efficacy and safety of the treatment of pyruvate dehydrogenase deficiency patients with glycerol phenylbutyrate (ravicti)

Conditions: Pyruvate Dehydrogenase Complex Deficiency Disease

Summary: this is a phase ii, multicenter, prospective, non-comparative clinical trial to assess the efficacy and safety of the treatment of pyruvate dehydrogenase deficiency (pdh) patients with glycerol phenylbutyrate (ravicti®). the trial will be conducted with three visits: 3 day hospitalizations including clinical consultations and paramedical procedures at month 0 (m0), month 3 (m3), month 6 (m6). during all the research, ae/sae and treatment compliance will be recorded. patients will keep their usual treatment during the study time: vitamin b1, ketogenic diet, possible anti-epileptic and/or dystonic treatment(s). the efficacy on fatigue, polyhandicap, neurodevelopmental functioning, quality of life and seizure amount for epileptic patients will be evaluated at 0, 3 and 6 months. biological balance will be assed with regular quantification of pdh deficiency markers, lactate concentration and amino acid plasma quantification.

pdh deficiencies are mainly characterized by primary lactic acidosis associated with neurological disorders. the diagnosis is suspected in the presence of an increase of pyruvate and lactate with a normal or low lactate/pyruvate ratio, especially in postprandial period, in the blood and/or cerebrospinal fluid. neurological disorders are explained by the energy deficit associated with the absence of aerobic oxidation of glucose, their preferential energy substrate, which cannot be compensated by the catabolism of fatty acids. phenylbutyrate was therefore proposed to increase the enzymatic activity of pdh in pdh deficits, particularly in patient cells and mouse model: it has reduced the phosphorylated form in these models and thus increased the enzymatic activity of the pdh complex. phenylbutyrate would be more active when the pdh deficit is linked to missense variants, and less effective in the presence of non-meaning variant, with the exception of variants on the pdhx gene which are mostly non-sense variants. the study plan is to treat these patients with glycerol phenylbutyrate (ravicti®) 1.1 g/ml oral fluid (or in enteral tube or gastrostomy). sodium phenylbutyrate and glycerol phenylbutyrate are commonly used in inherited metabolic diseases in urea cycle diseases, for chelating ammonia, in children and adults. the expectation is to obtain an improvement of patients' fatigue and neurodevelopmental disability for pdh patients. phenylbutyrate prevents pdh kinase from phosphorylating the pdh complex, allowing the complex to remain active. it acts on different isoforms of pdh kinase.

Eligibility criteria:
inclusion criteria: * child from 2 to 17 years of age or * adult from 18 to 25 years of age * with a pdh deficiency confirmed by molecular biology: * a class 4 or 5- missense variant on the pdha1 gene or * one homozygous variant or two mixed heterozygous variants of class 4 or 5 that are missense variants on pdhb or dlat genes or * one homozygous variant or two mixed heterozygous variants of class 4 or 5 on pdhx genes (including non-sense and frameshift variants, and intragenic deletions * for females of childbearing potential, negative bhcg and effective method of contraception (sexual abstinence, hormonal contraception containing ethinylestradiol and levonorgestrel, intrauterine device or hormone-releasing system, cap, diaphragm or sponge with spermicide, condom) until 30 days after the end of study. for male, an effective method of contraception (sexual abstinence, condom) until 30 days after the end of study * signature of consent by the legal representative * beneficiary of a social security coverage (affiliated or entitled) exclusion criteria: * patient with e3 deficiency due to pathogenic mutation in dld gene * male patient with a class 4 or 5 non-sense variant on the pdha1, pdhb or dlat gene * treatment change during the last 3 months prior inclusion (ketogenic diet and/or b1 vitamin) * hypersensitivity to glycerol phenylbutyrate or to any of the excipients * no disease requiring glycerol phenylbutyrate (hyperammonemia due to urea cycle disease or other aetiology) * pregnant or breastfeeding women * participation to another clinical trial on medicinal products for human use

Keywords: pyruvate dehydrogenase (pdh) enzyme pdh deficiency glycerol phenylbutyrate fatigue