Neumora Therapeutics, Inc.

Ladies and gentlemen, thank you for standing by. At this time, all participants are in listen-only mode. After the speaker's presentation, there will be a question and answer session. Please be advised that today's conference is being recorded. I would like to turn the conference over to Helen Rubenstein, Vice President of Investor Relations and Communications. Please go ahead.

Good morning, and thank you for joining UMORA Therapeutics' fourth quarter and full year 2024 Financial Results Conference call. Before we begin, I encourage everyone to go to the Investors and Media section of our website at numoratx.com, where you can find the press release related to today's call. With me on the call are Numora's Chief Executive Officer, Paul Burns, President, Josh Pinto, Chief Operating and Development Officer, Bill Arora, and Chief Financial Officer, Mike 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 details. 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 Numora 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 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 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 diseases. I'm excited to take on this expanded role as president of Pneumora as we make important updates to our pipeline and prepare for a productive year. Beginning with Nevacoprant, 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 280 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 Novacoprant in MVD, which Bill will walk through shortly. We remain confident in the potential of Nevacoprant as a novel treatment for MDD and anhedonia. Multiple positive clinical studies from independent sponsors, including data from our own Phase II study with Nevacoprant in MDD, the NIH-run FASMAS study, and the Atikoprant 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 Nevacoprant 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 Coastal 3 in the first quarter of 2026 and Coastal 2 in the second quarter of 2026. additionally this morning we announced that we discontinued the phase 2 clinical trial investigating nevacopram for the treatment of bipolar depression while we still believe that nevacopram 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 nevacoprine in bipolar depression and other indications beyond MDD in the future. Beyond nevacoprine, 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 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 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 PAMs may offer. 2025 is going to be an important year for Newmora. 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. Bill?

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 Nuvacopran, 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 Novacoprant did not demonstrate a statistically significant improvement on the primary or key secondary endpoint in the Coastal 1 study. Coastal 1 is the first of three randomized placebo-controlled double-blind Phase 3 studies that comprise the Pivotal Coastal Program. Following the announcement of top-line results from the Coastal 1 study, we paused recruitment for Coastal 2 and 3 and conducted extensive analyses to identify factors that might have contributed to the study outcome. With the benefit of data on nevacoprant in more than 600 patients across Coastal 1 and our Phase 2 study, we are in a strong position to make meaningful changes to improve Coastal 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're 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. SAFR 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 SAFR 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 Coastal 2 and 3 studies. This is an additive approach to the clinical trial subject database we use in Coastal 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 COASTAL program because we believe in the potential of an evac print to make a real difference for patients. Historically, there have been many approved blockbuster medicines in MDD and psychiatry broadly. that have failed phase three studies but ultimately succeeded in multiple studies and became important treatments. We designed the COSTRO program with these historical challenges in mind, knowing that we would need two of three trials to be successful in order to file an NDA. Beyond Evacoprant, we are currently evaluating NMRA511, 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 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 muscarinics that have the potential to deliver antipsychotic efficacy in multiple indications. We believe that we are well positioned to become a leader in muscarinics, 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 strong biological 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'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 program. 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 31st, 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 three program for Novacoprint, ongoing studies across the rest of our portfolio, and investments to support the growth of our business. As of December 31st, 2024, we ended the year with $307.6 million in cash, cash equivalents, and marketable security, 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 Novacopran, 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?

Thank you. To ask a question, please press star 1-1. If your question has been answered and you'd like to remove yourself from the queue, please press star 1-1 again. Our first question comes from Brian Abrahams with RBC Capital Markets. Your line is open.

Hey, good morning. Thanks for taking my question. Can you elaborate a little bit more on some of the differences between the vendor that you utilized for Coastal 1 and SAFER, and any changes in the site auditing and patient caps that you utilized in Coastal 1 that you'll apply for Coastal 2 and 3? Thanks.

Good morning, Brian. This is Bill Arora.

Thanks for your question. We take a look at the approach we are taking for Coastal 2 and 3 What we are looking to do is enhance the medical monitoring to confirm the patients that are being enrolled have an independently verified diagnosis for MDE, 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 CTNI group, to institute SAFR. So as you may be familiar, SAFR is an independent review conducted by clinical psychiatrists MGH to verify the diagnosis and the appropriateness of the patient population. Our internal medical team will partner with the 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 COSTAL 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 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 Sao with HC Wainwright. Your line is open.

Hi. Good morning. Thanks for taking the questions. I guess a couple for me, maybe just as a starting point, I think it might be helpful if you could provide some perspectives in terms of how far along into enrollment Coastal 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 effect or differences in effect that we saw between male and female patients in Coastal 1. Thank you.

Great. Thanks, Doug. This is Josh. I'll answer the second part of the question, then turn it over to Bill to really hit on the first part. And so as we think about Nevacopran and just the prospects of moving it forward, I think first we have to look at the target here and really the clinical validation that the Kappa Opioid Receptor Antagonist class has produced to date. We've seen, you know, important positive studies from a multitude of independent sponsors, including our Phase II study with the VACPRINT MDD, the NIMH-run FASTMAS study, as well as the ATICOPRANT Phase II studies. And so, we feel like the body of evidence out there really suggests that the COSTAL-1 results might be an anomaly within this class. And as we've talked about before, we truly believe that NavaxPrint 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 were able to pull out is we saw that site experience in relation to their performance in other recent positive MDD monotherapy phase three studies was another key driver of ultimately 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 performed quite well. And in the population that was not at sites that had recent experiences 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 is all led to 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 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, but 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're running three studies in parallel, knowing that we only need two for a successful MDD study. And so now I'll transition it over to Bill to really highlight, you know, where we are with the K2, K3 studies as the current element.

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 a quarter of the population in K1. So we're not talking about, you know, 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 2023 before being paused in January of 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 the timelines 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. Coastal 2 and 3 are already different than K1 as an example. They've 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 Sanuha with Guggenheim. Your line is open.

Hi, this is Delma Furiati. Thanks for taking our questions. So when you look retrospectively at patients with exaggerated placebo response in COSTEL1, what was their moderate score at baseline, if you can give any cue on that? Was it lower than average? And in terms of adjustment of clinical sites now for COSTEL2 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 COSL1? Thank you.

Thanks for the question. You know, at this time, we're not providing details in terms of the average baseline, you know, score, you know, for patients in sites that had a high placebo response. But, you know, what we can say is that, you know, we do believe that the changes that we're making to Coastal 2 and 3 will help to, you know, improve on how we executed Coastal 1 and ultimately support what we really want to. As we've looked at the data, what's clear to us is that, you know, site selection is absolutely critical and, you know, we have removed some of the sites from Coastal 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 COSA-1, we have added the safer, you know, 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 COSR2 and 3?

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

Thank you so much.

Thank you. Our next question comes from Paul Matisse with Stiefel. Your line is open.

Hey, thanks for taking the question. I guess one thing I'm a little bit confused about is during Coastal 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 raiders. I guess as you look back or you look back to 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 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 You know, what's your thought process there? And I guess how comfortable are you to go into these readouts with materially less than 12 months? Thanks so much.

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 came close to a 14-point placebo response in we realized we could do more with 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, strengthen the medical monitoring that was already in place. And quite frankly, MTH and SAFER will help us do that to verify the baseline degree of severity, the diagnosis, which we know is critically important.

Hey, 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 enables us to achieve multiple catalysts, not just with the backer, 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 and 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.

Yeah, and Paul, this is Josh. I'll just summarize a few of the comments. You know, we had obviously, you know, deployed a number of, you know, enhanced measures as we were thinking about executing Coastal 1 beyond what we had done in Phase 2. 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 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. And so we're going to continue that path as we move through 2025 and look forward to continuing to through this year into 2026.

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

Our next question comes from Miles Mentor with William Blair. Your line is open.

Hi team, this is John on for miles. Thanks so much for taking our questions. Maybe two from us. So first I was just wondering if you have any updates on the PK data from coastal one and if there was anything you could clean 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 two and three? And if so, is 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 1 were consistent with the results from the base 2 study. And so, in that context, the exposures were, as we expected consistent with phase 2, where we didn't see the robust efficacy of the severe population. We believe that the 80 mg 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.

Yeah, and then, John, on the guidance and timing piece, you know, I think we built in the flexibility in all three of the coastal studies, Coastal 1, 2, and 3, to increase the sample size by up to 25%, and so we have that flexibility in Coastal 2 and 3 as well. In terms of our timelines, you know, 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, but we have factored that into ultimately the guidance that we've come out with.

Thank you.

Thank you. Our next question comes from Greg Savanova of 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 postal 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 you and the rest of the team apprised of how we're thinking about that, but nothing has changed.

Got it. Thank you.

Thank you. Our next question comes from Ami Fadja with Needham & Company. Your line is open.

Hi, this is Purnia. I'm for Ami. Thank you for taking my question. I'm sorry if you've already asked this before, but have you taken any interim analysis for the other two courses? Sorry, Purnia.

We can't hear you. Are you able to speak up a little bit?

Can you hear me now?

It's a little better, but you're pretty muffled.

So just wondering if you've built in any interim analysis for the other two coastal studies that could provide some insights this year. And has there been any further discussions with the FDA or internally in order to understand what approach can you take if you continue to see a gender-based efficacy in the other coastal 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 six weeks. And so, you know, as we have looked at it, you know, putting an interim analysis into or a futility analysis, ultimately, you know, we didn't feel would yield any benefits, you know, for the Coastal 2 and 3 studies. That is not planned for these. And I'll pass it over to Bill to just maybe talk about, you know, where we are in terms of, you know, 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're replicated in K2 and K3. But we've been thinking a bit more about 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 Tess Romero with JPMorgan. Your line is open.

Hi. Good morning, Dean. Thanks so much for taking our question. 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 preclinically with the product are specific to the candidate itself? Thanks.

Hey, thanks, Tess. This is Josh. I'll address that question. And so, you know, we've been working through Um, 266 ultimately to determine if we can move it off of clinical old and in parallel, we've been progressing, you know, the follow on franchise 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. convulsions, you know, 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, you know, we'll be coming forward with a fulsome update on the M4 franchise when we move our next program into the clinic, you know, over the coming months.

Thank you.

Thank you, everyone. That was a really good That will conclude the Q&A portion of today's call. With that, I'll turn it back over to Mr. Burns for closing remarks.

Very great. Thank you, operator, and thanks to all of you for joining us this morning. I think it's pretty clear we believe that more is poised to create significant value for patients and shareholders. By bringing forward the next generation of novel therapies, 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 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 Newark 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.