UX007

The annualized LC-FAOD MCE rate, inclusive of skeletal myopathy (rhabdomyolysis), hepatic (hypoglycemia) and cardiomyopathy events, defined as any visit to the emergency room (ER)/acute care, hospitalization, emergency intervention (i.e. any unscheduled administration of therapeutics at home or in the clinic), or any similar event whether caused primarily by LC-FAOD or by an intercurrent illness complicated by LC-FAOD. The annualized event rate was calculated at the number of events divided by the duration of data collection period in days/365.25

The annualized LC-FAOD MCE rate, inclusive of skeletal myopathy (rhabdomyolysis), hepatic (hypoglycemia) and cardiomyopathy events, defined as any visit to the emergency room (ER)/acute care, hospitalization, emergency intervention (i.e. any unscheduled administration of therapeutics at home or in the clinic), or any similar event whether caused primarily by LC-FAOD or by an intercurrent illness complicated by LC-FAOD. The annualized event rate was calculated at the number of events divided by the duration of data collection period in days/365.25

An adverse event (AE) was defined as any untoward medical occurrence, whether or not considered drug related. A serious adverse event (SAE) results in any of the following outcomes: death; a life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or disability; a congenital anomaly/birth defect; an important medical event. AEs were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (mild=1, moderate=2, severe=3, life-threatening=4, death=5).

Reduction from baseline to Week 8 in frequency of seizures (normalized to a 4-week rate): observable seizures measured for 6 weeks after 2-week titration by diary and absence seizures measured overnight by EEG. Observable seizures from the diary include generalized tonic-clonic, generalized tonic, generalized clonic, generalized atonic, partial/focal with secondary generalization, myoclonic, myoclonic (astatic) atonic, myoclonic tonic, complex partial/focal, simple partial/focal motor, simple partial/focal sensory, and simple partial/focal psychological. Absence seizures from EEG include absence awake (\>=10 sec), absence sleep (\>=10 sec), indeterminate absence awake (3-10 sec), and indeterminate absence sleep (3-10 sec). A negative value indicates an increase in frequency.

An adverse event (AE) was defined as any untoward medical occurrence, whether or not considered drug related. A serious AE was defined as an AE or suspected adverse reaction that at any dose resulted in any of the following outcomes: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital anomaly/birth defect, or an important medical event that may have jeopardized the subject and may have required medical or surgical intervention to prevent one of the outcomes listed in the definition. An AE was considered a TEAE if it occurred or worsened in severity on or after the date of the first dose of study drug. An AE was considered a UX007 emergent adverse event if it occurred or worsened in severity on or after the first date of first dose of UX007 during the study.

An AE was defined as any untoward medical occurrence, whether or not considered drug related. A serious AE was defined as an AE or suspected adverse reaction that at any dose resulted in any of the following outcomes: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital anomaly/birth defect, or an important medical event that may have jeopardized the subject and may have required medical or surgical intervention to prevent one of the outcomes listed in the definition. An AE was considered a TEAE if it occurred or worsened in severity on or after the date of the first dose of study drug. An AE was considered a UX007 emergent adverse event if it occurred or worsened in severity on or after the first date of first dose of UX007 during the study.

To evaluate the impact 24 weeks of treatment with UX007 has on exercise intolerance, the change from Baseline in time adjusted-AUC (AUC/time) for workload during 40-minute cycle ergometry tests at Week 24 were assessed using the generalized estimation equation (GEE) model. A cycle ergometer can measure the work performed by an individual over time during physical exercise, the work was measured every 10 minutes from 0 to 40 minutes at Baseline and Week 24. The GEE model included the change from Baseline as the dependent variable, time as the categorical variable, and adjusted for Baseline measurement with compound symmetry covariance structure. An increase in AUC is reflective of improved exercise tolerance; a negative change from Baseline indicates worsening.

Change from baseline in time-adjusted-AUC for respiratory exchange ratio (RER) during cycle ergometry at Week 24, assessed using the GEE model, which included change from baseline as dependent variable, time as categorical variable, and adjusted for baseline measurement with compound symmetry covariance structure. RER during exercise is calculated as volume of carbon dioxide/volume of oxygen. RER measures whether carbohydrates or fats are being used as fuel. RER ≥1.0 indicates carbohydrates are the predominate fuel source. RER \<1.0 and RER \>0.70 indicates both fats and carbohydrates are the predominate fuel source. RER approximately =0.70 means fat is the predominant fuel source. RER would be expected to be lower, at similar exercise intensities, if a participant is able to utilize fat as an energy source. Therefore, an increase in RER (positive change from baseline) would suggest participants are still utilizing carbohydrates rather than fat, reflective a physiological response.

To evaluate the impact of 24 weeks of treatment with UX007 on exercise intolerance, the change from Baseline in actual duration of exercise during 40-minute cycle ergometry tests at Week 24 was assessed using the GEE model. The GEE model included the change from Baseline as the dependent variable, time as the categorical variable, and adjusted for Baseline measurement with compound symmetry covariance structure. Duration of exercise is expected to increase as exercise tolerance improves.

To evaluate the impact 18 weeks of treatment with UX007 has on muscle function, the change from Baseline in distance traveled during a 12MWT at Week 18 was assessed using the GEE model. The GEE model included the change from Baseline as the dependent variable, time as the categorical variable, and adjusted for Baseline measurement with compound symmetry covariance structure. Distance traveled during the 12MWT is expected to increase as muscle function increases.

To evaluate the impact 18 weeks of treatment with UX007 has on muscle function, the change from Baseline of EEI during the 12MWT at Week 18 was assessed using the GEE model. The GEE model included the change from Baseline as the dependent variable, time as the categorical variable, and adjusted for Baseline measurement with compound symmetry covariance structure. EEI is quantified as the post-test heart rate minus the pre-test heart rate (in beats/min) divided by overall velocity, and is valued in beats/meter. A decrease in EEI when walking a similar distance or no change when walking longer distances, may indicate improved exercise tolerance.

To evaluate the impact 18 weeks of treatment with UX007 has on muscle function, the change from Baseline in the percentage of the predicted distance traveled during the first 6 minutes (6MWT) of the 12MWT at Week 18 was assessed using the GEE model. A participant's mathematical formula to calculate their percent predicted (PP) distance walked in the 6MWT was based on their demographics at baseline. For participants \< 20 years old, the formula used was referenced from (Gieger, et. al. 2007) which calculated PP distance walked based on age, gender, and height. For participants \>= 20 years old, the formula used was referenced from (Gibbons, et. al. 2001) and calculated the PP distance walked based on age and gender. The GEE model included the change from Baseline as the dependent variable, time as the categorical variable, and adjusted for Baseline measurement with compound symmetry covariance structure. Percent predicted values are expected to increase as muscle function increases.

To evaluate the impact treatment with UX007 has on functional disability and health in participants between 5 and 17 years of age, change from Baseline in the T-scores of the PHS-10 were assessed at Week 24 and analyzed using the GEE model. The GEE model included the change from Baseline as the dependent variable, time as the categorical variable, and adjusted for Baseline measurement with compound symmetry covariance structure. The SF-10 Health Survey for Children is a 10-item caregiver-completed assessment designed to measure children's health-related quality of life. The PHS-10 of the SF-10 is scored such that higher scores indicate more favorable functioning. The T-score based scoring signifies that scale scores are centered so that a score of 50 corresponds to the average score in a comprehensive sample of US population (scale scores are standardized to a mean of 50 and a standard deviation of 10).

To evaluate the impact treatment with UX007 has on functional disability and health in participants between 5 and 17 years of age, changes from Baseline in the T-scores of the PSS-10 were assessed at Week 24 and analyzed using the GEE model. The GEE model included the change from Baseline as the dependent variable, time as the categorical variable, and adjusted for Baseline measurement with compound symmetry covariance structure. The PSS-10 of the SF-10 is scored such that higher scores indicate more favorable functioning. The T-score based scoring signifies that scale scores are centered so that a score of 50 corresponds to the average score in a comprehensive sample of US population (scale scores are standardized to a mean of 50 and a standard deviation of 10). Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Higher values are indicative of more favorable functioning/better health.

Changes from baseline in T-scores as assessed by the PCS-12 Short-Form Health Survey, version 2 (SF-12v2) at Week 24 were assessed using the GEE model, which included the change from Baseline as the dependent variable, time as the categorical variable, and adjusted for Baseline measurement with compound symmetry covariance structure. PCS-12 scores were calculated from the individual responses to those questions that contribute to physical health. Raw scores range from 0 to 100 with higher scores indicating better health. The T-score based scoring signifies that scale scores are centered so that a score of 50 corresponds to the average score in the US general population (scale scores are standardized to a mean of 50 and a standard deviation of 10). Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Higher values are indicative of more favorable functioning/better health.

Changes from baseline of T-scores as assessed by the MCS-12 of the SF-12v2 at Week 24 were assessed using the GEE model, which included the change from Baseline as the dependent variable, time as the categorical variable, and adjusted for Baseline measurement with compound symmetry covariance structure. MCS-12 scores were calculated from the individual responses to those questions that contribute to mental health. Raw scores range from 0 to 100 with higher scores indicating better health. The T-score based scoring signifies that scale scores are centered so that a score of 50 corresponds to the average score in the US general population (scale scores are standardized to a mean of 50 and a standard deviation of 10). Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Higher values are indicative of more favorable functioning/better health.

Major clinical events are defined as adverse events (AEs) resulting in hospitalizations, emergency room (ER) visits, and emergency intervention.

Major clinical events are defined as AEs resulting in hospitalizations, ER visits, and emergency intervention.

Rhabdomyolysis is a condition in which damaged skeletal muscle breaks down rapidly. Major rhabdomyolysis clinical events are defined as those AEs resulting in hospitalizations, ER visits, and emergency intervention.

Rhabdomyolysis is a condition in which damaged skeletal muscle breaks down rapidly. Major rhabdomyolysis clinical events are defined as those AEs resulting in hospitalizations, ER visits, and emergency intervention.

Major hypoglycemia clinical events are defined as those AEs resulting in hospitalizations, ER visits, and emergency intervention.

Major hypoglycemia clinical events are defined as those AEs resulting in hospitalizations, ER visits, and emergency intervention.

Major cardiac clinical events are defined as those AEs resulting in hospitalizations, ER visits, and emergency intervention.

Major cardiac clinical events are defined as those AEs resulting in hospitalizations, ER visits, and emergency intervention.