Study of the Safety and Tolerability of HPN-100 Compared to Sodium Phenylbutyrate in Children With Urea Cycle Disorders

Protocol HPN-100-005 was the first study of HPN-100 in pediatric subjects with urea cycle disorders (UCDs) and was a fixed-sequence, open-label, switch over study of HPN-100 with a long-term (12 month) safety extension designed to assess the safety of HPN-100 and to prospectively assess its ability to control blood ammonia as compared with Sodium Phenylbutyrate (NaPBA). Upon DSMB review of the first ten subjects who completed the switch over part of the study, and with DSMB approval, up to an additional 20 subjects were enrolled into the safety extension part of the study. HPN-100 is a triglyceride that has a similar mechanism of action as NaPBA. It is a liquid with minimal taste and odor. Three teaspoons of HPN-100 (\~17.4mL) delivers an equivalent amount of PBA to 40 tablets of NaPBA.

This was a fixed-sequence, open-label, switch over study of HPN-100 with a long-term (12 month) safety extension part designed to assess the safety of HPN-100 in pediatric subjects and to prospectively assess the ability of HPN-100 to control blood ammonia compared with NaPBA. For those subjects who participated in the switch over, NaPBA was dosed three times daily (TID) with meals during the first week and the same PBA mole-equivalent dose of HPN-100 during the second week. If there were safety concerns regarding a single-step transition from NaPBA to HPN-100, at the investigator's discretion, the transition could occur in 2 steps such that in the second week, subjects might receive 50% of the PBA equivalent dose as NaPBA and 50% as HPN-100 before receiving 100% of the PBA equivalent dose as HPN-100 in the third week. Serial blood samples were collected for PK and blood ammonia assessments after each drug reached steady state, which was achieved approximately 4 days after initiation of 100% NaPBA or HPN-100 treatment. The subjects who completed the switch over part of the study, and up to 20 additional subjects, were offered the opportunity to continue in the study by entering the safety extension part of the study to continue receiving open-label HPN-100 for up to 12 months. Subjects who prematurely terminated the study during the switch-over period after enrollment had safety assessments, including safety labs and a single blood sample drawn for measurement of phenylbutyrate (PBA), the active metabolite phenylacetate (PAA), and the terminal metabolite phenylacetylglutamine (PAGN). Subjects who had enrolled in the safety extension period of the study, either directly or following the switch over, but prematurely terminated the study prior to completing the extension period had Month 12 procedures performed, or at a minimum, had safety assessments including safety labs and ammonia had drawn. The time of day at which the blood sample was drawn was recorded as well as the time since the last dose of medication was taken. Subjects followed a stable diet throughout the study, as prescribed by the investigator, and dietary compliance was recorded at each study visit for both the switch over and safety extension parts of the study. Study acquired from Horizon in 2024.