Introduction

The therapeutic landscape of Alzheimer's disease has been reshaped over the past five years by the emergence of amyloid-modifying monoclonal antibodies (mAbs). While lecanemab has secured regulatory approval and donanemab is advancing rapidly toward the market, a third candidate, Remternetug (LY3372993), is now in Phase III testing. Developed by Eli Lilly, Remternetug represents a rationally designed evolution of donanemab, preserving its aggressive plaque clearance capability while engineering away some of its liabilities.

Understanding where Remternetug fits requires examining the unique molecular epitope it targets, the biological rationale for selecting pyroglutamate-modified amyloid-beta (AβpE3), the early clinical biomarker outcomes, and its potential advantages and limitations relative to existing therapies.

Mechanistic Rationale: Targeting Pyroglutamate Abeta

Pyroglutamate-modified Aβ (pE3-Aβ, or N3pG-Aβ) is not simply another fibrillar species - it is a pathogenic anchor point for plaque nucleation. The post-translational modification (cyclization of glutamate at position 3) yields a peptide that is more hydrophobic, aggregation-prone, and protease-resistant than full-length Aβ. In vitro, pE3-Aβ seeds fibrils at rates up to 250-fold faster than unmodified Aβ, and in vivo, it is found almost exclusively within the core of mature plaques.

This localization gives Remternetug two critical theoretical advantages:

1. Specificity - By binding only to deposited plaques and not soluble monomers or protofibrils, the antibody avoids off-target interactions with circulating Aβ or precursor proteins.
2. Potency - Targeting the “keystone” seeding species could destabilize plaques from within, producing rapid and complete clearance.

Donanemab demonstrated the clinical validity of this approach, but its development was complicated by high immunogenicity (anti-drug antibodies in ~90%) and a non-trivial rate of infusion reactions. Remternetug was engineered as a fully humanized IgG1 to reduce ADA formation and systemic reactivity while maintaining microglial Fc-mediated phagocytic clearance of plaques.

Early Clinical Data: Proof-of-Concept Plaque Removal

The multiple ascending-dose Phase I study (2020, NCT04451408) provided the first real evidence that Remternetug could match - and possibly exceed - donanemab's plaque clearance.

• Dosing Regimens: Monthly IV infusions at 250-2800 mg, with or without titration.
• Primary Outcomes: Amyloid PET clearance, safety, pharmacokinetics.
• Results: At 6 months, all participants on the highest dose (2800 mg) became amyloid-negative, achieving plaque reductions on the order of 90-100 centiloids. Even at 700-1400 mg, 75% of participants cleared plaques below the amyloid-positive threshold within 24 weeks.

This degree of clearance is remarkable when contextualized against lecanemab, which required 18 months to drive mean plaque reductions of ~55 centiloids, and even against donanemab, where clearance took 6-12 months. Remternetug's kinetic profile is aggressive - it appears capable of eliminating amyloid within half a year.

Safety: The ARIA Problem and Engineering Gains

The liabilities of the class remain front and center. In Phase I, approximately 29% of patients developed ARIA (E or H), mostly asymptomatic and MRI-detected, with one clinically symptomatic case resolving after discontinuation. This incidence is essentially indistinguishable from donanemab and higher than lecanemab.

Yet two important differentiators emerged:

• No infusion-related systemic reactions were reported in Phase I.
• No anti-drug antibodies (ADA) were detected, in contrast to donanemab's near-universal immunogenicity.

This suggests that Remternetug's Fc engineering and sequence optimization achieved their design goals, potentially allowing for cleaner pharmacokinetics and longer durability in practice. The clinical implication is not trivial: if ADA titers do not rise, Remternetug could maintain consistent exposure over years without loss of efficacy or increased adverse reactions.

Phase III Trials: TRAILRUNNER-ALZ Program

Two major pivotal trials define the Remternetug roadmap:

1. TRAILRUNNER-ALZ 1 (NCT05463731)
   • ~600 participants with early symptomatic AD.
   • Randomized to Remternetug vs placebo, administered by either IV or subcutaneous injection.
   • Primary endpoint: Amyloid plaque clearance at 52 weeks.
   • Design includes a one-year crossover extension, ensuring all participants receive drug exposure.
2. TRAILRUNNER-ALZ 3 (NCT06653153)
   • Event-driven outcomes trial, ~600 participants.
   • Primary endpoint: Time to clinical progression (CDR-based).
   • Incorporates decentralized assessments to streamline trial burden.
   • Expected completion: ~2030.

Additionally, Remternetug is entering prevention trials in autosomal-dominant AD (DIAN-TU). Here, it will be given quarterly to asymptomatic carriers as young as 18, testing whether amyloid build-up can be prevented decades before symptoms.

Comparison Across the Class

• Lecanemab (Leqembi): Targets soluble protofibrils. Demonstrated 27% slowing of decline in Phase III. Lower ARIA incidence (~12%). IV every 2 weeks, with SC formulation in development.
• Donanemab: Targets the same pyroglutamate epitope. Demonstrated 35% slowing in low-to-intermediate tau subgroup. Higher ARIA (~24%). Monthly IV dosing, discontinued upon amyloid clearance. High ADA formation.
• Remternetug: Next-generation donanemab. Phase I demonstrated faster and complete plaque clearance with no ADA and no infusion reactions. Phase III testing IV and SC administration, potentially monthly or even quarterly dosing.

The central question is whether Remternetug's rapid clearance kinetics, combined with lower immunogenicity and a subcutaneous delivery option, can achieve cognitive outcomes equal to or surpassing donanemab's while maintaining safety at a clinically acceptable level.

Regulatory Outlook

If TRAILRUNNER-ALZ 1 demonstrates robust PET clearance in 2025, Lilly is expected to seek accelerated FDA approval by 2026, paralleling the pathway Aducanumab and Lecanemab pursued. Confirmatory evidence will hinge on TRAILRUNNER-ALZ 3. The prevention trial adds a bold dimension, potentially positioning Remternetug as the first antibody tested for true primary prevention of AD pathology.

Clinical Implications for Providers

From a practicing neurologist's perspective, several points are salient:

• Potency vs Safety: Remternetug clears plaques rapidly, but this raises ARIA risk. APOE e4 carriers may be particularly vulnerable. Strict MRI monitoring will be essential.
• Convenience: Subcutaneous administration could be a game-changer in clinical practice, shifting care from infusion centers to home-based or outpatient self-injection models.
• Treatment Paradigm: Lilly may pursue a "treat-to-clear" approach, similar to donanemab, potentially reducing exposure once patients become amyloid-negative. This could lower cumulative ARIA risk and overall cost.
• Future Positioning: If approved, Remternetug could complement or compete with lecanemab and donanemab, with its differentiators being convenience, engineered safety improvements, and possibly faster clearance kinetics.

Conclusion

Remternetug represents the logical next iteration of plaque-directed immunotherapy - targeting the same toxic core epitope as donanemab but optimized for safety, immunogenicity, and delivery. Its early data suggest it may match or surpass donanemab in biomarker efficacy while offering a more clinician-friendly route of administration. Whether these gains translate into meaningful cognitive benefit and an improved risk-benefit ratio will be determined by the TRAILRUNNER program. For now, Remternetug stands as one of the most promising investigational agents in the Alzheimer's pipeline, with the potential to both refine and expand the clinical use of amyloid immunotherapy.

References

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• FierceBiotech. (2023, March 31). Lilly’s next-gen Alzheimer’s drug Remternetug clears amyloid quickly, with manageable ARIA in early trial. Fierce Biotech. https://www.fiercebiotech.com/biotech
• Rijal, G., & Schmidt, S. D. (2025). A preclinical evaluation of ABBV-916, a pyroglutamate Aβ monoclonal antibody, in models of Alzheimer’s disease. Acta Neuropathologica, 150(6), 819–835. https://doi.org/10.1007/s00401-025-03045-9
• Sperling, R., Cummings, J., & Doody, R. (2021). Donanemab and the case for targeting pyroglutamate-modified Aβ in Alzheimer’s disease. The Lancet Healthy Longevity, 2(7), e381–e383. https://doi.org/10.1016/S2666-7568(21)00153-4