GNE myopathy is a rare autosomal recessive inborn error of metabolism caused by mutations in GNE, the gene that encodes the rate-limiting enzyme in sialic acid biosynthesis. GNE myopathy is characterized by adult-onset, slowly progressive skeletal muscle weakness and atrophy leading to significant disability including wheelchair use and dependent care. There is no approved therapy, but promising therapeutic candidates have been identified. Clinical trial designs for GNE myopathy are complicated by the small patient population and slow disease progression. To overcome this challenge, we generated a disease progression model to understand the rate of muscle decline using longitudinal quantitative strength data collected from a diverse cohort of 42 patients enrolled in “A Natural History Study of GNE Myopathy” (ClinicalTrials.gov NCT01417533). Quantitative muscle assessment (QMA, Aeverl Medical) was determined to be the most sensitive measure of disease progression; it assesses force (kg) in individual muscle groups and is expressed as the proportion of strength predicted for subjects' age, gender and BMI. ‘Disease age’ was determined by fitting a logistic decay model to knee flexion (KF) strength; disease age was defined as zero when KF strength equalled 0.5. Of the 42 patients enrolled, 38 (90%) were able to complete the QMA, compared to only 27 (64%) who completed the 6-minute walk test (6MWT). When strength for individual muscle groups was plotted as a function of disease age, a characteristic pattern of sequential muscle involvement became evident, with the anterior tibialis muscle (ankle dorsiflexion; ADF) affected first, followed by KF, shoulder abduction (SA), grip and elbow flexion (EF). Individual muscles had different rates of progression, with the quadriceps (knee extension; KE) progressing the slowest. The model estimated proportions of strength at disease age 0 as: ADF 0.03, KF 0.5, SA 0.55, KE 0.7, grip 0.78 and EF 0.84. The disease ages at which each muscle has strength of 0.5 are: ADF −8.1, KF 0, SA 2.6, EF 9.6 and grip 11.2. Distance walked on the 6MWT was b400 m at disease age ∼5 and b200 m at disease age ∼20. The median disease ages at which patients reported functional deficits were: falls 0.2; braces 8.8; cane or walker 12.8; lost ambulation 28; dependent on activities of daily living (ADLs) 32.7. Clinical trial designs were simulated to calculate power under different endpoints, where a treatment effect of γ = 0.5 corresponds to a 50% reduction in the rate of decline. A trial with QMA as the primary endpoint and the primary analysis based the progression model, can determine efficacy in 2 years with 50 subjects (98% power; γ = 0.5), compared to 370 and 232 subjects with the 6MWT or composite upper extremity strength as primary endpoints, respectively (80% power; γ = 0.5). Novel endpoints are needed to catalyze the development of therapies for rare diseases, particularly those that are slowly progressive. The GNE myopathy progression model allowed us to determine the rate of disease progression, predict progression across the spectrum of the disease, and design evidence-based clinical trials.
