Acumen Pharmaceuticals, Inc. Q4 FY2025 Earnings Call

Ladies and gentlemen, thank you for standing by. Welcome to the Acumen Pharma Fourth Quarter 2025 Conference Call and Webcast. Please be advised that today's conference is being recorded. I would like now to turn the conference over to Alex Braun, Head of Investor Relations. Please go ahead.

Thanks, Michelle. Good morning, and welcome to the Acumen conference call to discuss our business update and financial results for the year ended December 31, 2025. With me today are Daniel O'Connell, our Chief Executive Officer; Dr. Jim Doherty, our President and Chief Development Officer; and Matt Zuga, our CFO and Chief Business Officer. They will have brief prepared remarks, and then we'll open the call for questions. Joining for the Q&A session, we also have Dr. Eric Siemers, our Chief Medical Officer. Before we begin, we encourage listeners to go to the Investors section of the Acumen website to find our press release issued this morning that we'll discuss today. Please note that during today's conference call, we may make forward-looking statements within the meaning of the federal securities laws, including statements concerning our financial outlook and expected business plans. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. Please see Slide 2 of our corporate presentation, our press release issued this morning and our most recent annual and quarterly reports filed with the SEC for important risk factors that could cause our actual results to differ materially from those expressed or implied in the forward-looking statements. We undertake no obligation to update or revise the information provided on this call or in the accompanying presentation as a result of new information or future results or developments. And with that, I'll turn the call over to Dan.

Great. Thanks, Alex. Good morning, everyone, and thanks for joining us today. 2025 can be defined as a year of execution and expansion at Acumen. We made demonstrable clinical progress for our lead program, sabirnetug, in our Phase II ALTITUDE-AD trial, which we consider an important test of our core hypothesis that synaptotoxic amyloid beta oligomers play a pivotal role in the development and progression of Alzheimer's disease. ALTITUDE is a well-powered Phase II study that is investigating sabirnetug, our monoclonal antibody with high selectivity for A-beta oligomers. Sabirnetug's selectivity for toxic oligomers is central to why we believe it could unlock potentially greater clinical efficacy and improved safety relative to amyloid plaque-directed antibodies. We are closely tracking to plan with ALTITUDE. We completed enrollment about a year ago, and the participant transition into the 12-month open-label study that started last November continues to be smooth and with a high rate of conversion. In 2025, we also expanded our pipeline in our persistent pursuit of innovation, which aligns with our mission of improved treatment options for people impacted by Alzheimer's. Our Enhanced Brain Delivery, or EBD partnership with JCR Pharmaceuticals, which combines Acumen's A-beta oligomer targeted therapeutic cargo with JCR's validated blood-brain barrier carrier technology holds potential to produce a truly next-generation differentiated therapy for Alzheimer's disease. We think of EBD as supercharging our antibodies to significantly increase brain penetration and distribution with potentially lower safety risks and in a convenient subcutaneous dosing format. We believe our EBD approach is well suited for study in the preclinical or presymptomatic AD population. And though not contemplated in our immediate clinical development plans, we foresee that population as an attractive opportunity for the future. 2026 is poised to be a transformative year for Acumen. We expect to read out ALTITUDE-AD late this year, inclusive of key clinical efficacy and safety measures. We believe the study results will inform our development strategy in the field more generally in terms of better understanding of the impact of clearing A-beta oligomers in Alzheimer's patients. Our optimism for the success of ALTITUDE is based in part on imaging and fluid biomarker data from our Phase Ib INTERCEPT-AD study. For instance, after just 3 doses at the final 3-month time point, sabirnetug showed positive effects on pTau181 and neurogranin levels in CSF. These are competitive indicators in the AD space and continue to gain acceptance as diagnostic and clinical markers of disease. We view these data as supportive of sabirnetug's potential in Phase II, which assesses safety and efficacy of sabirnetug over 18 months of treatment. We're obviously very excited to see these data later this year. Our EBD program is also gaining momentum. Just last week, we announced preclinical data, including in vitro, in vivo and nonhuman primate study results that support multiple potential development candidates in the program. Jim will speak more about these results in just a minute. Importantly, the candidate profiles achieved exceeded our target product profile for the EBD program and catalyzed the roughly $36 million private placement. As of now, we are targeting a filing of an IND for a clinical candidate in mid-2027. A final note on the sentiment in the AD field. We just returned from the AD/PD conference in Denmark, where the energy and momentum in the Alzheimer's space was palpable. Between real-world data supporting the currently marketed therapies, the growing evidence that targeting A-beta is clinically beneficial as well as the adoption of blood-based biomarkers to streamline development, diagnosis and treatment, this is a hopeful time for Alzheimer's patients and their families. It's also important to realize we are still in the beginning of the treatment evolution in AD and ample opportunity exists to provide improved benefit-risk options for patients. Between sabirnetug's ALTITUDE-AD results and our next-generation EBD program advancing this year, we at Acumen believe our commitment to scientific innovation and track record of execution will enable us to deliver differentiated treatment options for Alzheimer's patients. And with that, I'll turn the call over to Jim.

Thanks, Dan. And to everyone on the call, happy to be here with you today. As Dan said, we're very pleased with the candidate profiles generated in our preclinical EBD program and impressed with the level of expertise contributed by our partner, JCR Pharmaceuticals. Each EBD candidate consists of two elements: a cargo, in this case, an A-beta soluble oligomer targeting antibody and a carrier, which is JCR's transferrin-based blood-brain barrier receptor-mediated transcytosis technology. Sabirnetug has demonstrated robust fluid biomarker results in the INTERCEPT Phase I study, as Dan just mentioned, and also showed relatively low rates of ARIA-E and infusion-related reactions. JCR has clinically validated their technology, which is used in an approved therapy in Japan with little observed anemia. By combining these components, we aim to develop a therapy for AD with enhanced efficacy, low ARIA-E and anemia risk and subcutaneous dosing. We've been working diligently with our JCR colleagues over the last 18 months to combine our soluble AD targeting monoclonal antibodies with their EBD technology to develop novel EBD candidates that significantly enhance brain distribution while maintaining our soluble A-beta oligomer targeting profile. Our testing cascade included measures of transferrin-receptor affinity, single chain or VHH architecture, valency, stability and functional selectivity of our antibodies for oligomers following attachment of the JCR carriers. We brought a number of these candidates into a nonhuman primate study, which demonstrated between 14- and 40-fold higher brain levels when compared to the native antibody control at a time point of 24 hours post dosing. Hematology data in nonhuman primates indicate potential for anemia with no observed change in red blood cell count, hematocrit, hemoglobin or reticulocyte counts at 24 hours after subcutaneous dosing. Stability was also favorable and supportive of subcutaneous dosing with low-volume devices. These profiles exceeded our expectations for a target profile in our program, meaning that we now have diversity and flexibility in nominating an IND candidate, which is targeted for mid-2027. With optimized cargo and carrier components, we believe we are on a path to developing a potential next-generation EBD treatment for people living with Alzheimer's disease. And now I'll hand the call over to Matt.

Thank you, Jim. As a reminder, our full year 2025 financial results are available in the press release we issued this morning and in our 10-K we will file later today. We ended 2025 with $116.9 million in cash and marketable securities on our balance sheet, which is expected to support our current clinical and operational activities into early 2027. R&D expenses were $104.9 million in 2025. The increase over the prior year was primarily due to an increase in manufacturing and materials associated with our ALTITUDE-AD clinical trial as well as personnel-related costs and research expenses, including EBD research. G&A expenses were $18.9 million in 2025, the decrease primarily due to reductions in recruiting expenses, corporate insurance expenses and consulting costs. This led to a loss from operations and a net loss of $121.3 million in 2025. As Dan mentioned, on March 16, 2026, we closed a private placement in support of our EBD program that grossed $35.75 million before offering expenses, which were minimal. We believe this involvement from committed institutional investors strongly validates our portfolio and our Enhanced Brain Delivery strategy. Proceeds from the financing are expected to primarily support our EBD program, including ongoing preclinical development work to support the nomination of a lead clinical candidate molecule and for working capital and other general corporate purposes. We are confident in our scientific innovation and strong track record of execution as we work towards our Phase II ALTITUDE-AD readout later this year and advance our EBD program. We remain dedicated to building value with our portfolio of A-beta oligomer targeted antibodies for Alzheimer's patients, caregivers and stakeholders. And with that, we can open the call for Q&A. Operator?

Michelle, are we ready for Q&A?

Our first question will come from Pete Stavropoulos with Cantor Fitzgerald.

This is Samantha on the line for Pete. So my first question related to the ALTITUDE-AD study: how has patient retention been so far? How is it trending relative to your initial assumptions? And you previously announced that the first patient enrolled in the OLE in November. Can you give us a sense of how rollover into the OLE has progressed overall? Any details you can give would be very helpful. And what, if anything, does the retention rate and rollover rate suggest to you about safety and tolerability? And how do they compare to other studies such as lecanemab and donanemab?

Thanks, Samantha. Jim, do you want to take a first pass at that?

Yes, absolutely. Happy to give you a response, Samantha, and I'll ask Eric to comment when I'm done. So you asked about retention and rollover rates for the ALTITUDE study. As Dan had said in his prepared remarks, we've been very pleased with the overall progress of the ALTITUDE study, and that includes what we're seeing both in terms of retention in the study, which we think is in line with what's been observed in many of the other major Alzheimer's trials conducted recently. From a rollover perspective, we've been very pleased with the rate at which people are rolling over into the open-label extension. In both cases, the metrics are consistent with the trial progressing nicely. Regarding how those numbers relate to overall safety and conduct in the trial: of course, this is a blinded study, and we don't take too many interpretations away from those metrics other than to say, given that the metrics are well in line with other studies and are consistent with the overall progression in the study, we're not seeing anything that we feel to be out of line based on those numbers. So at this point, the study continues forward. Eric, anything you'd like to add?

Yes. No, that's a good summary. As you mentioned, this is an ongoing blinded study, so many of the questions you're asking we'll see at the end of the study. But so far, the study has run remarkably smoothly. We have not had to alter the protocol for dosing or similar changes. The retention rate has been good, and the rollover rate of people going into the open-label extension has been very satisfying. I think it's a good sign that people like the study and are satisfied with the safety profile. We're looking forward to the results at the end of this year. There's a limited amount that you can know for an ongoing blinded study, but for instance, comparisons to CLARITY, which is the patient population probably closest to what we're studying, we'll make those comparisons at the end of the year when we're unblinded.

And if I could just sneak in one more question. For the EBD candidates: so you've generated different versions of sabirnetug with JCR's blood-brain barrier crossing technology as well as another anti A-beta oligomer antibody from your portfolio. What have you seen in preclinical studies thus far in rodent models and primate studies that suggest you have viable candidates and that one candidate may ultimately have better efficacy over others? And what gives you confidence that you're on the right track?

Thanks, Samantha. As I said, we're really pleased with the progress. In a typical discovery program you make many analogs, and because there are several variants of JCR's transferrin-targeting technology, we evaluated how best to combine the two pieces. We examined the cargo—either sabirnetug or a related oligomer-targeting antibody—and various versions of the JCR technology. We mixed and matched to determine which combination had the best overall profile. One of the most attractive things is that there are actually multiple candidates we like. Often, you search for a single lead, but we're in a position of liking the profiles of a number of candidates. It's a combination of enhanced brain penetration— as I mentioned earlier, in the primate study we observed 14- to 40-fold improvements in overall brain exposure, which is a substantial change in brain levels and we believe will have multiple positive implications— and the overall profile, including pharmacokinetics and distribution. All of that together supports a favorable overall profile. Multiple candidates met not only our target profile for progression but what we consider an ideal profile. There's plenty of work left to be done, but currently we think we're in a strong position with multiple robust candidate molecules.

And our next question is going to come from Paul Matteis with Stifel.

Yes, please, Jim.

Yes. So to your first question around will we be presenting more data: over the last few major scientific meetings, we've been increasingly presenting data from the EBD program. We've shown data from the humanized mouse with humanized transferrin-receptor expression, and we have some mouse constructs as well. One of the challenges with experiments around transferrin targeting constructs is that transferrin itself is very species specific. It's difficult to do experiments with the candidate molecules in a mouse or rodent system, so you either use humanized mice or analogs that have the mouse transferrin-receptor, which are not your clinical candidates but are the mouse versions. We've done both kinds of experiments and started to publish on those. We've talked about some of the data from the nonhuman primate study. As we continue, we have more preclinical work to do ahead of the IND, and we'll continue to present the data at scientific meetings. Regarding sabirnetug, we already really like its profile. As Dan called it, we think this is supercharging that profile. We expect to improve distribution of antibodies with this technology. The absolute change in magnitude—the 14- to 40-fold improvement—is, of course, advantageous. Beyond that, because transferrin receptors are localized in small capillaries throughout the brain, the pattern of where the antibody gets into the brain changes with the EBD constructs. We expect that to provide additional value versus a non-carrier-mediated antibody. Multiple groups have presented data showing a broader pattern of distribution with EBD technology, supporting the notion of an enhanced profile with our EBD program.

And our next question will come from Jason Zemansky with Bank of America.

Congrats on the great progress. Maybe just a follow-up to your previous comment. As you think about the potential of an EBD-enhanced molecule, what is your sense right now, and I appreciate this may be somewhat theoretical, of the distribution within the brain of the different A-beta species? Is there a sense that the oligomers are deep in the brain where an enhanced antibody might penetrate? And then secondarily, could you speak to why you think you're seeing lower rates of impact on reticulocytes and anemia that some of the other transferrin antibodies have shown?

Yes, absolutely, Jason. On distribution of oligomers: while somewhat theoretical, immunohistochemistry data provide good evidence that soluble oligomers are broadly distributed across multiple cortical and subcortical regions. The soluble oligomer pattern is not terribly different from overall A-beta distribution and, because oligomers are small and soluble, you often see an even wider distribution than with plaque. That supports the attraction of EBD delivery: transferrin receptors at capillaries are everywhere in the brain parenchyma, so there is no part of the brain that is not within a couple hundred microns of a capillary. You get broad overall distribution. Presentations at recent conferences show that non-EBD antibodies often enter in leaky parts of the blood-brain barrier and tend to penetrate more superficially, whereas EBD constructs can provide broader penetration including deeper cortical layers. That broader distribution could be beneficial for function. Regarding lower anemia rates: one reason we worked with JCR is their clinical experience with a drug used in Japan to deliver enzyme into the brain for Hunter syndrome, where they observed lower rates of anemia. We think JCR's technology may result in lower anemia risk likely due to the specific epitopes they target on the transferrin receptor. We were pleased to see a similar pattern in our nonhuman primate study: at 24 hours, when you'd expect to see reticulocyte count effects, we did not observe meaningful changes, consistent with their clinical findings.

And our next question will come from Tom Shrader with BTIG.

A lot of good questions so far. You're quoting numbers for uptake that are significantly higher than your competitors. I think Roche quotes numbers around 10. Are you sure you're better? And you're quoting ratios—do you have data on the absolute amount that you're getting in? Because obviously the ratio depends a little bit on where you start. And then I have an OLE follow-up.

Tom, when we're quoting numbers, we are quoting the ratio relative to brain penetration from the enhanced antibodies compared to native antibody controls. That's the appropriate way to present it. I try to avoid statements like 'better' or 'worse' because these are not head-to-head comparisons. What we can say is that we're seeing robust increases in levels of antibodies relative to control values, and that's how we look at it. Those improvements compare well with what other groups report, but I avoid direct head-to-head claims unless studies are done together. On your OLE follow-up: Eric is best positioned to answer questions about what will be measured in the OLE and plaque expectations, so I'll hand that over to him.

For open-label extensions, typically we measure the same endpoints but generally less frequently to reduce patient burden. Everyone is on active drug at this point, so there is no placebo group; the OLE allows us to observe longer-term outcomes for those originally on active treatment and to see the effect once prior placebo patients go on active treatment. Regarding plaque reduction, it's hard to predict what we'll see at 18 months. In Phase I, after three months at the highest doses, we did see some plaque reduction, roughly similar to what was seen with lecanemab after three months. What plaque reduction will be at 18 months is unknown—that's why we conduct the study. Importantly, our mechanism targets oligomers rather than plaque, so plaque reduction is not necessary for our mechanism, but it will be an interesting part of the readout when we unblind at the end of the year.

And our next question is going to come from Geoff Meacham with Citi.

This is Mary-Kate on for Geoff. First, with an IND targeted for mid-2027 for your EBD program, could you walk us through how you're looking at trial design for an early-stage trial here? Then a separate question on sabirnetug: as you approach Phase II data later this year, could you walk us through the type of feedback you're receiving from physicians on where sabirnetug could address unmet need in the space?

Mary-Kate, on trial design for EBD: it's early days, and we're still working on the design. We intend to take advantage of our clinical experience with sabirnetug in designing the study, including the value we gained from including Alzheimer's patients in the Phase I INTERCEPT study. That provided safety and tolerability data and valuable biomarker information—both imaging and fluid biomarkers—which we expect to leverage for the EBD program. We'll evaluate study length and dosing in the context of the preclinical and clinical data, and final decisions on design have not yet been made. Eric, I'll ask you to comment on physician feedback and positioning for sabirnetug.

In terms of positioning, once we have our data, we will make comparisons with the drugs currently approved in the U.S. There is room for improvement with the available therapies. Over time, the field has learned that the key safety concern is symptomatic ARIA, and severe symptomatic ARIA is the event of greatest concern. Most ARIA cases are asymptomatic—just a radiographic finding on MRI. Roughly 20% of people who have ARIA experience some symptoms, and most of those are fairly mild, such as headaches for a few days or brief gait difficulty. The most concerning are the rare serious cases with events like status epilepticus or large hemorrhages, and there have been some fatalities in that context. Those rare but serious events are key to monitor. Our antibody is an IgG2; the marketed antibodies are IgG1s. IgG1 triggers more effector function and immune response. IgG2 has less effector function, so one question for the field and for our data is whether IgG2 versus IgG1 makes a clinical difference. We'll see that when we read out our data at the end of this year.

And our next question comes from Dev Prasad with Lucid.

Congrats on the update. A couple of questions: the OLE is dosing at 35 mg per kg rather than 50 mg per kg—can you remind us and add some color around what drove the dose selection? If ALTITUDE-AD is positive, what are your current thoughts on Phase III design: would you plan a single pivotal trial or two? Would you pursue a single dose or two-dose regimen? Then on the NHP data showing 14- to 40-fold exposure range: can you help us understand what's driving the variability? Is the 40x candidate also the one with the best anemia profile?

Thanks, Dev. I'll address the variability and candidate anemia profile, then turn dosing selection to Eric. Regarding the variability in the 14- to 40-fold range: we measured brain levels across multiple regions, so summary numbers reflect an overall range across regions—frontal cortex versus hippocampus, for example. There's always some variance between regions, but the variability we observed is more between candidates than between brain regions for a single candidate, which is encouraging. Most candidates showed good consistency and generally low anemia risk at the 24-hour time point after subcutaneous dosing. Multiple candidates had attractive profiles overall, giving us flexibility in candidate selection. On Phase III design, we think the ALTITUDE design is a robust model. Based on current thinking and interactions with the FDA, our base case is that one additional Phase III study, likely larger and with a design similar to ALTITUDE, should be sufficient to file a BLA for early Alzheimer's disease. Nothing is finalized, but our current assumption is one additional Phase III trial. For the OLE dosing choice and dose selection rationale, I'll hand that to Eric.

Thanks. A couple of additional remarks: regarding Phase III strategy, for context, the donanemab TRAILBLAZER program had a Phase II followed by a single larger pivotal trial that supported approval. We view our situation as somewhat similar. On dose selection: from the Phase I INTERCEPT study we generated robust target engagement data showing how much antibody crosses the blood-brain barrier and binds oligomers. Across the dose range tested in Phase I, we observed saturation—an Emax—where doses higher than 60 mg per kg were not yielding substantially more target engagement. Our modeling suggested that at 35 mg per kg you have good target engagement at both peak and trough, so 35 mg per kg is a viable dose for efficacy testing. The 50 mg per kg dose was a conservative choice in case more plaque reduction was needed, as higher doses might increase the likelihood of plaque reduction. Both doses are viable in terms of potential efficacy, and we'll compare safety profiles at the end of the study. There are also historical monkey studies where 20 mg per kg showed viable target engagement, so 35 mg per kg is a reasonable and viable dose.

And I am showing no further questions in the queue at this time. I would now like to turn the call back over to Alex for closing remarks.

Thanks, Michelle, and thank you to everyone for tuning in and spending time with us today. If you have any other questions, we are always available at the company. Please contact us. With that, have a great day.

This concludes today's conference call. Thank you for participating, and you may now disconnect.