Jill Mayhew, PT1; Jerry Vockley, MD, PhD2; Barbara Burton, MD3; Gerard Berry, MD4; Nicola Longo, MD5; John Phillips, MD6; Amarilis Sanchez-Valle, MD7; Pranoot Tanpaiboon, MD8; Stephanie Grunewald, MD, PhD9; Elaine Murphy, MD10; Wencong Chen, PhD1; Chao-Yin Chen, PhD1; Jason Cataldo, DO1; Deborah Marsden, MD1; Alexandra Bowden, PhD1; Emil Kakkis, MD, PhD1; Alison Skrinar, PhD1; Reed Humphrey, PhD11
1 Ultragenyx Pharmaceutical Inc., Novato, CA, USA; 2 University of Pittsburgh, Pittsburgh, PA, USA; 3 Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, USA; 4 Boston Children’s Hospital, Boston, MA, USA; 5 University of Utah, Salt Lake City, UT, USA; 6 Vanderbilt University Medical Center, Nashville, TN, USA; 7 USF Health, Morsani College of Medicine, Tampa, FL, USA; 8 Children’s National Health System, Washington DC, USA; 9 Great Ormond Street, UCL Institute of Child Health, London, UK; 10 National Hospital for Neurology and Neurosurgery, London, UK; 11University of Montana, Missoula, MT
Corresponding author: Alexandra Bowden firstname.lastname@example.org
Phone: (415) 483-8865
LC-FAOD are autosomal recessive genetic disorders caused by defects in mitochondrial fatty acid oxidation enzymes active with long-chain substrates. These defects lead to a general deficiency of energy intermediates and accumulation of toxic fatty acid intermediates resulting in serious clinical manifestations. In a Phase 2 open-label study, the effect of UX007 (a highly purified, synthetic seven carbon fatty acid triglyceride) on exercise tolerance and muscle function was investigated.
Exercise intolerance was reported in the LC-FAOD specific medical histories of 21/29 (72%) of subjects enrolled in the Phase 2 study. Tests of exercise tolerance and muscle function were performed in the cohort of subjects ≥6 years of age that were able to comply and follow test instructions safely and reliably. Cycle ergometry was included as a measure of exercise tolerance and performed at an intensity and duration conducive to the reduction of glycogen stores and oxidation of fatty acids by exercised muscle to evaluate the effect of UX007 treatment in subjects with inherent defects in fatty acid oxidation. Exercise tolerance was assessed by workload and duration at a fixed heart rate during a 40-minute protocol. A 12minute walk test (12MWT) was incorporated into the study design as a measure of muscle function. The distance walked in meters was assessed at 6 and 12 minutes.
In the ergometry test, improvements were observed in both workload (watts) and duration (minutes) following UX007 treatment (n=7). After 24 weeks of UX007 treatment, mean workload increased by 60% from 744.6 to 1191.4 watts (median: 127.5; minimum, maximum: -388, +2438; Least Squares (LS) mean change: 423.6, p=0.1518). Improvements in duration were also noted with mean test times improving from 9.3 ± 5.1 minutes (range: 5-15) to 20.4 ± 17.0 minutes (range: 10-40) in the 3 subjects unable to complete the 40-minute exercise protocol at Baseline. No further improvements were noted after an additional 48 weeks of treatment however, the interpretation was limited by a smaller sample size.
In the 12MWT, the mean distance walked increased 28% from 673.4 meters to 861.4 meters after 18 weeks of UX007 treatment (median: 93.5; minimum, maximum: -80, +880; LS Mean change: 181.4, p=0.0830) (n=8). This increase was maintained after an additional 42 weeks of treatment.
These data suggest UX007 treatment improves exercise tolerance and muscle function in LC-FAOD patients and supports the use of these assessments in this patient population.