Urea Cycle Disorders
Conditions
Keywords
Buphenyl, Sodium Phenylbutyrate, Urea Cycle Disorder, UCD
Brief summary
The purpose of this study is to determine whether HPN-100 is safe and tolerable in subjects with Urea Cycle Disorders.
Detailed description
When protein is broken down in the body, nitrogen is formed. In healthy individuals, the body combines this nitrogen with other molecules to create a harmless substance called urea, which is excreted in the urine. Patients with Urea Cycle Disorders (UCD) are unable to create as much urea from nitrogen, and therefore, toxic levels of nitrogen can accumulate in the body, causing harm. To treat these patients, doctors usually have the patient consume less protein and supplement certain amino acids that may be lacking. A drug called Buphenyl® is sometimes prescribed as an adjunctive treatment for the chronic maintenance of UCD patients in order to keep ammonia levels down. Some issues with Buphenyl® include a high pill burden (up to 40 pills per day), bad taste and odor, and high sodium content. Like Buphenyl®, HPN-100 provides an alternate way for the body to dispose of nitrogen, other than through the urea cycle. Unlike Buphenyl®, HPN-100 is an odorless, tasteless, concentrated oil that does not contain large amounts of sodium. Study acquired from Horizon in 2024.
Interventions
DRUGHPN-100
Subjects will be taking prescribed dose of Buphenyl® TID (not to exceed 20g/day) at least two weeks prior to enrollment. Subjects will take prescribed dose of Buphenyl® TID for first week of study, and then switch over to HPN-100 TID during a dose-escalation phase. The dose of HPN-100 will be increased and the dose of Buphenyl® will be decreased each week by 50 mg/kg until entire daily dose of phenylbutyrate is HPN-100. Target HPN-100 dose will contain the same amount of phenylbutyrate as the subject's prescribed daily dose of Buphenyl®. Subject will take HPN-100 alone for one week and then switch back to previous dose of Buphenyl for the last week of the study.
DRUGBUPHENYL®
BUPHENYL® (sodium phenylbutyrate) tablets and powder have been approved for marketing in the United States since 1996 as an adjunctive therapy in the long-term management of patients with UCDs involving deficiencies of CPS, OTC, or ASS.
Sponsors
Amgen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male and female patients at least 18 years old * Signed written informed consent by patient or patient's representative * Diagnosis of urea cycle enzyme deficiency confirmed via enzymatic or genetic testing * Currently treated with Buphenyl® TID for a minimum of 2 weeks prior to Visit 1 * Able to perform study activities (including the ability to collect all urine in the clinic, i.e., no patients in diapers) * Negative pregnancy test for all females of childbearing potential. All females of childbearing potential must agree to use an acceptable method of contraception throughout the study
Exclusion criteria
* Use of any investigational drug within 30 days of Buphenyl® Visit 1 * Active infection (viral or bacterial) or any other condition that may increase ammonia levels * Laboratory values outside the normal range that are determined to be clinically significant by the investigator * Any clinical or laboratory abnormality of Grade 3 or greater severity according to the Common Terminology Criteria for Adverse Events v3.0 (CTCAE) (or for conditions not covered by the CTCAE, a severe or life-threatening toxicity); except that Grade 3 elevations in liver enzymes are allowed in an otherwise clinically stable patient * Use of any medication known to significantly affect renal clearance (e.g., probenecid) or to increase protein catabolism (e.g., corticosteroids), or other medication (e.g., valproate) known to increase ammonia levels, within the 24 hours prior to Visit 1 * Preexisting QTc interval prolongation (\> 450 msec for males or \> 460 msec for females) * Other severe chronic medical conditions * Known hypersensitivity to PAA, PBA, or benzoate * Creatinine levels equal to or greater than 1.5 × ULN * Liver transplant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Venous Ammonia Levels at the Peak and Mean TNUAC Time-normalized Area Under the Curve) | At steady state (1 week) on each medication (Buphenyl® alone, HPN-100 alone), and at steady state (1 week) after each dose escalation | Data were collected at pre-first dose and at 30 minutes and 1, 2, 4, 5, 6, 8, 10, 12, and 24 hours post first dose. |
| Number of Subjects Experienced Adverse Events | during the period on 100% Buphenyl (up to 4 weeks) or HPN-100 (up to 10 weeks) | — |
| Number of Subjects Experienced Serious Adverse Events | during the period subjects on 100% Buphenyl (up to 4 weeks) or HPN-100 (up to 10 weeks) | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics (Plasma and Urine PK Parameters of Study Drugs and Their Metabolites) | At steady state (1 week) on each medication (Buphenyl® alone, HPN-100 alone) | measured AUC0-24 (Area under the curve from time 0 (pre-dose) to 24 hours) for each metabolite in plasma. Data were collected at 30 minutes and 1, 2, 4, 5, 6, 8, 10, 12, and 24 hours post-first dose. |
| Drug Preference for HPN-100 or Buphenyl® (as Assessed by Global Preference Question) | End of Study | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Buphenyl to HPN-100 HPN-100 : Subjects will be taking prescribed dose of Buphenyl® TID (not to exceed 20g/day) at least two weeks prior to enrollment. Subjects will take prescribed dose of Buphenyl® TID for first week of study, and then switch over to HPN-100 TID during a dose-escalation phase. The dose of HPN-100 will be increased and the dose of Buphenyl® will be decreased each week by 50 mg/kg until entire daily dose of phenylbutyrate is HPN-100. Target HPN-100 dose will contain the same amount of phenylbutyrate as the subject's prescribed daily dose of Buphenyl®. Subject will take HPN-100 alone for one week and then switch back to previous dose of Buphenyl for the last week of the study. | 14 |
| Total | 14 |
Baseline characteristics
| Characteristic | Buphenyl to HPN-100 |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants |
| Age, Continuous | 35.7 years STANDARD_DEVIATION 16.3 |
| Region of Enrollment United States | 14 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 7 / 14 | 5 / 10 |
| serious Total, serious adverse events | 1 / 14 | 0 / 10 |
Outcome results
Primary
Number of Subjects Experienced Adverse Events
Time frame: during the period on 100% Buphenyl (up to 4 weeks) or HPN-100 (up to 10 weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NaPBA Steady State | Number of Subjects Experienced Adverse Events | 7 participants |
| HPN-100 Steady State | Number of Subjects Experienced Adverse Events | 5 participants |
Primary
Number of Subjects Experienced Serious Adverse Events
Time frame: during the period subjects on 100% Buphenyl (up to 4 weeks) or HPN-100 (up to 10 weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NaPBA Steady State | Number of Subjects Experienced Serious Adverse Events | 1 participants |
| HPN-100 Steady State | Number of Subjects Experienced Serious Adverse Events | 0 participants |
Primary
Venous Ammonia Levels at the Peak and Mean TNUAC Time-normalized Area Under the Curve)
Data were collected at pre-first dose and at 30 minutes and 1, 2, 4, 5, 6, 8, 10, 12, and 24 hours post first dose.
Time frame: At steady state (1 week) on each medication (Buphenyl® alone, HPN-100 alone), and at steady state (1 week) after each dose escalation
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| NaPBA Steady State | Venous Ammonia Levels at the Peak and Mean TNUAC Time-normalized Area Under the Curve) | in peak | 79.1 μmol/L | Standard Deviation 40.1 |
| NaPBA Steady State | Venous Ammonia Levels at the Peak and Mean TNUAC Time-normalized Area Under the Curve) | in TNAUC (time-normalized area under the curve) | 38.4 μmol/L | Standard Deviation 19.6 |
| HPN-100 Steady State | Venous Ammonia Levels at the Peak and Mean TNUAC Time-normalized Area Under the Curve) | in peak | 56.3 μmol/L | Standard Deviation 27.9 |
| HPN-100 Steady State | Venous Ammonia Levels at the Peak and Mean TNUAC Time-normalized Area Under the Curve) | in TNAUC (time-normalized area under the curve) | 26.5 μmol/L | Standard Deviation 10.7 |
Secondary
Drug Preference for HPN-100 or Buphenyl® (as Assessed by Global Preference Question)
Time frame: End of Study
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NaPBA Steady State | Drug Preference for HPN-100 or Buphenyl® (as Assessed by Global Preference Question) | prefer HPN-100 | 9 participants |
| NaPBA Steady State | Drug Preference for HPN-100 or Buphenyl® (as Assessed by Global Preference Question) | prefer Buphenyl | 1 participants |
Secondary
Pharmacokinetics (Plasma and Urine PK Parameters of Study Drugs and Their Metabolites)
measured AUC0-24 (Area under the curve from time 0 (pre-dose) to 24 hours) for each metabolite in plasma. Data were collected at 30 minutes and 1, 2, 4, 5, 6, 8, 10, 12, and 24 hours post-first dose.
Time frame: At steady state (1 week) on each medication (Buphenyl® alone, HPN-100 alone)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| NaPBA Steady State | Pharmacokinetics (Plasma and Urine PK Parameters of Study Drugs and Their Metabolites) | AUC0-24 PBA (phenylbutyrate) in plasma | 740 μg*h/mL | Standard Deviation 363 |
| NaPBA Steady State | Pharmacokinetics (Plasma and Urine PK Parameters of Study Drugs and Their Metabolites) | AUC0-24 PAA (phenylacetate) in plasma | 596 μg*h/mL | Standard Deviation 738 |
| NaPBA Steady State | Pharmacokinetics (Plasma and Urine PK Parameters of Study Drugs and Their Metabolites) | AUC0-24 PAGN (phenylacetylglutamine) in plasma | 1133 μg*h/mL | Standard Deviation 352 |
| HPN-100 Steady State | Pharmacokinetics (Plasma and Urine PK Parameters of Study Drugs and Their Metabolites) | AUC0-24 PBA (phenylbutyrate) in plasma | 540 μg*h/mL | Standard Deviation 325 |
| HPN-100 Steady State | Pharmacokinetics (Plasma and Urine PK Parameters of Study Drugs and Their Metabolites) | AUC0-24 PAA (phenylacetate) in plasma | 575 μg*h/mL | Standard Deviation 970 |
| HPN-100 Steady State | Pharmacokinetics (Plasma and Urine PK Parameters of Study Drugs and Their Metabolites) | AUC0-24 PAGN (phenylacetylglutamine) in plasma | 1098 μg*h/mL | Standard Deviation 485 |