Switching to Glycerol Phenylbutyrate in 48 Patients with Urea Cycle Disorders: Clinical Experience in Spain

Abstract

Background and objectives: Glycerol phenylbutyrate (GPB) has demonstrated safety and efficacy in patients with urea cycle disorders (UCDs) by means of its clinical trial program, but there are limited data in clinical practice. In order to analyze the efficacy and safety of GPB in clinical practice, here we present a national Spanish experience after direct switching from another nitrogen scavenger to GPB. Methods: This observational, retrospective, multicenter study was performed in 48 UCD patients (age 11.7 ± 8.2 years) switching to GPB in 13 centers from nine Spanish regions. Clinical, biochemical, and nutritional data were collected at three different times: prior to GPB introduction, at first follow-up assessment, and after one year of GPB treatment. Number of related adverse effects and hyperammonemic crisis 12 months before and after GPB introduction were recorded. Results: GPB was administered at a 247.8 ± 102.1 mg/kg/day dose, compared to 262.6 ± 126.1 mg/kg/day of previous scavenger (46/48 Na-phenylbutyrate). At first follow-up (79 ± 59 days), a statistically significant reduction in ammonia (from 40.2 ± 17.3 to 32.6 ± 13.9 μmol/L, p < 0.001) and glutamine levels (from 791.4 ± 289.8 to 648.6 ± 247.41 μmol/L, p < 0.001) was observed. After one year of GPB treatment (411 ± 92 days), we observed an improved metabolic control (maintenance of ammonia and glutamine reduction, with improved branched chain amino acids profile), and a reduction in hyperammonemic crisis rate (from 0.3 ± 0.7 to less than 0.1 ± 0.3 crisis/patients/year, p = 0.02) and related adverse effects (RAE, from 0.5 to less than 0.1 RAEs/patients/year p < 0.001). Conclusions: This study demonstrates the safety of direct switching from other nitrogen scavengers to GPB in clinical practice, which improves efficacy, metabolic control, and RAE compared to previous treatments.

Clinical experience with glycerol phenylbutyrate in 20 patients with urea cycle disorders at a UK paediatric centre

“…The reasons for these observed findings are multi‐factorial but are likely to include the prolonged action of GPB and its good tolerability, even at higher doses, which facilitates tighter control of ammonia. These findings are consistent with results of other studies 1,5–7,12–14 . Overall, we have reduced the exposure of patients to PG and sodium and demonstrated biochemical improvements.…”

“…GPB is an alternative scavenger therapy and evidence from clinical trials and real-world data studies suggest GPB is achieving better clinical outcomes than the earlier-generation sodiumbased scavengers. 1,[5][6][7][12][13][14] In our study, the mean ammonia level decreased significantly overall once patients started GPB. Glutamine was also reduced significantly in the balanced sub-group analysis.…”

“…These findings are consistent with results of other studies. 1,[5][6][7][12][13][14] Overall, we have reduced the exposure of patients to PG and sodium and demonstrated biochemical improvements. These have appeared to translate into positive short-term clinical outcomes and have the potential to confer longerterm benefits, as well as improve quality of life.…”

Long-Term Management of Patients with Mild Urea Cycle Disorders Identified through the Newborn Screening: An Expert Opinion for Clinical Practice

“…It is indicated for the treatment of all patients with neonatal-onset presentation and those with late-onset disease who have a history of hyperammonemic encephalopathy [ 29 ]. It is very effective in lowering ammonia, but the regimen is challenging because of the poor palatability, body odor, large volume, high salt content and high frequency of administration [ 30 ].…”

“…GPB consists of a tasteless, odorless and is administered in a small volume, resulting in increased ease of the therapeutic regimen [ 31 , 32 ]. Experiences in switching patients from either sodium benzoate or NaPB to GPB have been reported to maintain metabolic balance and improve the quality of life of patients and caregivers [ 27 , 30 , 33 , 34 ]. Overall, the evolution of nitrogen scavengers progressively improved the management of UCDs, increasing adherence to treatment and quality of life, thus indirectly resulting in improved outcomes.…”