title: UX007 for the treatment of long chain-fatty acid oxidation disorders: Safety and efficacy in children and adults following 24weeks of treatment.
abstract: Long-chain fatty acid oxidation disorders (LC-FAOD) lead to accumulation of high concentrations of potentially toxic fatty acid intermediates. Newborn screening and early intervention have reduced mortality, but most patients continue to experience frequent hospitalizations and significant morbidity despite treatment. The deficient energy state can cause serious liver, muscle, and heart disease, and may be associated with an increased risk of sudden death. Triheptanoin is a medium odd-chain fatty acid. Anaplerotic metabolites of triheptanoin have the potential to replace deficient tricarboxylic acid (TCA) cycle intermediates, resulting in net glucose production as a novel energy source for the treatment of LC-FAOD.
  
  
  
  A single-arm, open-label, multicenter Phase 2 safety and efficacy study evaluated patients with severe LC-FAOD evidenced by ongoing related musculoskeletal, cardiac, and/or hepatic events despite treatment. After a four-week run-in on current regimen, investigational triheptanoin (UX007) was titrated to a target dose of 25-35% of total daily caloric intake. Patients were evaluated on several age/condition-eligible endpoints, including submaximal exercise tests to assess muscle function/endurance (12-minute walk test; 12MWT) and exercise tolerance (cycle ergometry), and health related quality of life (HR-QoL). Results through 24weeks of treatment are presented; total study duration is 78weeks.
  
  
  
  Twenty-nine patients (0.8 to 58years) were enrolled; most qualified based on severe musculoskeletal disease. Twenty-five patients (86%) completed the 24-week treatment period. At Week 18, eligible patients (n=8) demonstrated a 28% increase (LS mean=+181.9 meters; p=0.087) from baseline (673.4meters) in 12MWT distance. At Week 24, eligible patients (n=7) showed a 60% increase in watts generated (LS mean=+409.3W; p=0.149) over baseline (744.6W) for the exercise tolerance test. Improvements in exercise tests were supported by significant improvements from baseline in the adult (n=5) self-reported SF-12v2 physical component summary score (LS mean=+8.9; p<0.001). No difference from baseline was seen in pediatric parent-reported (n=5) scores (SF-10) at Week 24. Eighteen patients (62%) had treatment-related adverse events, predominantly gastrointestinal (55%), mild-to-moderate in severity, similar to that seen with prior treatment with medium chain triglyceride (MCT) oil. One patient experienced a treatment-related serious adverse event of gastroenteritis. One patient discontinued from study due to diarrhea of moderate severity; the majority of patients (25/29; 86%) elected to continue treatment in the extension period.
  
  
  
  In patients with severe LC-FAOD, UX007 interim study results demonstrated improved exercise endurance and tolerance, and were associated with positive changes in self-reported HR-QoL.
authors.affiliation: University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA. Electronic address: gerard.vockley@chp.edu.
authors.forename: J
authors.initials: J
authors.lastname: Vockley
authors.affiliation: Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
authors.forename: B
authors.initials: B
authors.lastname: Burton
authors.affiliation: Boston Children's Hospital, Boston, MA, USA.
authors.forename: G T
authors.initials: GT
authors.lastname: Berry
authors.affiliation: University of Utah, Salt Lake City, UT, USA.
authors.forename: N
authors.initials: N
authors.lastname: Longo
authors.affiliation: Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Phillips
authors.affiliation: University of South Florida, Morsani College of Medicine, Tampa, FL, USA.
authors.forename: A
authors.initials: A
authors.lastname: Sanchez-Valle
authors.affiliation: Children's National Medical Center, Washington, DC, USA.
authors.forename: P
authors.initials: P
authors.lastname: Tanpaiboon
authors.affiliation: Great Ormond Street Hospital, UCL Institute of Child Health, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Grunewald
authors.affiliation: Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: E
authors.initials: E
authors.lastname: Murphy
authors.affiliation: University of Montana, Missoula, MT, USA.
authors.forename: R
authors.initials: R
authors.lastname: Humphrey
authors.affiliation: Ultragenyx Pharmaceutical Inc., Novato, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Mayhew
authors.affiliation: Ultragenyx Pharmaceutical Inc., Novato, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Bowden
authors.affiliation: Ultragenyx Pharmaceutical Inc., Novato, CA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Ultragenyx Pharmaceutical Inc., Novato, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Cataldo
authors.affiliation: Ultragenyx Pharmaceutical Inc., Novato, CA, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Marsden
authors.affiliation: Ultragenyx Pharmaceutical Inc., Novato, CA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Kakkis
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005227:Fatty Acids / Q000633:toxicity*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008052:Lipid Metabolism, Inborn Errors / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D010807:Physical Endurance / Q000187:drug effects*; D011446:Prospective Studies; D011788:Quality of Life; D016896:Treatment Outcome; D014280:Triglycerides / Q000008:administration & dosage* / Q000494:pharmacology; D000070857:Walk Test; D055815:Young Adult
chemical_list: D005227:Fatty Acids; D014280:Triglycerides; C531010:triheptanoin
keywords: FAOD; Fatty acid oxidation disorders; LC-FAOD; LCHAD; Metabolic disorders; Triheptanoin; UX007; VLCAD