From Pharmacodynamic Biomarker to Evaluating Treatment Response: Biomarkers in Primary Mitochondrial Diseases

Primary mitochondrial diseases (PMDs) result from genetic variants in nuclear DNA and mitochondrial DNA which commonly lead to aberrant oxidative phosphorylation. The clinical complexity, often attributed to the underlying genetics, includes several distinct syndromes (e.g., Barth syndrome; Pearson syndrome; Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes), some with overlapping symptoms. PMDs are highly heterogenous and affect multiple organs and tissues, prominently those with high energy demand such as muscle and neurologic tissues. Disease-modifying therapies for PMDs approved by the United States Food and Drug Administration are few and disease-specific, and treatment remains largely supportive in nature. The lack of robust biomarkers contributes to challenges associated with quantifying treatment responses in drug development. Recognizing this area of critical need, we sought to understand the landscape of molecular biomarkers that may inform treatment response, support clinical trials, and may be useful for regulatory decision-making. In this review, we assess the extent of evidence and challenges for each biomarker. We propose considerations for future biomarker development to measure treatment response and facilitate early drug development in PMDs by guiding dose selection and trial enrichment.