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Updated: Jul 12, 2026
07:40
Preparation of Peripheral Blood Mononuclear Cell Pellets and Plasma from a Single Blood Draw at Clinical Trial Sites for Biomarker Analysis
Published on: March 20, 2021
Biomarkers and surrogate endpoints for drug development in propionic acidemia
Agnieszka Jurecka1, Sabine Scholl-Bürgi2, Barbara Burton3
1Harvard T.H. Chan School of Public Health, Boston, MA, USA; Savita Institute, Chapel Hill, NC, USA.
Molecular Genetics and Metabolism
|July 9, 2026
Summary
Developing treatments for propionic acidemia (PA) requires validated clinical trial endpoints. This review evaluates biomarkers for PA, finding fibroblast growth factor 21 and 13C-propionate oxidation most promising for future drug development.
Area of Science:
- Biochemistry
- Metabolic Disorders
- Clinical Pharmacology
Background:
- Propionic acidemia (PA) is a severe inherited metabolic disorder lacking disease-modifying therapies.
- Clinical trials for PA are hindered by the absence of validated endpoints for chronic disease modification.
- Regulatory approval pathways necessitate robust biomarkers that predict clinical benefit.
Purpose of the Study:
- To critically evaluate candidate biomarkers for propionic acidemia (PA) as potential surrogate or response endpoints.
- To assess the suitability of biomarkers reflecting propionate metabolism and secondary mitochondrial dysfunction.
- To outline a framework for biomarker readiness and evidence requirements for PA clinical trials.
Main Methods:
- Review of existing literature on PA biomarkers, including methylcitric acid, propionylcarnitine, ammonia, 13C-propionate oxidation, and fibroblast growth factor 21.
- Assessment of biomarkers based on biological plausibility, empirical evidence, clinical data, response durability, and regulatory considerations.
- Evaluation of the linkage between biomarker changes and clinically meaningful outcomes.
Main Results:
- Most routinely used PA biomarkers lack the specificity, stability, or proven clinical linkage for surrogate endpoint use.
- Fibroblast growth factor 21 and 13C-propionate oxidation demonstrate the strongest potential as response biomarkers in specific contexts.
- Significant gaps persist in prospective validation, standardization, and correlation with clinical outcomes for PA biomarkers.
Conclusions:
- Advancing PA drug development requires rigorous biomarker evaluation and qualification.
- Fibroblast growth factor 21 and 13C-propionate oxidation show promise but need further validation.
- A clear framework is needed to guide biomarker development towards surrogate endpoint qualification for PA.
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