Long-term effectiveness of carglumic acid in patients with propionic acidemia (PA) and methylmalonic acidemia (MMA): a randomized clinical trial

Abstract

Background Propionic acidemia (PA) and methylmalonic acidemia (MMA) are rare, autosomal recessive inborn errors of metabolism that require life-long medical treatment. The trial aimed to evaluate the effectiveness of the administration of carglumic acid with the standard treatment compared to the standard treatment alone in the management of these organic acidemias. Methods The study was a prospective, multicenter, randomized, parallel-group, open-label, controlled clinical trial. Patients aged ≤ 15 years with confirmed PA and MMA were included in the study. Patients were followed up for two years. The primary outcome was the number of emergency room (ER) admissions because of hyperammonemia. Secondary outcomes included plasma ammonia levels over time, time to the first episode of hyperammonemia, biomarkers, and differences in the duration of hospital stay. Results Thirty-eight patients were included in the study. On the primary efficacy endpoint, a mean of 6.31 ER admissions was observed for the carglumic acid arm, compared with 12.76 for standard treatment, with a significant difference between the groups (p = 0.0095). Of the secondary outcomes, the only significant differences were in glycine and free carnitine levels. Conclusion Using carglumic acid in addition to standard treatment over the long term significantly reduces the number of ER admissions because of hyperammonemia in patients with PA and MMA.

Management of methylmalonic acidemia (MMA) with N‐carbamylglutamate: A case report from Italy

“…The objective of the study was to compare the efficacy of adding CA (50 mg/kg/day in divided doses, twice daily) to standard treatment in patients with PA and MMA. Results, of what the authors describe as the first prospective clinical trial to evaluate the efficacy of long term of CA, confirmed that CA is well tolerated and significantly reduces the number of hospital admissions due to hyperammonemia in patients with PA and MMA (Alfadhel et al, 2021). Thirty‐eight patients (21 received CA and 17 standard therapy) were included in the study and on the primary efficacy endpoint, a mean of 6.31 emergency room admissions was observed for the CA arm, compared with 12.76 for standard treatment, with a significant difference between the groups ( p = .0095).…”

Congenital disorder of glycosylation with defective fucosylation 2 (FCSK gene defect): The third report in the literature with a mild phenotype

“…Furthermore, parenteral genetic screening/diagnosis is the best strategy for managing this disease, which currently has no therapy (Alfadhel et al, 2019 ; Alyafee, Al Tuwaijri, et al, 2021 ; Alyafee, Alam, et al, 2021 ). Reporting additional cases associated with this gene would help identify genotype–phenotype correlations and lead to clinical trials in the future (Alfadhel et al, 2021 ). This study further proves with essential evidence that variants of FCSK cause mild‐to‐severe CDG in humans.…”

Orphan Drug Use in Patients With Rare Diseases: A Population-Based Cohort Study

“…MMA is an autosomal recessive inherited rare disease of metabolism involving pathogenic variants of the genes encoding for methylmalonic-CoA mutase (MMA mut type) or involved in the synthesis of its cofactor adenosylcobalamin (MMA cbl type) ( Chakrapani et al, 2018 ; Nashabat et al, 2019 ). The consequent accumulation of methylmalonic-CoA results in the competitive inhibition of N-acetylglutamate synthase and carbamoyl phosphate synthase 1 (CPS 1), an enzyme involved in the first and rate-limiting step of the urea cycle, causing hyperammonemia ( Alfadhel et al, 2021 ). Carglumic acid restores the function of the urea cycle by activating CPS 1 and normalizes blood ammonia levels during acute decompensation episodes ( Chakrapani et al, 2018 ; Nashabat et al, 2019 ).…”

“…All these medications are safe and generally well-tolerated, but they have different therapeutic indications, hence a direct comparison on their prevalence of use would lead to incorrect evaluations. Current guidelines recommend the use of carglumic acid during decompensation episodes, which carry a high risk of mortality and neurological complications if not promptly treated ( Valayannopoulos et al, 2016 ; Häberle et al, 2018 ; Nashabat et al, 2019 ), whereas there is still limited evidence on the long-term efficacy of carglumic acid in MMA ( Alfadhel et al, 2021 ). In addition, the frequent poor adherence of patients to carglumic acid and its current use mainly in hospitalized patients with severe disease may further account for the low prevalence of this orphan drug use found in our cohort.…”