Module 2.6 — Nonclinical Written & Tabulated Summaries
| Field | Value |
|---|---|
| Document ID | M26 |
| Version | 2.0 (full) |
| Compound | GLPI-103 (GLP-1/APJ dual agonist) |
| Standard | ICH M4S(R2) §2.6.1–2.6.7 |
| Confidentiality | Confidential |
[MOCK]Illustrative written and tabulated summaries; complements M2.4 and the M4 study reports.
Change History
| Version | Date | Author | Summary |
|---|---|---|---|
| 1.0 | 2026-06-29 | Nonclinical | Initial |
| 2.0 | 2026-06-29 | Nonclinical | Full — expanded tabulated PK/tox |
2.6.1 Introduction
Dual GLP-1R/APJ agonist peptide; nonclinical program per ICH M3(R2)/S-series (M2.4).
2.6.2 Pharmacology Written Summary
Primary PD: potent full agonism at GLP-1R (EC₅₀ ≈14 pM) and APJ (≈48 pM) with no GIP/glucagon-receptor activity; in db/db and DIO models, superior HbA1c (−1.8% vs −1.1%) and weight (−18% vs −12%) effects vs the GLP-1R-only comparator, with improved insulin sensitivity (+58% clamp GIR), vascular/cardiac function, and reduced NT-proBNP/hsCRP. Safety pharmacology (S7A/S7B): no CNS/respiratory/QT liability; transient mechanism-related heart-rate changes.
2.6.3 Pharmacology Tabulated Summary [MOCK]
| Assay | System | Result |
|---|---|---|
| GLP-1R cAMP | human GLP-1R cells | full agonist, EC₅₀ ≈14 pM |
| APJ signalling | human APJ cells | full agonist, EC₅₀ ≈48 pM (G-protein-biased) |
| Glucose lowering | db/db mouse | ↓HbA1c vs control / GLP-1R-only |
| Weight | DIO mouse | ↓ dose-dependent |
| Cardiac function | rat HF model | ↑contractility, ↓NT-proBNP |
| Safety pharm (CV/CNS/resp) | dog/monkey/rat | no adverse effect |
| hERG | patch clamp | no significant inhibition |
2.6.4 Pharmacokinetics Written Summary
Dose-proportional exposure; long t½ (QW IV); oral bioavailability with enhancer; proteolytic catabolism; minimal CYP/transporter involvement; low-titre non-neutralizing ADA.
2.6.5 Pharmacokinetics Tabulated Summary [MOCK]
| Parameter | Rat | Monkey |
|---|---|---|
| t½ | ~24–48 h | ~60–90 h |
| Exposure (AUC) | dose-proportional | dose-proportional |
| Vd / CL | low / proteolytic | low / proteolytic |
| Bioavailability (oral+SNAC) | low (~1–2%) | low (~1–2%) |
| Plasma protein binding | >99% (albumin) | >99% (albumin) |
| ADA | low, non-neutralizing | low, non-neutralizing |
2.6.6 Toxicology Written Summary
Repeat-dose (≤26-wk rat / ≤39-wk monkey): reversible GI signs and IV injection-site reactions; adequate NOAEL margins. Genotoxicity negative; carcinogenicity with class C-cell monitoring; repro/dev maternal effects only; acceptable local tolerance/immunogenicity.
2.6.7 Toxicology Tabulated Summary [MOCK]
| Study | Species | Duration | Key finding | NOAEL margin |
|---|---|---|---|---|
| Single-dose | rat/monkey | — | well tolerated | — |
| Repeat-dose | rat | 26 wk | reversible exaggerated-pharmacology | ≈25× |
| Repeat-dose | monkey | 39 wk | injection-site, exaggerated-pharmacology | ≈20× |
| Ames / IVCA / micronucleus | — | — | negative | — |
| Carcinogenicity | rat / rasH2 | 2 yr | rodent-specific C-cell adenoma | low human relevance (ISS-012) |
| Fertility / EFD / PPND | rat/rabbit | — | maternal effects only | — |
| Local tolerance | rabbit | — | acceptable | — |
Conclusion
Adequate to support clinical development; monitorable risks (GI, thyroid C-cell, pancreatitis, cardiovascular/HR) reflected in the clinical AESIs and RMP.