Investigator's Brochure — GLPI-103

Nonclinical content is [MOCK — deep-knowledge assumption] (see M2.4 / M2.6 / M4). Early clinical content (Phase 1/2) is illustrative [MOCK]; pivotal Phase 3 data are sourced from CSR-301 (outputs/). Parameters cite REF-002.

Change History

1. Summary

GLPI-103 is a first-in-class synthetic peptide dual agonist of the GLP-1 and apelin (APJ) receptors in development for type 2 diabetes mellitus (T2DM), with lifecycle interest in obesity and heart failure with preserved ejection fraction. Nonclinical studies established robust, dose-dependent glycaemic and body-weight effects exceeding those of a GLP-1 receptor-only comparator, together with favourable cardiometabolic effects and a class-consistent, monitorable safety profile with adequate exposure margins. First-in-human single- and multiple-ascending-dose studies and a Phase 2 dose-finding study confirmed acceptable safety and tolerability, characterized human pharmacokinetics, and demonstrated a clear dose–response. In the pivotal Phase 3 study (GLPI103-301), GLPI-103 (intravenous and oral) was superior to oral semaglutide on HbA1c at Week 52, with substantially greater weight reduction and a manageable, gastrointestinal-predominant safety profile. This brochure provides investigators the information required to conduct studies of GLPI-103 safely and effectively.

2. Introduction

T2DM is a progressive disease in which many patients fail to achieve glycaemic and weight targets and retain substantial cardiometabolic risk. GLP-1 receptor agonists provide glycaemic and weight benefits, but single-mechanism efficacy is limited. GLPI-103 was designed to engage both the GLP-1 receptor (insulinotropic, glucagonostatic, appetite- and gastric-emptying effects) and the APJ receptor (insulin sensitivity, endothelial and myocardial function, anti-inflammatory effects), with the goal of greater metabolic efficacy and cardiometabolic benefit. The development program is summarized in the Clinical Development Plan and Target Product Profile (TPP-001).

3. Physical, Chemical, and Pharmaceutical Properties and Formulation

GLPI-103 is a synthetic peptide dual agonist with a defined primary sequence incorporating fatty-acid acylation (to extend half-life) and non-natural residues (to confer protease resistance). It is supplied as: (a) a sterile aqueous solution for intravenous administration (once weekly), and (b) an immediate-release tablet for oral administration (once daily) formulated with a permeation enhancer to enable peptide absorption. Storage, handling, preparation, and administration are described in the Pharmacy/IMP Manual (TMF-PHARM); quality attributes and stability are summarized in Module 3 (M3 / M3-S / M3-P). [MOCK]

4. Nonclinical Studies

4.1 Nonclinical Pharmacology

In vitro, GLPI-103 is a potent full agonist at both the human GLP-1 receptor (EC₅₀ ≈14 pM) and the human APJ receptor (EC₅₀ ≈48 pM), with no activity at the GIP or glucagon receptors. In vivo, in db/db and diet-induced obese rodent models, GLPI-103 produced dose-dependent reductions in HbA1c and body weight that exceeded those of a GLP-1 receptor-only comparator at matched exposure, with improved insulin sensitivity and favourable cardiometabolic biomarkers (NT-proBNP, hsCRP) consistent with APJ engagement (M4-2.1; M2.6.2). Safety pharmacology (ICH S7A/S7B) demonstrated no central nervous system, respiratory, or QT/hERG liability, with only transient, mechanism-related changes in heart rate.

4.2 Pharmacokinetics and Product Metabolism in Animals

GLPI-103 exhibited approximately dose-proportional exposure in rat and monkey, with a long terminal half-life supporting once-weekly intravenous dosing, adequate oral bioavailability with the permeation enhancer, proteolytic catabolism, negligible cytochrome-P450 involvement (low drug-interaction potential), and low-titre, non-neutralizing anti-drug antibodies (M4-2.2; M2.6.4).

4.3 Toxicology

The toxicology package comprised single- and repeat-dose studies (≤26-week rat and ≤39-week monkey), genotoxicity, carcinogenicity, and reproductive/developmental studies, conducted in compliance with Good Laboratory Practice. Findings were limited to reversible exaggerated-pharmacology effects (reduced food intake and body-weight gain) and injection-site reactions, with no adverse target-organ toxicity at the doses tested; genotoxicity was negative; class-appropriate thyroid C-cell monitoring was incorporated; and reproductive findings were limited to maternal effects. No-observed-adverse-effect levels provided adequate exposure margins to the clinical dose (M4-2.3; M2.4 §4–5).

5. Effects in Humans

5.1 Pharmacokinetics and Metabolism in Humans

Human pharmacokinetics were consistent with the nonclinical profile: a long half-life supporting once-weekly intravenous dosing, oral bioavailability adequate for once-daily dosing with the permeation enhancer, proteolytic catabolism with low drug-interaction potential, and low immunogenicity (M2.7.2). [MOCK]

5.2 Safety and Efficacy in Humans

• Phase 1 (GLPI103-101, SAD, N=40; GLPI103-102, MAD, N=40): acceptable safety and tolerability with no dose-limiting toxicity; dose-dependent pharmacokinetics; pharmacodynamic engagement (HbA1c, body weight, plasma apelin, NT-proBNP, hsCRP) (CSR-101/102). [MOCK]
• Phase 2 (GLPI103-201, N=240, 24 weeks): a clear dose–response for HbA1c reduction with dose-dependent weight loss; gastrointestinal adverse events were the most common and were dose-related; the data supported the Phase 3 doses (CSR-201). [MOCK]
• Phase 3 (GLPI103-301, N=900): GLPI-103 IV and Oral were superior to oral semaglutide on HbA1c change from baseline at Week 52 (IV −0.68%, 95% CI −0.81, −0.55; Oral −0.34%, 95% CI −0.49, −0.23; both p<0.001), with substantially greater weight reduction (−14.5 and −10.3 kg versus −7.6 kg) and higher responder rates. The safety profile was gastrointestinal-predominant; nausea was more frequent with the intravenous formulation (32.3% versus 21.4% for semaglutide; p=0.003), reflecting the expected efficacy–tolerability trade-off managed by titration; hypoglycaemia was infrequent and balanced; and 10 serious adverse events and 2 deaths (none treatment-related) were recorded (CSR-301).

6. Summary of Data and Guidance for the Investigator

The accumulated nonclinical and clinical data indicate that GLPI-103 has a favourable benefit–risk profile in adults with T2DM inadequately controlled on metformin. Investigators should:

• Administer GLPI-103 according to the protocol-defined titration schedule and use dose-modification provisions to manage gastrointestinal tolerability (PROT-301 §6.3; Appendix C).
• Monitor for adverse events of special interest — gastrointestinal events, acute pancreatitis, thyroid C-cell neoplasia (MTC), hypoglycaemia (particularly with concomitant insulin secretagogues), and cardiovascular/heart-rate changes — and follow the AESI and SAE procedures (PROT-301 §10; Appendices B and E).
• Apply the contraindications (personal/family history of MTC or MEN 2; hypersensitivity) and warnings (pancreatitis, gastrointestinal effects, hypoglycaemia) consistently.
• Report serious adverse events to the sponsor within 24 hours per the Safety Management Plan (TMF-SMP).

7. Reference Safety Information (RSI)

For the assessment of expectedness of serious adverse events, the following adverse reactions are considered expected for GLPI-103:

• Very common / common: nausea, vomiting, diarrhoea, decreased appetite, constipation; injection-site reactions (intravenous formulation); headache; fatigue.
• Common / uncommon: hypoglycaemia (especially in combination with insulin secretagogues). Serious adverse events not listed above are considered unexpected and are subject to expedited reporting (SUSAR) per ICH E2A. Boxed-warning-level risks under class monitoring (thyroid C-cell tumours; pancreatitis) are described in the labeling (USPI/SmPC/KR label). The RSI is reviewed and updated at each IB revision in line with accumulating data and the Risk Management Plan (RMP-EU/US/KR).