TY - JOUR
T1 - UX007 for the treatment of long chain-fatty acid oxidation disorders
T2 - Safety and efficacy in children and adults following 24 weeks of treatment
AU - Vockley, J.
AU - Burton, B.
AU - Berry, G. T.
AU - Longo, N.
AU - Phillips, J.
AU - Sanchez-Valle, A.
AU - Tanpaiboon, P.
AU - Grunewald, S.
AU - Murphy, E.
AU - Humphrey, R.
AU - Mayhew, J.
AU - Bowden, A.
AU - Zhang, L.
AU - Cataldo, J.
AU - Marsden, D. L.
AU - Kakkis, E.
N1 - Publisher Copyright:
© 2017 The Authors
PY - 2017/4/1
Y1 - 2017/4/1
N2 - Background 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. Study design 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 24 weeks of treatment are presented; total study duration is 78 weeks. Results Twenty-nine patients (0.8 to 58 years) 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 (673.4 meters) in 12MWT distance. At Week 24, eligible patients (n = 7) showed a 60% increase in watts generated (LS mean = + 409.3 W; p = 0.149) over baseline (744.6 W) 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. Conclusions 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.
AB - Background 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. Study design 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 24 weeks of treatment are presented; total study duration is 78 weeks. Results Twenty-nine patients (0.8 to 58 years) 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 (673.4 meters) in 12MWT distance. At Week 24, eligible patients (n = 7) showed a 60% increase in watts generated (LS mean = + 409.3 W; p = 0.149) over baseline (744.6 W) 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. Conclusions 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.
KW - FAOD
KW - Fatty acid oxidation disorders
KW - LC-FAOD
KW - LCHAD
KW - Metabolic disorders
KW - Triheptanoin
KW - UX007
KW - VLCAD
UR - http://www.scopus.com/inward/record.url?scp=85011891317&partnerID=8YFLogxK
U2 - 10.1016/j.ymgme.2017.02.005
DO - 10.1016/j.ymgme.2017.02.005
M3 - Article
C2 - 28189603
AN - SCOPUS:85011891317
SN - 1096-7192
VL - 120
SP - 370
EP - 377
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
IS - 4
ER -