we ended the year with $307.6 million in cash, cash equivalents and marketable securities, which we expect to support operations into mid-2026. We believe this runway places us in a very strong financial position to execute on appropriate next steps for navacaprant, and NMRA-511, our M4 franchise and the rest of our pipeline. With that, I'll now hand the call over to Helen to manage Q&A with the operator. Helen?

Thanks, Mike. Before I turn it over to the operator, I'll ask that you limit yourself to one question. If you have an additional question, please feel free to return to the queue. Now I'll turn it over to the operator to handle Q&A. Operator?

[Operator Instructions] Our first question comes from Brian Abrahams with RBC Capital Markets.

Can you elaborate a little bit more on some of the differences between the vendor that you utilized for KOASTAL-1 and SAFER? And any changes in the site auditing and patient caps that you've utilized in KOASTAL-1 that you'll apply for KOASTAL-2 and 3?

Brian, this is Bill Aurora. Thanks for your question. When we take a look at the approach we are taking for KOASTAL-2 and 3, what we are looking to do is enhance the medical monitoring to confirm the patients for being enrolled have an 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, their CT&I Group that institute SAFER. So as you may be familiar, SAFER 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 the 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 add SAFER is really above and beyond all of the measures that we had already instituted in the KOASTAL program. And so we are not swapping anything out to replace it with SAFER. We are continuing to do the full approach we had been doing up to this point, and then adding SAFER on top of that to really help, as Bill highlight it, ensure that we're randomizing the most appropriate patients based on the eligibility criteria.

Our next question comes from Douglas Tsao with H.C. Wainwright.

I guess a couple for 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 into enrollment KOASTAL-2 and 3 are right now? And just broadly, how impactful do 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 factor difference as an effect that we saw between male and female patients in KOASTAL-1?

Great. Thanks, Doug. This is Josh. I'll answer the second part of the question and then turn it over to Bill to really hit on the first part. And so as we think about navacaprant 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 kappa opioid receptor agonist class has produced to date. We've seen important positive studies from a multitude of independent sponsors, including our Phase 2 study with navacaprant and MDD, the NIMH run FAST-MAS study as well as the aticaprant Phase 2 studies. And so we feel like the body of evidence out there really suggests that the KOASTAL-1 results might be an anomaly within this class. And as we talked about before, we truly believe that navacaprant has best-in-class pharmacology here. As we've unpacked KOASTAL-1 a bit more, beyond the gender differences that we have previously highlighted, we also looked at sites to see were there any factors that particularly impacted how sites performed? And one of the things that we're able to pull out is we saw that site experience, in relation to their performance in other recent positive MDD monotherapy Phase 3 studies, was another key driver of ultimately how performance was measured. And so sites that have participated in other recent positive MDD Phase 3 studies tended to perform much better, not only in females, but the males in those sites actually performed quite well. And in the population that was not at sites that had recent experience, as we've defined, you can see that the female 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 is all less of the modifications that we're making for 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 SAFER in the VCT database 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 3 study, but ultimately succeeded to become blockbuster medicines. And so that was part of the reason why we designed the KOASTAL study the way we did, where we are running 3 studies in parallel, knowing that we only need to 2 for a successful MDD study. And so now I'll transition it over to Bill to really highlight where we are with the K2, K3 studies at 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 constituted about 1/4 of the population in K1. So we're not talking about a de-minimis 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 2023 before being paused in January at '25. We're now guiding to those studies resuming for another 12 to 15 months. This gives us confidence that the changes we are making along with time lines and the patients yet to be enrolled in the study have the potential to make a meaningful difference on the outcome of the overall trials. KOASTAL-2 and 3 are already different than K1 as an example, that both already enrolled a higher portion of females relative to males that are more aligned to historical MDD studies.

Our next question comes from Yatin Suneja with Guggenheim.

This is Delma for Yatin. So when you look retrospectively, at patients with exaggerated placebo response in KOASTAL-1, what was the MADRS score at baseline, if you can give any queue on that? Was it lower than average? And in terms of adjustment of clinical sites now for KOASTAL-2 and 3, can you provide any granularity on the number of sites that will be removed? And what was the average number of patients per site in KOASTAL-1?

Delma, thanks for the question. As I said, we're not providing details in terms of the average baseline score for 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 KOASTAL-2 and 3 will help to improve on how we executed KOASTAL-1 and ultimately support what we really want to. As we 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 KOASTAL-2 and 3, 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 inclusion/exclusion criteria. So as Bill highlighted, beyond all of the measures we already had in KOASTAL-1, we have added the SAFER approach from MGH as well as the VCT database.

Got it. And do you expect the number of patients per site to increase now with KOASTAL-3 and 3?

In terms of the number of patients per site, we don't necessarily know that they'll increase. As you can recall, KOASTAL-2 and 3 are sized the same way that KOASTAL-1 is, where the target number of patients enrolled in each is about 332. We do want to make sure that for the remainder of KOASTAL-2 and 3, we are focused on the highest quality sites. But ultimately, we can't comment in terms of final number of sites at this point.

Our next question comes from Paul Matteis with Stifel.

I guess one thing I'm a little bit confused about is during KOASTAL-1, 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 2 study and using central raters. And so I guess as you look back or you look back to kind of your thought process 6 to 9 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 12 months?

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 do see an outsized placebo response in K1 and -- particularly in males where we -- and close to a 14-point placebo response. And we realized we could do more with both K2 and K3 moving ahead. And one of the most important steps is really to further enhance what we believe we had in place was the medical monitoring, strengthen medical monitoring. Those are 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 a substantial number of patients to enroll.

Paul, this is Mike. For 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 labels achieved multiple catalysts, not just with navacaprant, but across the pipeline. Our current balance sheet, as you noted and we noted, provides cash runway in the mid-26. As a company, we're always opportunistic, looking at ways to fund the business, and that won't change in the upcoming year. There are a variety of funding mechanisms, including debt, 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 KOASTAL-1 on beyond what we had done in Phase 2. And I think what we've seen through the KOASTAL-1 results is that we can do more beyond what we had done. And I think in addition to the measures that were deployed, 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 inclusion exclusion 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 our ability to opportunistically finance the company. So we're going to continue that path as we move through 2025 and look forward to continuing to progress the business as we move through this year and into 2026.

Our next question comes from Myles Minter with William Blair.

This is John on for Myles. Maybe 2 from us. So first, I was just wondering if you have any updates on the PK data from KOASTAL-1. 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 KOASTAL-2 and 3? And if so, is that included in your time line guidance?

John, this is Bill. Let me take the first question here with respect to the PK data. The exposures from KOASTAL-1 were consistent with the results from the Phase 2 study. And so in that context, the exposures were as we expected, consistent with Phase 2 where we did see the robust efficacy in the moderate to severe population. We believe that the 80-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've built in the flexibility in all 3 of the KOASTAL studies, KOASTAL-1, 2 and 3 to increase the sample size by up to 25% percent. And so we have that flexibility in KOASTAL-2 and 3 as well. In terms of our time line, we have looked at a range of potential outcomes in terms of the number of patients that could come into the 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 of that we’ve done.

Our next question comes from Graig Suvannavejh from Mizuho.

This is Sam on for Graig. You may have alluded to this a bit earlier, but as a result of the KOASTAL trial modifications, have there been any changes to the powering assumptions?

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

Our next question comes from Ami Fadia with Needham & Company.

This is Funan for Ami. I'm sorry if you were asked before, but are you taking any interim analysis for the other 2 KOASTAL studies?

Sorry. We can't hear you -- a little bit?

Can you hear me now?

A little bit, but you're pretty muffled.

So just wondering if you've built an interim analysis for the other 2 KOASTAL studies that could provide some insights this year? And has there been discussed -- any further discussions with the FDA or internally in order to understand what approach can you take if you continue to see agenda-based efficacy in the other KOASTAL studies?

So 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 6 weeks. And so as we have looked at putting an interim analysis into or a futility analysis, ultimately, we didn't feel would yield any benefits for the KOASTAL-2 and 3 studies that is not planned for these. And then I'll pass it over to Bill to just maybe talk about where we are in terms of discussions with the regulators around gender differences --.

Sure. We don't typically comment on our interactions with the FDA. Clearly, 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 replicated in K2 and K3. So we've been thinking a bit more about if those findings are replicated, how we might be able to take those forward., we'll comment on those at a later time point if appropriate.

Our next question comes from Tess Romero with JPMorgan.

So NMRA-266 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 pre-clinically with the product or specific to the candidate itself?

Thanks, Tess. This is Josh. I'll address that question. And so we've been working through 266 ultimately determine if we can move it off of clinical hold. And in parallel, we've been progressing the follow-on franchises to 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 2025. We do have a lot of confidence in the follow-on franchise. And in terms of the rabbit convulsion, we would agree it would be logical for us to look to de-risk 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 the Q&A portion of today's call. With that, I'll turn it back over to Mr. Berns for closing remarks.

Okay. Great. Thank you, operator, and thanks to all of you for joining us this morning. I think it's pretty clear, we believe Neumora is poised to create significant value for patients and shareholders. And by bringing forward the next-generation of novel therapy, we aim 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 of a strong financial position that allows us to drive the programs forward in 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 Neumora team members, for their steadfast dedication and commitment to patients that we serve. Thanks again. Great questions today. Have a wonderful day, everybody.