Module 4.2.1 — Pharmacology Study Reports — GLPI-103
| Field | Value |
|---|---|
| Document ID | M4-2.1 |
| Version | 2.0 (expanded) |
| Compound | GLPI-103 (GLP-1/APJ dual agonist) |
| Standard | ICH M4S; M3(R2); S7A/S7B; GLP (safety pharmacology core battery) |
| Confidentiality | Confidential |
[MOCK — deep-knowledge assumption]Nonclinical pharmacology study reports; all data illustrative but technically representative. Interpretive overview in M2.4; tabulated summary in M2.6.
Change History
| Version | Date | Author | Summary |
|---|---|---|---|
| 1.0 | 2026-06-29 | Nonclinical | Initial study reports |
| 2.0 | 2026-06-30 | Nonclinical | Expanded — in-vitro potency/selectivity, quantitative in-vivo efficacy, mechanistic (APJ) cardiac/vascular readouts, safety-pharmacology margins |
4.2.1.1 Primary Pharmacodynamics
Report PD-IVT-01 — In-vitro receptor pharmacology (non-GLP)
Objective: Characterise potency, efficacy, and selectivity at the two intended targets.
| Assay | Readout | GLPI-103 [MOCK] |
GLP-1R-only comparator |
|---|---|---|---|
| Human GLP-1R | cAMP accumulation (EC₅₀) | 14 pM (full agonist, Emax 101%) | 9 pM |
| Human APJ (apelin receptor) | cAMP inhibition (EC₅₀) | 48 pM (full agonist) | inactive (>10 µM) |
| Human APJ | β-arrestin-2 recruitment (EC₅₀) | 220 pM (G-protein-biased ~5×) | inactive |
| Human GIP receptor | cAMP | inactive (>10 µM) | inactive |
| Human glucagon receptor | cAMP | inactive (>10 µM) | inactive |
| Species cross-reactivity (mouse/rat/monkey GLP-1R, APJ) | cAMP | within 3-fold of human | — |
Interpretation: GLPI-103 is a potent, full dual agonist of GLP-1R and APJ with no meaningful activity at the related GIP or glucagon receptors; the modest G-protein bias at APJ is consistent with the intended cardiometabolic (rather than purely β-arrestin) signalling.
Report PD-PRIM-01 — In-vivo efficacy in db/db and DIO mice (non-GLP)
Rationale: GLP is not required for primary efficacy pharmacology (ICH M3(R2)). Design: Male db/db mice (glycaemia) and diet-induced obese (DIO) mice (weight); randomised to vehicle, GLPI-103 low/mid/high (3/10/30 nmol/kg/day SC), or the GLP-1R-only comparator at matched exposure; 4-week dosing; OGTT, hyperinsulinaemic-euglycaemic clamp, body composition (NMR), and cardiometabolic biomarkers.
Endpoint (high dose) [MOCK] |
Vehicle | GLP-1R-only | GLPI-103 |
|---|---|---|---|
| HbA1c change (%, 4 wk) | +0.3 | −1.1 | −1.8 |
| Body-weight change (%) | +2 | −12 | −18 |
| Cumulative food intake | reference | −22% | −28% |
| OGTT glucose AUC | reference | −34% | −47% |
| Clamp glucose-infusion rate (insulin sensitivity) | reference | +30% | +58% |
| Plasma NT-proBNP | reference | −10% | −34% |
| hsCRP | reference | −15% | −41% |
Mechanistic (APJ) substudy (echocardiography/telemetry): GLPI-103 produced a modest, apelin-consistent increase in cardiac fractional shortening and improved endothelial (flow-mediated) vasodilation not seen with the GLP-1R-only comparator, supporting APJ engagement in vivo. Conclusion: GLPI-103 delivers dual-mechanism efficacy exceeding GLP-1R agonism alone at matched exposure, with cardiometabolic benefit attributable to APJ — the translational basis for the clinical hypothesis.
4.2.1.2 Secondary Pharmacodynamics — Report PD-SEC-01 (non-GLP)
Broad off-target screen (~80 receptors, ion channels, transporters and enzymes; radioligand/functional): no inhibition or activation ≥50% at 10 µM except the intended targets. No relevant secondary pharmacology liability.
4.2.1.3 Safety Pharmacology — Report PD-SAFP-01 (GLP)
Core battery per ICH S7A/S7B, conducted under GLP (21 CFR 58 / OECD):
| System | Model | Result [MOCK] |
Margin to clinical Cmax |
|---|---|---|---|
| hERG current | HEK293 patch clamp | IC₅₀ > 30 µM | >1,000× |
| Cardiovascular | telemetered cynomolgus monkey | no QTc prolongation; transient HR +10–15% (mechanism-related), resolving | >30× |
| Central nervous system | rat Irwin / functional observational battery | no adverse neurobehavioural effects | >50× |
| Respiratory | rat whole-body plethysmography | no effect on rate/tidal volume/minute volume | >50× |
Conclusion: No safety-pharmacology liability at therapeutic exposures; the transient heart-rate effect is the anticipated, monitorable class/mechanism effect (APJ/GLP-1).
4.2.1.4 Pharmacodynamic Drug Interactions — Report PD-DDI-01 (non-GLP)
Co-administration with metformin in db/db mice produced additive glucose lowering without adverse pharmacodynamic interaction, supporting the clinical add-on-to-metformin design. [MOCK]