title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Reference Centre for Inherited Metabolic Disorders (MaMEA) and IMAGINE Institiute, Necker-Enfants Malades Hospital, 149 Rue de Sevres, 75743, Paris, Cedex 15, France. vassili.valaya@nck.aphp.fr.
authors.forename: Vassili
authors.initials: V
authors.lastname: Valayannopoulos
authors.affiliation: Reference Center for Metabolic Diseases, Pediatric Neurology & Metabolic diseases, Robert Debre University Hospital, Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Baruteau
authors.affiliation: Unidad de Nutrición y Metabolismo, Hospital Infantil Sevilla, Sevilla, Spain.
authors.forename: Maria Bueno
authors.initials: MB
authors.lastname: Delgado
authors.affiliation: Centre de Référence des Maladies Héréditaires du Métabolisme, CHU Timone Enfants, Marseille, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Cano
authors.affiliation: Complejo Hospitalario Universitario de Santiago de Compostela (CHUS), Santiago de Compostela, Spain.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Couce
authors.affiliation: Servicio de Neurologíia Infantil, Hospital Vall d'Hebrón, Barcelona, Spain.
authors.forename: Mireia
authors.initials: M
authors.lastname: Del Toro
authors.affiliation: Reference Center for Inherited Metabolic and Muscular Disease AOU, Meyer, Firenze, Italy.
authors.forename: Maria Alice
authors.initials: MA
authors.lastname: Donati
authors.affiliation: Hospital Sant Joan de Déu and CIBER-ER, Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: Angeles
authors.initials: A
authors.lastname: Garcia-Cazorla
authors.affiliation: Hospital Universitario Virgen de la Arrixaca, Murcia, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Gil-Ortega
authors.affiliation: Hospital Clínico Universitario de Salamanca, UCI Pediátricia, Salamanca, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Gomez-de Quero
authors.affiliation: Reference Centre of Inherited Metabolic Disorders, Femme Mère Enfant Hospital, Lyon, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Guffon
authors.affiliation: Department of Metabolic Diseases, Wilhelmina Children's Hospital, Utrecht, The Netherlands.
authors.forename: Floris C
authors.initials: FC
authors.lastname: Hofstede
authors.affiliation: Department of Pediatric Metabolism and Nutrition, Ege University Medical Faculty, Izmir, Turkey.
authors.forename: Sema
authors.initials: S
authors.lastname: Kalkan-Ucar
authors.affiliation: Department of Pediatric Metabolism and Nutrition, Ege University Medical Faculty, Izmir, Turkey.
authors.forename: Mahmut
authors.initials: M
authors.lastname: Coker
authors.affiliation: Hospital Infantil Universitario La Paz, Madrid, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Lama-More
authors.affiliation: Unidad Enfermedades Metabólicas Servicio de Pediatria, Hospital Universitario Ramón Y Cajal Ctra, Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Martinez-Pardo Casanova
authors.affiliation: Unidad de Cuidados Intensivos Pediáticos, Hospital Clinic Universitario de Valencia, UCI Neonatal, Valencia, Spain.
authors.forename: Agustin
authors.initials: A
authors.lastname: Molina
authors.affiliation: Reference Center for Metabolic Diseases, Pediatric Neurology & Metabolic diseases, Robert Debre University Hospital, Paris, France.
authors.forename: Samia
authors.initials: S
authors.lastname: Pichard
authors.affiliation: UOC of Metabolic and Genetic Diseases, Children's Hospital Giovanni XXIII, Bari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Papadia
authors.affiliation: Unidad de Cuidados Intensivos Pediáticos, Hospital Clinic Universitario de Valencia, UCI Neonatal, Valencia, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Rosello
authors.affiliation: Medical Affairs, Orphan Europe, Paris, France.
authors.forename: Celine
authors.initials: C
authors.lastname: Plisson
authors.affiliation: Medical Affairs, Orphan Europe, Paris, France.
authors.forename: Jeannie
authors.initials: J
authors.lastname: Le Mouhaer
authors.affiliation: Reference Center for Metabolic Diseases, Pediatric Neurology & Metabolic diseases, Robert Debre University Hospital, Paris, France.
authors.forename: Anupam
authors.initials: A
authors.lastname: Chakrapani
mesh_terms: D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D000592:Amino Acid Metabolism, Inborn Errors / Q000097:blood / Q000188:drug therapy; D000641:Ammonia / Q000097:blood; D005971:Glutamates / Q000627:therapeutic use; D022124:Hyperammonemia / Q000097:blood / Q000188:drug therapy; D056693:Propionic Acidemia / Q000097:blood / Q000188:drug therapy; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D000641:Ammonia; C528449:carglumic acid; D005971:Glutamates
keywords: Carglumic acid; Hyperammonaemia; OA decompensation episodes; Organic acidurias (OAs)