Open-label clinical trial of bezafibrate treatment in patients with fatty acid oxidation disorders in Japan

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.

Open-label clinical trial of bezafibrate treatment in patients with fatty acid oxidation disorders in Japan; 2nd report QOL survey

“…In our previous 50-week study, the average total QOL score was significantly elevated after the administration period compared to baseline [11]. Herein we similarly found elevated QOL scores from baseline in all cases except VL-3, while the total QOL score over the extended evaluation time was further elevated compared with those at week 50 in VL-1, −2, and − 5 (Table 2).…”

“…Our current study is a follow-up of previously reported results [11], using the same subjects and study design.…”

“…A French group undertook the first study of bezafibrate treatment for FAODs [9]. Based on that work, we undertook the next prospective clinical study in compliance with GCP standards and as officially approved by the Health, Labor and Welfare Ministry of Japan [5,11]. Our findings revealed a short-term efficacy for bezafibrate in patients with FAODs and suggested that the subjective QOL of patients was improved during the 50-week study.…”

“…Recent reports implicated bezafibrate as a promising drug for fatty acid oxidation disorders (FAODs) based on enhanced transcription of several β-oxidation enzymes in vitro [[4], [5], [6], [7], [8], [9], [10]]. We also recently reported on the efficacy of bezafibrate for FAODs in a recent clinical trial [11], wherein patients showed improvements in some quality of life (QOL) components during a 6-month survey, but no significant changes in the frequency of myopathic attacks, the levels of creatine kinase (CK) and acylcarnitines (ACs, C14:1 or C16 + C18:1), and visual analog scale (VAS) values during the attacks. We suspected that these endpoints could not be adequately evaluated due to several limitations, including the small trial population.…”

Mitochondrial Genetic Disorders: Cell Signaling and Pharmacological Therapies

“…This appears in contrast with our results, however, the patients enrolled in this trial presented a very mild phenotype compared to ours, since, for instance, no muscle symptoms or rhabdomyolysis episodes were reported during the six-month trial period. Finally, the most recent trial was performed in two CPT2 and six VLCAD patients receiving BZ at various dosages during six months [139]. In this trial, no data were provided regarding the in vivo or ex vivo FAO capacities in the panel of patients, before or after treatment by BZ.…”