The efficacy of RAVICTI in pediatric patients 2 years to 17 years of age with UCDs was evaluated in 2 fixed-sequence, open-label, sodium phenylbutyrate to RAVICTI switchover studies (Studies 3 and 4). Study 3 was 7 days in duration and Study 4 was 10 days in duration.

These studies compared ammonia levels of patients on RAVICTI to ammonia levels of patients on sodium phenylbutyrate in 26 pediatric patients between 2 months and 17 years of age with UCDs. Four patients less than 2 years of age were excluded from this analysis due to insufficient data. The dose of RAVICTI was calculated to deliver the same amount of PBA as the dose of sodium phenylbutyrate that patients were taking when they entered the trial. Sodium phenylbutyrate or RAVICTI were administered in divided doses with meals. Patients adhered to a low-protein diet throughout the study. After a dosing period with each treatment, all patients underwent 24 hours of venous ammonia measurements, as well as blood and urine pharmacokinetic assessments.

UCD subtypes included OTC (n=12), ASL (n=8), and ASS deficiency (n=2), and patients received a mean RAVICTI dose of 8 mL/m2/day (8.8 g/m2/day), with doses ranging from 1.4 to 13.1 mL/m2/day (1.5 to 14.4 g/m2/day). Doses in these patients were based on previous dosing of sodium phenylbutyrate.

The 24-hour AUCs for ammonia (AUC0-24h) in 11 pediatric patients 6 years to 17 years of age with UCDs (Study 3) and 11 pediatric patients 2 years to 5 years of age with UCDs (Study 4) were similar between treatments. In pediatric patients 6 years to 17 years of age, the ammonia AUC0-24h was 604 micromol∙h/L vs 815 micromol∙h/L on RAVICTI vs sodium phenylbutyrate, respectively. In patients between 2 years and 5 years of age with UCDs, the ammonia AUC0-24h was 632 micromol∙h/L vs 720 micromol∙h/L on RAVICTI versus sodium phenylbutyrate, respectively.

The mean ammonia levels over 24 hours in open-label, short-term Studies 3 and 4 at common time points are displayed in Figure 4. Ammonia values across different laboratories were normalized to a common normal range of 9 to 35 micromol/L using the following formula after standardization of the units to micromol/L:

Normalized ammonia (micromol/L) = ammonia readout in micromol/L × (35/ULN of a laboratory reference range specified for each assay)

Figure 4: Ammonia Levels in Pediatric Patients 2 Years to 17 Years of Age with UCDs in Short-Term Treatment Studies 3 and 4

Open-Label, Uncontrolled, Extension Studies in Pediatric Patients 2 Years to 17 Years of Age

Long-term (12-month), uncontrolled, open-label studies were conducted to assess monthly ammonia control and hyperammonemic crises over a 12-month period. In two studies (Study 2, which also enrolled adults, and an extension of Study 3, referred to here as Study 3E), a total of 26 pediatric patients ages 6 years to 17 years were enrolled and all but 1 had been converted from sodium phenylbutyrate to RAVICTI. Mean fasting venous ammonia levels were within normal limits (range 17 to 23 micromol/L) during long-term treatment with RAVICTI. Of the 26 pediatric patients 6 years to 17 years of age participating in these two trials, 5 patients (19%) reported a total of 5 hyperammonemic crises. The fasting ammonia levels measured during these two extension studies in patients 6 years to 17 years are displayed in Figure 5. Ammonia values across different laboratories were normalized to a common normal range of 9 to 35 micromol/L.

Figure 5: Ammonia Levels in Pediatric Patients 2 Years to 17 Years of Age with UCDs in Long-Term Treatment Studies 2 and 3E

In an extension of Study 4 (referred to as Study 4E), after a median time on study of 4.5 months (range: 1 to 5.7 months), 2 of 16 pediatric patients ages 2 years to 5 years had experienced three hyperammonemic crises.

Open-Label, Long-Term Study in Pediatric Patients 1 Year to 17 Years of Age

An open-label, long-term study (Study 5) was conducted to assess ammonia levels in pediatric patients with UCD. The study enrolled patients with UCDs who had completed Studies 2, 3E and 4E. A total of 45 pediatric patients ages 1 year to 17 years were included in the study. The median length of treatment was 1.7 years (range 0.2 to 4.6 years). Venous ammonia levels were monitored at a minimum every 6 months. Mean ammonia values in pediatric patients in Study 5 were within normal limits during long-term (24 months) treatment with RAVICTI (range: 15.4 to 25.1 micromol/L). Of the 45 pediatric patients participating in the open-label treatment with RAVICTI, 11 patients (24%) reported a total of 22 hyperammonemic crises. Ammonia values across different laboratories were normalized to a common normal range of 10 to 35 micromol/L.