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Glycerol Phenylbutyrate (Ravicti) [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2017 Apr.
Urea cycle disorders (UCDs) result from genetic mutations that cause defects in any of the five enzymes of the urea cycle in the liver: carbamoyl phosphate synthetase 1 (CPS1), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase, and arginase; in the co-factor producer N-acetyl glutamate synthetase; or in the ornithine transporter and citrin. The estimated incidence of UCDs ranges from one in 22,179 births to one in 53,717 births. The most recent estimate of incidence of UCDs for the US is around one in 35,000 births. It is estimated that approximately 11 new cases of UCDs will be diagnosed each year in Canada. The incidence of OTC deficiency (one in 56,500 live births) is higher than other UCDs. Deficiencies in the urea cycle may result in excessive ammonia levels due to impaired metabolism, which can be life-threatening and result in permanent neurological damage if left untreated. Treatment should be initiated as soon as a diagnosis of a UCD is suspected and should proceed simultaneously with the diagnostic evaluation.
The goals of long-term management of UCDs are to achieve normal development, to prevent hyperammonemia, and to maintain a good quality of life (QoL). These are achieved through a low-protein diet (and sometimes essential amino acids and other essential nutrients supplementation), pharmacotherapies to increase waste nitrogen excretion, and liver transplantation in selected patients. Sodium phenylbutyrate (NaPBA) is the mainstay of pharmacological therapy in chronic management of UCDs; however, its use is associated with decreased appetite, taste disturbances, body odour and menstrual dysfunction/amenorrhea. More recently, glycerol phenylbutyrate (GPB, brand name Ravicti) was approved as a nitrogen-scavenging therapy. This is a triglyceride containing three molecules of phenylbutyric acid. Its major metabolite, phenylacetic acid, conjugates with glutamine through acetylation in the liver and kidneys to form phenylacetylglutamine, which is excreted by the kidneys. GPB is administered orally with a recommended total dose ranging from 4.5 mL/m2 per day to 11.2 mL/m2 per day (5.0 g/m2 per day to 12.4 g/m2 per day). For patients who have been previously treated with NaPBA, the total daily dose of GPB can be calculated based on the total daily dose of NaPBA.
The objective of this systematic review is to examine the beneficial and harmful effects of GPB as a nitrogen-binding agent adjunctive to dietary protein restriction and dietary supplements for chronic management of adult and pediatric (at least two years of age) patients with UCDs.
HPN-100-006 was a phase III, multi-centre, randomized, double-blind (DB), crossover, active-controlled, noninferiority trial that met the inclusion criteria for this systematic review. The primary objective of this study was to assess the noninferiority of GPB to NaPBA by evaluating blood ammonia levels in adult patients with UCDs. The study population included adult patients with a confirmed diagnosis of a UCD and on a stable dose of NaPBA (the mean baseline NaPBA dose was 14.54 ± 6.808 g [mean ± standard deviation] per day) for at least one week before study entry. Excluded were patients with baseline ammonia level ≥ 100 μmol/L or signs and symptoms indicative of hyperammonemia during the two-week period preceding screening or with any clinical or laboratory abnormality or medical condition that may put the patient at increased risk by participating in the study. Eligible patients were randomly assigned to two groups in a DB manner: Arm A — two-week NaPBA followed by two-week GPB, and Arm B — two-week GPB followed by two-week NaPBA. The dose of GPB was calculated from the NaPBA dose determined by the investigator for each patient. The maximum allowed GPB dose was 17.4 mL per day, which was equivalent to 20 g per day of NaPBA. The dose of NaPBA was determined by the investigator at the screening visit and was based on a variety of factors, including severity of the patient’s enzyme deficiency and diet. The maximum dose levels were 600 mg/kg per day in patients weighing less than 20 kg, and 13 g/m2 per day in patients weighing 20 kg or more. There were no washout periods between the two treatments because of safety considerations. The primary outcome was the mean of the 24-hour area under the curve (AUC0–24) for blood ammonia on days 14 and 28. Other efficacy outcomes included maximum blood ammonia values observed on NaPBA versus GPB, and percentage of blood ammonia values above the upper limit of normal (ULN) on NaPBA versus GPB. The number and severity of hyperammonemic crises (HACs) were assessed as well. Safety outcomes measured included adverse events (AEs), serious adverse events (SAEs), and withdrawals due to adverse events. In total, 46 patients were randomized, and 44 patients completed the study. Treatment compliance was high in both treatment groups, with 97.7% and 100% of patients being at least 80% compliant with the NaPBA and GPB treatments, respectively.
No deaths were reported in study HPN-100-006.
No patients had an HAC during GPB treatment. One patient on NaPBA treatment had an HAC.
In the per-protocol (PP) population, the mean AUC0–24 values for blood ammonia were 12% lower with GPB treatment compared with NaPBA (868.29 ± 668.145 μmol·h/L versus 985.47 ± 873.578 μmol·h/L, respectively). GPB achieved noninferiority to NaPBA, as the upper bound of the 95% confidence interval (CI) of the ratio of the geometric means of blood ammonia AUC0–24 between GPB and NaPBA was 1.030, which was below the predefined noninferiority margin of 1.25. Consistent results were observed in the intention-to-treat (ITT) population.
Twenty-four-hour Cmax values for blood ammonia were numerically lower with GPB treatment compared with NaPBA treatment in the patient populations. In the ITT population, mean Cmax values for blood ammonia were 14% lower with GPB treatment compared with NaPBA (60.94 ± 46.213 μmol/L versus 70.83 ± 66.71 μmol/L, respectively). The between-group difference did not reach statistical significance.
The number of ammonia samples above the ULN was similar with GPB and NaPBA treatments in the ITT population (35.6% and 36.2% of samples, respectively).
Cognitive development, anthropometric measurements, and health-related quality of life (HRQoL) were not assessed in study HPN-100-006.
Findings from three longer-term, open-label, non-comparative studies suggested that, after one year of treatment with GPB, the effects of GPB on blood ammonia and glutamine levels appeared to be maintained in both children and adults. In addition, the number of HACs per patient reduced compared with the values 12 months before screening. HRQoL improved in children, whereas it appeared to decrease in adults assessed using generic QoL assessment tools. Neuropsychological testing results were inconsistent across trials, age groups, and across assessment tools.
Overall, the proportion of patients reporting an AE was higher in the GPB group compared with the NaPBA group. Most AEs were considered mild. Treatment of GPB was associated with more lower gastrointestinal (GI) tract disorders, whereas treatment with NaPBA was associated with more upper GI tract disorders. Two patients reported treatment-emergent SAEs: one patient reported acute gastroenteritis on GPB treatment, and one patient reported a grade 3 HAC on NaPBA treatment. No patients discontinued GPB treatment, whereas one patient discontinued NaPBA treatment because of high ammonia levels on day 1. After the treatment with GPB, the report on UCD treatment-specific symptoms such as decreased appetite and body odour reduced compared with baseline.
In the longer-term extension studies, almost all patients experienced AEs after one year of treatment with GPB. Infections, infestations, and GI tract disorders were the most frequently experienced AEs.
One phase III, DB, crossover randomized controlled trial (RCT) conducted in the US and Canada that evaluated the noninferiority of GPB to NaPBA in adult patients with UCDs was included in this review. Study HPN-100-006 enrolled patients with a diagnosis of CPS1, OTC, or ASS deficiencies who had been on dietary protein restriction and/or amino acid supplementation. The patients were required to be on a stable dose of NaPBA at least one week before study entry. A total of 46 patients were randomized (44 evaluable) to receive two weeks NaPBA followed by two weeks GPB, or two weeks GPB followed by two weeks NaPBA. Results from this study suggest that GPB is noninferior to NaPBA in ammonia control, measured with AUC0–24 for blood ammonia levels at study end points, according to the predefined noninferiority margin of 1.25. GPB also showed similar effects on maximum blood ammonia values and the percentage of ammonia samples above the ULN when compared with NaPBA. However, interpretation of results is limited, as no minimal clinically important difference is available to evaluate changes in ammonia levels. There were no HACs during the treatment of GPB, whereas one HAC occurred during the treatment of NaPBA, which led to treatment discontinuation. Cognitive development and HRQoL were not assessed in this study. Patients in the GPB group reported higher risks of AEs compared with those in the NaPBA. These events were generally mild. GPB treatment was associated with more symptoms of lower GI tract disorders, whereas the NaPBA treatment was associated with more symptoms of upper GI tract disorders. One HAC that led to treatment discontinuation was observed in the NaPBA group. After being treated with GPB, patients reported fewer UCD treatment-specific symptoms such as bad taste and body odour.
Findings from longer-term, open-label, non-comparative studies suggested that, after one year of treatment with GPB, the effects of GPB on blood ammonia and glutamine levels appeared to be maintained in both children and adults. The number of HACs per patient reduced compared with the values 12 months before screening. Almost all patients experienced AEs after one year of treatment with GPB. The interpretation of results from these long-term studies is challenging because of several important limitations, such as the study design, sample size, and the study duration.
| GPB (N = 44) | NaPBA (N = 45) | |
|---|---|---|
| Efficacya | ||
| AUC0–24, μmol·h/L (PP Populationb) | ||
| Mean, SD | 868.29 (668.15) | 985.47 (873.58) |
| Difference between GPB and NaPBA, mean (SD) | −117.18 (584.22) | |
| Ratio of geometric means (95% CI) | 0.90 (0.792 to 1.030) | |
| P value c | 0.196 | |
| 24-h Cmax, μmol/L (ITT Population) | ||
| Mean, SD | 60.94 (46.21) | 70.83 (66.71) |
| Difference between GPB and NaPBA, mean (SD) | −9.89 (43.10) | |
| P value | 0.135 | |
| Percentage of Blood Ammonia Values Above the ULN (ITT Population) | ||
| Number of samples > ULN (%)d | 122 (35.6) | 125 (36.2) |
| Harms | ||
| N | 44 | 45 |
| Deaths | 0 | 0 |
| AEs, n (%) | 27 (61.4) | 23 (51.1) |
| SAEs, n (%) | 1 (2.3) | 1 (2.2) |
| WDAEs, n (%) | 0 | 1 (2.2) |
AE = adverse event; AUC = area under the curve; CI = confidence interval; GPB = glycerol phenylbutyrate; ITT = intention-to-treat; NaPBA = sodium phenylbutyrate; PP = per-protocol; SAE = serious adverse event; SD = standard deviation; ULN = upper limit of normal; WDAE = withdrawal due to adverse event.
Results were presented by treatment; therefore, week two and week four data were combined if they derived from the same treatment group.
Per-protocol population: GPB, N = 43; NaPBA, N = 43.
P value for between-group comparison.
Samples from all time points at day 14 and day 28 were analyzed.
Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at http://creativecommons.org/licenses/by-nc-nd/4.0/
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