Phase 2 study of sodium phenylbutyrate in ALS.
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. Sodium phenylbutyrate, a histone deacetylase inhibitor, improves transcription and post-transcriptional pathways, promoting cell survival 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 outcome measures included adverse events, blood histone acetylation levels, and NaPB blood levels at each dosage. Twenty-six participants completed the 20-week treatment phase. NaPB was safe and tolerable. No study deaths or clinically relevant laboratory changes occurred with NaPB treatment. Histone acetylation was decreased by approximately 50% in blood buffy-coat specimens at screening and was significantly increased after NaPB administration. Blood levels of NaPB and the primary 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.
Cudkowicz
Merit E
ME
Massachusetts General Hospital, Neurology Clinical Trials Unit, 13th Street, Charlestown, MA 02129, USA. mcudkowicz@partners.org
Andres
Patricia L
PL
Macdonald
Sally A
SA
Bedlack
Richard S
RS
Choudry
Rabia
R
Brown
Robert H
RH
Zhang
Hui
H
Schoenfeld
David A
DA
Shefner
Jeremy
J
Matson
Samantha
S
Matson
Wayne R
WR
Ferrante
Robert J
RJ
D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy*; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000187:drug effects / Q000201:enzymology; D010648:Phenylacetates / Q000008:administration & dosage / Q000097:blood; D010654:Phenylbutyrates / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*
D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D010648:Phenylacetates; D010654:Phenylbutyrates; D006655:Histone Deacetylases; C025136:phenylacetic acid