Module 4.2.3 — Toxicology Study Reports — GLPI-103
| Field | Value |
|---|---|
| Document ID | M4-2.3 |
| Version | 2.0 (expanded) |
| Compound | GLPI-103 (GLP-1/APJ dual agonist) |
| Standard | ICH M4S; M3(R2); S1A-B, S2(R1), S3, S4, S5(R3), S6(R1), S8; GLP |
| Confidentiality | Confidential |
[MOCK — deep-knowledge assumption]Study reports; illustrative but technically representative data. The pivotal repeat-dose study is presented in full; other studies as report summaries.GLP statement: All pivotal toxicology studies (repeat-dose, genotoxicity, carcinogenicity, reproductive/developmental, local tolerance) were conducted in compliance with Good Laboratory Practice (21 CFR Part 58 / OECD GLP), with a signed compliance statement and Study Director in each report.
Change History
| Version | Date | Author | Summary |
|---|---|---|---|
| 1.0 | 2026-06-29 | Nonclinical Toxicology | Initial reports |
| 2.0 | 2026-06-30 | Nonclinical Toxicology | Expanded — dose levels, NOAELs with AUC-based exposure margins, quantitative findings, thyroid C-cell human-relevance analysis |
Exposure-margin basis: clinical reference exposure = steady-state AUC at the maintenance dose (IV 4 mg QW / Oral 8 mg QD). Margins below are NOAEL animal AUC ÷ clinical AUC.
4.2.3.1 Single-Dose Toxicity — TOX-SD-01/02 (summary)
Single subcutaneous and intravenous doses in rat and cynomolgus monkey were well tolerated with no acute target-organ toxicity; the maximum tolerated dose was not reached at feasible dose volumes. [MOCK]
4.2.3.2 Repeat-Dose Toxicity — Report TOX-RD-01 (PIVOTAL, full)
Title: A 26-Week Subcutaneous Repeat-Dose Toxicity Study of GLPI-103 in the Rat with Toxicokinetics and a 4-Week Recovery Period (GLP). Design: Sprague-Dawley rats (6–8 wk), 15/sex/group + recovery; vehicle and 0.3 / 1.0 / 3.0 mg/kg/week SC; 26 weeks + 4-week recovery; full clinical, clinical-pathology, TK, organ-weight and histopathology endpoints (including thyroid C-cells, pancreas, injection site).
| Domain | Finding [MOCK] |
|---|---|
| Mortality | None treatment-related |
| Clinical signs | Dose-related reduced food intake; minor, reversible injection-site oedema/erythema |
| Body weight | ↓ weight gain up to 18% at 3.0 mg/kg (exaggerated pharmacology, not adverse) |
| Clinical pathology | No adverse haematology/coagulation/chemistry/urinalysis changes |
| Organ weights / histopathology | No adverse target-organ toxicity; no thyroid C-cell or pancreatic findings at 26 weeks; injection-site changes minimal and reversible |
| Toxicokinetics | ~dose-proportional AUC; minimal accumulation (≈1.3×); no sex difference |
| Recovery | All findings fully reversible by week 4 |
NOAEL = 3.0 mg/kg/week (high dose) → ≈25× clinical AUC. TOX-RD-02 (39-week cynomolgus monkey, GLP): analogous findings limited to exaggerated pharmacology and reversible injection-site reactions; NOAEL high dose ≈ 20× clinical AUC.
4.2.3.3 Genotoxicity — TOX-GEN-01 (summary, ICH S2(R1))
Complete battery negative: bacterial reverse mutation (Ames, ±S9), in-vitro micronucleus (human lymphocytes), and in-vivo rat bone-marrow micronucleus — consistent with a non-DNA-reactive peptide.
4.2.3.4 Carcinogenicity — TOX-CARC-01 (summary, ICH S1)
- 2-year rat (SC): a dose-related increase in thyroid C-cell hyperplasia and C-cell adenoma (and a low incidence of C-cell carcinoma at the high dose) — the expected GLP-1-receptor-agonist class effect in rodents. No other treatment-related neoplasm.
- 26-week rasH2 transgenic mouse: negative.
- Human-relevance analysis: rodent C-cells express a high density of GLP-1 receptors and are uniquely sensitive to sustained GLP-1R agonism (C-cell proliferation/calcitonin release); human C-cells express GLP-1R at very low levels, and large clinical/epidemiological datasets for the class have not established a causal MTC signal. The finding is therefore considered largely rodent-specific and of low human relevance, but is conservatively carried as a class risk — contraindication in personal/family history of medullary thyroid carcinoma (MTC) or MEN-2, with labeling and pharmacovigilance (RMP).
4.2.3.5 Reproductive & Developmental Toxicity — TOX-REPRO-01 (summary, ICH S5(R3))
- Fertility (rat): no effect on mating/fertility indices at exposures below overt maternal toxicity.
- Embryo-foetal development (rat & rabbit): at maternally toxic doses (reduced food intake/weight), associated reductions in foetal weight and increased skeletal variations; no unique malformation/teratogenic signal; developmental NOAEL defined with margins.
- Pre/postnatal (rat): reduced pup weight secondary to maternal effects; no functional deficits.
- Use in pregnancy is not recommended (class labeling).
4.2.3.6–7 Local Tolerance, Immunotoxicity & Impurity Qualification (summary)
Acceptable IV/SC local tolerance; no adverse immunotoxicity (ICH S8); drug-substance and SNAC-related impurities qualified at or above the levels in the clinical product (ICH Q3A/Q3B).
Integrated NOAEL / Margin Summary
| Study | Species | NOAEL | Exposure margin (AUC) |
|---|---|---|---|
| 26-wk repeat-dose | Rat | 3.0 mg/kg/wk | ≈25× |
| 39-wk repeat-dose | Monkey | high dose | ≈20× |
| EFD | Rat/Rabbit | maternal-toxicity-limited | adequate developmental margin |
| Carcinogenicity | Rat | C-cell effect (rodent-specific) | class risk → RMP |
Integrated conclusion: The nonclinical safety package supports clinical use, with adverse findings limited to reversible exaggerated pharmacology and reversible injection-site reactions, adequate exposure margins, a negative genotoxicity battery, and a rodent-specific thyroid C-cell carcinogenicity signal of low human relevance that is conservatively managed as a labeled class risk (GI tolerability, MTC, pancreatitis, and cardiovascular/heart-rate effects carried as clinical AESIs and into the RMP; M2.4 §6).