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

Phase 2

Completed

Conditions: Urea Cycle Disorders

Interventions: Drug: HPN-100
Drug: NaPBA

Registration Number: NCT00947544

Lead Sponsor: Amgen

Brief 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.

Study acquired from Horizon in 2024.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 17

Inclusion Criteria

Male and female subjects 6-17 years old.
Signed informed consent by subject's legally acceptable representative and assent by subject, as applicable.
Diagnosis of urea cycle disorder (enzyme or transporter deficiency) confirmed via enzymatic, biochemical, or genetic testing.
On a stable dose of NaPBA for a diagnosis of UCD for at least 1 week prior to the Day 1 visit.

*Subjects who are not on a stable dose of NaPBA at the initial screening visit may be converted to a stable dose of NaPBA during the screening period and enrolled as long as they are on a stable dose of NaPBA at least 1 week prior to Day 1
Able to perform and comply with study activities, including blood draws and urine collections.
Negative pregnancy test for all females of childbearing potential.
All females of childbearing age and all sexually active males must agree to use an acceptable method of contraception throughout the study.

Exclusion Criteria

Screening ammonia level of ≥100 μmol/L or signs and symptoms indicative of hyperammonemia; subjects may be re-screened after their ammonia is controlled, at the discretion of the investigator.
History of 4 or more hyperammonemic events as defined in Section 3.5.1 in the preceding 12 months.
Use of any investigational drug within 30 days of Day 1.
Active infection (viral or bacterial) or any other condition that may increase ammonia levels.
Any clinical or laboratory abnormality of Grade 3 or greater severity according to the CTCAE v3.0, except Grade 3 elevations in liver enzymes, defined as levels 5-20 times ULN in ALT/SGPT, aspartate aminotransferase (AST/SGOT), or gamma glutamyl transpeptidase (GGT) in a clinically stable subject.
Any clinical or laboratory abnormality or medical condition that, at the discretion of the investigator, may put the subject at increased risk by participating in this study.
Use of any medication known to significantly affect renal clearance (e.g., probenecid) or to increase protein catabolism (e.g., corticosteroids), or other medication known to increase ammonia levels (e.g., valproate), within the 24 hours prior to Day 1 and throughout the study.
History of QTc interval prolongation or QTc interval > 450 msec at screening or baseline.
Known hypersensitivity to PAA or PBA.
Liver transplant, including hepatocellular transplant.
Currently treated with sodium benzoate or Carbaglu® (carglumic acid). At the discretion of the investigator, subjects on sodium benzoate who are otherwise eligible to participate may be switched to 100% NaPBA during the 30 day screening period as part of the study, and at least 7 days prior to Day 1 (Visit 2).
Breastfeeding or lactating females.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
HPN-100 and NaPBA	NaPBA	1 week of NaPBA treatment followed by 1 week of HPN-100 treatment.
HPN-100 and NaPBA	HPN-100	1 week of NaPBA treatment followed by 1 week of HPN-100 treatment.

Primary Outcome Measures

Name	Time	Method
Rate of Adverse Events During the Switchover Part of the Study Rate of Adverse Events (Number of Participants Showing Adverse Events)	1 week on each treatment for a total of 2 week.	To evaluate the safety and PK characteristics of HPN-100 compared with sodium phenylbutyrate (NaPBA) in pediatric patients with urea cycle disorders (UCDs)

Secondary Outcome Measures

Name	Time	Method
Number and Causes of Hyperammonemic Events (Safety Extension)	1 year	Number of Subjects with at Least One Hyperammonemic Crisis. Hyperammonemic crisis is defined as follows: • Clinical symptoms associated with ammonia of ≥ 100 µmol/L
Blood Ammonia Control	Day 7 (NaPBA) and Day 14 (HPN-100)	To evaluate control of blood ammonia by HPN-100 compared with NaPBA in pediatric patients with UCDs.
NH3 Cmax on NaPBA vs. HPN-100 on the Last Day of Treatment With Each Drug	Day 7 (NaPBA) and Day 14 (HPN-100)	blood samples were collected at pre-dose, 4, 8, 12, 16, 20, and 24 hour post dose on both Day 7 (NaPBA) and Day 14 (HPN-100).
Average Ammonia Values on NaPBA vs. HPN-100 on the Last Day of Treatment With Each Drug (Switch Over)	Day 7 (NaPBA) and Day 14 (HPN-100)	blood samples were collected at pre-dose, 4, 8, 12, 16, 20, and 24 hour post dose on both Day 7 (NaPBA) and Day 14 (HPN-100).
Rate (Percentage) of Ammonia Values Above Upper Limit of Normal (ULN) on NaPBA vs. HPN-100	Day 7 (NaPBA) and Day 14 (HPN-100)	blood samples were collected at pre-dose, 4, 8, 12, 16, 20, and 24 hour post dose on both Day 7 (NaPBA) and Day 14 (HPN-100).
Urinary PAGN 24-hour Excretion Values on NaPBA vs. HPN-100 (Switch Over)	Day 7 (NaPBA) and Day 14 (HPN-100)	Urinary PAGN (phenylacetylglutamine) 24-hour excretion. Urine was collect during 0-12 hrs and 12-24 hrs.
Plasma PBA (Phenylbutyrate) AUC0-24 Values on NaPBA vs. HPN-100 on on the Last Day of Treatment With Each Drug	Day 7 (NaPBA) and Day 14 (HPN-100)	blood samples were collected at pre-dose, 4, 8, 12, 16, 20, and 24 hour post dose on both Day 7 (NaPBA) and Day 14 (HPN-100).
Quality of Life Assessed by the SF-15 Questionnaire	1 year	change from baseline to Month 12. The SF 15 questionnaire consists of 15 questions that assess the following: * Physical functioning (5 questions) * Emotional functioning (4 questions) * Social functioning (3 questions) * School functioning (3 questions) Items were scored on a 5-point Likert scale from 0 (never) to 4 (almost always) or a 3-point scale (0 \[not at all\], 2 \[sometimes\], or 4 \[a lot\] for the young child self-report). Items were reverse-scored and linearly transformed to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, and 4=0. Total score was 0-100 scale (averaged from each functional areas). In the 0-100 scale, 0 is the worst score and 100 is best score. Improved quality of life was shown by increased total score from baseline to Month 12.
Plasma PAA (Phenylacetate) AUC0-24 Values on NaPBA vs. HPN-100 on on the Last Day of Treatment With Each Drug	Day 7 (NaPBA) and Day 14 (HPN-100)	blood samples were collected at pre-dose, 4, 8, 12, 16, 20, and 24 hour post dose on both Day 7 (NaPBA) and Day 14 (HPN-100).
Plasma PAGN AUC0-24 Values on NaPBA vs. HPN-100 on on the Last Day of Treatment With Each Drug	Day 7 (NaPBA) and Day 14 (HPN-100)	blood samples were collected at pre-dose, 4, 8, 12, 16, 20, and 24 hour post dose on both Day 7 (NaPBA) and Day 14 (HPN-100).

Trial Locations

Locations (8): Seattle Children's Hospital
🇺🇸
Seattle, Washington, United States
UCLA
🇺🇸
Los Angeles, California, United States
The George Washington DC Children's National Medical Center
🇺🇸
Washington, District of Columbia, United States
Mount Sinai School of Medicine
🇺🇸
New York, New York, United States
Baylor College of Medicine
🇺🇸
Houston, Texas, United States
Medical College of Wisconsin
🇺🇸
Milwaukee, Wisconsin, United States
University of Pittsburgh
🇺🇸
Pittsburgh, Pennsylvania, United States
The Hospital for Sick Children
🇨🇦
Toronto, Ontario, Canada