Addressing the Research Gap in Mitochondrial Myopathy with Validated Outcome Measures and Natural History

ABSTRACT Primary Mitochondrial disease (PMD) is a clinically heterogeneous group of >350 gene disorders due to pathogenic or likely pathogenic variants in either nuclear DNA or mitochondrial (mt)DNA, and collectively affect at least 1 in 4,300 people across all ages. Mitochondrial Myopathy (MM) refers to a subset of

individuals with PMD who predominantly express weakness, exercise intolerance, muscle fatigue, and/or imbalance. Although PMD is one of the most common genetic disorders and is significantly burdensome, causing a mean of 16 symptoms, there are no FDA approved therapies. Historically, there has been a lack of

validated outcome measures that reliably capture MM disease progression. Meaningful metabolic biomarkers of MM do not exist. Prospective natural history studies in MM are lacking. In recent years, there has been an expansion in the pharmaceutical repertoire of MM therapies, leading to a burgeoning emergence of clinical trials. This has created a pressing need for MM outcome measures and natural history.

At the Children’s Hospital of Philadelphia (CHOP) Mitochondrial Medicine Frontier Program (MMFP), we have designed and validated the MM Composite Assessment Tool (MM-COAST), the first performance- based outcome measure that quantifies MM key domains of muscle strength and fatigue, exercise intolerance,dexterity, and imbalance as a single composite score. MM-COAST assessments generate

continuous data in each domain to facilitate capture of incremental change that is typical of MM. More recently, we designed and validated a complimentary tool, the MM-Function Scale, to quantify motor function. MM-COAST and MM- Function Scale facilitate longitudinal assessment that was not previously

possible. We have also designed the MM-IMPACT, a MM-disease specific patient-reported outcome measure (PROM) to assess quality of life (QoL). Currently, our Mitochondrial Myopathy IRB protocol has enrolled 210 genetically confirmed MM subjects from clinic, with ~5 new patients identified each month. In

Aim 1, we will obtain real-world longitudinal MM-COAST and MM-Function Scale measures and define their minimum clinically important difference (MCID) in 175 symptomatic MM children (≥ 5-years old) and adults up to 60-years with mtDNA genetic etiologies. We hypothesize that longitudinal MM-COAST and MM-

Function Scale assessments will demonstrate incremental change over time that varies depending on the individual’s mobility level with or without fatigue, using our new IMPROVE Classification. In Aim 2, we will validate our remote MM Function Scale-R assessment. We hypothesize that remote assessments will be as

valid and reliable as in-person MM-Function Scale assessments. In Aim 3, we will refine and validate the MM-IMPACT PROM. We hypothesize that MM-IMPACT will be more meaningful as compared to generic QoL scales. This timely proposal will be significantly impactful in transforming future MM clinical trial design.