Abstract
IntroductionFatty acid oxidation disorders (FAODs) are rare diseases caused by defects in mitochondrial fatty acid oxidation (FAO) enzymes. While the efficacy of bezafibrate, a peroxisome proliferator-activated receptor agonist, on the in vitro FAO capacity has been reported, the in vivo efficacy remains controversial. Therefore, we conducted a clinical trial of bezafibrate in Japanese patients with FAODs. Materials and methodsThis trial was an open-label, non-randomized, and multicenter study of bezafibrate treatment in 6 patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency and 2 patients with carnitine palmitoyltransferase-II (CPT-2) deficiency (median age, 8.2 years; ranging from 5.8 to 26.4 years). Bezafibrate was administered for 6 months following a 6-month observation period. The primary endpoint was the frequency of myopathic attacks, and the secondary endpoints were serum acylcarnitines (ACs, C14:1 or C16 + C18:1), creatine kinase (CK) levels, degree of muscle pain (VAS; visual analog scale) during myopathic attacks, and quality of life (QOL; evaluated using validated questionnaires). ResultsThe frequency of myopathic attacks after bezafibrate administration decreased in 3 patients, increased in 3, and did not change in 2. The CK, AC, and VAS values during attacks could be estimated in only three or four patients, but a half of the patients did not experience attacks before or after treatment. Changes in CK, AC, and VAS values varied across individuals. In contrast, three components of QOL, namely, physical functioning, role limitation due to physical problems (role physical), and social functioning, were significantly elevated. No adverse drug reactions were observed. ConclusionIn this study, the frequency of myopathic attacks and CK, AC, and VAS values during the attacks could not be evaluated due to several limitations, such as a small trial population. Our findings indicate that bezafibrate improves the QOL of patients with FAODs, but its efficacy must be examined in future investigations.
Highlights
Fatty acid oxidation disorders (FAODs) are rare diseases caused by defects in mitochondrial fatty acid oxidation (FAO) enzymes
Our findings indicate that bezafibrate improves the quality of life (QOL) of patients with FAODs, but its efficacy must be examined in future investigations
AC levels during myopathic attacks In Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, the C14:1 level during myopathic attacks increased in two patients (VLCADD-1 and VLCADD-2) after treatment, whereas this level was reduced in VLCADD-5
Summary
Fatty acid oxidation disorders (FAODs) are rare diseases caused by defects in mitochondrial fatty acid oxidation (FAO) enzymes. While the efficacy of bezafibrate, a peroxisome proliferator-activated receptor agonist, on the in vitro FAO capacity has been reported, the in vivo efficacy remains controversial. We conducted a clinical trial of bezafibrate in Japanese patients with FAODs. Bezafibrate [2-(p-(2-(p-chlorobenzamido)ethyl)-phenoxy)-2-methyl propionic acid] is a peroxisome proliferator-activated receptor (PPAR). Recent reports demonstrated that bezafibrate may represent a promising drug for FAODs by enhancing the transcription of several β-oxidation enzymes in vitro [8,9,10,11]. The clinical efficacy of bezafibrate for CPT-2 or multiple acyl-CoA dehydrogenase (MAD) deficiencies was recently reported by French and Japanese groups, respectively [12,13,14]. We evaluated the efficacy and safety of bezafibrate for treating patients with FAODs by a clinical trial resembling the study design of a previously reported French clinical trial [12]
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