Carglumic acid enhances rapid ammonia detoxification in classical organic acidurias with a favourable risk-benefit profile: a retrospective observational study

Abstract

BackgroundIsovaleric aciduria (IVA), propionic aciduria (PA) and methylmalonic aciduria (MMA) are inherited organic acidurias (OAs) in which impaired organic acid metabolism induces hyperammonaemia arising partly from secondary deficiency of N-acetylglutamate (NAG) synthase. Rapid reduction in plasma ammonia is required to prevent neurological complications. This retrospective, multicentre, open-label, uncontrolled, phase IIIb study evaluated the efficacy and safety of carglumic acid, a synthetic structural analogue of NAG, for treating hyperammonaemia during OA decompensation.MethodsEligible patients had confirmed OA and hyperammonaemia (plasma NH3 > 60 μmol/L) in ≥1 decompensation episode treated with carglumic acid (dose discretionary, mean (SD) first dose 96.3 (73.8) mg/kg). The primary outcome was change in plasma ammonia from baseline to endpoint (last available ammonia measurement at ≤18 hours after the last carglumic acid administration, or on Day 15) for each episode. Secondary outcomes included clinical response and safety.ResultsThe efficacy population (received ≥1 dose of study drug and had post-baseline measurements) comprised 41 patients (MMA: 21, PA: 16, IVA: 4) with 48 decompensation episodes (MMA: 25, PA: 19, IVA: 4). Mean baseline plasma ammonia concentration was 468.3 (±365.3) μmol/L in neonates (29 episodes) and 171.3 (±75.7) μmol/L in non-neonates (19 episodes). At endpoint the mean plasma NH3 concentration was 60.7 (±36.5) μmol/L in neonates and 55.2 (±21.8) μmol/L in non-neonates. Median time to normalise ammonaemia was 38.4 hours in neonates vs 28.3 hours in non-neonates and was similar between OA subgroups (MMA: 37.5 hours, PA: 36.0 hours, IVA: 40.5 hours). Median time to ammonia normalisation was 1.5 and 1.6 days in patients receiving and not receiving concomitant scavenger therapy, respectively. Although patients receiving carglumic acid with scavengers had a greater reduction in plasma ammonia, the endpoint ammonia levels were similar with or without scavenger therapy. Clinical symptoms improved with therapy. Twenty-five of 57 patients in the safety population (67 episodes) experienced AEs, most of which were not drug-related. Overall, carglumic acid seems to have a good safety profile for treating hyperammonaemia during OA decompensation.ConclusionCarglumic acid when used with or without ammonia scavengers, is an effective treatment for restoration of normal plasma ammonia concentrations in hyperammonaemic episodes in OA patients.

Pathophysiology of propionic and methylmalonic acidemias. Part 2: Treatment strategies

“…Third, there is controversy about the use of N ‐carbamylglutamate in acute and chronic hyperammonemia. While acute amelioration of hyperammonemia due to N ‐carbamylglutamate is unequivocal, and no serious side effects due to N ‐carbamylglutamate are noted, other toxic metabolites do not decrease concurrently with ammonia . Since ammonia is the main biochemical parameter indicating acute metabolic decompensation, there is a risk of not recognizing and hence not managing (impending) acute metabolic decompensations adequately.…”

Methylmalonic and propionic acidemias: clinical management update

“…Inhibition of carbamylphosphate synthetase I (CPS1), a urea cycle enzyme, by accumulating metabolites in OAs causes secondary hyperammonemia in these disorders [167]. N-carbamylglutamate, an N-acetylglutamate analogue, allosterically activates CPS1 and inhibits the secondary effects of the propionate metabolites on CPS1 [36, 45, 189, 192–195]. Once catabolism has been reversed and acidosis corrected, complete nutrition should be reinitiated as soon as possible, preferably via the enteral route.…”

N‐carbamoylglutamate‐responsive carbamoyl phosphate synthetase 1 (CPS1) deficiency: A patient with a novel CPS1 mutation and an experimental study on the mutation's effects

“…One such therapy could be N ‐carbamoyl‐ l ‐glutamate (NCG) use. This deacylase‐resistant analogue of N ‐acetyl‐ l ‐glutamate (NAG), the essential activator of CPS1, is used in primary NAG synthase (NAGS) deficiency and the hyperammonemia of organic acidemias . It could be valuable in partial CPS1D if NAG fails to saturate CPS1 in vivo, which might be common in urea cycle disorders if liver glutamate levels (needed for NAG synthesis; NAGS has a high K m for glutamate) are low due to therapeutic protein restriction and to increased glutamate conversion to glutamine.…”