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

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 (NH 3 ) scavengers compared with scavengers alone for reducing plasma NH 3 levels in patients with OAs and hyperammonaemia (plasma NH 3 > 60 μmol/L) during decompensation episodes. NH 3 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 NH 3 scavengers (22 patients) and 27 with carglumic acid combined with NH 3 scavengers (27 patients). Overall, 45% (carglumic acid group), 46% (NH 3 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 NH 3 scavenger group. Median baseline NH 3 level was: 199 μmol/L, carglumic acid; 122 μmol/L, NH 3 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 NH 3 levels were higher in the combination and carglumic acid groups, mean reduction in NH 3 levels to 72 h in both groups was greater than the NH 3 scavengers' group; reductions were greatest in the combination group. Mean change in plasma NH 3 vs baseline in the carglumic acid, NH 3 scavengers and combination groups, respectively, was - 13, + 12% and - 27% at 0-12 h (p < 0.05 NH 3 scavengers 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 NH 3 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 NH 3 scavengers, the reduction in NH 3 was greater than with NH 3 scavengers alone in the first 72 h.