Protofibril vs. plaque: how lecanemab and donanemab target amyloid differently

Lecanemab and donanemab both belong to the anti-amyloid monoclonal antibody class, but they engage distinct molecular species of amyloid-beta — a distinction with direct consequences for ARIA risk, patient selection, and the speed of amyloid clearance. Lecanemab selectively binds amyloid-beta protofibrils, which are soluble oligomeric aggregates widely considered to be among the most neurotoxic forms of amyloid-beta in the Alzheimer’s disease cascade. Donanemab (Kisunla, developed by Eli Lilly) targets insoluble amyloid plaques, specifically those containing pyroglutamate-modified amyloid-beta (pyroGlu-Aβ), which are a characteristic feature of established plaque burden.

This molecular selectivity difference is not merely academic. The protofibril-targeting profile of lecanemab means it engages amyloid at an earlier aggregation state, potentially intercepting neurotoxic species before they deposit as mature plaques. Donanemab’s pyroglutamate-plaque focus, by contrast, is designed to clear established plaque burden rapidly — which may explain its observed ability to allow treatment discontinuation once amyloid clearance thresholds are met, a feature not currently associated with lecanemab’s label. According to data published in NEJM and reviewed by Alzforum, both agents demonstrated statistically significant slowing of clinical decline in their pivotal trials, but with different ARIA incidence profiles that inform patient selection criteria.

From biweekly IV to subcutaneous self-injection: the dosing regimen race

The single most commercially significant differentiator emerging between lecanemab and donanemab is not molecular — it is logistical. Donanemab (Kisunla) already holds a frequency advantage over current lecanemab with its monthly intravenous infusion schedule, compared to lecanemab’s biweekly IV requirement. Each IV infusion demands a clinic visit, nursing time, infusion suite capacity, and patient travel — costs and inconveniences that accumulate rapidly over a multi-year treatment course targeting early-stage patients who may otherwise be functionally independent.

“The shift from biweekly IV infusion to subcutaneous self-administration represents a critical commercial and clinical differentiator in the emerging anti-amyloid immunotherapy category.”

BioArctic and Eisai are advancing a subcutaneous (SC) formulation of lecanemab that would allow patients to self-administer the drug at home via injection under the skin — analogous to how patients with other chronic conditions self-administer biologics such as adalimumab or insulin. The SC programme under investigation targets weekly or biweekly dosing intervals. If validated, this would represent a step-change in the patient experience relative to both the current biweekly IV lecanemab regimen and Kisunla’s monthly IV schedule: eliminating clinic infusion visits entirely for maintenance dosing.

The site-of-care economics of this shift are substantial. Infusion suites at memory clinics and neurology centres face capacity constraints as the eligible patient population — those with early symptomatic Alzheimer’s confirmed by amyloid biomarker testing — is expected to grow as awareness and diagnostic infrastructure expand. A subcutaneous option would decompress infusion capacity, reduce payer costs associated with administration, and potentially widen access to patients in geographically underserved areas without specialist infusion facilities.

Formulation IP and patent strategy: BioArctic, Eisai, and Eli Lilly

The intellectual property architecture underlying lecanemab reflects a bifurcated originator-licensor structure that distinguishes it from most large-pharma antibody programmes. BioArctic AB, the Swedish biotech, holds foundational IP covering the protofibril-selective antibody originally designated BAN2401 — the antibody that became lecanemab. This foundational IP encompasses the antibody’s molecular design and its selectivity for protofibrils over monomers and mature plaques. Eisai, as the development and commercialisation partner, holds formulation and manufacturing patents that cover the drug product as commercialised under the Leqembi brand.

The subcutaneous programme is expected to generate a new layer of IP filings at USPTO and EPO under both assignees. These filings are anticipated to cover subcutaneous delivery device configurations, concentration optimisation for SC injection volumes, excipient selection for subcutaneous tolerability, and auto-injector or prefilled syringe formats. Device and formulation patents of this type typically extend commercial protection well beyond the composition-of-matter patent expiry of the antibody itself, making the SC programme strategically important not only for market access but for lifecycle management.

Eli Lilly’s donanemab IP estate covers composition-of-matter claims for the pyroglutamate-targeting antibody, method-of-treatment claims for early Alzheimer’s disease, and process patents associated with manufacturing at scale. Lilly’s IP strategy has also included claims around the amyloid clearance endpoint used to define treatment discontinuation — a clinically novel concept that, if broadly granted, could represent a defensible differentiator in the monthly IV regimen. Patent watchers tracking filings at WIPO should monitor both assignee portfolios for new SC-related filings as the lecanemab development programme advances through Phase 3.

Clinical translation: subcutaneous bioequivalence, ARIA monitoring, and trial design

Translating a biologic from intravenous to subcutaneous administration requires demonstrating pharmacokinetic bioequivalence — that SC dosing achieves sufficient systemic exposure to replicate the amyloid clearance kinetics established in the IV pivotal trials. For a high-molecular-weight antibody such as lecanemab, SC bioavailability is typically lower than IV (often in the range of 50–80% for IgG antibodies as a class), necessitating dose adjustments and potentially different dosing intervals to achieve equivalent trough concentrations at the target tissue.

Key clinical programmes investigating lecanemab in early Alzheimer’s disease include the AHEAD 3-45 study, which evaluates lecanemab in preclinical Alzheimer’s (elevated amyloid, no symptoms), and the STAR studies, which are specifically evaluating the subcutaneous administration route. These trials examine bioequivalence endpoints, amyloid clearance kinetics as measured by amyloid PET, and adapted ARIA monitoring protocols for the SC route. The ARIA monitoring question is particularly important: current IV lecanemab protocols require MRI surveillance at defined intervals, and regulators will need to be satisfied that SC administration does not alter the ARIA incidence or severity profile in ways that require modified surveillance.

ARIA — Amyloid-Related Imaging Abnormalities — encompasses brain oedema (ARIA-E) and microhaemorrhages (ARIA-H) that can occur as a pharmacodynamic consequence of amyloid clearance by anti-amyloid antibodies. ARIA rates differ between lecanemab and donanemab, and are influenced by APOE4 genotype status: APOE4 homozygotes carry substantially higher ARIA risk with both agents. Patient stratification by APOE4 genotype has therefore become a standard element of both prescribing information and clinical trial eligibility criteria for this drug class, as documented in regulatory submissions to the FDA and reviewed in publications by Nature Medicine.

Commercial implications and the path to market leadership

The competitive dynamics between lecanemab and donanemab will be shaped by four converging factors: dosing convenience, ARIA risk profile, IP durability, and payer acceptance. In the near term, donanemab’s monthly IV schedule gives it a practical convenience advantage over biweekly IV lecanemab, which translates into fewer clinic visits and lower administration burden for patients and health systems. However, if the lecanemab SC programme achieves regulatory approval, this advantage reverses decisively — subcutaneous self-administration at home eliminates the infusion clinic entirely for the majority of the treatment course.

Payer dynamics add another dimension. Health technology assessment bodies in the EU and the National Institute for Health and Care Excellence (NICE) in the UK have historically scrutinised anti-amyloid therapies for incremental clinical benefit relative to cost. The administration route directly affects the cost-effectiveness calculation: IV administration incurs nursing, facility, and pharmacy preparation costs that SC self-injection avoids. A subcutaneous lecanemab option would therefore strengthen the health economics case in markets where IV administration costs are explicitly modelled in reimbursement assessments.

Longer-term pipeline considerations include tau-targeting combination strategies and biomarker-guided maintenance dosing. As the field matures, combination approaches targeting both amyloid and tau pathology — the two hallmark proteinopathies of Alzheimer’s disease — are under investigation by multiple programmes. Post-plaque-clearance maintenance regimens, particularly relevant for donanemab given its discontinuation-on-clearance approach, represent an open clinical and commercial question: whether patients require ongoing low-dose maintenance to prevent amyloid re-accumulation, and whether subcutaneous delivery is better suited to that maintenance phase than periodic IV infusion. The innovation intelligence needed to navigate these converging dynamics — across patent filings, clinical trial registrations, and regulatory submissions — is precisely the type of analysis that platforms such as PatSnap Eureka are designed to synthesise.