Orphanet Journal of Rare Diseases | Real-World Efficacy of Glycerol Phenylbutyrate in Saudi Pediatric Patients with Urea Cycle Disorders

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This study evaluated the real-world efficacy of glycerol phenylbutyrate (GPB) in 37 pediatric patients with urea cycle disorders (UCDs) in Saudi Arabia. The results showed that GPB significantly reduced blood ammonia levels and improved treatment adherence and tolerability, providing important evidence for clinical practice.

 

Literature Overview

The article titled 'Impact of glycerol phenylbutyrate on biochemistry and outcomes in paediatric patients with urea cycle disorders: a multicentre case series from Saudi Arabia', published in the journal Orphanet Journal of Rare Diseases, reviews and summarizes a multicenter retrospective cohort study conducted across three medical centers in Saudi Arabia, assessing the biochemical and clinical outcomes of glycerol phenylbutyrate (GPB) in pediatric patients with urea cycle disorders (UCDs). The study systematically analyzed the therapeutic efficacy and tolerability of GPB by comparing blood ammonia levels, hyperammonemic crises (HACs), hospitalization frequency and duration, growth z-scores, and adverse events before and after GPB initiation. Caregiver surveys were also included to evaluate treatment preferences. Results indicated that GPB significantly improved ammonia control and demonstrated favorable trends across clinical burden metrics. This study provides crucial evidence from a high-incidence region supporting the real-world clinical application of GPB.

Background Knowledge

Urea cycle disorders (UCDs) are a group of rare autosomal recessive metabolic diseases caused by deficiencies in key enzymes of the urea cycle, leading to the inability to effectively convert ammonia into urea, resulting in hyperammonemia that can cause brain damage, coma, or even death in severe cases. In Saudi Arabia, the high rate of consanguineous marriages (approximately 51–56%) has led to a significantly increased incidence of UCDs, making it a major public health concern. Traditional nitrogen scavengers such as sodium benzoate (NaBz) and sodium phenylbutyrate (NaPBA) can promote alternative ammonia excretion but have limitations including poor taste, high sodium load, large administration volumes, and the presence of propylene glycol, all of which affect long-term adherence and safety. Glycerol phenylbutyrate (GPB) is a sodium-free, propylene glycol-free triglyceride prodrug that slowly releases phenylbutyrate via pancreatic lipase, which is then metabolized to phenylacetylglutamine (PAGN) and excreted in urine, enabling smoother and more sustained ammonia clearance. Its pharmacokinetic advantages make it a more attractive therapeutic option. However, real-world efficacy data on GPB, especially in pediatric populations in regions with high genetic burden, remain limited. This study fills that gap by evaluating the actual effectiveness of GPB in Saudi pediatric patients, offering significant clinical and public health implications.

 

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Research Methods and Experiments

This study is a multicenter, retrospective cohort analysis that included 37 UCD patients aged 0–22 years from three major hospitals in Saudi Arabia (KFSH, NGH, PSMC). All patients were initiated on GPB and had complete medical records before and after treatment initiation. Key outcome measures included plasma ammonia levels, annualized incidence of hyperammonemic crises (HACs), HAC-related hospitalizations and duration, growth z-scores, and adverse events. Data were extracted from electronic health records and analyzed using paired comparisons before and after treatment. To correct for differences in follow-up duration, clinical outcomes were annualized. Statistical analyses used paired t-tests or Wilcoxon signed-rank tests based on data distribution. Additionally, a questionnaire was administered to caregivers of 15 patients to assess their preferences regarding GPB versus traditional medications (NaBz/NaPBA) in terms of taste, adherence, and metabolic control.

Key Conclusions and Findings

• GPB significantly reduced routine plasma ammonia levels, with a median reduction of 21% (from 72.0 to 57.0 µmol/L, p = 0.011), and the proportion of patients with elevated ammonia decreased from 74% to 42%
• The annualized HAC rate decreased by 55% (from 2.2 to 1.0 episodes/year), HAC-related hospitalizations dropped by 27% (from 1.12 to 0.76 episodes/year), and hospital days decreased by 24% (from 3.35 to 2.54 days/year); although these changes did not reach statistical significance, they show clear trends toward clinical improvement
• Height and weight z-scores showed slight upward trends (+0.19 and +0.21), but differences were not statistically significant, possibly due to short follow-up duration
• GPB was well tolerated with no drug-related adverse events reported. All 15 caregivers who participated in the survey expressed a preference for GPB, rating it as equal or superior to traditional therapies in ammonia control and adherence, and 85% found its taste better
• In the study, 97% of patients discontinued NaPBA and 73% discontinued NaBz after starting GPB, indicating that GPB can effectively replace traditional combination therapy as a single nitrogen scavenger

Research Significance and Outlook

This study provides strong real-world evidence for the use of GPB in pediatric UCD patients from a region with high consanguinity rates. Results show that GPB not only significantly improves biochemical control but also demonstrates favorable trends in reducing clinical event burden, with very high caregiver preference. These advantages may stem from its stable pharmacokinetics, sodium-free formulation, improved taste, and smaller dosing volume, enhancing long-term adherence and safety.

Although some clinical endpoints did not reach statistical significance, likely due to small sample size and individual heterogeneity, the direction and magnitude of effects are consistent. Combined with strong patient-reported preferences, this supports the clinical value of GPB. The findings support using GPB as a first-line treatment for newly diagnosed patients or as an escalation therapy for those with inadequate control or intolerance to traditional treatments. Future large-scale, multinational prospective studies are needed to further validate long-term growth, neurodevelopmental, and quality-of-life outcomes to optimize overall UCD management strategies.

 

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Conclusion

This multicenter retrospective study systematically evaluated the real-world efficacy of glycerol phenylbutyrate (GPB) in 37 pediatric patients with urea cycle disorders (UCDs) in Saudi Arabia. The study found that, compared to traditional nitrogen scavengers, GPB significantly reduced routine plasma ammonia levels by a median of 21% and nearly halved the proportion of patients with abnormal ammonia levels. Although improvements in hyperammonemic crisis (HAC) frequency, hospitalization frequency, and length of stay did not reach statistical significance, they showed clinically meaningful downward trends. GPB was well tolerated with no treatment-related adverse events reported. Notably, all participating caregivers clearly preferred GPB, citing better metabolic control, improved adherence, and superior taste compared to traditional medications. The results indicate that GPB offers significant advantages in improving biochemical markers, reducing treatment burden, and enhancing patient acceptability, supporting its use as a first-line or escalation therapy for children with UCDs. This study provides important evidence to optimize UCD management in regions with high genetic burden.

 

Rawan Hejazi, Thamer H Alghamdi, Rihab Salih, Zuhair N Al-Hassnan, and Moeenaldeen AlSayed. Impact of glycerol phenylbutyrate on biochemistry and outcomes in paediatric patients with urea cycle disorders: a multicentre case series from Saudi Arabia. Orphanet Journal of Rare Diseases.