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

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.

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