Phase 2 study of sodium phenylbutyrate in ALS

摘要

The objective of the study was to establish the safety and pharmacodynamics of escalating dosages of sodium phenylbutyrate(NaPB) in participants with ALS. Transcription dysregulation may play a role in the pathogenesis of ALS. Sodiumphenylbutyrate, a histone deacetylase inhibitor, improves transcription and post-transcriptional pathways, promoting cellsurvival in a mouse model of motor neuron disease. Forty research participants at eight sites enrolled in an open-label study.Study medication was increased from 9 to 21 g/day. The primary outcome measure was tolerability. Secondary outcomemeasures included adverse events, blood histone acetylation levels, and NaPB blood levels at each dosage. Twenty-sixparticipants completed the 20-week treatment phase. NaPB was safe and tolerable. No study deaths or clinically relevantlaboratory changes occurred with NaPB treatment. Histone acetylation was decreased by approximately 50% in bloodbully-coat specimens at screening and was significantly increased after NaPB administration. Blood levels of NaPB and theprimary metabolite, phenylacetate, increased with dosage. While the majority of subjects tolerated higher dosages of NaPB,the lowest dose (9 g/day), was therapeutically efficient in improving histone acetylation levels.