Effect of carglumic acid with or without ammonia scavengers on hyperammonaemia in acute decompensation episodes of organic acidurias

Anupam ChakrapaniEmail author,
Vassili Valayannopoulos,
Nuria García Segarra,
Mireia Del Toro,
Maria Alice Donati,
Angeles García-Cazorla,
María Julieta González,
Celine Plisson and
Vincenzo Giordano

Orphanet Journal of Rare Diseases201813:97

https://doi.org/10.1186/s13023-018-0840-4

Received: 13 July 2017

Accepted: 11 June 2018

Published: 20 June 2018

Abstract

Background

Hyperammonaemia is a key sign of decompensation in organic acidurias (OAs) and can contribute to severe neurological complications, thus requiring rapid treatment.

Methods

A post-hoc analysis of two retrospective studies analysed the efficacy of carglumic acid ± ammonia (NH3) scavengers compared with scavengers alone for reducing plasma NH3levels in patients with OAs and hyperammonaemia (plasma NH3 > 60 μmol/L) during decompensation episodes. NH3 was analysed in 12-h periods at 0–48 h and 24-h periods at 48–120 h. Treatment-emergent adverse events (TEAEs) were recorded.

Results

Of 98 episodes, 38 were treated with carglumic acid (34 patients), 33 with NH3scavengers (22 patients) and 27 with carglumic acid combined with NH3 scavengers (27 patients). Overall, 45% (carglumic acid group), 46% (NH3 scavengers group) and 74% (combination group) of episodes occurred in neonates. Median episode duration was 6 days for the carglumic acid and combination groups, and 9 days for the NH3scavenger group. Median baseline NH3 level was: 199 μmol/L, carglumic acid; 122 μmol/L, NH3 scavengers; and 271 μmol/L, combination; 13, 30 and 11% of episodes required extracorporeal detoxification (ED), respectively. Data were censored at ED initiation. While baseline NH3 levels were higher in the combination and carglumic acid groups, mean reduction in NH3 levels to 72 h in both groups was greater than the NH3scavengers’ group; reductions were greatest in the combination group.

Mean change in plasma NH3 vs baseline in the carglumic acid, NH3 scavengers and combination groups, respectively, was − 13, + 12% and − 27% at 0–12 h (p < 0.05 NH3scavengers vs combination); − 47, − 22% and − 52% at 12–24 h (not significant); − 44, − 5% and − 61% at 24–48 h; and − 66, − 16% and − 76% at 48–72 h (p < 0.05 carglumic acid/combination groups vs NH3 scavengers for both timepoints). The number of TEAEs was similar between groups and mainly related to the disease/condition.

Conclusions

Carglumic acid is a well-tolerated and efficacious treatment for OA decompensation episodes. When given alone or combined with NH3 scavengers, the reduction in NH3was greater than with NH3 scavengers alone in the first 72 h.