Module 2.7.4 — Summary of Clinical Safety
| Field | Value |
|---|---|
| Document ID | M274 |
| Version | 2.0 (full) |
| Compound | GLPI-103 (GLP-1/APJ dual agonist) |
| Standard | ICH M4E(R2) §2.7.4 |
| Confidentiality | Confidential |
Synthesizes safety across the program; pivotal figures trace to
outputs/(reconciled). See ISS-301.
Change History
| Version | Date | Author | Summary |
|---|---|---|---|
| 1.0 | 2026-06-29 | Clinical | Initial |
| 2.0 | 2026-06-29 | PV / Biostat | Full — TEAEs by SOC/PT, AESIs, hypoglycaemia, labs, exposure |
1. Exposure
Safety Set N=900 (IV 300, Oral 301, Semaglutide 299); 52-week double-blind exposure with 8-week titration (PROT-301 §6).
2. Overall Adverse Events
Any TEAE: IV 75.7% / Oral 67.8% / Semaglutide 72.2%. Dominant SOC: Gastrointestinal disorders (56.7% / 45.8% / 48.8%). Predominantly mild (649 events) or moderate (337); 87 severe; 752/1,073 events treatment-related.
3. Common Adverse Events by SOC / Preferred Term (subject incidence)
| SOC / PT | IV | Oral | Sema |
|---|---|---|---|
| Gastrointestinal | 56.7% | 45.8% | 48.8% |
| — Nausea | 32.3% | 22.6% | 21.4% |
| — Diarrhoea | 15.3% | 15.3% | 16.4% |
| — Vomiting | 11.0% | 12.3% | 17.7% |
| — Constipation | 12.7% | 8.6% | 9.4% |
| Metabolism/nutrition | 18.7% | 21.9% | 30.1% |
| — Decreased appetite | 16.3% | 20.3% | 25.8% |
| — Hypoglycaemia | 3.0% | 3.3% | 6.4% |
| General | 11.0% | 8.3% | 11.4% |
| — Injection-site reaction | 5.0% | 2.0% | 3.3% |
| Nervous system — Headache | 11.0% | 9.3% | 11.0% |
| Infections — URTI | 7.0% | 6.3% | 4.0% |
Nausea was significantly more frequent with GLPI-103 IV (32.3%) than semaglutide (21.4%) — a difference of +10.9 percentage points (p=0.003), reflecting the efficacy–tolerability trade-off of greater GLP-1 engagement in the higher-exposure IV arm; vomiting and decreased appetite were more frequent with semaglutide. Injection-site reactions were, as expected, highest with the IV route (5.0%).
4. Adverse Events of Special Interest
- Gastrointestinal: as above; manageable by titration.
- Hypoglycaemia: infrequent; numerically higher with semaglutide (6.4%) than GLPI-103 (~3%); recurrent-event rate ratio not significantly different (quasi-Poisson;
outputs/stats/recurrent_results.csv); no severe events of concern. - Pancreatitis / thyroid C-cell (MTC): none recorded; monitored as class risks.
- Cardiovascular / heart rate (APJ): no clinically meaningful signal.
5. Deaths, SAEs, Discontinuations
10 serious adverse events including 2 deaths (none treatment-related) were reported. Overall discontinuation 9.3% (84/900); AE-related discontinuations were infrequent (n=9). Reasons: lost to follow-up (28), withdrawal by subject (25), physician decision (18), adverse event (9), death (2), lack of efficacy (2).
6. Laboratory & Vital Signs
Hepatic (ALT/AST) and renal (eGFR) parameters were stable (mean changes near zero across arms); vital signs including heart rate showed no clinically meaningful change. ECG [MOCK].
7. Safety Conclusions
GLPI-103 has a class-consistent, manageable safety profile dominated by gastrointestinal events, with a tolerability trade-off (higher nausea) in the higher-exposure intravenous formulation addressed by titration. Hepatic safety was assessed by eDISH (ALT vs total bilirubin): no Hy's-law cases and only 1 subject with ALT >3×ULN (SAR-301 §10; Figure 4). The profile supports a favourable benefit–risk (M2.5.6) with routine risk minimization (RMP suite). Limitations: simulated dataset (ECG not captured).