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Integrated Summary of Efficacy (ISE) — GLPI-103

Field	Value
Document ID	ISE-301
Version	2.0 (full)
CTD	Module 5.3.5.3
Standard	FDA integrated summaries (21 CFR 314.50); ICH E3 / E9 / E9(R1)
Confidentiality	Confidential

Integrates efficacy across the GLPI-103 clinical program (first-in-human GLPI103-101/102; Phase 2 dose-finding GLPI103-201; pivotal Phase 3 GLPI103-301). All pivotal Phase 3 figures trace to the executed analyses (outputs/stats/, SAR-301, ARM-301) and are reconciled to source by tools/reconcile_csr.py. Early-phase pooled figures are illustrative [MOCK]. Design parameters cite REF-002.

Change History

Version	Date	Author	Summary
1.0	2026-06-29	Biostatistics	Initial ISE (synopsis level)
2.0	2026-06-30	Biostatistics	Full integrated summary — pooled population, integrated dose-response, primary estimands & sensitivity, secondary/responder, subgroup, time-to-event, durability, special populations

1. Background and Objectives of the Integrated Analysis

The integrated efficacy analysis characterizes the glycaemic and body-weight efficacy of GLPI-103 — a dual agonist of the GLP-1 and apelin (APJ) receptors — across the clinical development program in adults with type 2 diabetes mellitus (T2DM). The confirmatory evidence derives from the pivotal Phase 3 study GLPI103-301; the Phase 2 study GLPI103-201 establishes the dose–response that supports the Phase 3 dose selection; and the first-in-human studies provide early pharmacodynamic engagement. Because the program comprises a single confirmatory study with two dose-finding/early studies of differing design and duration, the integration is presented as a structured cross-study synthesis (with the pivotal study analysed in full) rather than a patient-level meta-analysis.

2. Studies Contributing to the Integrated Database

Study	Phase	Design	N	Duration	Contribution to efficacy
GLPI103-101	1 (SAD)	Randomized, DB, PBO-controlled	40	single dose	PD engagement (apelin, NT-proBNP) [MOCK]
GLPI103-102	1b (MAD)	Randomized, DB, PBO-controlled	40	≤12 wk	Early HbA1c/weight signal [MOCK]
GLPI103-201	2	Randomized, DB, PBO-controlled (PBO/Low/Med/High)	240	24 wk	Dose–response (PoC)
GLPI103-301	3 (pivotal)	Randomized, DB, double-dummy, active-controlled (IV/Oral/Sema)	900	52 wk	Confirmatory primary & secondary

3. Pooled Population and Baseline Characteristics

The pivotal study randomized 900 subjects (GLPI-103 IV 300, GLPI-103 Oral 301, semaglutide 299) drawn from a realistic Korean T2DM source population. Baseline characteristics were well balanced across arms (CSR-301 §11.2): mean age ≈59–60 years (≈33–41% ≥65 years), ≈53–55% male, mean BMI ≈28–29 kg/m², mean baseline HbA1c ≈7.9–8.0%, and mean disease duration ≈11–12 years. The population is representative of T2DM inadequately controlled on metformin and provides the demographic basis for the subgroup analyses in §7. Phase 2 enrolled a comparable on-metformin T2DM population.

4. Integrated Dose–Response (Phase 2 → Phase 3)

The Phase 2 study established a monotonic dose–response for HbA1c reduction (placebo −0.2%, low −1.0%, medium −1.4%, high −1.8% at Week 24), with parallel dose-dependent weight loss (up to −8.2 kg at the high dose). An Emax characterization of these data (exposure_response.csv; SAR-301 §12) yielded E0 ≈ −0.2%, Emax ≈ 2.4%, and ED50 ≈ 4 mg, placing the Phase 3 maintenance doses on the upper plateau of the dose–response curve. The Phase 3 efficacy (below) is directionally consistent with and exceeds the Phase 2 high-dose effect, supporting the selected doses and the dual-mechanism hypothesis.

5. Primary Efficacy (Confirmatory) — HbA1c at Week 52

On the Full Analysis Set, both GLPI-103 formulations were superior to oral semaglutide for change from baseline (CFB) in HbA1c at Week 52 (ANCOVA; SAR-301 §3; CSR-301 §11.3):

Arm	LS-mean CFB (%)	Difference vs semaglutide	p
GLPI-103 IV	−2.57	−0.68 (95% CI −0.81, −0.55)	<0.001
GLPI-103 Oral	−2.23	−0.36 (95% CI −0.49, −0.23)	<0.001
Semaglutide	−1.89	—	—

Superiority was preserved across the estimand framework (ICH E9(R1)): the treatment-policy and hypothetical (no-rescue) estimands gave closely concordant differences (IV −0.67 vs −0.69; Oral −0.38 vs −0.40), confirming the conclusion does not depend on the intercurrent-event strategy (SAR-301 §2). A Bayesian re-analysis with a weakly-informative prior placed the posterior probability of superiority above 0.999 for both arms (SAR-301 §11).

6. Robustness — Missing-Data and Sensitivity Analyses

With 9.3% discontinuation in the pivotal study, robustness to missing data was assessed (SAR-301 §4). Reference-based multiple imputation produced effects essentially unchanged from the primary analysis, including the conservative jump-to-reference assumption (IV −0.65; Oral −0.37). A tipping-point analysis showed the primary conclusion did not reverse even under an extreme MNAR penalty of +2.0% applied to all imputed active-arm values (IV −0.40, p≈6×10⁻⁷). The efficacy conclusion is therefore robust.

7. Secondary and Supportive Efficacy

Treatment effects were consistent and clinically meaningful across the key secondary endpoints (CSR-301 §11.5; SAR-301 §6):

Endpoint at Week 52	IV	Oral	Sema
Body-weight CFB (kg)	−14.5	−10.3	−7.6
≥10% weight loss, %	100.0	86.7	48.2
HbA1c <7.0%, % (completers)	96.3	92.8	83.4
FPG CFB (mmol/L)	−5.0	−4.3	−3.5

Responder analyses using conservative non-responder imputation confirmed significantly higher odds of achieving target on both glycaemic (IV OR 2.03; CMH p=0.004) and weight-loss endpoints (IV OR 9.47; p<0.001), with the weight-loss advantage especially pronounced — consistent with the additive metabolic effect of dual GLP-1/APJ agonism.

8. Subgroup Consistency

The primary HbA1c treatment effect (GLPI-103 IV vs semaglutide) was consistent across all pre-specified subgroups — baseline HbA1c (<8.5 / ≥8.5%), BMI (<30 / ≥30 kg/m²), age (<65 / ≥65 years), and sex — with overlapping confidence intervals (overall −0.68; range −0.53 to −0.80) and no significant treatment-by-subgroup interaction (all interaction p>0.05; sex borderline at 0.051, interpreted descriptively) (SAR-301 §7; Figure 3 forest plot). No subgroup showed a qualitatively different or attenuated effect.

9. Time to Glycaemic Target and Durability

Time-to-event analyses reinforce the magnitude and durability of effect (SAR-301 §8): GLPI-103 subjects reached the glycaemic target (HbA1c <7.0%) substantially faster than comparator subjects (IV hazard ratio 1.93, p=4×10⁻¹⁰; Oral 1.40, p=0.001), and were far less likely to require rescue medication for persistent hyperglycaemia (IV hazard ratio 0.17, p=0.004). The longitudinal MMRM showed between-arm separation from the first post-baseline visit (Week 4) that was maintained through Week 52, indicating an early-onset, durable effect.

10. Special Populations and Intrinsic Factors

Efficacy was consistent in older subjects (≥65 years), across the BMI range, and in both sexes (§8). No dedicated renal- or hepatic-impairment efficacy studies were conducted in the program; subjects with eGFR <45 mL/min/1.73 m² or significant hepatic abnormality were excluded by protocol. Intrinsic/extrinsic factor effects on exposure are addressed in clinical pharmacology (M2.7.2) [MOCK].

11. Conclusions

The integrated efficacy data robustly establish the superiority of GLPI-103 — in both intravenous and oral formulations — over a guideline-recommended GLP-1 receptor agonist (oral semaglutide) on glycaemic control at Week 52, accompanied by substantially greater body-weight reduction and markedly higher responder rates. The conclusion is confirmed under the estimand framework, reference-based imputation, tipping-point, and Bayesian analyses; is consistent across all subgroups; is supported by faster time-to-target and lower rescue use; and is directionally consistent with the Phase 2 dose–response. These findings support the efficacy basis of the marketing application (M2.5; M2.7.3) and are consistent with the dual GLP-1/APJ mechanism of action.