UX007 for the treatment of long chain-fatty acid oxidation disorders: Safety and efficacy in children and adults following 24 weeks of treatment

Vockley, Jerry; Burton, Barbara K.; Berry, Gerard T.; Longo, Nicola; Phillips, John G.; Sanchez‐Valle, Amarilis; Tanpaiboon, Pranoot; Grünewald, Stéphanie; Murphy, Elaine; Humphrey, Reed; Mayhew, J.; Bowden, Alexandra; Zhang, L.; Cataldo, Jason; Marsden, Deborah; Kakkis, Emil

doi:10.1016/j.ymgme.2017.02.005

Cited by 68 publications

(104 citation statements)

References 26 publications

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“…Since no long-term studies on the effects of mediumchain fatty acids have been performed to date, the impact of the metabolic/ morphologic adaptation on the muscular clinical phenotype is unknown yet. In addition, very recent studies show that despite the slight positive effects of triheptanoin on the cardiac ejection fraction and exercise endurance and tolerance in patients with long-chain fatty acids oxidation defects, the incidence of rhabdomyolysis episodes did not improve [52,53].…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial fatty acid biosynthesis and muscle fiber plasticity in very long‐chain acyl‐CoA dehydrogenase‐deficient mice

et al. 2018

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The white skeletal muscle of very long-chain acyl-CoA-dehydrogenase-deficient (VLCAD ) mice undergoes metabolic modification to compensate for defective β-oxidation in a progressive and time-dependent manner by upregulating glucose oxidation. This metabolic regulation seems to be accompanied by morphologic adaptation of muscle fibers toward the glycolytic fiber type II with the concomitant upregulation of mitochondrial fatty acid biosynthesis (mFASII) and lipoic acid biosynthesis. Dietary supplementation of VLCAD mice with different medium-chain triglycerides over 1 year revealed that odd-chain species has no effect on muscle fiber switch, whereas even-chain species inhibit progressive metabolic adaptation. Our study shows that muscle may undergo adaptive mechanisms that are modulated by dietary supplementation. We describe for the first time a concomitant change of mFASII in this muscular adaptation process.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial fatty acid biosynthesis and muscle fiber plasticity in very long‐chain acyl‐CoA dehydrogenase‐deficient mice

et al. 2018

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“…A subsequent case series of ten patients with LC-FAOD and acute heart failure in whom triheptanoin had been initiated for compassionate or emergency use demonstrated return of normal EF within 3 weeks of initiation; only two of these patients had CACT deficiency (Vockley et al 2016). Now, a single-arm, open-label, multicenter Phase 2 trial has been published demonstrating safety and efficacy in pediatric and adult patients at 24 weeks of treatment; CACT deficiency patients were excluded from this study due to the severity of the condition (Vockley et al 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Long-chain fatty acid oxidation disorders (LC-FAOD) are a group of autosomal recessive inborn errors of metabolism wherein genetic defects in specific mitochondrial enzymes lead to an inability to convert long-chain fatty acids to energy during periods of physiologic stress (Vockley et al 2017). Amongst the most uncommon fatty acid oxidation disorders, carnitine-acylcarnitine translocase (CACT) deficiency is caused by mutations in SLC25A20 (Rubio- Gozalbo et al 2004).…”

Section: Introductionmentioning

confidence: 99%

Triheptanoin: A Rescue Therapy for Cardiogenic Shock in Carnitine-acylcarnitine Translocase Deficiency

Mahapatra¹,

Ananth²,

Baugh³

et al. 2017

JIMD Reports

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Carnitine-acylcarnitine translocase (CACT) deficiency is a rare long-chain fatty acid oxidation disorder (LC-FAOD) with high mortality due to cardiomyopathy or lethal arrhythmia. Triheptanoin (UX007), an investigational drug composed of synthetic medium odd-chain triglycerides, is a novel therapy in development for LC-FAOD patients. However, cases of its safe and efficacious use to reverse severe heart failure in CACT deficiency are limited. Here, we present a detailed report of an infant with CACT deficiency admitted in metabolic crisis that progressed into severe cardiogenic shock who was successfully treated by triheptanoin. The child was managed, thereafter, on triheptanoin until her death at 3 years of age from a cardiopulmonary arrest in the setting of acute respiratory illness superimposed on chronic hypercarbic respiratory failure.

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“…In this study, 29 patients who had ongoing symptoms despite their current treatment regimen were given triheptanoin for 6 months. Patients reported an improved quality of life and many demonstrated improved exercise performance and tolerance [85, 86]. A larger open-label study is now underway to further explore the benefits of triheptanoin over current MCT therapy.…”

Section: Advances In Therapymentioning

confidence: 99%

Advances in the Understanding and Treatment of Mitochondrial Fatty Acid Oxidation Disorders

Goetzman

2017

Curr Genet Med Rep

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Purpose of review This review focuses on advances made in the past three years with regards to understanding the mitochondrial fatty acid oxidation (FAO) pathway, the pathophysiological ramifications of genetic lesions in FAO enzymes, and emerging therapies for FAO disorders. Recent findings FAO has now been recognized to play a key energetic role in pulmonary surfactant synthesis, T-cell differentiation and memory, and the response of the proximal tubule to kidney injury. Patients with FAO disorders may face defects in these cellular systems as they age. Aspirin, statins, and nutritional supplements modulate the rate of FAO under normal conditions and could be risk factors for triggering symptoms in patients with FAO disorders. Patients have been identified with mutations in the ACAD9 and ECHS1 genes, which may represent new FAO disorders. New interventions for long-chain FAODs are in clinical trials. Finally, post-translational modifications that regulate fatty acid oxidation protein activities have been characterized that represent important new therapeutic targets. Summary Recent research has led to a deeper understanding of FAO. New therapeutic avenues are being pursued that may ultimately cause a paradigm shift for patient care.

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UX007 for the treatment of long chain-fatty acid oxidation disorders: Safety and efficacy in children and adults following 24 weeks of treatment

Abstract: In patients with severe LC-FAOD, UX007 interim study results demonstrated improved exercise endurance and tolerance, and were associated with positive changes in self-reported HR-QoL.

Cited by 68 publications

References 26 publications

Mitochondrial fatty acid biosynthesis and muscle fiber plasticity in very long‐chain acyl‐CoA dehydrogenase‐deficient mice

Mitochondrial fatty acid biosynthesis and muscle fiber plasticity in very long‐chain acyl‐CoA dehydrogenase‐deficient mice

Triheptanoin: A Rescue Therapy for Cardiogenic Shock in Carnitine-acylcarnitine Translocase Deficiency

Advances in the Understanding and Treatment of Mitochondrial Fatty Acid Oxidation Disorders

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