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

Area of Science:

• Biochemistry
• Clinical Medicine
• Genetics

Background:

• Primary mitochondrial diseases are often characterized by lactic acidosis, a serious metabolic imbalance.
• Pyruvate dehydrogenase deficiency and mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) are debilitating conditions.
• Investigating therapeutic agents like phenylbutyrate is crucial for managing these complex diseases.

Purpose of the Study:

• To evaluate the safety and efficacy of phenylbutyrate in reducing lactic acidosis in pediatric and adult patients with primary mitochondrial diseases.
• To explore the in vivo-in vitro correlation of phenylbutyrate's effects using patient-derived skin fibroblasts and cybrids.

Main Methods:

• A 6-month, single-arm, phase I/II, open-label clinical trial (PHEMI) involving 3 children and 6 adults.
• Safety assessment included vital signs, clinical evaluations, blood samples, and adverse event monitoring.
• Efficacy was measured by biochemical and clinical endpoints, alongside in vitro analyses of phenylbutyrate's impact on patient cells.

Main Results:

• Initial high-dose phenylbutyrate (10 g/m²/day) reduced lactic acidosis by 13% but caused adverse events in all adults.
• A reduced dose (5 g/m²/day) was well-tolerated but did not meet the primary efficacy outcome.
• In vitro studies demonstrated phenylbutyrate's ability to decrease lactate, enhance cellular respiration, and slightly improve Respiratory Chain Complex activity.

Conclusions:

• Phenylbutyrate warrants further investigation for treating lactic acidosis in primary mitochondrial diseases.
• Future research should prioritize developing more bioavailable and easily administered phenylbutyrate formulations for lower dosage regimens.
• Optimizing drug delivery and formulation could enhance therapeutic benefits while minimizing adverse events.