Exploring the Relationship Between Surrogate and Long-Term Outcomes in Lysosomal Storage Diseases: A Targeted Literature Review

OBJECTIVES: Clinical trials in lysosomal storage diseases (LSDs) rely on surrogate endpoints, which serve as proxy outcomes due to rare disease-related limitations, such as sample size and trial design. However, these endpoints are commonly challenged by payers and/or health technology assessment bodies. This review evaluates multiple surrogate endpoints commonly used across LSD trials by checking their possible association with long-term outcomes.

METHODS: Published evidence was reviewed using EMBASE^® (inception to 2022) to identify suitable surrogate endpoints. Studies reporting correlation coefficient or hazard ratio were considered for characterizing the association. Selected endpoints were reduced estimated glomerular filtration rate (eGFR) (indirectly measured in different studies), left ventricular mass index, myocardial T1 values, timed 25-foot walk (T25FW), 9-hole peg test (9HPT) and spleen volume. Although T25FW and 9HPT are used in LSD trials, no relevant evidence on LSDs reporting their association with long-term outcomes was identified. Hence, evidence from Multiple sclerosis (MS) was considered for these endpoints.

RESULTS: In patients with Fabry disease, reduced eGFR was associated with decreased quality of life (QoL) and increased risk of cardiovascular/neurological/renal events and mortality; left ventricular hypertrophy showed association with increased risk of cardiovascular morbidity/mortality; and myocardial T1 values exhibited a negative correlation with morbidity. In patients with Acid sphingomyelinase deficiency, increased spleen volume was associated with increased mortality risk. In patients with MS, worsening of T25FW and 9HPT was associated with walking disability, Guy’s Neurological Disability Scale worsening and cognitive disability.

CONCLUSIONS: The review of studies using eGFR, T25FW, 9HPT and spleen volume as outcome measures showed that the worsening of these measures is associated with long-term morbidity/mortality/decreased QoL. Results from publications on surrogate endpoints and their association with long-term outcomes demonstrate the effectiveness of proposed set of surrogates in improving long-term outcomes.