Clinical Trials

Date: 2018-01-04

Type of information: update on patient enrollment

phase: 2

Announcement: results

Company: Ultragenyx Pharmaceutical (USA - CA)

Product: triheptanoin (UX007)

Action mechanism:

• triglyceride.Triheptanoin is a purified, pharmaceutical-grade, specially designed synthetic triglyceride compound created via a multi-step chemical process. Triheptanoin is metabolized to and intended to provide patients with heptanoate, which can diffuse across the blood-brain barrier and be converted into glucose. Heptanoate can also be further metabolized to four- and five-carbon ketone bodies in the liver that also cross the blood-brain-barrier and provide an additional energy source to the brain. Heptanoate and five-carbon ketone bodies can also regenerate new glucose in the brain, which is deficient in these patients.
• The European Commission has granted orphan medicinal product designation for triheptanoin for the treatment of Very Long-Chain Acyl-CoA Dehydrogenase (VLCAD) deficiency (VLCAD) deficiency, and for the treatment of three other subtypes of LC-FAOD: Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase (LCHAD) deficiency, Trifunctional Protein (TFP) deficiency, and carnitine palmitoyltransferase II deficiency. These four subtypes are estimated to represent more than 90% of the patients born with LC-FAOD each year.

Disease: long-chain fatty acid oxidation disorder (LC-FAOD)

Therapeutic area: Rare diseases - Cardiovascular diseases

Country: UK, USA

Trial details:

• UX007-CL201 is an open-label Phase 2 study to assess the safety and clinical effects of UX007 in subjects with LC-FAOD. Following a 4 week run in period on current therapy, subjects will cross over to daily UX007 treatment for an initial 24 week treatment period, followed by an additional 54 week extension period. Approximately 30 subjects at least 6 months of age inclusive with severe LC-FAOD, specifically VLCAD, LCHAD, CPT 2, or TFP disorders, will be enrolled and treated with UX007. (NCT01886378)

Latest news:

• • On January 4, 2018, Ultragenyx Pharmaceutical  announced an update to its development plan for UX007 in patients with long-chain fatty acid oxidation disorder (LC-FAOD). Following an end-of-phase 2 meeting with the FDA, the company is working to provide additional information to submit to FDA for consideration of an early filing based on the results from the Phase 2 study. The company is simultaneously completing the design of a Phase 3 study that could be used for registrational or confirmatory purposes. The company expects that a decision on a potential filing for approval based on Phase 2 data will be made in mid-2018.
• The data submitted to FDA for evaluation included the Phase 2 study results, a retrospective medical record review, emergency IND cardiomyopathy cases and a randomized controlled study showing an effect on cardiac function. In the Phase 2 study, the data showed a 48.1 percent reduction in the mean annualized rate of MCEs (Major Clinical Events) and a 50.6 percent reduction in the median annualized rate of MCEs after 78 weeks of treatment, compared to the annualized rates in the 18 months prior to treatment with UX007. There was a 50.3 percent reduction in the mean annualized duration of all MCEs and a 76.7 percent reduction in the median annualized duration of MCEs following 78 weeks of UX007 treatment. The safety profile was consistent with what has been previously observed with UX007.
• In the end-of-phase 2 meeting, the FDA indicated that they are willing to continue to work with the company to determine if the current data could support an initial New Drug Application (NDA), provided that Ultragenyx submit additional information to support that the improvement demonstrated was likely due to UX007 and not any other changes. The clinical effect observed was considered important, but it was not clear if there were dietary or other changes in the regimen as each patient crossed over onto UX007 that might have accounted for the improvement. After this information is submitted and evaluated by FDA, Ultragenyx plans to determine with the FDA whether an early submission could be pursued.
• Ultragenyx is simultaneously finalizing a full protocol for a Phase 3, randomized, controlled study examining major clinical events as the primary endpoint as discussed with the FDA. Regardless of filing timeline, the company feels this study would provide additional information that would be important in utilization and reimbursement long-term for UX007. If the FDA agrees to an early submission based on the Phase 2 study, the Phase 3 study would serve as a post-approval commitment for label expansion. Alternatively, the Phase 3 study could serve as a registrational study if an early filing is not possible.
• • On November 30, 2016, Ultragenyx Pharmaceutical announced positive 78-week data from the Phase 2 study of UX007 (triheptanoin) in patients with long-chain fatty acid oxidation disorder (LC-FAOD). The frequency and duration of major medical events were reduced significantly during treatment with UX007, and patients demonstrated improved exercise tolerance and quality of life during the study.The major clinical event (MCE) rate aggregates events from the 29-patient open-label Phase 2 study related to hypoglycemia, cardiomyopathy and rhabdomyolysis. For this study, events that qualified included those that led to a hospitalization, emergency room visit, or an emergency intervention at home. There was a 48.1 percent reduction (p=0.0208) in the mean annualized rate of MCEs and a 50.3 percent reduction (p=0.0284) in the mean annualized duration of all MCEs after 78 weeks of treatment, compared to the mean annualized number and duration of events in the 18 to 24 months prior to treatment with UX007. The major clinical event (MCE) rate aggregates events from the 29-patient open-label Phase 2 study related to hypoglycemia, cardiomyopathy and rhabdomyolysis. For this study, events that qualified included those that led to a hospitalization, emergency room visit, or an emergency intervention at home. There was a 48.1 percent reduction (p=0.0208) in the mean annualized rate of MCEs and a 50.3 percent reduction (p=0.0284) in the mean annualized duration of all MCEs after 78 weeks of treatment, compared to the mean annualized number and duration of events in the 18 to 24 months prior to treatment with UX007. Exercise Tolerance: Eight patients performed the twelve minute walk test (12MWT) at baseline and at Week 60, and showed a 29.7 percent improvement (mean increase: +199.8 meters; median: 149.5; min,max: -122, 1000) from a baseline of 673.4 meters. These results demonstrate that the increase in distance walked observed at 18 weeks was maintained through 60 weeks. The cycle ergometry test at 78 weeks was inconclusive and uninterpretable due to missing data as a result of scheduling conflicts, withdrawal of consent, intercurrent illness and other factors.
• Quality of Life Assessment: Health Related Quality of life was assessed in the Phase 2 study using age appropriate SF-10™ (5-17 years, n=3) and SF-12v2® (>18 years, n=5) Health Surveys. Significant improvements in the impaired physical summary measures (SF-12v2 Physical Component Summary and SF-10 Physical Health Summary) reported at the start of the study were observed after 78 weeks of treatment with UX007.
• Safety/Tolerability Results: Five of the 29 enrolled patients discontinued treatment over the course of the study. One patient discontinued due to diarrhea in week 1, which resolved within a few days of discontinuation, and four patients withdrew consent (weeks 1, 8, 8, 78) for reasons not attributed to treatment with UX007. There were no deaths. There was one previously reported treatment-related serious adverse event for moderate gastroenteritis with vomiting. This patient completed the study and maintained dosing throughout the event, which has now resolved. Overall, 19 patients (66%) had treatment-related adverse events, most of which were mild-to-moderate in nature. The most common treatment-related adverse events were diarrhea, abdominal/gastrointestinal pain, and vomiting. Some gastrointestinal events were managed by adjusting dosing or dosing with food. The most common adverse events, including those not deemed treatment-related, were diarrhea, rhabdomyolisis, vomiting, viral infections, gastrointestinal disorders, headache and fever.
• Phase 2 Study Design and Baseline Characteristics: The single-arm, open-label Phase 2 study evaluated 29 pediatric and adult patients across three main symptom groups (musculoskeletal, liver/hypoglycemia, and cardiac). Patients needed to have moderate to severe FAOD with significant disease in at least one of these domains or a frequent medical events history in order to enroll. The study began with a four-week run-in period to assess baseline data while on the standard of care therapy including medium-chain triglyceride (MCT) oil, if applicable.
• Twenty-five patients completed 24 weeks of treatment, at which point the acute effects of UX007 treatment on the muscular aspects of the disease were evaluated.  Twenty-four patients opted to continue to be treated for a total of 78 weeks with one who withdrew consent late during this period on turning 18 years old. Safety and quality of life assessments were also measured throughout the study. These Phase 2 results are based on open-label uncontrolled treatment referenced to baseline run-in period using careful medical chart reviews for each patient, but the lack of a randomized parallel control group does limit definitive conclusions about efficacy and safety.
• The majority of patients enrolled presented with musculoskeletal disease compared to a limited number who presented with liver and cardiac symptoms. Patients spanned a wide age range from ten months to 58 years old. Patients with four LC-FAOD genotypes were enrolled: twelve (41%) with VLCAD, ten (35%) with LCHAD, four (14%) with CPT-II, and three (10%) with TFP. Prior to initiating treatment with UX007, 27 of the 29 patients were on the standard of care MCT oil therapy. UX007 was then titrated to a target dose of 25-35% of total daily caloric intake.
• Patients performed only the assessments that were appropriate and valid for their age when they entered the study; therefore not all patients performed all assessments included in the study design. Due to the small number of patients who completed a number of the assessments in this Phase 2 study, the results would need to be confirmed in a larger controlled study.

• • On October 13, 2015, Ultragenyx Pharmaceutical announced positive interim data on the acute effects of the investigational treatment UX007 (triheptanoin) at the end of the initial 24-week treatment period of the Phase 2 study in long-chain fatty acid oxidation disorder (LC-FAOD) patients. The single-arm, open-label Phase 2 study evaluated 29 pediatric and adult patients across three main symptom groups (musculoskeletal, liver/hypoglycemia, and cardiac). Patients needed to have moderate to severe FAOD with significant disease in at least one of these domains or a frequent medical events history in order to enroll. The study began with a four-week run-in period to assess baseline data while on the standard of care therapy including medium-chain triglyceride (MCT) oil, if applicable. The patients were then followed to evaluate the effects of UX007 treatment over 24 weeks on several endpoints, including cycle ergometer performance, 12-minute walk test (12MWT), liver disease/hypoglycemia, cardiac disease, and quality of life. The 24-week analysis mainly evaluated the acute effects of UX007 on the musculoskeletal aspects of the disease. The last assessment in this analysis occurred at 18 weeks for the 12MWT and at 24 weeks for the cycle ergometry assessment. The administration of these tests was staggered in order to avoid patient exhaustion during a single visit. Patients who opt to continue will be treated for a total of 78 weeks, and rates of major medical events, such as rhabdomyolysis, hypoglycemia and cardiac events, will be monitored and compared to rates for the two years prior to treatment with UX007. The goal of the study is to evaluate the safety and tolerability of UX007 and to determine both the appropriate patient population as well as endpoints for evaluation in a Phase 3 study. These Phase 2 interim results are based on open-label uncontrolled treatment referenced to baseline run-in period for each patient, which limits definitive conclusions about efficacy and safety.
• The majority of patients enrolled presented with musculoskeletal disease compared to a limited number presented with liver and cardiac symptoms. Patients spanned a wide age range from ten months to 58 years old. Patients with four LC-FAOD genotypes were enrolled: twelve (41%) with VLCAD, ten (35%) with LCHAD, four (14%) with CPT-II, and three (10%) with TFP. Prior to initiating treatment with UX007, 27 of the 29 patients were on the standard of care MCT oil therapy. UX007 was then titrated to a target dose of 25-35% of total daily caloric intake. The average dose of UX007 through 24 weeks was 30% of total daily caloric intake.
• Four of the 29 enrolled patients discontinued prior to 24 weeks, one of which was attributed to an adverse event (diarrhea) from treatment with UX007. Patients performed only the assessments that were appropriate and valid for their age when they entered the study; therefore not all patients performed all assessments included in the study design. Of the 25 patients who continued on UX007 for all 24 weeks, 7 and 8 patients met the age (over six years old) and other eligibility requirements for the cycle ergometry test and 12MWT and completed tests for 24 week analyses, respectively. All but one patient performed both tests. 17 out of the 25 patients were either too young to complete the exercise testing (14/17) or unable to complete the testing due to other physical constraints (3/17). These patients will be reported on at the 78 week analysis.
• Improvements were observed in both measures of exercise tolerance in patients who performed the tests. Improvements in adult patient-reported quality of life scores were also observed in those patients, but no difference was seen in parent-reported scores for pediatric patients. Overall major medical events appeared to decrease in the 25 patients who completed the 24 weeks of treatment when compared to the reported event rate in these patients in the 18-24 months prior to treatment with UX007. These data are preliminary and require significantly more time for proper evaluation at the 78 week time-point. The major medical event rate aggregates events related to hypoglycemia, rhabdomyolysis, and cardiomyopathy.
• Cycle Ergometry: Seven qualified patients of the appropriate age performed the test at baseline and week 24. The three areas of evaluation with cycle ergometry included workload (measured in watts produced at a fixed heart rate), respiratory exchange ratio (RER), a measure of energy supply, and duration of cycling. Patients showed improvements in both workload and duration and no change in RER. At week 24, the seven patients produced a 60% increase in watts over baseline representing a mean increase of +446.8 watts (median: +127.5; min, max: -388, +2438) from baseline of 744.6 watts. These results suggest an increase in muscle performance at a steady level of cardiac exertion as measured by heart rate.
• Of the patients who completed all 40 minutes of the cycle ergometry test at baseline and at week 24, no patients had a reduced duration between baseline and week 24. For the patients (n=3) who were not able to complete all 40 minutes at baseline, mean duration increased 11.1 minutes at week 24 from 11.5 minutes at baseline, representing an increase of 97%.
• 12 Minute Walk Test (12MWT): Eight qualified patients performed the test at baseline and at week 18 and showed a mean increase of +188 meters (median: 93.5; min, max: -80, 880) from a baseline mean of 673.4 meters, representing an increase of 28%. An improvement in the mean energy expenditure index (EEI), the ratio of heart rate per meter walked, was also observed that suggests an increase in exercise efficiency during the walk test. The data on the 12MWT and cycle ergometry together support an improvement in muscle function and exercise efficiency in a small number of patients that would need to be confirmed in larger controlled studies.
• Liver/Hypoglycemia and Cardiac Patients: Patients with liver/hypoglycemia and cardiac disease make up a limited number of patients who completed week 24 of the study; 3 and 2 patients, respectively. There were limited data on glucose or liver enzymes to evaluate ongoing disease in these younger patients but these patients qualified for entry due to frequent history of events and will contribute to the event rate measurement over 78 weeks. Hypoglycemia events/interventions in patients with liver disease will continue to be monitored over time. None of the patients were observed to have decompensated heart failure through the 24 weeks, but cardiomyopathy and related events will also be monitored over the complete 78 weeks of the study. Other Efficacy Results: Quality of life was assessed via two separate surveys in the Phase 2 study. In the SF-12 patient-reported survey completed by adult patients (n=6) who participated in the cycle ergometry and 12MWT, significant improvements were reported in both the physical health and mental health composite scores as well as all subscores after 24 weeks of treatment with UX007. While impairment in the physical health summary of the SF-10 parent-reported survey for pediatric patients (n=8) was reported, there was no change at week 24. There was no impairment and change reported in the psychosocial summary of the SF-10 survey at baseline and at week 24, respectively. The Peabody Developmental Motor Score (PDMS-2), an assessment of gross motor skills in patients under six years old, and the Pediatric Disability Inventory (PEDI-CAT), a care-giver score of functional disability, also showed no impairment in the overall patient population at baseline and no change after 24 weeks.
• Safety/Tolerability Results: Four of the 29 enrolled patients discontinued prior to 24 weeks. One patient discontinued due to diarrhea in week 1, which resolved within a few days of discontinuation, and three patients withdrew consent (weeks 1, 8, 8) for reasons not attributed to treatment with UX007. All other patients opted to continue treatment in the extension phase of the study. There have been no deaths. One serious related adverse event for moderate gastroenteritis with vomiting was considered treatment-related. A viral infection was suspected, but the investigator could not rule out cause by UX007 given the proximity to dosing. That patient continues to be treated in the study and maintained dosing throughout the event, which has now resolved. Overall, 18 patients (62%) had treatment-related adverse events, most of which were mild-to-moderate in nature. The most common treatment-related adverse events were diarrhea, abdominal/gastrointestinal pain, and vomiting. Some gastrointestinal events were managed by adjusting dosing or dosing with food. The most common adverse events, including those not deemed treatment-related, were viral infections, gastrointestinal disorders, rhabdomyolysis, fever, and headache.
• All 25 patients opted to continue to be treated for a total of 78 weeks. Data after 78 weeks, including rates of major medical events before and after treatment with UX007, are expected to be released in the second half of 2016. Based on these interim Phase 2 data, Ultragenyx intends to begin planning for a Phase 3 study of UX007 in LC-FAOD. An update on the design and timing of the Phase 3 study will be provided after discussions with regulatory authorities in the first half of 2016.

Is general: Yes