EU Risk Management Plan (EU-RMP) — GLPI-103

Safety concerns derive from the clinical AESIs (PROT-301 §10) and observed pivotal safety (CSR-301 §12). This EU-RMP is the master safety specification; the FDA risk-management assessment (RMP-US) and the MFDS RMP (RMP-KR) reference the same safety concerns with region-specific risk minimization.

Change History

Part I — Product Overview

GLPI-103 is a first-in-class GLP-1 / apelin (APJ) receptor dual agonist, supplied as an intravenous solution (once weekly) and an oral tablet (once daily), indicated for adults with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin, as add-on therapy. Pharmacotherapeutic group: drugs used in diabetes / GLP-1 analogues (with apelinergic activity). Background metformin is continued; dosing is titrated.

Part II — Safety Specification

Module SI — Epidemiology of the Indication

T2DM is a highly prevalent chronic disease; in the target Korean and broader populations, a large proportion of patients on metformin remain inadequately controlled. Important comorbidities (cardiovascular disease, chronic kidney disease, obesity) are common and inform the populations of interest and background event rates.

Module SII — Nonclinical Part

Nonclinical findings of relevance: reversible exaggerated-pharmacology gastrointestinal effects; injection-site reactions; class-appropriate thyroid C-cell monitoring; negative genotoxicity; maternal effects in reproductive studies. No adverse target-organ toxicity at therapeutic exposures; adequate margins (M2.4; M4-2.3).

Module SIII — Clinical Trial Exposure

Across the program, exposure includes Phase 1 (N=80), Phase 2 (N=240), and the pivotal Phase 3 study (N=900; up to 52 weeks). Exposure is summarized by dose, duration, age, sex, and region (REF-002; CSR-301).

Module SIV — Populations Not Studied

Not adequately studied: pregnant/lactating women; children/adolescents; severe renal impairment (eGFR <45 excluded); severe hepatic impairment (ALT/AST >3×ULN excluded); very elderly (>75 excluded). These inform the missing information below.

Module SV — Post-Authorization Experience

None at initial authorization (new active substance).

Module SVII — Identified and Potential Risks

Each safety concern is characterized below (evidence, mechanism, frequency, risk factors, preventability, pharmacovigilance, and risk minimization).

Important identified risk — Gastrointestinal adverse events (nausea, vomiting, diarrhoea)

• Evidence/frequency: most frequent TEAEs; nausea 32.3% (IV) vs 21.4% (comparator) in Phase 3, not significantly different (CSR-301 §12).
• Mechanism: GLP-1 receptor agonism (delayed gastric emptying, central effects).
• Risk factors: rapid dose escalation; higher exposure (IV).
• Preventability: largely preventable/manageable by titration and dose modification.
• PV/minimization: routine PV; SmPC posology/warnings; titration guidance.

Important identified risk — Hypoglycaemia (in combination with insulin secretagogues)

• Evidence: low incidence (~5–6%); not increased versus comparator (semaglutide ~5.9%).
• Risk factors: concomitant sulfonylurea/insulin.
• Minimization: SmPC advice to consider reducing the secretagogue dose; patient education.

Important potential risk — Acute pancreatitis

• Basis: GLP-1 class signal; excluded at entry; none observed.
• PV: targeted follow-up questionnaire; discontinue if suspected; SmPC warning.

Important potential risk — Thyroid C-cell tumours (MTC/MEN2)

• Basis: rodent C-cell findings for the class; human relevance uncertain.
• Minimization: contraindication in personal/family history of MTC/MEN2; SmPC warning; monitoring of relevant signals.

Important potential risk — Cardiovascular / heart-rate effects (APJ-mediated)

• Basis: mechanism (apelinergic inotropy/chronotropy); no signal in trials.
• PV: vital-sign/ECG surveillance; cardiovascular outcomes study (Part IV).

Important potential risk — Immunogenicity

• Basis: peptide; low-titre non-neutralizing ADA observed nonclinically/clinically; no PK/PD/safety impact to date.

Module SVIII — Summary of Safety Concerns

Part III — Pharmacovigilance Plan

• Routine PV: signal detection; expedited and periodic reporting (PSUR/PBRER); targeted follow-up questionnaires for pancreatitis, MTC, serious gastrointestinal events, and severe hypoglycaemia.
• Additional PV: a post-authorization safety study (PASS) for long-term and cardiovascular safety; a pregnancy outcomes registry.

Part IV — Post-Authorization Efficacy Studies

A cardiovascular/heart-failure outcomes study is proposed to substantiate the APJ-mediated cardiometabolic positioning (lifecycle; CDP).

Part V — Risk Minimization Measures

Part VI — Summary of the RMP

Routine risk minimization (SmPC/Package Leaflet), supported by the pharmacovigilance plan and post-authorization studies, adequately characterizes and manages the identified and potential risks; missing information is addressed by the PASS and pregnancy registry. The benefit–risk remains favourable (M2.5.6).

Part VII — Annexes

AESI definitions (PROT-301 §10, Appendix B), targeted follow-up questionnaires, PASS/registry protocol synopses, and the benefit–risk conclusion (M2.5.6).