Efficacy and Safety of HPN-100 for the Treatment of Adults With Urea Cycle Disorders

A Phase 3, Randomized, Double-Blind, Cross-Over, Active-Controlled Study of the Efficacy and Safety of HPN-100, Glyceryl Tri-(4-phenylbutyrate), for the Treatment of Adults With Urea Cycle Disorders (Help UCD)

This was a randomized, active-controlled, double-blind, cross-over study designed to enroll subjects with UCDs who are being treated with NaPBA.

This was a randomized, active-controlled, double-blind, cross-over study designed to enroll subjects with UCDs who are being treated with NaPBA. Subjects were randomly assigned to receive either HPN-100 + NaPBA placebo or NaPBA + HPN 100 placebo for 2 weeks, and then crossed over to receive the other treatment for 2 weeks. Venous ammonia was the primary outcome measure. Subjects were admitted to the clinical research unit for 24 hours of pharmacokinetic (PK) blood and urine sampling (including an overnight stay) at the end of each treatment period, by which time the study drug had reached steady state.

Subjects followed a stable diet throughout the study as prescribed by the investigator and dietician. Throughout the study, diet diaries were completed by the subject and dietary protein intake were assessed by a dietician based on completed dietary diaries and consultation with the subject.

Subjects who completed this study and met the study entry criteria, were offered the opportunity to enroll in the HPN-100 open-label safety protocol (HPN-100-007).

Study acquired from Horizon in 2024.

Inclusion Criteria:

• Diagnosis of UCD (Urea Cycle Disorder) involving deficiencies of Carbamyl phosphate synthetase (CPS), Ornithine transcarbamylase (OTC), or Arginosuccinate (ASS), confirmed via enzymatic, biochemical, or genetic testing
• Adult UCD subjects 18 years of age or older who are being treated with Buphenyl/Sodium phenylbuterate (NaPBA) for their UCD; subjects must be on a stable dose of NaPBA for at least 1 week prior to the Day 1 visit. Subjects who are not receiving NaPBA at the initial screening visit, but who have the potential to benefit from treatment, may start receiving NaPBA during the screening period and be enrolled as long as they are on a stable dose of NaPBA for at least 1 week prior to Day 1.
• No clinical evidence of hyperammonemia associated with an ammonia level of ≥ 100 μmol/L during the 2 weeks preceding screening
• Signed informed consent by subject
• Able to perform and comply with study activities, including blood draws and 24-hour urine samples
• 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. Appropriate contraceptive methods include hormonal contraceptives (oral, injected, implanted, or transdermal), tubal ligation, intrauterine device, hysterectomy, vasectomy, or double barrier methods. Abstinence is an acceptable form of birth control, though appropriate contraception must be used if the subject becomes sexually active.

Exclusion Criteria:

• Screening or baseline ammonia level of ≥ 100 μmol/L or signs and symptoms indicative of hyperammonemia during the 2-week period preceding screening or enrollment; subjects may be re-screened after their ammonia is controlled and are stable for at least 14 days, at the discretion of the investigator
• Use of any investigational drug within 30 days of Day 1
• Active infection (viral or bacterial) or any other intercurrent condition (apart from UCD) that may increase ammonia levels
• Any clinical or laboratory abnormality of Grade 3 or greater severity according to the Common Terminology Criteria for Adverse Events (CTCAE) v3.0, except Grade 3 elevations in liver enzymes, defined as levels 5-20 times upper limit of normal (ULN) in alanine aminotransferase (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
• Use of sodium benzoate within one week of Day 1
• History of corrected QT interval (QTc) prolongation or QTc interval > 450 msec at screening or baseline
• Known hypersensitivity to phenylacetate (PAA) or phenylbutyrate (PBA)
• Liver transplant, including hepatocellular transplant
• Breastfeeding or lactating females