Session VII — Drug Discovery III: Repair Pathways, Receptor Engineering, and the Incretin Century

Session VII — Drug Discovery III

When Biology Becomes the Drug: Repair, Receptor Engineering, and the Incretin Century

Three architects — Anthony Adamis (Merck), Jay Bradner (Amgen), and Kenneth Custer (Lilly) — on retinal repair, GLP-1 receptor engineering, and the incretin roadmap.

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Anthony Adamis — Retinal Repair Beyond Anti-VEGF

• Anti-VEGF plateaued at ~50% of patients with complete fluid resolution
• Tiespectus — direct TIE2 agonist + VEGF inhibition; >95% complete fluid resolution within one week (Phase 3)
• Restoret — Wnt/Frizzled-4 agonist; rebuilds the blood-retinal barrier itself (Phase 3)
• Three layers: VEGF (triggers pathology) → TIE2 (repairs endothelium) → Wnt/Frizzled-4 (encodes the barrier)

Jay Bradner — Maritide

• Antibody-peptide conjugate: GIPR antagonist + two GLP-1 agonist peptides at a specific spatial position
• Induces GLP-1R/GIPR heterodimerization → deep central appetite suppression
• Phase 2: sustained weight loss without plateau through 52 weeks, monthly dosing
• Phase 3 ongoing; quarterly dosing also successful
• The geometry is the drug — peptide position on antibody scaffold determines heterodimerization

Kenneth Custer — The Incretin Roadmap

Current

• Tirzepatide (dual GIP/GLP-1) — ~21-22% weight loss
• Orforglipron — oral small-molecule GLP-1R agonist; FDA-approved; manufacturable at 2-billion-patient scale

Next

• Retatrutide — GIP/GLP-1/glucagon triple agonist; 28.7% weight loss at 68 weeks (Phase 3 TRIUMPH-4); ~75% WOMAC pain reduction
• Amylin agonism — ~20% weight loss; GI vomiting rate ~1 in 52 (vs ~21% semaglutide)

Beyond Cardiometabolic

• Phase 3 trials in substance use disorder, MDD, schizophrenia, bipolar, alcohol/tobacco/opioid use disorder
• Phase 2/3 in asthma, IBS, IBD, psoriasis, chronic lower back pain

Cross-Cutting Themes

1. Repair over suppression — activating endogenous repair programs, not just blocking pathological signals
2. Geometry as pharmacology — Tiespectus and Maritide both depend on precise 3D presentation
3. The scale imperative — oral small molecules and monthly dosing needed to reach 2 billion patients
4. The ceiling is always visible — and always broken — each generation reveals the limit of the last