Study of the Safety and Tolerability of HPN-100 Compared to Sodium Phenylbutyrate in Children With Urea Cycle Disorders
Condition: Urea Cycle Disorders
MeSH terms: Urea Cycle Disorders, Inborn
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): HPN-100; NaPBA
Intervention type(s): Drug; Drug
Intervention description(s): 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 equivalent amount of PBA that 40 tablets of NapBA do.; NaPBA tablets for oral administration and NaPBA powder for oral, nasogastric, or gastrostomy tube administration contain the active ingredient sodium phenylbutyrate. NaPBA is a prodrug and is rapidly metabolized to PAA, the metabolically active compound that conjugates with glutamine via acetylation to form PAGN, which is excreted by the kidneys.
Other intervention name(s): GT4P, Glyceryl tri-(4-phenylbutyrate); GT4P, Glyceryl tri-(4-phenylbutyrate)
Intervention MeSH terms: 4-phenylbutyric acid
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Urea Cycle Disorder; UCD; GT4P; Buphenyl; hyperammonemia; sodium phenylbutyrate