Abstract
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder which primarily affects the gastrointestinal and nervous systems. This disease is caused by mutations in the nuclear TYMP gene, which encodes for thymidine phosphorylase, an enzyme required for the normal metabolism of deoxynucleosides, thymidine, and deoxyuridine. The subsequent elevated systemic concentrations of deoxynucleosides lead to increased intracellular concentrations of their corresponding triphosphates, and ultimately mitochondrial failure due to progressive accumulation of mitochondrial DNA (mtDNA) defects and mtDNA depletion. Currently, there are no treatments for MNGIE where effectiveness has been evidenced in clinical trials. This Phase 2, multi-centre, multiple dose, open label trial without a control will investigate the application of erythrocyte-encapsulated thymidine phosphorylase (EE-TP) as an enzyme replacement therapy for MNGIE. Three EE-TP dose levels are planned with patients receiving the dose level that achieves metabolic correction. The study duration is 31 months, comprising 28 days of screening, 90 days of run-in, 24 months of treatment and 90 days of post-dose follow-up. The primary objectives are to determine the safety, tolerability, pharmacodynamics, and efficacy of multiple doses of EE-TP. The secondary objectives are to assess EE-TP immunogenicity after multiple dose administrations and changes in clinical assessments, and the pharmacodynamics effect of EE-TP on clinical assessments.
Highlights
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a fatal and rare autosomal recessive disorder of nucleotide metabolism caused by mutations in the nuclear thymidine phosphorylase gene (TYMP), which encodes cytosolic thymidine phosphorylase, the enzyme required for the normal metabolism of pyrimidine deoxynucleosides, thymidine, and deoxyuridine [1,2]
The aim of this study is to investigate the safety, tolerability, pharmacodynamics, and efficacy of encapsulated thymidine phosphorylase (EE-TP) in patients with MNGIE
The secondary objectives are to assess the immunogenicity of EE-TP after multiple dose administrations, evaluate changes in clinical assessments, and assess the pharmacodynamics effect of EE-TP on clinical assessments
Summary
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a fatal and rare autosomal recessive disorder of nucleotide metabolism caused by mutations in the nuclear thymidine phosphorylase gene (TYMP), which encodes cytosolic thymidine phosphorylase, the enzyme required for the normal metabolism of pyrimidine deoxynucleosides, thymidine, and deoxyuridine [1,2]. Elevated systemic concentrations of these deoxynucleosides lead to increased intracellular concentrations of their corresponding triphosphates This perturbs the physiological equilibrium of the deoxynucleoside triphosphate pools within the mitochondria, thereby interfering with the normal replication of mitochondrial mtDNA, leading to multiple deletions, somatic point mutations and depletion of mtDNA [5,8,10,11], and mitochondrial failure [5,6,8]. Patients typically present with gastrointestinal symptoms including early satiety, nausea, dysphagia, gastroesophageal reflux, postprandial emesis, episodic abdominal pain, episodic abdominal distention, and diarrhoea. These symptoms are secondary to alimentary dysmotility caused by degeneration of the alimentary autonomic nervous system [2]. On magnetic resonance imaging (MRI) there is, in the majority of cases, leukoencephalopathy with diffuse increased T2 signal in the deep white matter of the cerebral hemispheres, but this is generally believed to be asymptomatic [5,12]
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