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. 2025 Jul;16(7):1399-1415.
doi: 10.1007/s13300-025-01752-5. Epub 2025 May 13.

LY3522348, A New Ketohexokinase Inhibitor: A First-in-Human Study in Healthy Adults

Tsuyoshi Fukuda  1 , Brian R Thompson  1 , Bram Brouwers  1 , Hui-Rong Qian  1 , Wei Wang  1 , Bridget L Morse  1 , Elizabeth Smith LaBell  1 , Timothy B Durham  1 , Manige Konig  1 , Axel Haupt  1 , Charles T Benson  1 , James MacKrell  2
Affiliations

LY3522348, A New Ketohexokinase Inhibitor: A First-in-Human Study in Healthy Adults

Tsuyoshi Fukuda et al. Diabetes Ther. 2025 Jul.

Abstract

Introduction: This study aimed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses of the ketohexokinase inhibitor LY3522348 in healthy participants.

Methods: This first-in-human phase 1 study evaluated LY3522348, a highly selective, oral dual inhibitor of human ketohexokinase (KHK) isoforms C and A. The study was conducted in two parts: a single-ascending dose (SAD) study and a multiple-ascending dose (MAD) study, including a drug-drug interaction analysis with midazolam. Participants in the SAD study received single oral doses of LY3522348 ranging from 5 to 380 mg, while participants in the MAD study received once-daily doses of 50 mg, 120 mg, and 290 mg for 14 days.

Results: A total of 65 healthy participants were included; of these 40 were in the SAD study (placebo = 10; LY3522348: 5 mg = 6; 15 mg = 6; 50 mg = 6; 150 mg = 6; 380 mg = 6) and 25 in the MAD study (placebo = 6; LY3522348: 50 mg = 6; 120 mg = 6; 290 mg = 7). LY3522348 was well tolerated, with the majority of the reported adverse events being mild. PK analysis showed an approximately dose-proportional increase in LY3522348 exposure, and the half-life ranged from 23.7 to 33.8 h. PD analysis indicated a dose-dependent increase in plasma fructose concentrations following the administration of a fructose beverage, supporting the inhibition of fructose metabolism by LY3522348.

Conclusions: LY3522348 demonstrated a favorable safety profile and well-behaved pharmacokinetics following once-daily oral dosing, and effective inhibition of fructose metabolism. The study was registered on ClinicalTrials.gov (NCT04559568).

Keywords: Keto hexokinase inhibitor; LY3522348; MASH; PK/PD.

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Conflict of interest statement

Declarations. Conflict of Interest: Jim MacKrell, Bram Brouwers, Timothy B Durham, Wei Wang, Charles T Benson, Axel Haupt, Bridget Morse, Brian Thompson, Hui-Rong Qian, and Elizabeth Smith LaBell are the employees and stakeholders of Eli Lilly and Company. Manige Konig and Tsuyoshi Fukuda were employees of Eli Lilly and Company at the time of this study. Ethical Approval: The study was conducted in compliance with the principles of the Declaration of Helsinki, the Council for International Organizations of Medical Sciences International Ethical Guidelines, and the International Council for Harmonization Good Clinical Practice guidelines. The protocol was reviewed and approved by the Midlands Independent Review Board and the study was registered on ClinicalTrials.gov (NCT04559568). All participants provided written informed consent before participation.

Figures

Fig. 1
Fig. 1
The mean (SD) linear and semi-logarithmic LY3522348 plasma concentration–time profiles in the SAD study (a and b, respectively) and following the last dose in the MAD study (c and d, respectively). *200 μg midazolam was coadministered on day − 1 and day 15. h hours, MAD multiple-ascending dose, SAD single-ascending dose, SD standard deviation
Fig. 2
Fig. 2
The mean (SD) fructose plasma concentration–time profiles during a fructose tolerance test on a day 1 in the SAD study, b day 1 in the MAD study, and c day 14 in the MAD study. *200 μg midazolam was coadministered on day − 1 and day 15. The 13-h post-dose fructose concentration data was missing for all participants in the 50 mg MAD cohort on day 14 and thus this timepoint is not plotted. h hours, MAD multiple-ascending dose, SAD single-ascending dose, SD standard deviation
Fig. 3
Fig. 3
Ratio of fructose AUC(0–24) geometric least squares mean (90% CI) [p value] (LY3522348:placebo) during a fructose tolerance test on a day 1 in the SAD study and b day 1 and day 14 in the MAD study. *200 μg midazolam was coadministered on day − 1 and day 15. The 13-h post-dose fructose concentration data was missing for all participants in the 50 mg MAD cohort on day 14 and thus this AUC(0–24) was not calculated and is not included in the analyses. Vertical dotted line corresponds to a geometric least squares means ratio of 1. AUC(0–24) area under the concentration–time curve from time zero to 24 h, CI confidence interval, SAD single-ascending dose, MAD multiple-ascending dose
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