Population pharmacokinetic/pharmacodynamic modeling of plasma lyso-sphingomyelin response to enzyme replacement therapy olipudase alfa in patients with acid sphingomyelinase deficiency
Xiaoyan Zhang(1), Jing Li(1), Aurelie Brunet(1), Catherine Ortemann-Renon(2), Indrani Nandy(3), Ana Cristina Puga(3)#, Alison Schecter(3), Vanaja Kanamalaru(1)*, Qiang Lu(1)*
(1) Pharmacokinetics, Dynamics, & Metabolism, Translational Medicine and Early Development, Sanofi, Bridgewater, NJ; (2) Translational Medicine and Clinical Pharmacology, Sanofi, Bridgewater, NJ; (3) Rare Disease Development, Sanofi Genzyme, Cambridge, MA. # currently ProQR Therapeutics. * Co-Corresponding author.
Background: Olipudase alfa (recombinant human acid sphingomyelinase (rhASM)) is an intravenous (IV) enzyme replacement therapy under investigation for the treatment of nonneurological manifestations of acid sphingomyelinase deficiency (ASMD), historically known as Niemann-Pick disease types A and B. ASMD is a rare lysosomal storage disorder resulting in the accumulation of sphingomyelin in multiple organs of the body due to the deficiency of ASM, and is associated with significant morbidity and mortality affecting both adults and pediatrics. To date, there are no approved etiologic-specific treatments for ASMD. Results of a Phase 1a study led to an intra-patient dose-escalation strategy, which the slow catabolism of the accumulated sphingomyelin, the less production of ceramide (and its downstream derivatives) associated with adverse drug reactions, enabled the achievement of higher target doses levels. The results of a Phase 1b study using the dose escalation strategy showed a favorable safety profile as well as clinically relevant improvements in adult ASMD patients including: 1) reduction in organomegaly, 2) improvement of pulmonary function and 3) improvement in lipid profile. Lyso-sphingomyelin (lyso-SPM) is a secondary catabolite of sphingomyelin. Plasma lyso-SPM level is often substantially increased in ASMD patients and may be a useful biomarker for monitoring treatment outcomes. Plasma lyso-SPM levels continuously decreased over the course of dose escalation in the Phase 1b study, reflecting a decrease in the accumulation of sphingomyelin with treatment.
Objectives: The current analysis aimed to develop a population pharmacokinetic/ pharmacodynamics (popPK/PD) model to characterize the exposure-response effect of olipudase alfa on the time course of plasma lyso-SPM in adult ASMD patients.
Methods: The lyso-SPM popPK/PD model was developed with PK data from 11 adult patients receiving single doses (no intra-patient dose escalation) of olipudase alfa ranging from 0.03 to 1 mg/kg in a Phase 1a study, and with PK and lyso-SPM data from 5 adult patients (4 of whom also participated in the Phase 1a study) following intra-patient dose-escalation from 0.1 to 3.0 mg/kg in a Phase 1b study (all patients reaching the target dose of 3.0 mg/kg). A sequential modeling approach was applied using NONMEM software: a population PK model was developed first to describe plasma olipudase alfa concentration-time profiles, followed by popPK/PD model development. Model-predicted individual olipudase alfa concentrations were used to develop a popPK/PD model for plasma lyso-SPM over time in adult ASMD patients. The performance of the final popPK/PD model was evaluated by visual predictive checks.
Results: The PK of olipudase alfa was adequately described by a two compartment PK model with parallel linear and nonlinear Michaelis-Menten pharmacokinetic elimination. The estimated key PK parameters are: linear clearance of 0.372 L/h, steady-state volume of distribution of 11.3 L. Body weight was identified as a covariate on both clearance and volume which supported body weight based dosing regimen.The time course of plasma lyso-SPM change was best described by a modified indirect response model with a time-varying production rate, whereas the model-predicted olipudase alfa concentrations (PK) drove the dose-dependent inhibition of lyso-SPM, attributing to both short-term production inhibition of lyso-SPM and long-term decrease in pre-infusion baseline. The estimated key PD parameters are: Lyso-SPM degradation rate constant of 0.0431 day-1 and IC50 of 2.75 ng/ml.The correlation between lyso-SPM and clinical efficacy endpoints is being investigated to further enable the utility of this model to provide the link between PK, PD and clinical endpoints.
Conclusions: A population PK/PD model has been developed to characterize the time course of plasma lyso-SPM responses in adult ASMD patients following olipudase alfa treatment. Further optimization of the model is ongoing as more data becomes available. This model will serve as a critical tool to support the extrapolation of drug efficacy from adult to pediatric patients.