Safety and efficacy of pharmacological inhibition of ketohexokinase in hereditary fructose intolerance
Evi J.C. Koene, … , Patrick Schrauwen, Martijn C.G.J. Brouwers
Evi J.C. Koene, … , Patrick Schrauwen, Martijn C.G.J. Brouwers
Published February 11, 2025
Citation Information: J Clin Invest. 2025;135(6):e187376. https://doi.org/10.1172/JCI187376.
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Research Letter Endocrinology Metabolism

Safety and efficacy of pharmacological inhibition of ketohexokinase in hereditary fructose intolerance

Abstract

Authors

Evi J.C. Koene, Amée M. Buziau, David Cassiman, Timothy M. Cox, Judith Bons, Jean L.J.M. Scheijen, Casper G. Schalkwijk, Steven J.R. Meex, Aditi R. Saxena, William P. Esler, Vera B. Schrauwen-Hinderling, Patrick Schrauwen, Martijn C.G.J. Brouwers

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Figure 1

Fructose metabolism in MASLD and fructose tolerance in HFI upon PF-06835919.

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Fructose metabolism in MASLD and fructose tolerance in HFI upon PF-06835...
(A) Fructose can serve as a substrate for gluconeogenesis, oxidation, and de novo lipogenesis in the liver. Upon fructose ingestion in HFI, ALDOB deficiency results in the accumulation of Fru-1P and depletion of ATP and Pi. These conditions impair gluconeogenesis and glycogenolysis and consequently induce hypoglycemia. It is hypothesized that pharmacological inhibition of KHK by PF-06835919 will mitigate these biochemical derangements. Created in BioRender. Brouwers, M. (2025) https:// BioRender.com/q91c888. (B and C) In vivo changes in hepatic PME and Pi concentrations in response to a 60-gram oral fructose load after placebo and PF-06835919 treatment in participants with MASLD (n = 14). Data are presented as mean ± SEM. (D–O) Changes in urinary fructose, urinary glucose, phosphate and pH, and serum phosphate and blood glucose after an oral fructose load (2.5 g [blue], 5.0 g [green], 7.5 g [orange]) in patients A (D–G), B (H–K), and C (L–O) treated with PF-06835919. Gray lines represent upper, lower, and mean reference ranges obtained from five healthy individuals (not treated with PF-06835919) after 7.5 g oral fructose. Black lines/dots represent fasted samples.