Executive Summary / Key Takeaways

• Acumen Pharmaceuticals is advancing sabirnetug, a differentiated monoclonal antibody designed to selectively target toxic soluble amyloid-beta oligomers (AßOs), believed to be a primary driver of Alzheimer's pathology.
• The company achieved a significant operational milestone by completing enrollment of its pivotal Phase 2 ALTITUDE-AD trial (542 participants) in Q1 2025, ahead of schedule, demonstrating strong execution and interest in its approach.
• Topline results from the ALTITUDE-AD trial, evaluating clinical efficacy (iADRS primary endpoint) and safety, are expected in late 2026, representing the next major value inflection point.
• Acumen is also developing a subcutaneous formulation of sabirnetug, having completed a Phase 1 study showing favorable systemic exposure, aiming to offer greater convenience and optionality for patients and providers.
• With $197.9 million in cash and marketable securities as of March 31, 2025, the company expects its existing capital to fund operations into early 2027, providing runway through the anticipated ALTITUDE-AD data readout, though future funding will be required for potential commercialization.

The Oligomer Hypothesis: A Differentiated Approach to Alzheimer's

Acumen Pharmaceuticals is built on a foundational scientific premise: that soluble amyloid-beta oligomers (AßOs), distinct from amyloid monomers and plaques, are the most toxic form of amyloid driving the initiation and propagation of Alzheimer's disease (AD) pathology. This perspective, pioneered by the company's scientific founders, positions Acumen with a potentially differentiated approach in the increasingly crowded AD therapeutic landscape.

The company's lead and sole clinical-stage asset, sabirnetug (ACU193), is a recombinant humanized IgG2 monoclonal antibody specifically engineered to selectively target these AßOs. This targeted mechanism is central to Acumen's strategy, aiming to offer an improved benefit-to-risk profile compared to therapies that broadly target amyloid plaques or monomers. The strategic intent is that by neutralizing the most toxic species, sabirnetug could potentially slow or halt the neurodegenerative process more effectively or with fewer side effects.

Early clinical data from the Phase 1 INTERCEPT-AD trial in early AD patients provided initial validation for this approach. The trial demonstrated that sabirnetug was well-tolerated and achieved dose-dependent target engagement of AßOs. Furthermore, even after just three doses, the study showed encouraging directional changes in several key biomarkers, including the A-beta 42/40 ratio, various p-tau species, GFAP (an astrocyte marker), and synaptic markers like VAMP2 and neurogranin. These biomarker shifts, particularly the movement towards normalization, suggest central pharmacological activity and potential positive impact on synaptic health, a critical aspect of cognitive function in AD. While a short Phase 1 study, these results provided the necessary conviction to advance sabirnetug into a larger, potentially pivotal Phase 2 trial.

Advancing Sabirnetug: Operational Excellence and Strategic Expansion

Building on the INTERCEPT-AD results, Acumen initiated the Phase 2 ALTITUDE-AD clinical trial in May 2024. This is a randomized, double-blind, placebo-controlled, three-arm study designed to evaluate the clinical efficacy and safety of sabirnetug in up to 540 participants with mild cognitive impairment or mild dementia due to AD. The primary endpoint is the change from baseline to 18 months on the Integrated Alzheimer’s Disease Rating Scale (iADRS), a composite measure of cognition and activities of daily living.

A significant operational achievement highlighted by management is the rapid pace of enrollment in the ALTITUDE-AD trial. Enrollment was completed in Q1 2025, approximately 10 months after the first patient was dosed, which was notably faster than originally projected. This accelerated timeline is attributed to several factors: the perceived therapeutic potential of sabirnetug based on its mechanism and Phase 1 data, strong relationships with clinical trial sites across North America, the U.K., and the EU, and the innovative use of a plasma phospho-tau 217 assay for participant screening. This p-tau 217 screening procedure significantly improved enrollment efficiency by reducing the incidence of negative amyloid PET scans by about 50% compared to the Phase 1 study, with 81% of screened individuals meeting the p-tau threshold testing positive on amyloid PET. This operational success underscores the team's execution capabilities and the clinical community's interest in sabirnetug.

In parallel with the intravenous (IV) formulation being tested in ALTITUDE-AD, Acumen is also exploring a subcutaneous (subcu) administration option for sabirnetug. This strategic initiative, supported by a license agreement with Halozyme (HALO) for drug delivery technology, aims to provide greater convenience and optionality for patients and caregivers. A Phase 1 PK comparison study of the subcu formulation in healthy volunteers was completed in Q1 2025, demonstrating that the formulation was well-tolerated with systemic exposure supporting continued development. Next steps involve ongoing formulation and drug delivery assessments, with the team evaluating the most efficient pathway forward, potentially integrating a subcu arm into a future Phase 3 IV study or conducting a standalone study. The goal is to achieve a dosing regimen for the subcu formulation that targets the same therapeutic range as the IV formulation.

Financial Health and The Path to Data Readout

As a clinical-stage biopharmaceutical company, Acumen has consistently incurred operating losses since its inception, a trend expected to continue as it invests heavily in research and development. For the three months ended March 31, 2025, the company reported a net loss of $28.8 million, contributing to an accumulated deficit of $353.9 million. Operating expenses totaled $30.4 million in Q1 2025, a significant increase from $17.8 million in the same period of 2024. This increase was primarily driven by a $12.9 million rise in Research and Development expenses, largely due to increased spending on CRO costs for the ALTITUDE-AD trial ($7.0 million increase) and manufacturing and materials ($4.7 million increase), reflecting the ramp-up of the pivotal study. General and administrative expenses remained relatively stable.

The company's operations have been funded through various means, including equity financing (IPO, ATM program), debt (term loan), and prior collaborations. As of March 31, 2025, Acumen held $197.9 million in cash and cash equivalents and marketable securities. This financial position is critical as it provides the necessary runway to advance sabirnetug through its next major clinical milestone. Management has guided that this existing capital is expected to fund operating expenses and capital expenditure requirements into early 2027.

This cash runway is projected to extend beyond the anticipated topline data readout for the ALTITUDE-AD trial, which is expected in late 2026. This alignment of financial resources with the key data milestone is a crucial aspect of the investment thesis, as it suggests the company is funded through a period of significant potential value inflection. However, it is important to note that this estimate is based on current operating plans and assumptions that could change. The company will require substantial additional funding beyond early 2027 to support potential future activities such as initiating a Phase 3 program, building commercial capabilities (if pursuing commercialization independently), and expanding its pipeline. The ability to raise this future capital will depend on market conditions, the success of the ALTITUDE-AD trial, and the terms available, which could include dilution for existing stockholders.

Competitive Positioning in a Dynamic Landscape

The Alzheimer's therapeutic landscape is highly competitive and rapidly evolving, with several companies pursuing different approaches to target amyloid pathology. Key competitors include large pharmaceutical companies like Eli Lilly (LLY) with approved Donanemab (Kisunrot) and Biogen (BIIB) with its partnership on Lecanemab (Leqembi), as well as other clinical-stage companies like Prothena (PRTA). While these approved therapies target amyloid plaques or protofibrils, Acumen's focus on soluble AßOs represents a distinct mechanistic approach.

Acumen positions sabirnetug as a potential "next-generation" treatment option, aiming for an improved benefit-to-risk profile. A key area of differentiation is the potential for a lower incidence of Amyloid-Related Imaging Abnormalities (ARIA), a common side effect with current amyloid-targeting antibodies. Acumen's premise is that sabirnetug's selective binding to soluble oligomers rather than widespread plaque could reduce off-target effects leading to ARIA. While Phase 1 data showed relatively low ARIA rates, this needs to be confirmed in the larger Phase 2 trial. Management acknowledges that ARIA management remains a controversial and evolving area for clinicians using currently approved mAbs, suggesting that a therapy with a potentially lower ARIA burden could be highly attractive.

The adoption of currently marketed anti-A-beta treatments has faced initial challenges, partly due to infrastructure limitations for IV administration and patient/physician education, but is expected to grow and form a cornerstone of AD treatment. This growing market awareness and infrastructure build-out could benefit future entrants like sabirnetug. Furthermore, advancements in blood-based biomarkers, such as plasma p-tau 217, are improving the ability to identify and screen appropriate patients for trials and potentially clinical practice. Acumen's successful use of p-tau 217 screening in ALTITUDE-AD demonstrates its ability to leverage these advancements for operational efficiency and potentially better patient selection.

While competitors like Roche (RHHBY) (with Trontinemab) are also exploring synaptic biomarkers, Acumen's early data from INTERCEPT-AD showing directional changes in these markers provides initial support for its oligomer-targeting hypothesis impacting synaptic function. The competitive landscape highlights both the significant market opportunity in AD and the need for therapies that offer clear advantages in terms of efficacy, safety, or convenience. Acumen's strategy is to demonstrate that sabirnetug's selective AßO targeting translates into a compelling clinical profile that differentiates it within this competitive environment.

Conclusion

Acumen Pharmaceuticals is at a critical juncture, having successfully completed enrollment in its pivotal Phase 2 ALTITUDE-AD trial for sabirnetug, its lead candidate targeting toxic soluble amyloid-beta oligomers. This achievement, ahead of schedule and supported by innovative screening methods, underscores the company's operational capabilities and the interest in its differentiated scientific approach. With topline results expected in late 2026, the company's current financial resources are projected to provide runway through this key data catalyst.

The investment thesis for ABOS hinges on the successful translation of its AßO-targeting hypothesis into a clinically meaningful benefit-to-risk profile in the ALTITUDE-AD trial. Positive results could position sabirnetug as a compelling next-generation treatment option in the evolving AD landscape, potentially offering advantages in safety (e.g., lower ARIA) or efficacy compared to existing therapies. The exploration of a subcutaneous formulation further enhances the long-term potential by addressing patient convenience. While significant clinical and financial risks remain, including the need for substantial future funding and navigating the competitive market dynamics, the completion of Phase 2 enrollment marks a pivotal step towards potentially validating Acumen's differentiated approach to combating Alzheimer's disease. Investors will be keenly awaiting the late 2026 data readout as the primary determinant of the company's future trajectory.