Efficacy of N-carbamoyl-L-glutamic acid for the treatment of inherited metabolic disorders

Abstract

Introduction N-carbamoyl-L-glutamic acid (NCG) is a synthetic analogue of N-acetyl glutamate (NAG) that works effectively as a cofactor for carbamoyl phosphate synthase 1 and enhances ureagenesis by activating the urea cycle. NCG (brand name, Carbaglu) was recently approved by the United States Food and Drug Administration (US FDA) for the management of NAGS deficiency and by the European Medicines Agency (EMA) for the treatment of NAGS deficiency as well as for the treatment of hyperammonenia in propionic, methylmalonic and isovaleric acidemias in Europe. Areas covered The history, mechanism of action, and efficacy of this new drug are described. Moreover, clinical utility of NCG in a variety of inborn errors of metabolism with secondary NAGS deficiency is discussed. Expert commentary NCG has favorable pharmacological features including better bioavailability compared to NAG. The clinical use of NCG has proven to be so effective as to make dietary protein restriction unnecessary for patients with NAGS deficiency. It has been also demonstrated to be effective for hyperammonemia secondary to other types of inborn errors of metabolism. NCG may have additional therapeutic potential in conditions such as hepatic hyperammonemic encephalopathy secondary to chemotherapies or other liver pathology.

Management of late onset urea cycle disorders—a remaining challenge for the intensivist?

“…N -Carbamoyl- l -glutamic acid (NCG or Carbaglu®) is a structural analogue of N -acetyl glutamate (NAG) that restores urea cycle function in inherited NAGS and CPS1 deficiency [ 45 ]. It works by replacing NAG which is an essential activator of CPS1 [ 46 ]. NCG has also shown its effectiveness in OTC deficiency.…”

Hyperammonaemia in classic organic acidaemias: a review of the literature and two case histories

“…Treatment with N-carbamyl-L-glutamate (NCG; Carbaglu®, Orphan Europe), a stable synthetic analogue of NAG, the essential co-factor of CPS-1, can stimulate the first step of the urea cycle (Fig. 1 ), enabling the formation of carbamyl phosphate and reducing ammonia levels in patients with secondary hyperammonaemia [ 6 , 56 , 57 ]. Two retrospective observational studies [ 35 , 58 ] and case reports [ 56 , 59 , 60 ] indicate that NCG can reduce ammonia levels in neonates and older patients with PA, MMA or IVA, irrespective of the use of scavenger medication [ 6 ].…”

“…1 ), enabling the formation of carbamyl phosphate and reducing ammonia levels in patients with secondary hyperammonaemia [ 6 , 56 , 57 ]. Two retrospective observational studies [ 35 , 58 ] and case reports [ 56 , 59 , 60 ] indicate that NCG can reduce ammonia levels in neonates and older patients with PA, MMA or IVA, irrespective of the use of scavenger medication [ 6 ]. NCG is recommended for the management of patients with undiagnosed symptomatic hyperammonaemia, and is also included in the 2014 European guidance for managing PA and MMA [ 3 ].…”

“…Organic acidaemias (OAs), a group of rare, inherited, metabolic disorders, typically present in neonates or infants as acute, potentially life-threatening, metabolic decompensation [ 1 – 3 ], which follows an initial symptom-free period of a few days [ 3 , 4 ]. An increase in plasma ammonia to toxic levels is often a key feature of metabolic decompensation [ 5 , 6 ], which needs to be addressed promptly since it can lead to life-threatening neurological complications [ 7 ]. Paediatricians, who do not have specialist knowledge of metabolic disorders, have the challenging task of initiating treatment while obtaining a timely diagnosis.…”

First report of carglumic acid in a patient with citrullinemia type 1 (argininosuccinate synthetase deficiency)

“…By directly replacing NAG, which is an essential activator of carbamoyl phosphate synthetase 1 (CPS1), carglumic acid offers an almost curative medication for NAGS deficiency. Additionally, given its capacity to function as a urea cycle activator, carglumic acid has been proposed as a potential therapy for secondary hyperammonaemia resulting from organic acidaemias, hepatic encephalopathy and valproate‐induced hyperammonaemia . Recently, it has been proposed that carglumic acid may have clinical efficacy for other UCDs, such as ornithine transcarbamylase (OTC) deficiency and CPS1 deficiency .…”