Trial readiness and endpoint assessment in LGMDR1 (treating-LGMDR1) - the overall goal of this project is to develop reliable and valid clinical outcome assessments (coas) and biomarkers for limb…

Trial readiness and endpoint assessment in LGMDR1 (treating-LGMDR1) - the overall goal of this project is to develop reliable and valid clinical outcome assessments (coas) and biomarkers for limb girdle muscular dystrophy R1 (LGMDR1) to hasten therapeutic development. LGMDR1 is an autosomal recessive form of lgmd due to a loss of function in muscle structural gene CAPN3. This loss of function leads to progressive weakness of the shoulder and HIP girdle muscles and therefore progressive disability, including loss of ambulation or the ability to maintain a job. There are no FDA approved treatments for LGMDR1, which represents a large unmet medical need. LGMDR1 is amenable to gene replacement therapies; and in recent years, a systemic gene therapy has been approved for spinal muscular atrophy and is in development for LGMDR4. At least five companies have gene-targeted therapies or regenerative medicine approaches in development for LGMDR1, creating a situation where therapeutic development has outstripped our ability to prepare for clinical trials. The rationale for this study is that the northstar ambulatory assessment for lgmd (nsad), modified from a widely accepted functional assessment in a related disorder, requires validation as a primary endpoint in LGMDR1. Given the slowly progressive nature of the condition, we also anticipate that a biomarker, such as muscle FAT fraction, is required for early phase therapeutic trials to provide an early signal of effect. We propose the following specific aims: 1) to validate the nsad as a primary endpoint for LGMDR1; and 2) to validate quantitative muscle MRI as a monitoring biomarker in LGMDR1. To achieve our aims, we plan to leverage an existing lgmd clinical research network to conduct a 24-month longitudinal observational study of 100 clinically affected, ambulatory and genetically defined LGMDR1 individuals at 12 sites on our lgmd research network. We hypothesize that the nsad will be amenable to multi-site training, reliable, related to patient-identified areas of disease impact, and useful for power and sample size planning for forthcoming clinical trials. The muscle FAT fraction is likely to demonstrate progression in advance of change on the nsad. Combined, we will model disease progression to define the range of scores on the nsad that would define the optimal therapeutic trial population. At the completion of this study, we will have validated the nsad as a primary endpoint for LGMDR1; validated muscle FAT fraction as an ideal biomarker for LGMDR1; established the clinical trial characteristics, including inclusion/exclusion criteria, sample size, and clinically important difference for therapeutic trials. Given the significant progress in therapeutic development for LGMDR1, the development of appropriate coas and biomarkers for this population is an urgent need.