Results from a 78-week Single-arm, Open-label Phase 2 Study to Evaluate UX007 in Pediatric and Adult Patients with Moderate to Severe Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD)

Jerry Vockley, MD, PhD1; Barbara Burton, MD2; Gerard Berry, MD3; Nicola Longo, MD4;
John Phillips, MD5;  Amarilis Sanchez-Valle, MD6; Pranoot Tanpaiboon, MD7; Stephanie Grunewald, MD, PhD8; Elaine Murphy, MD9; Alexandra Bowden, PhD10; Wencong Chen, PhD10; Chao-Yin  Chen, PhD10; Jason Cataldo, DO10;  Deborah Marsden, MD10; Emil Kakkis, MD, PhD10

1 University of Pittsburgh, Pittsburgh, PA, USA; 2 Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, USA; 3 Boston Children’s Hospital, Boston, MA, USA; 4 University of Utah, Salt Lake City, UT, USA; 5 Vanderbilt University Medical Center, Nashville, TN, USA; 6 USF Health, Morsani College of Medicine, Tampa, FL, USA; 7 Children’s National Health System, Washington DC, USA; 8
Great Ormond Street, UCL Institute of Child Health, London, UK;  9 National Hospital for Neurology
and Neurosurgery, London, UK;  10 Ultragenyx Pharmaceutical Inc., Novato, CA, USA

Corresponding author:  Jerry Vockley    gerard.vockley@chp.edu        Office: (412) 692-7746

A single-arm, open-label Phase 2 study was conducted to evaluate safety and efficacy of UX007 (a highly purified, synthetic seven carbon fatty acid triglyceride) for 78 weeks in 29 pediatric and adult patients with moderate-to-severe LC-FAOD (24 subjects completed 78 weeks). LC-FAOD are autosomal recessive genetic disorders caused by defects in mitochondrial fatty acid oxidation enzymes active with long-chain substrates that lead to a general deficiency of energy intermediates and accumulation of toxic fatty acid intermediates causing a variety of serious clinical manifestations. UX007 is being investigated as treatment for LC-FAOD. The mechanism of action of UX007 in restoring energy metabolism is dependent on its medium chain length and odd-carbon properties.  UX007 was titrated to a target dose of 25-35% of total daily caloric intake (mean 31%). Major clinical events (hospitalizations, emergency room visits, and emergency home interventions due to rhabdomyolysis, hypoglycemia, and cardiomyopathy) were captured retrospectively from medical records for 18-24 months prior to UX007 initiation and compared with the 18 months post-UX007. Prior to initiating UX007, 93% subjects were on MCT therapy.

UX007 treatment significantly reduced the number and duration of major clinical events. The overall mean annualized event rates decreased from 1.69 to 0.88 events/year (p=0.0208) and the mean annualized duration rate decreased from 5.96 to 2.96 days/year (p=0.0284) following UX007

initiation. Hospitalizations due to rhabdomyolysis, the predominant major clinical event, also decreased from 1.03 to 0.63 events/year (p=0.1044) following UX007 initiation. Initiation of UX007 eliminated hypoglycemia events leading  to hospitalization (0.30 vs 0 hospitalization events/year; p=0.0667) and ICU care (0.05 vs 0 ICU events/year; p=0.1609). Adult subjects reported significant improvements in the SF-12 Physical Component Summary Scale (n=5, p=0.0354), while pediatric subjects reported significant improvements in the SF-10 Physical Summary Scores (n=3, p<0.0001).

Finally, UX007 treatment reduced cardiomyopathy events by 69.6% (0.07 vs 0.02 events/year; p=0.3090). The most common related treatment-emergent adverse events (TEAEs) were diarrhea, abdominal or gastrointestinal pain, vomiting, and acne, with most mild to moderate in severity.

Conclusion: Major clinical events were significantly reduced following UX007 treatment in contrast to pre-treatment, during which most subjects were treated with MCT.