Triheptanoin: First Approval

Shirley, Matt

doi:10.1007/s40265-020-01399-5

Cited by 25 publications

(25 citation statements)

References 20 publications

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“…Alternatively, C7 is utilized for the production of ketone bodies [7] , [8] , [9] . Triheptanoin has been used in various metabolic disorders and refractory epilepsy [9] , [10] , [11] and has recently been approved in the USA for the treatment of patients with long-chain fatty acid oxidation disorders LC-FAOD (12) . In a patient cohort with LC-FAOD, triheptanoin significantly reduced hospitalization days/year and the hospitalization rate (13) .…”

Section: Introductionmentioning

confidence: 99%

Triheptanoin – Novel therapeutic approach for the ultra-rare disease mitochondrial malate dehydrogenase deficiency

Laemmle

Steck

Schaller

et al. 2021

Molecular Genetics and Metabolism Reports

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Mitochondrial malate dehydrogenase (MDH2) deficiency (MDH2D) is an ultra-rare disease with only three patients described in literature to date. MDH2D leads to an interruption of the tricarboxylic acid (TCA) cycle and malate-aspartate shuttle (MAS) and results in severe early onset encephalopathy. Affected infants suffer from psychomotor delay, muscular hypotonia and frequent seizures. Laboratory findings are unspecific, including elevated lactate in blood and cerebrospinal fluid. Brain magnetic resonance imaging reveals delayed myelination and brain atrophy. Currently there is no curative therapy to treat this devastating disease. Here, we present a female patient diagnosed with MDH2D after a stroke-like episode at 18 months. Trio-whole exome sequencing revealed compound heterozygous missense variants in the MDH2 gene: c.398C>T, p.(Pro133Leu) and c.445delinsACA, p.(Pro149Hisfs*22). MDH2 activity assay and oxygraphic analysis in patient's fibroblasts confirmed the variants were pathogenic. At the age of 36 months, a drug trial with triheptanoin was initiated and well tolerated. The patient's neurologic and biochemical phenotype improved and she had no further metabolic decompensations during the treatment period suggesting a beneficial effect of triheptanoin on MDH2D. Further preclinical and clinical studies are required to evaluate triheptanoin treatment for MDH2D and other TCA cycle and MAS defects.

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Section: Introductionmentioning

confidence: 99%

Triheptanoin – Novel therapeutic approach for the ultra-rare disease mitochondrial malate dehydrogenase deficiency

Laemmle

Steck

Schaller

et al. 2021

Molecular Genetics and Metabolism Reports

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“…Since a multitude of published data and our recent results point to a defect in mitochondrial function in A-T cells, we concluded that compounds that enhanced mitochondrial function would be beneficial to patients’ cells. We selected heptanoate, a metabolite of triheptanoin, an edible odd-chain fatty acid triglyceride, which is metabolized, in turn, to acetyl-CoA and propionyl-CoA, both of which enter the TCA cycle to replenish intermediates and supply energy to the cell [ 28 ]. Our results showed a complete correction of the cell-killing effect of glycolysis inhibition by heptanoate.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, it protects ATM-deficient cells against hypersensitivity to nutrient stress-induced cell killing. The parent compound triheptanoin has been employed for the treatment of a range of metabolic disorders and other diseases where energy deficiency is implicated [ [27] , [28] , [29] , [30] ]. It received its first regulatory approval in June 2020 as a source of calories and fatty acids for the treatment of paediatric and adult patients with confirmed long-chain fatty acid oxidation disorders [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

“…The parent compound triheptanoin has been employed for the treatment of a range of metabolic disorders and other diseases where energy deficiency is implicated [ [27] , [28] , [29] , [30] ]. It received its first regulatory approval in June 2020 as a source of calories and fatty acids for the treatment of paediatric and adult patients with confirmed long-chain fatty acid oxidation disorders [ 28 ]. We consider an excellent candidate for the treatment of patients with A-T since it would be predicted to address the mitochondrial deficit in these patients.…”

Section: Discussionmentioning

confidence: 99%

“…Triheptanoin, a triglyceride of the three odd-chain fatty acids (heptanoate, C7), has been applied for the treatment of several neurological diseases and those due to disturbed glucose metabolism, in which the energy supply from citric acid cycle intermediates or fatty acid degradation is impaired [ 27 ]. It recently received its first regulatory approval for use in the US as a source of calories and fatty acids for the treatment of paediatric and adult patients with molecularly confirmed long-chain fatty acid oxidation disorders [ 28 ]. Triheptanoin functions as an anaplerotic agent replenishing tricarboxylic acid (TCA) cycle intermediates by metabolism to heptanoate (C7) and subsequently acetyl-CoA and propionyl-CoA that feed into the TCA cycle to supply energy [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

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An anaplerotic approach to correct the mitochondrial dysfunction in ataxia-telangiectasia (A-T)

Yeo

Subramanian

Chong

et al. 2021

Molecular Metabolism

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Background ATM, the protein defective in the human genetic disorder, ataxia-telangiectasia (A-T) plays a central role in response to DNA double-strand breaks (DSBs) and in protecting the cell against oxidative stress. We showed that A-T cells are hypersensitive to metabolic stress which can be accounted for by a failure to exhibit efficient endoplasmic reticulum (ER)-mitochondrial signalling and Ca2 + transfer in response to nutrient deprivation resulting in mitochondrial dysfunction. The objective of the current study is to use an anaplerotic approach using the fatty acid, heptanoate (C7), a metabolic product of the triglyceride, triheptanoin to correct the defect in ER-mitochondrial signalling and enhance cell survival of A-T cells in response to metabolic stress. Methods We treated control cells and A-T cells with the anaplerotic agent, heptanoate to determine their sensitivity to metabolic stress induced by inhibition of glycolysis with 2- deoxyglucose (2DG) using live-cell imaging to monitor cell survival for 72 h using the Incucyte system. We examined ER-mitochondrial signalling in A-T cells exposed to metabolic stress using a suite of techniques including immunofluorescence staining of Grp75, ER-mitochondrial Ca 2+ channel, the VAPB-PTPIP51 ER-mitochondrial tether complexes as well as proximity ligation assays between Grp75-IP3R1 and VAPB1-PTPIP51 to establish a functional interaction between ER and mitochondria. Finally, we also performed metabolomic analysis using LC-MS/MS assay to determine altered levels of TCA intermediates A-T cells compared to healthy control cells. Results We demonstrate that heptanoate corrects all aspects of the defective ER-mitochondrial signalling observed in A-T cells. Heptanoate enhances ER-mitochondrial contacts; increases the flow of calcium from the ER to the mitochondrion; restores normal mitochondrial function and mitophagy and increases the resistance of ATM-deficient cells and cells from A-T patients to metabolic stress-induced killing. The defect in mitochondrial function in ATM-deficient cells was accompanied by more reliance on aerobic glycolysis as shown by increased lactate dehydrogenase A (LDHA), accumulation of lactate, and reduced levels of both acetyl CoA and ATP which are all restored by heptanoate. Conclusions We conclude that heptanoate corrects metabolic stress in A-T cells by restoring ER-mitochondria signalling and mitochondrial function and suggest that the parent compound, triheptanoin, has immense potential as a novel therapeutic agent for patients with A-T.

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Population Pharmacokinetics of Heptanoate in Healthy Subjects and Patients With Long‐Chain Fatty Acid Oxidation Disorders Treated With Triheptanoin

Lee

Gosselin

Jomphe

et al. 2022

Clinical Pharm in Drug Dev

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Triheptanoin is an odd‐carbon, medium‐chain triglyceride consisting of three fatty acids with seven carbons each on a glycerol backbone, indicated for the treatment of adult and pediatric patients with long‐chain fatty acid oxidation disorders (LC‐FAOD). A total of 562 plasma concentrations of heptanoate, the most abundant and pharmacologically active metabolite of triheptanoin, from 13 healthy adult subjects and 30 adult and pediatric subjects with LC‐FAOD were included in the population pharmacokinetic (PK) analyses. Multiple peaks of heptanoate observed in several subjects were characterized by dual first‐order absorption with a lag time in the second absorption compartment. The disposition of heptanoate in human plasma was adequately described by one‐compartmental distribution with a linear elimination. The apparent clearance (CL/F) and apparent volume of distribution were allometrically scaled with body weight to describe PK data across a wide range of age groups in subjects with LC‐FAOD. The typical CL/F in adult subjects with LC‐FAOD was ≈19% lower than that in healthy subjects. Model‐estimated elimination half‐life for LC‐FAOD patients was ∼1.7 hours, supporting a recommended dosing frequency of ≥4 times per day. Covariate analyses indicate that age, race, and sex did not lead to clinically meaningful changes in the exposure of heptanoate.

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Triheptanoin: First Approval

Cited by 25 publications

References 20 publications

Triheptanoin – Novel therapeutic approach for the ultra-rare disease mitochondrial malate dehydrogenase deficiency

Triheptanoin – Novel therapeutic approach for the ultra-rare disease mitochondrial malate dehydrogenase deficiency

An anaplerotic approach to correct the mitochondrial dysfunction in ataxia-telangiectasia (A-T)

Population Pharmacokinetics of Heptanoate in Healthy Subjects and Patients With Long‐Chain Fatty Acid Oxidation Disorders Treated With Triheptanoin

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