Effects of tetrathiomolybdate on copper metabolism in healthy volunteers and in patients with Wilson disease

TY - JOUR

T1 - Effects of tetrathiomolybdate on copper metabolism in healthy volunteers and in patients with Wilson disease

AU - Kirk, Frederik

AU - Munk, Ditte Emilie

AU - Swenson, Eugene Scott

AU - Quicquaro, Adam Michael

AU - Holm Vendelbo, Mikkel

AU - Larsen, Agnete

AU - Schilsky, Michael L.

AU - Ott, Peter

AU - Sandahl, Thomas Damgaard

PY - 2024/4

Y1 - 2024/4

N2 - BACKGROUND & AIMS: In Wilson Disease (WD), copper accumulates in the liver and brain causing disease. Bis-choline tetrathiomolybdate (TTM) is a potent copper chelator that may have a lower risk of inducing paradoxical neurological worsening than conventional therapy for neurologic WD. To better understand the mode of action of TTM, we investigated the effects of TTM on copper absorption and biliary excretion.METHODS: In a double-blind randomized setting, hepatic 64Cu activity after orally administered 64Cu was examined by PET/CT in 16 healthy volunteers before and after 7 days of TTM treatment (15 mg/d) or placebo. Oral 64Cu was administered 1 h after final TTM dose. Changes in hepatic 64Cu activity reflected changes in intestinal 64Cu uptake. Additionally, in four WD patients, distribution of 64Cu in venous blood, liver, gallbladder, kidney, and brain were followed after i.v. 64Cu dosing for up to 68 hours before and after seven days of TTM (15 mg/d), using PET/MRI. Increased gallbladder 64Cu activity was taken as evidence of increased biliary 64Cu excretion. RESULTS: In healthy subjects TTM reduced intestinal 64Cu uptake by 82% 15 hours after the oral 64Cu dose. In WD patients, gallbladder 64Cu activity was negligible before and after TTM, while TTM effectively retained 64Cu in the blood, significantly reduced hepatic 64Cu activity at all time points and significantly reduced cerebral 64Cu activity 2 h after the intravenous 64Cu dose. CONCLUSIONS: While we did not show an increase in biliary excretion of 64Cu following TTM administration, we demonstrated that TTM effectively inhibited most intestinal 64Cu uptake and retained 64Cu in the blood stream, limiting 64Cu exposure to organs like the liver and the brain. IMPACT AND IMPLICATIONS: Bis-choline tetrathiomolybdate (TTM) is an investigational copper chelator for treatment of Wilson Disease. In animal studies of Wilson Disease models, TTM has been shown to facilitate biliary copper excretion. In the present human study, TTM surprisingly did not facilitate biliary copper excretion but instead reduced intestinal copper uptake to a clinically significant degree. Our study improves the understanding of human copper metabolism and the mechanism of action of TTM.CLINICAL TRIAL NUMBER: Data is presented from two clinical trials:Absorption study: EudraCT 2020-005832-31Excretion study: EudraCT 2021-000102-25.

AB - BACKGROUND & AIMS: In Wilson Disease (WD), copper accumulates in the liver and brain causing disease. Bis-choline tetrathiomolybdate (TTM) is a potent copper chelator that may have a lower risk of inducing paradoxical neurological worsening than conventional therapy for neurologic WD. To better understand the mode of action of TTM, we investigated the effects of TTM on copper absorption and biliary excretion.METHODS: In a double-blind randomized setting, hepatic 64Cu activity after orally administered 64Cu was examined by PET/CT in 16 healthy volunteers before and after 7 days of TTM treatment (15 mg/d) or placebo. Oral 64Cu was administered 1 h after final TTM dose. Changes in hepatic 64Cu activity reflected changes in intestinal 64Cu uptake. Additionally, in four WD patients, distribution of 64Cu in venous blood, liver, gallbladder, kidney, and brain were followed after i.v. 64Cu dosing for up to 68 hours before and after seven days of TTM (15 mg/d), using PET/MRI. Increased gallbladder 64Cu activity was taken as evidence of increased biliary 64Cu excretion. RESULTS: In healthy subjects TTM reduced intestinal 64Cu uptake by 82% 15 hours after the oral 64Cu dose. In WD patients, gallbladder 64Cu activity was negligible before and after TTM, while TTM effectively retained 64Cu in the blood, significantly reduced hepatic 64Cu activity at all time points and significantly reduced cerebral 64Cu activity 2 h after the intravenous 64Cu dose. CONCLUSIONS: While we did not show an increase in biliary excretion of 64Cu following TTM administration, we demonstrated that TTM effectively inhibited most intestinal 64Cu uptake and retained 64Cu in the blood stream, limiting 64Cu exposure to organs like the liver and the brain. IMPACT AND IMPLICATIONS: Bis-choline tetrathiomolybdate (TTM) is an investigational copper chelator for treatment of Wilson Disease. In animal studies of Wilson Disease models, TTM has been shown to facilitate biliary copper excretion. In the present human study, TTM surprisingly did not facilitate biliary copper excretion but instead reduced intestinal copper uptake to a clinically significant degree. Our study improves the understanding of human copper metabolism and the mechanism of action of TTM.CLINICAL TRIAL NUMBER: Data is presented from two clinical trials:Absorption study: EudraCT 2020-005832-31Excretion study: EudraCT 2021-000102-25.

KW - 64 copper

KW - ALXN1840

KW - Copper absorption

KW - PET

KW - WTX-101

KW - copper chelation

KW - copper excretion

KW - placebo

KW - randomized

KW - rare disease

KW - tetrathiomolybdate

U2 - 10.1016/j.jhep.2023.11.023

DO - 10.1016/j.jhep.2023.11.023

M3 - Journal article

C2 - 38081365

SN - 0168-8278

VL - 80

SP - 586

EP - 595

JO - Journal of Hepatology

JF - Journal of Hepatology

IS - 4

ER -