PHEMI—Phenylbutyrate in Patients With Lactic Acidosis: A Pilot, Single Arm, Phase I/II, Open–Label Trial

Purpose: The 6 months pilot, single arm, phase I/II, open-label clinical trial PHEMI investigated the safety and efficacy of daily administration of phenylbutyrate in reducing lactic acidosis by at least 20% in 3 children (ages 7–10 yrs) with pyruvate dehydrogenase deficiency and 6 adults with mitochondrial myopathy encephalopathy lactic acidosis and stroke-like episodes. As a side study, we investigated the response to phenylbutyrate treatment in skin fibroblasts and cybrids derived from PHEMI patients with the aim of unraveling a possible in vivo-in vitro correlation. Methods: Safety was assessed through the collection of vital signs, clinical evaluations, blood samples, and reported adverse events. Efficacy was evaluated on biochemical and clinical endpoints. In vitro analysis explored the effects of phenylbutyrate in patients’ fibroblasts and cybrids. Findings: At the starting dosage regimen of 10 g/m2/day, phenylbutyrate was effective in reducing lactic acidosis (by a mean of 13%), but lead to the development of adverse events in all adults. The reduced dose of 5 g/m²/day was well tolerated but did not meet the study's primary outcome. In parallel, the in vitro analyses confirmed that phenylbutyrate led to a reduction in lactate measured in culture medium, an increase in cellular respiration, and a slight increase in the activity of the Respiratory Chain Complexes. Implications: Our study fosters further research on phenylbutyrate in individuals with primary mitochondrial disease suffering from lactic acidosis. Future investigation should focus on a highly bioavailable, easier-to-administer drug formulation that allows the administration of a lower dosage regimen.