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Effect of Carglumic Acid with Or Without Ammonia Scavengers On Chakrapani et al. Orphanet Journal of Rare Diseases (2018) 13:97 https://doi.org/10.1186/s13023-018-0840-4 RESEARCH Open Access Effect of carglumic acid with or without ammonia scavengers on hyperammonaemia in acute decompensation episodes of organic acidurias Anupam Chakrapani1*, Vassili Valayannopoulos2,9, Nuria García Segarra3,10, Mireia Del Toro4, Maria Alice Donati5, Angeles García-Cazorla6, María Julieta González6, Celine Plisson7 and Vincenzo Giordano8 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 (NH3) scavengers compared with scavengers alone for reducing plasma NH3 levels in patients with OAs and hyperammonaemia (plasma NH3 >60μmol/L) during decompensation episodes. NH3 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 NH3 scavengers (22 patients) and 27 with carglumic acid combined with NH3 scavengers (27 patients). Overall, 45% (carglumic acid group), 46% (NH3 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 NH3 scavenger group. Median baseline NH3 level was: 199 μmol/L, carglumic acid; 122 μmol/L, NH3 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 NH3 levels were higher in the combination and carglumic acid groups, mean reduction in NH3 levels to 72 h in both groups was greater than the NH3 scavengers’ group; reductions were greatest in the combination group. Mean change in plasma NH3 vs baseline in the carglumic acid, NH3 scavengers and combination groups, respectively, was − 13, + 12% and − 27% at 0–12 h (p < 0.05 NH3 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 NH3 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 NH3 scavengers, the reduction in NH3 was greater than with NH3 scavengers alone in the first 72 h. Keywords: Carglumic acid, Ammonia scavengers, Organic aciduria, Hyperammonaemia, Decompensation, Extracorporeal detoxification * Correspondence: [email protected] 1Metabolic Medicine Department, Great Ormond Street Hospital NHS Foundation Trust, Great Ormond Street, London WC1N 3JH, UK Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Chakrapani et al. Orphanet Journal of Rare Diseases (2018) 13:97 Page 2 of 9 Background such as sodium phenylbutyrate and sodium benzoate, Organic acidurias (OAs) are rare, inherited metabolic bypass the urea cycle to increase removal of NH3 from disorders, in which impaired metabolism of organic the blood, by conjugation of benzoate with glycine to acids results in the build-up of toxic metabolites in the generate hippurate, or phenylacetate with glutamine to blood, urine and tissues [1, 2]. The classical OAs include generate phenylacetylglutamine [5, 6]. These conjugates three types of inherited disorders of branched-chain have a higher renal clearance than NH3 itself, and there- amino acids: isovaleric aciduria (IVA), methylmalonic fore accelerate its excretion in the urine [10]. aciduria (MMA) and propionic aciduria (PA) [1] . IVA is Carglumic acid is a synthetic structural analogue of caused by mutations in the gene encoding isovaleryl co- N-acetylglutamate (NAG), which promotes NH3 detoxi- enzyme A (CoA) dehydrogenase, resulting in defective fication by mimicking the effects of NAG on breakdown of leucine. MMA occurs due to a deficiency carbamoyl-phosphate synthetase I (CPS-I) [2]. CPS-I is a of methylmalonyl CoA mutase or due to defects of vita- key enzyme of ureagenesis that catalyses the first and min B12 metabolism. PA occurs as a result of propionyl rate-limiting step of the urea cycle [10, 11]. A recent CoA carboxylase deficiency. These disorders affect the large, retrospective, observational study found that car- metabolism of isoleucine, valine, methionine and threo- glumic acid was an efficacious and well-tolerated treat- nine [1]. Secondary inhibition of the enzyme ment for hyperammonaemia during OA N-acetylglutamate synthase (NAGS) through accumula- decompensation episodes [2] . The objective of the tion of isovaleryl CoA, methylmalonyl CoA and propio- current analysis was to further evaluate the specific effi- nyl CoA in OAs is thought to be one of the pathogenic cacy of the therapy in reducing raised NH3 levels associ- mechanisms impeding elimination of ammonia (NH3) ated with metabolic decompensation episodes in through the urea cycle, resulting in hyperammonaemia patients with OAs, without the confounding influences [2, 3]. In addition, the inability to maintain adequate of NH3 scavengers or ED. levels of glutamine precursors secondary to a dysfunc- tional Krebs’ (tricarboxylic acid) cycle due to lack of suc- Methods cinyl CoA synthesis, impaired in both MMA and PA, is Study design and patient population also proposed as a mechanism of hyperammonaemia in This was a post-hoc pooled analysis of two retrospective, the OAs [4]. observational studies. The main results from one of the OAs typically manifest in the neonatal period, when studies have been published previously [2]. Data were col- they are characterized by toxic encephalopathy present- lected from January 1995 to October 2009 in six European ing within the first few days of life, with symptoms in- countries (Italy, France, Germany, The Netherlands, Spain cluding vomiting, poor feeding and sepsis-like symptoms and the United Kingdom) and Turkey. [5]. If untreated, the condition may progress to lethargy, Patients were included if they had a confirmed diagnosis seizures, coma and multiorgan failure [1]. The most of OA and hyperammonaemia (plasma NH3 >60 μmol/L common misdiagnosis of MMA and PA is sepsis. Meta- before treatment), treated for at least one full decompen- bolic acidosis, elevation of lactate and anion gap, urinary sation episode. Patients with severe hepatic insufficiency ketosis and disturbances of glucose metabolism may at the time of carglumic acid treatment, inherited hepatic help to differentiate MMA and PA from other disorders malformation or conditions (other than OA) that might [6]. The disease course of OA consists of acute meta- have contributed to hyperammonaemia were excluded. bolic decompensation episodes, during which aspects Mean patient age at baseline in the carglumic acid, NH3 such as acidosis and hyperammonaemia should be con- scavenger and combination groups were 34.3 months, sidered. Importantly, these decompensation episodes are 24.6 months, and 19.9 months, respectively. medical emergencies and may lead to severe neuro- The study protocols and amendments were approved logical complications if not treated rapidly [1, 7]. A by the local independent ethics committees (IECs) and/ longer duration of hyperammonaemia and higher NH3 or institutional review boards. Written informed con- levels are associated with poorer neurological outcomes sent/assent was obtained before data were collected. that can lead to serious consequences [1, 5, 8, 9]. There- Cases in which it was not possible to obtain consent fore, one of the main goals of treatment during OA de- (due to death, loss to follow-up) were handled on a compensation episodes is to reduce plasma NH3 levels case-by-case basis with the relevant IEC. The studies as quickly as possible [5, 9]. were conducted in accordance with the principles of the Current guidelines recommend various strategies for Declaration of Helsinki. hyperammonaemia management during OA decompen- sation episodes, including use of NH3 scavengers and Treatments carglumic acid and, in the more severe cases, extracor- Patients were divided into three study groups for ana- poreal detoxification (ED) [2]. Ammonia scavengers, lysis based on the treatment that they received: Chakrapani et al. Orphanet Journal of Rare Diseases (2018) 13:97 Page 3 of 9 carglumic acid (Carbaglu®, Orphan Europe, Paris, study treatment and had a confirmed diagnosis of IVA, France) alone; NH3 scavengers (sodium benzoate and/or MMA or PA. Safety analyses were undertaken on the sodium phenylbutyrate) alone; and carglumic acid com- safety set, which included all decompensation episodes bined with NH3 scavengers (combination).
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