Quantitative Systems Pharmacology Modeling of Acid Sphingomyelinase Deficiency and the Enzyme Replacement Therapy Olipudase Alfa Is an Innovative Tool for Linking Pathophysiology and Pharmacology

Abstract

Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder with heterogeneous clinical manifestations, including hepatosplenomegaly and infiltrative pulmonary disease, and is associated with significant morbidity and mortality. Olipudase alfa (recombinant human acid sphingomyelinase) is an enzyme replacement therapy under development for the non-neurological manifestations of ASMD. We present a quantitative systems pharmacology (QSP) model supporting the clinical development of olipudase alfa. The model is multiscale and mechanistic, linking the enzymatic deficiency driving the disease to molecular-level, cellular-level, and organ-level effects. Model development was informed by natural history, and preclinical and clinical studies. By considering patient-specific pharmacokinetic (PK) profiles and indicators of disease severity, the model describes pharmacodynamic (PD) and clinical end points for individual patients. The ASMD QSP model provides a platform for quantitatively assessing systemic pharmacological effects in adult and pediatric patients, and explaining variability within and across these patient populations, thereby supporting the extrapolation of treatment response from adults to pediatrics.

Figure 1

(upper panel) Overview of the structure of the quantitative systems pharmacology (QSP) model for acid sphingomyelinase deficiency (ASMD) and the response to olipudase alfa. (lower panel) Enhanced view of molecular level of model, describing the production of sphingomyelin (SM), its conversion to ceramide by endogenous ASM and olipudase alfa (rhASM), and to lysosphingomyelin (lyso‐SM) by deacylases such as acid ceramidase, the intracellular metabolism of both ceramide and lysosphingomyelin, and the export of these biomarker species into the plasma. All reactions are described in all three cell types, except SM uptake via phagocytosis is limited to the splenic and alveolar macrophages. DLco, diffusing capacity of the lung for carbon monoxide; PBPK, physiologically‐based pharmacokinetics.

Figure 2

(upper panel) Calibration of the molecular‐level submodel to plasma ceramide clinical data from the phase Ib study. The model describes both the short‐term and long‐term trends in plasma ceramide (normal range: 1.8–6.5 μg/mL) over time and across increasing doses (0.1–3 mg/kg). (lower panel) Calibration of the molecular‐level submodel to plasma lysosphingomyelin clinical data from the phase Ib study. The model describes the long‐term improvement in plasma lysosphingomyelin (normal range: <10 ng/mL) due to olipudase alfa treatment.

Figure 3

(upper panel) Calibration of the organ‐level submodel to spleen volume (in multiples of normal (MN)) clinical data from the phase 1b study and its long‐term extension. The model describes the long‐term improvement of spleen volume due to olipudase alfa treatment. (lower panel) Calibration of the organ‐level submodel to lung function clinical data in terms of hemoglobin (Hb)‐adjusted % predicted diffusing capacity of the lung for carbon monoxide (DLco) from the phase Ib study and its long‐term extension. The model describes the long‐term improvement of lung function due to olipudase alfa treatment.

Figure 4

Predicted differential responses in the spleen and lung for alternative olipudase alfa maintenance doses (3 mg/kg in solid blue vs. 1 mg/kg in dashed red) for virtual patients with varying disease severities at onset. The left and center columns show the temporal predictions of treatment response over 15 years of treatment, whereas the right column shows the response trajectory representations.

Figure 5

Predicted treatment response in spleen volume and Hb‐adjusted % predicted diffusing capacity of the lung for carbon monoxide (DLco) in a virtual acid sphingomyelinase deficiency (ASMD) patient population with pretreatment spleen volume >15 multiples of normal (MN) and pretreatment hemoglobin (Hb)‐adjusted % predicted DLco ≤50%. The left panel shows a scatterplot comparing virtual patients before treatment (black) with the same virtual patients after receiving 15 years of treatment at a maximum dose of 0.6 mg/kg (blue) or 3 mg/kg (red). The right panel shows the individual response trajectories of a subset of these virtual patients.