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

Majid Alfadhel,Mohammed Saleh,Muhammad Umair,Majed Al-Jeraisy ,Fuad Al Mutairi,Faroug Ababneh,Mohammed Elamin,Lina Alohali,Eissa Faqeih,Zuhair Rahbeeni,Ahmed Alfares,Bayan Albdah,Mohamed Hussein ,Hind Haidar Ahmed ,Marwan Nashabat,Ali Al Othaim,Abdulrahman Alswaid,Wafaa Eyaid,Mohammed Almannai,Ali Alasmari

doi:10.1186/s13023-021-02032-8

Abstract

BackgroundPropionic 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.MethodsThe 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.ResultsThirty-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.ConclusionUsing 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.

Highlights

Propionic acidemia (PA) and methylmalonic acidemia (MMA) are rare, autosomal recessive inborn errors of metabolism that require life-long medical treatment
We report the results of what we believe to be the first clinical trial to evaluate the efficacy of long-term administration of carglumic acid, in addition to standard treatment for the management of PA and Methylmalonic academia (MMA)
This study was approved by the institutional review boards (IRB) of the participating centers and by the Saudi Food and Drug Authority (SFDA) (33066)

Summary

Introduction

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 Organic acidemias, such as propionic acidemia (PA, OMIM #606054) and methylmalonic acidemia (MMA, OMIM #251000), are rare, autosomal recessive inborn errors of metabolism. Patients usually present symptoms such as acidosis, recurrent vomiting, and poor feeding in the neonatal period. MMA is caused by pathogenic variants of the MUT gene (OMIM #609058) encoding methylmalonyl-CoA mutase. These enzymes participate in the catabolism of branchedchain amino acids, synthesis of propionyl-CoA by normal gut flora, and breakdown of odd chain fatty acids [3]. A defect in their function will result in the accumulation of toxic levels of propionyl-CoA and methylmalonyl-CoA, which can cause metabolic decompensation, a common characteristic of both MMA and PA

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