Dose-Escalation Safety Study of HPN-100 to Treat Urea Cycle Disorders

Phase 2

Completed

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.

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
BUPHENYL® to HPN-100 vs. HPN-100	BUPHENYL®	Buphenyl treatment for one week was followed by dose escalation to HPN-100. Dose of Buphenyl was gradually decreased while HPN-100 dose was gradually increased until subject reached dosing of 100% HPN-100. HPN-100 at 100% of the dose was given for 1 week before subject was switched back to original Buphenyl treatment.
BUPHENYL® to HPN-100 vs. HPN-100	HPN-100	Buphenyl treatment for one week was followed by dose escalation to HPN-100. Dose of Buphenyl was gradually decreased while HPN-100 dose was gradually increased until subject reached dosing of 100% HPN-100. HPN-100 at 100% of the dose was given for 1 week before subject was switched back to original Buphenyl treatment.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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