Eli Lilly has developed a comprehensive multi-modal blood-brain barrier (BBB) delivery platform to enhance central nervous system (CNS) penetration of therapeutic antibodies for Alzheimer's disease and other neurodegenerative disorders. The platform combines advanced Fc engineering, receptor-mediated transcytosis (RMT) strategies, and combination approaches with emerging technologies like focused ultrasound [1].
Eli Lilly's BBB delivery efforts have been particularly successful with their amyloid-targeting programs. Donanemab (Kisunla), their anti-amyloid antibody, demonstrates significantly higher brain plaque clearance than competitor antibodies at comparable doses, suggesting superior brain penetration. The company is building on this success with next-generation programs including Remternetug and other pipeline assets [2].
Eli Lilly employs a multi-pronged strategy to overcome the BBB:
Lilly has developed proprietary Fc engineering to optimize brain delivery:
| Modification | Purpose | Effect |
|---|---|---|
| FcRn engagement | Extended half-life | Sustained brain exposure |
| FcγR reduction | Minimized effector function | Reduced ARIA risk |
| Affinity maturation | Enhanced target binding | Improved efficacy at lower doses |
The Fc modifications enable lower dosing while maintaining therapeutic efficacy, reducing both cost and potential side effects [3].
Lilly is developing RMT-targeted antibodies:
Partnerships with focused ultrasound companies:
Donanemab has demonstrated remarkable plaque clearance in clinical trials:
| Trial | Dose | Plaque Reduction | Timepoint |
|---|---|---|---|
| TRAILBLAZER-ALZ | 10 mg/kg Q4W | ~40% | 6 months |
| TRAILBLAZER-ALZ | 10 mg/kg Q4W | ~80% | 12 months |
| TRAILBLAZER-ALZ 2 | 10 mg/kg Q4W | ~84% | 18 months |
Donanemab's superior efficacy is attributed to:
The TRAILBLAZER-ALZ 2 trial demonstrated that donanemab not only removes existing plaques but also significantly slows clinical decline in early AD patients.
Remternetug (formerly LY3372993) is Eli Lilly's next-generation anti-amyloid antibody:
Remternetug is currently in clinical development for early Alzheimer's disease:
| Feature | Donanemab | Remternetug |
|---|---|---|
| Target | Aβ plaques | pE3-Aβ (more toxic species) |
| Dosing | IV infusion | Potential SC administration |
| Brain penetration | Enhanced | Further optimized |
Eli Lilly's BBB delivery platform supports multiple CNS programs:
| Program | Target | Stage | Delivery Approach |
|---|---|---|---|
| Donanemab | Aβ plaques | Approved | Fc engineered |
| Remternetug | pE3-Aβ | Phase 2/3 | Next-gen Fc |
| LY3886406 | Tau | Phase 1 | RMT-enhanced |
| Undisclosed | α-syn | Discovery | Platform |
Eli Lilly has explored combinations with focused ultrasound technology:
| Company | Primary Approach | Key Program | Brain Exposure |
|---|---|---|---|
| Eli Lilly | Fc engineering + RMT | Donanemab | High |
| Roche/Genentech | TfR bispecific | RG6102 | Very high |
| Biogen/Lundbeck | Antibody engineering | Aduhelm | Moderate |
| J&J | RMT platform | JNJ-712 | Moderate |
Eli Lilly's approach balances high brain exposure with established manufacturing and regulatory pathways.