Trial results for a Phase 1 study investigating Orforglipron (LY3502970) in participants with impaired and normal liver function were posted on ClinicalTrials.gov on 2026-05-27. The study found that the geometric mean Area Under the Concentration Versus Time Curve from time zero to infinity (AUC [0-∞]) for Orforglipron increased from 130 nanogram *hour per milliliter (ng*h/mL) in participants with normal hepatic function to 611 ng*h/mL in those with severe hepatic impairment.
Background
The study evaluated the pharmacokinetics of Orforglipron (LY3502970) in individuals with varying degrees of liver function. Understanding how liver impairment affects drug exposure is crucial for determining appropriate dosing and ensuring patient safety across diverse patient populations.
Trial design
This Phase 1 study (NCT05882032) was completed with an enrollment of 29 participants, including those with healthy liver function and those with hepatic insufficiency. The main purpose was to measure the pharmacokinetics of LY3502970, specifically how much of the drug gets into the bloodstream and how long it takes the body to eliminate it, in participants with mild, moderate, and severe impaired liver function compared to participants with normal liver function. The study also evaluated the safety and tolerability of LY3502970.
Key results
The study reported pharmacokinetic measurements for Orforglipron (LY3502970) across different hepatic function groups:
- Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC [0-∞]) of LY3502970
- In the 1 mg LY3502970 (Control: Normal Hepatic Function) group, the geometric mean AUC (0-∞) was 130 ng*h/mL with a Geometric Coefficient of Variation of 26.8.
- In the 1 mg LY3502970 (Mild Hepatic Impairment) group, the geometric mean AUC (0-∞) was 132 ng*h/mL with a Geometric Coefficient of Variation of 60.2.
- In the 1 mg LY3502970 (Moderate Hepatic Impairment) group, the geometric mean AUC (0-∞) was 209 ng*h/mL with a Geometric Coefficient of Variation of 32.6.
- In the 1 mg LY3502970 (Severe Hepatic Impairment) group, the geometric mean AUC (0-∞) was 611 ng*h/mL with a Geometric Coefficient of Variation of 84.6.
- PK: Area Under the Concentration Versus Time Curve From Time Zero to Last Time Point (AUC0-tlast) of LY3502970
- For 1 mg LY3502970 (Control: Normal Hepatic Function), the geometric mean AUC0-tlast was 109 ng*h/mL with a Geometric Coefficient of Variation of 29.1.
- For 1 mg LY3502970 (Mild Hepatic Impairment), the geometric mean AUC0-tlast was 112 ng*h/mL with a Geometric Coefficient of Variation of 64.0.
- For 1 mg LY3502970 (Moderate Hepatic Impairment), the geometric mean AUC0-tlast was 169 ng*h/mL with a Geometric Coefficient of Variation of 32.7.
- For 1 mg LY3502970 (Severe Hepatic Impairment), the geometric mean AUC0-tlast was 385 ng*h/mL with a Geometric Coefficient of Variation of 54.7.
- PK: Maximum Observed Concentration (Cmax) of LY3502970
- In the 1 mg LY3502970 (Control: Normal Hepatic Function) group, the geometric mean Cmax was 5.10 nanograms per milliliter (ng/mL) with a Geometric Coefficient of Variation of 21.0.
- In the 1 mg LY3502970 (Mild Hepatic Impairment) group, the geometric mean Cmax was 5.47 ng/mL with a Geometric Coefficient of Variation of 57.5.
- In the 1 mg LY3502970 (Moderate Hepatic Impairment) group, the geometric mean Cmax was 6.12 ng/mL with a Geometric Coefficient of Variation of 43.6.
- In the 1 mg LY3502970 (Severe Hepatic Impairment) group, the geometric mean Cmax was 5.95 ng/mL with a Geometric Coefficient of Variation of 36.1.
What this means
The results from this Phase 1 study indicate that hepatic impairment significantly impacts the pharmacokinetics of Orforglipron (LY3502970). Specifically, the systemic exposure, as measured by AUC (0-∞), increased substantially in participants with moderate and severe hepatic impairment compared to those with normal liver function. The geometric mean AUC (0-∞) was approximately 4.7 times higher in the severe hepatic impairment group (611 ng*h/mL) than in the normal function group (130 ng*h/mL). This suggests that dose adjustments may be necessary for patients with moderate to severe hepatic impairment to avoid potential overexposure and associated safety concerns. The maximum observed concentration (Cmax) showed less variability across the groups, indicating that the rate of absorption might be less affected than overall exposure.
Source
The information regarding these trial results was obtained from ClinicalTrials.gov, a public database of clinical studies. The results for the study NCT05882032, titled "A Study of LY3502970 in Participants With Impaired and Normal Liver Function", were posted on 2026-05-27 on clinicaltrials.gov.