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

Abstract

Background: Isovaleric 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.

Methods: Eligible 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.

Results: The 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.

Conclusion: Carglumic 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.

Keywords: Carglumic acid; Hyperammonaemia; OA decompensation episodes; Organic acidurias (OAs).

Fig. 1

Pathophysiology of hyperammonaemia in organic acidurias and action of carglumic acid. CoA, coenzyme A; CPS-I, carbamoyl-phosphate synthase I; NAG, N-acetylglutamate; NAGS, N-acetylglutamate synthase; -, inhibition; +, activation

Fig. 2

Participant flow. *Includes one patient treated twice as a neonate. ^†Some cases excluded for multiple reasons. IVA, isovaleric aciduria; MMA, methylmalonic aciduria; NH₃, ammonia; PA, propionic aciduria

Fig. 3

Ammonia profile in response to carglumic acid treatment. Endpoint NH₃ in response to treatment with Carbaglu® for each of the diagnostic groups was 52.5 μmol/L (IVA), 67.7 μmol/L (MMA) and 47.8 μmol/L (PA). The time to achieve endpoint was equivalent for the three groups. IVA, isovaleric aciduria; MMA, methylmalonic aciduria; PA, propionic aciduria. Analysis by episode for the total efficacy population and for diagnosis subpopulations

Fig. 4

Ammonia levels in response to carglumic acid therapy by age category.* Ammonia levels in the neonate group were higher than those in the non-neonate group at baseline; however, both groups achieved a similar endpoint ammonia level within the same timeframe (18 hours). *Analysis by episode in the efficacy population; shaded grey area is target plasma ammonia concentration