Quantitative Systems Pharmacology (QSP) models offer a promising approach to extrapolate drug efficacy across different patient populations, particularly in rare diseases. Unlike conventional empirical models, QSP models can provide a mechanistic understanding of disease progression and therapeutic response by incorporating current disease knowledge into the descriptions of biomarkers and clinical endpoints. This allows for a holistic representation of the disease and drug response. The mechanistic nature of QSP models is well suited to pediatric extrapolation concepts, providing a quantitative method to assess disease and drug response similarity between adults and pediatric patients. The application of a QSP-based assessment of the disease and drug similarity in adult and pediatric patients in the clinical development program of olipudase alfa, a treatment for Acid Sphingomyelinase Deficiency (ASMD), illustrates the potential of this approach.