Journal
JOURNAL OF INHERITED METABOLIC DISEASE
Volume 45, Issue 2, Pages 132-143Publisher
WILEY
DOI: 10.1002/jimd.12478
Keywords
biomarker; clinical trials; methylmalonic acidemia; pathophysiology; propionic acidemia; surrogate endpoint
Funding
- NIH [R01 DK.109907]
- CoA Therapeutics
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There is a need for the development and validation of biomarkers and surrogate endpoints for clinical trials in propionic acidemia (PA) and methylmalonic acidemia (MMA). This review examines the potential biomarkers and surrogate endpoints based on the pathophysiology and clinical consequences of PA and MMA.
There is an unmet need for the development and validation of biomarkers and surrogate endpoints for clinical trials in propionic acidemia (PA) and methylmalonic acidemia (MMA). This review examines the pathophysiology and clinical consequences of PA and MMA that could form the basis for potential biomarkers and surrogate endpoints. Changes in primary metabolites such as methylcitric acid (MCA), MCA:citric acid ratio, oxidation of C-13-propionate (exhaled (CO2)-C-13), and propionylcarnitine (C3) have demonstrated clinical relevance in patients with PA or MMA. Methylmalonic acid, another primary metabolite, is a potential biomarker, but only in patients with MMA. Other potential biomarkers in patients with either PA and MMA include secondary metabolites, such as ammonium, or the mitochondrial disease marker, fibroblast growth factor 21. Additional research is needed to validate these biomarkers as surrogate endpoints, and to determine whether other metabolites or markers of organ damage could also be useful biomarkers for clinical trials of investigational drug treatments in patients with PA or MMA. This review examines the evidence supporting a variety of possible biomarkers for drug development in propionic and methylmalonic acidemias.
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