Investor interest in Alzheimer’s disease (AD) ebbs and flows more than in most indications. Most investors should agree that AD is an enormous, underserved market, yet clinical and commercial success has been fleeting. The last bull market in AD was in 2021, following FDA’s surprise accelerated approval of Biogen’s amyloid plaque-targeting antibody, Aduhelm. Investors piled into all things AD, driving wild moves in many speculative development-stage companies. The poster child for this exuberance was Cassava Sciences (Nasdaq: SAVA), which surged to a high of $135 (07/28/2021), a 1,800% increase from where it started 2021, despite well-documented data integrity issues. However, investor enthusiasm for AD was short-lived as Aduhelm underwhelmed commercially and development-stage names, including Cassava, failed to deliver compelling data.
Today, despite the incredible turnaround in the biotech index, most pure-play development-stage AD names have not participated in this rally. At this stage, investor interest in AD appears latent, but if history is any indicator, it wouldn’t take much to spark it. With that in mind, we have our eye on two development-stage AD-focused companies with similar mechanisms and important clinical catalysts this year, where investor interest appears to be percolating.
Acumen Pharmaceuticals (Nasdaq: ABOS) and ProMIS Neurosciences (Nasdaq: PMN) are both developing antibodies that target soluble amyloid beta oligomers (ABOs). Acumen, with its modest $175 million market cap, is scheduled to report top-line data from a 542-patient “registration-quality” Phase 2 AD study by year-end. ProMIS had an even more affordable $25 million market cap when we started writing this note, but after this morning’s $75 million private placement and subsequent stock move, it now carries a similar cap to Acumen (we are using 9.4 million O/S post-financing). It also has important data later this year from its 144-patient Phase 1b AD study. Even after today’s move in ProMIS, we think both companies are very affordable and could see increased investor interest as they approach key data catalysts later this year.
From The Ashes Of Aduhelm
Aduhelm may have failed commercially, but big biopharma has not given up on the anti-amyloid plaque mechanism for early symptomatic AD. In 2023, Biogen and Eisai received FDA approval for Leqembi (lecanemab), and in 2024, Eli Lilly received FDA approval for Kisunla (donanemab). Both are plaque-removing antibodies. Unlike Aduhelm, Leqembi and Kisunla demonstrated a clear, albeit modest, clinical benefit across several AD cognition scales, leading to their full approvals.
All drugs in the anti-amyloid class carry a black-box warning for amyloid-related imaging abnormalities (ARIA). ARIA is a common side effect of plaque-removing therapies. It is divided into two subcategories: brain swelling, referred to as ARIA-E (edema/effusion), and brain bleeds/microhemorrhages, referred to as ARIA-H (haemosiderin). Of the two, ARIA-E is considered the more relevant and concerning in the context of anti-amyloid therapies.
In Eisai’s CLARITY AD pivotal study, the incidence of ARIA-E with Leqembi was 12.6% (combined ARIA-E + ARIA-H was 21.5%), and in Lilly’s TRAILBLAZER-ALZ 2 study, the incidence with Kisunla was 24% (combined ARIA-E + ARIA-H was 36.8%). Kisunla has updated its dosing post-approval, thereby reducing the incidence of ARIA-E. Although most incidences of ARIA are asymptomatic, symptomatic ARIA occurred in approximately 3-6% of patients, including three ARIA-related deaths in the Kisunla pivotal study.
The risk of developing ARIA is highest in patients who carry the Apolipoprotein E4 (APOE4) alleles. Patients who carry one (heterozygote) or two (homozygote) APOE4 alleles are at higher risk of developing AD and of experiencing ARIA if treated with a plaque-removing drug. It is estimated that 40-60% of AD patients have at least one APOE4 allele. Both Leqembi and Kisunla labels recommend screening patients for APOE4 status before starting treatment. Although neither Leqembi nor Kisunla is contraindicated for APOE4 carriers by FDA, in Europe, the EMA has restricted both drugs for use in APOE4 homozygote patients.
*ARIA rates have improved with modified dosing
Although neither drug has had a remarkable launch, Leqembi is expected to reach $500 million in sales for FY2025, and Kisunla between $200 and $300 in the same period. Despite their modest efficacy and known safety liabilities, most analysts expect both drugs to reach peak annual sales of $4-8 billion.
Better Approach?
Acumen and ProMIS are both developing anti-amyloid antibodies that target amyloid-beta oligomers (ABOs). ABOs are upstream of plaque formation and are believed to be the primary toxic culprits responsible for neurodegeneration in AD. Targeting ABOs rather than plaque is expected to reduce the incidence of ARIA. However, the key question is whether targeting ABOs will also improve efficacy compared with plaque-removing antibodies.
***Acumen’s January 2026 Investor Deck
Encouraging Early Evidence
Acumen has the most advanced ABO-targeting antibody, sabirnetug, in development. The company has completed a 65-patient Phase 1b study in patients with AD, in which sabirnetug demonstrated target engagement, positive biomarker results, and a lower incidence of ARIA-E (10%) than plaque-removing antibodies. The study also examined sabirnetug’s impact on common AD clinical cognition rating scales, including ADAS-Cog13, MMSE, and CDR-SB. However, given the small sample size and the study’s 3-month duration, there was no signal on these measures.
Regarding the Phase 1b biomarker results, sabirnetug showed positive effects on biomarkers implicated in tau pathology (p-tau181 and p-tau217) and in synaptic injury (VAMP2 and neurogranin). Interestingly, although this was only a three-month study, Acumen also reported that the highest dose of sabirnetug (60 mg/kg) produced a 25% reduction in amyloid plaques (measured by PET imaging). This level of plaque reduction at three months was surprising and consistent with Leqembi’s results at a similar time point. The fact that an ABO-targeting antibody, such as sabirnetug, would have the same plaque-removing efficacy as a plaque-targeting antibody, such as Leqembi, raises mechanistic questions about whether the reduction in plaque with sabirnetug is the result of its upstream effect on ABOs, or whether it is less selective for ABOs and binds more to plaque than originally thought. Something to consider once we discuss ProMIS below.
Important Answers Forthcoming
Acumen has completed enrolment in a Phase 2, randomized, double-blind, placebo-controlled clinical trial of 542 patients with early AD. The study is testing two doses of sabirnetug, 35 mg/kg and 50 mg/kg, every four weeks via IV, versus placebo. The primary endpoint is the change from baseline in the Integrated Alzheimer’s Disease Rating Scale (iADRS) at 18 months. Acumen has referred to this as a “registration-quality study”, implying it could serve as a pivotal if the clinical results are positive. Top-line data are expected to be available late this year.
Acumen is at the forefront of testing the oligomer hypothesis, which posits that ABOs, rather than plaques, are the primary culprits in AD. To support this hypothesis, Acumen needs sabirnetug to have equivalent, ideally superior, efficacy and less ARIA than the approved plaque-targeting antibodies. The latter seems likely, but the former remains unknown.
Acumen’s stock has been inching higher over the past week, yet it still carries a modest $175 million market cap. Investors have significant scar tissue from betting on development-stage AD names, and Acumen’s study is designed to assess clinical effect (not just biomarker-driven, as in Phase 1), making it highly binary. Nevertheless, the upside for investors, if Acumen hits on efficacy and safety, is multiples of its current valuation.
Similar But Different
ProMIS is developing its own ABO-targeted antibody, PMN310, which is mechanistically similar to sabirnetug but with distinct properties. ProMIS emphasizes PMN310’s strict selectivity for ABOs, with no binding to plaque, as supported by a recent November 2025 publication in Alzheimer’s & Dementia: Translational Research & Clinical Interventions. The company believes PMN310’s selectivity should lead to best-in-class safety among anti-amyloid agents. The company also emphasizes PMN310’s selectivity for low-molecular-weight ABOs, another differentiating factor. Relative to other anti-amyloid agents, including its ABO-targeting cousin sabirnetug, PMN310 is believed to have the greatest affinity for low-molecular-weight ABOs, which are considered the most toxic ABO species. In theory, if PMN310 does not bind to plaque and exhibits unique selectivity for what are believed to be the most toxic ABOs, it could have best-in-class safety and efficacy. But investors need to see data in AD patients before making this leap.
Speaking Confidently
ProMIS has completed enrolment in a Phase 1b study of 144 patients with early AD. This 12-month study is testing three doses of PMN310 (5 mg/kg, 10 mg/kg, and 20 mg/kg) administered IV once monthly versus placebo. Similar to the Acumen Phase 1b study, ProMIS will collect multiple biomarkers, including p-tau(s), neurogranin, and amyloid PET imaging. The study will also assess several clinical cognitive scales.
ProMIS’s CEO, Neil Warma, stated in his December Evercore webcast that he expects PMN310 to show a statistically significant improvement across several biomarkers compared with placebo. Furthermore, he hasn’t shied away from suggesting that, in a study of this size, it is important for PMN310 to show an efficacy trend in some clinical endpoints. He has also confidently stated that he expects PMN310 to have placebo-like ARIA rates. Unlike his confidence around efficacy, regarding safety, CEO Warma would have some breadcrumbs of evidence to support his claims of placebo-like ARIA rates. ARIA generally occurs within the first 3-6 months of dosing, and in ProMIS’s Phase 1b, the vast majority of patients have progressed beyond this period. CEO Warma can see ARIA rates in the blinded data, so his confidence is supported by evidence. He stated at Evercore, “The safety profile, as your correctly say, has been kind of superb to date. I mean, one of our positions here in differentiating factor is that we believe we eliminate much of the ARIA liability that we have seen with other drugs…so we’re expecting that PMN310 will be equivalent to placebo levels in ARIA incidence.”
***ProMIS January Corporate Deck
Jump Ahead
ProMIS plans to release interim blinded 6-month data in the middle of the year. This update will include safety and biomarker data, but not any clinical endpoints. The company is hopeful that these blinded data will reveal positive trends that investors can attribute to PMN310. The final 12-month top-line data are expected by year’s end. CEO Warma has openly discussed a best-case scenario in which PMN310 demonstrates placebo-like ARIA rates, a statistically significant improvement in several biomarkers, and a meaningful trend in clinical endpoints, enabling the company to move directly into a pivotal program. He stated at Evercore, “…if you get to that result, biomarkers, safety, and a strong clinical signal, then the ability to step into a pivotal phase three and avoid this whole middle several hundred million two- or three-year (Phase 2) trial would be huge.” In this scenario, ProMIS would substantially close the gap between itself and Acumen.
Another Player
We can’t talk about anti-amyloid therapies without mentioning another emerging drug, Roche’s trontinemab. Trontinemab is a monoclonal antibody targeting amyloid-beta and is intended to have improved permeability across the blood-brain barrier. Roche has reported Phase 1b/2a data showing a significant reduction in plaques and very low (<5%) ARIA rates. The plaque reduction without ARIA is very encouraging, but no meaningful clinical data on trontinemab have yet been reported. Nevertheless, Roche has just initiated a Phase 3 program with trontinemab
Final Thoughts
The Alzheimer’s market is large and significantly underserved. In our view, the market can accommodate multiple anti-amyloid antibodies, particularly if they have distinct mechanisms of action. Acumen and ProMIS are two very affordable AD-focused companies with unique mechanisms and important clinical catalysts later this year. Both are high-risk/high-reward names with highly asymmetric potential that should appeal to investors hardwired for this type of biotech investment.