Urea Cycle Disorders
Conditions
Keywords
Urea Cycle Disorder, UCD, hyperammonemia, Buphenyl, Sodium Phenylbutyrate
Brief summary
This was a long-term safety study HPN-100 in urea cycle disorder (UCD) subjects. Subjects were assessed regularly for safety and control of their venous ammonia. Hyperammonemic events were characterized with respect to contributing factors, such as intercurrent illness, diet, and noncompliance with medication.
Detailed description
This was a one year long-term safety study of HPN-100 in UCD subjects. Subjects were assessed regularly for safety and control of their venous ammonia. Hyperammonemic events were characterized with respect to contributing factors, such as intercurrent illness, diet, and noncompliance with medication. Forty subjects with a diagnosis of UCD who completed Study HPN-100-006 were enrolled. Twenty additional UCD subjects ≥ 6 years of age were enrolled. These subjects included those who did not qualify for HPN-100-006 \[e.g., subjects between the ages of 6-17; subjects with other UCD subtypes or adult subjects who have not taken sodium phenylbutyrate (NaPBA) in the past 6 months, etc.\]. For adult subjects not receiving NaPBA in the past 6 months, subjects must, in the judgment of the investigator, be anticipated to benefit from the addition of a nitrogen-scavenging agent to their current treatment. See the inclusion criteria for examples of clinical evidence of potential benefit. Monthly assessments included safety laboratory tests, amino acid panel, vital signs, electrocardiogram (ECG) monitoring, venous ammonia, and blood and urine metabolites. Adverse events (AEs) and concomitant medications were recorded on an ongoing basis. Study acquired from Horizon in 2024.
Interventions
DRUGHPN-100
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 (\ 17.4 mL) delivers equivalent of PBA that 40 tablets of NaPBA do.
Sponsors
Amgen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male and female subjects who completed HPN-100-006: \*Additionally, approximately 20 UCD subjects ≥ 6 years of age may be enrolled who have not participated in HPN-100-006. These subjects may include those who did not qualify HPN-100-006 (e.g., subjects between the ages of 6-17 years, subjects with other UCD subtypes, or adult subjects who have not taken sodium phenylbutyrate (NaPBA) in the past 6 months, etc.). For adult subjects not receiving NaPBA in the past 6 months, subjects must, in the judgment of the investigator, be anticipated to benefit from the addition of a nitrogen-scavenging agent to their current treatment. Clinical evidence of potential benefit from introduction of an ammonia-scavenging agent might include a recent history (in the past year) of clinically overt hyperammonemia accompanied by a venous ammonia ≥ 100 μmol/L, a recent history (within the past year) of protein intolerance, or a history of abnormally high venous ammonia levels accompanied by symptoms (e.g., headache) that might reasonably be attributed to hyperammonemia. * Signed informed consent by subject and/or subject's legally acceptable representative. * Diagnosis of urea cycle disorder (enzyme or transporter deficiency) confirmed via enzymatic, biochemical, or genetic testing. * Able to perform and comply with study activities, including blood draws. * Negative pregnancy test for all females of childbearing potential. * All females of childbearing potential and all sexually active males must agree to use an acceptable method of contraception throughout the study.
Exclusion criteria
* Screening venous ammonia level of ≥ 100 μmol/L or signs and symptoms indicative of hyperammonemia; subjects may be re-screened after their venous 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. * Active infection (viral or bacterial) or any other condition that may increase venous ammonia levels. * 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 venous ammonia levels (e.g., valproate), within the 24 hours prior to Day 1 and throughout the study. * History of QTc (QT interval corrected) prolongation, or a QTc interval ≥ 450 msec or an increase of ≥ 60 msec during the previous HPN-100 study if applicable. * Known hypersensitivity to PAA or PBA. * Liver transplant, including hepatocellular transplant. * Breastfeeding or lactating females.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Rate of Adverse Events (Number of Participants Who Experienced Any AE Considered Related to Study Drug) | 1 year |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number and Causes of Hyperammonemic Events | 1 year | Number of hyperammonemic crises per patient |
| Blood Ammonia Levels | 1 Year | Venous Ammonia levels over time |
| Patient Satisfaction With HPN-100 | Month 1 post dose | Drug preference will be noted at week 3 |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| HPN-100 Patients who were treated with HPN-100 | 60 |
| Total | 60 |
Baseline characteristics
| Characteristic | HPN-100 |
|---|---|
| Age, Categorical <=18 years | 9 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 51 Participants |
| Age, Continuous | 28.83 years STANDARD_DEVIATION 13.933 |
| Region of Enrollment Canada | 6 participants |
| Region of Enrollment United States | 54 participants |
| Sex: Female, Male Female | 41 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 59 / 60 |
| serious Total, serious adverse events | 12 / 60 |
Outcome results
Primary
Rate of Adverse Events (Number of Participants Who Experienced Any AE Considered Related to Study Drug)
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HPN-100 | Rate of Adverse Events (Number of Participants Who Experienced Any AE Considered Related to Study Drug) | 33 participants |
Secondary
Blood Ammonia Levels
Venous Ammonia levels over time
Time frame: 1 Year
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| HPN-100 | Blood Ammonia Levels | Baseline | 27.623 Umol/L | Standard Deviation 15.8875 |
| HPN-100 | Blood Ammonia Levels | Month 12 | 24.202 Umol/L | Standard Deviation 20.6124 |
Secondary
Number and Causes of Hyperammonemic Events
Number of hyperammonemic crises per patient
Time frame: 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HPN-100 | Number and Causes of Hyperammonemic Events | 0.20 hyperammonemic events | Standard Deviation 0.514 |
Secondary
Patient Satisfaction With HPN-100
Drug preference will be noted at week 3
Time frame: Month 1 post dose
Population: all available questionnaires
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HPN-100 | Patient Satisfaction With HPN-100 | 90 % preferred HPN-100 |