title: Evaluation of safety and pharmacokinetics of sodium 2,2 dimethylbutyrate, a novel short chain fatty acid derivative, in a phase 1, double-blind, placebo-controlled, single-dose, and repeat-dose studies in healthy volunteers.
abstract: Pharmacologic induction of fetal globin synthesis is an accepted therapeutic strategy for treatment of the beta hemoglobinopathies and thalassemias, as even small increases in hemoglobin F (HbF) levels reduce clinical severity in sickle cell disease (SCD) and reduce anemia in beta thalassemia. Prior generation short chain fatty acid therapeutics, arginine butyrate (AB), and phenylbutyrate, increased fetal and total hemoglobin levels in patients, but were limited by high doses or intravenous (IV) infusion. A fetal globin-inducing therapeutic with convenient oral dosing would be an advance for these classic molecular diseases. Healthy adult human subjects were treated with a novel short chain fatty acids (SCFA) derivative, sodium 2,2 dimethylbutyrate (SDMB), or placebo, with 1 of 4 single dose levels (2, 5, 10, and 20 mg/kg) or daily doses (5, 10, or 15 mg/kg) over 14 days, and monitored for adverse clinical and laboratory events, drug levels, reticulocytes, and HbF assays. SDMB was well-tolerated with no clinically significant adverse events related to study medication. The terminal half-life ranged from 9 to 15 hours. Increases in mean absolute reticulocytes were observed at all dose levels in the 14-day study. The favorable pharmacokinetics (PK) profiles and safety findings indicate that SDMB warrants further investigation for treatment of anemic subjects with beta hemoglobinopathies.
authors.affiliation: HemaQuest Pharmaceuticals, Inc, Boston, MA 02110, USA. sperrine@hemaquest.com
authors.forename: Susan P
authors.initials: SP
authors.lastname: Perrine
authors.forename: William A
authors.initials: WA
authors.lastname: Wargin
authors.forename: Michael S
authors.initials: MS
authors.lastname: Boosalis
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Wallis
authors.forename: Sally
authors.initials: S
authors.lastname: Case
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Keefer
authors.forename: Douglas V
authors.initials: DV
authors.lastname: Faller
authors.forename: William C
authors.initials: WC
authors.lastname: Welch
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Berenson
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001682:Biological Availability; D001772:Blood Cell Count; D002087:Butyrates / Q000008:administration & dosage / Q000009:adverse effects* / Q000032:analysis / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000009:adverse effects* / Q000032:analysis / Q000493:pharmacokinetics*; D005260:Female; D005319:Fetal Hemoglobin / Q000032:analysis; D018565:Food-Drug Interactions; D006207:Half-Life; D006397:Hematinics / Q000008:administration & dosage / Q000009:adverse effects* / Q000032:analysis / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D010949:Plasma / Q000737:chemistry; D012156:Reticulocytes / Q000187:drug effects; D014556:Urine / Q000737:chemistry; D055815:Young Adult
chemical_list: D002087:Butyrates; D015507:Drugs, Investigational; D006397:Hematinics; D005319:Fetal Hemoglobin; C074677:2,2-dimethylbutyric acid