Gilles Tiraboschi (1), Jean-Marie Martinez (1), Monica Kumar (3), Sreeraj Macha (2), David Fabre (1), Jing Li (2).
(1) Pharmacokinetics-Dynamics and Metabolism (PKDM), Translational Medicine and Early Development, Sanofi, R&D, Montpellier, France (2) PKDM, Translational Medicine and Early Development, Sanofi, R&D, Bridgewater, NJ, USA (3) Rare Diseases & Rare Blood Disorders, Sanofi, R&D, Bridgewater, NJ, USA.
Introduction:
Acid sphingomyelinase deficiency (ASMD), historically known as Niemann-Pick disease types A and B, is a rare and potentially life-threatening lysosomal storage disease for which currently only symptomatic treatments are available. It is characterized by reduced ASM activity, which results in progressive lysosomal accumulation of sphingomyelin, leading to tissue damage and organ dysfunction, including splenomegaly and infiltrative lung disease.
Olipudase alfa is a recombinant human acid sphingomyelinase enzyme replacement therapy in late-stage development for non-central nervous system manifestations in ASMD patients. In clinical trials in adults and children with ASMD, olipudase alfa breaks down accumulated sphingomyelin, reduces spleen volume, and improves pulmonary function (measured by diffusing capacity of the lung for carbon monoxide, DLco) [1,2,3]. Lyso-sphingomyelin (lyso-SM), a deacylated form of sphingomyelin, is substantially elevated in plasma of ASMD. Since plasma lyso-SM is derived from target tissues, its reduction following IV infusion of olipudase alfa reflects its mechanism of action.
Objectives:
The objectives of these population pharmacokinetic (popPK) and population pharmacokinetic/pharmacodynamic (popPK/PD) analyses were:
- To characterize PK of olipudase alfa in adult and pediatric ASMD patients
- To characterize pharmacokinetic/pharmacodynamic relationships with plasma lyso-SM
- To characterize relationships for spleen volume and DLco efficacy endpoints with plasma lyso-SM
Methods:
The models were developed using data pooled from adult and pediatric patients who received intra-patient dose escalation (from 0.1 to 3 mg/kg for adult and from 0.03 to 3mg/kg for pediatric patients, with target maintenance dose of 3 mg/kg) administered every 2 weeks intravenously.
A sequential approach was used firstly, to develop the popPK model, followed by the development of the lyso-SM popPK/PD model, using the predicted olipudase alfa plasma concentrations. Then the predicted lyso-SM concentrations were used to develop two models to characterize the time course of spleen volume and DLco clinical endpoints. For each model, a covariate analysis was performed and significant covariates were selected through a forward/backward selection process.
Models were developed in NONMEM 7.4.1 [4] using FOCEI algorithm for optimization. The qualification step was assessed using Prediction-Corrected Visual Predictive Check [5] and Sampling Importance Resampling iterative [6] methods. For the computation of exposure parameters and simulations, the mrgsolve package [7] embedded in an in-house shiny application [8] was used.
Results:
Olipudase alfa plasma concentrations were best described by a three-compartment model with linear elimination from the central compartment. Time-varying bodyweight dependent allometric scaling factors (clearance and compartment volumes) were included into the model. However, olipudase alfa dosing is based on the patient’s bodyweight. As a result, the bodyweight effect translated into an increase in Cmax and AUC exposure parameters.
The lyso-SM data were best characterized by a turnover response model (type I – loss of induction) through an Imax drug effect equation. The time-varying bodyweight decreased the effect of olipudase alfa on lyso-SM plasma level and Age was found to decrease the plasma Lyso-SM turnover time. Near maximal reduction of plasma lyso-SM was achieved.
The spleen volume data were best described by a turnover response model (type III – stimulation of induction) with a power function for the stimulatory effect of plasma lyso-SM.
The DLco data were best described by a turnover response model (type IV – stimulation of loss) with a linear function for the stimulatory effect of plasma lyso-SM.
Conclusions:
A sequential modeling approach was used to characterize the relationship between olipudase alfa plasma concentrations and reduction of plasma lyso-SM, and subsequent reduction of spleen volume or elevation of DLco over the time course of treatment.
Olipudase alfa exposures were lower in pediatric patients than in adult patients. However, for both adult and pediatric populations, plasma concentrations are maintained above IC50 value, leading to comparable reduction of plasma lyso-SM.
The simulated responses of spleen volume decrease and DLco increase were similar in pediatric and adult patients.
References:
[1] Wasserstein MP, Diaz GA, Lachmann RH, et al. Olipudase alfa for treatment of acid sphingomyelinase deficiency (ASMD): safety and efficacy in adults treated for 30 months. J Inherit Metab Dis. 2018;41(5):829-838.
[2] Diaz GA, Jones SA, Scarpa M, et al. One-year results of a clinical trial of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency. Genet Med. 2021;8:1543-1550.
[3] Wasserstein MP, Barbato A, Gallagher RC, et al. Continued improvement in adults with acid sphingomyelinase deficiency after 2 years of olipudase alfa in the ASCEND placebo-controlled trial. Genet Med 2022 24(3): S176-177.
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Reference: PAGE 30 (2022) Abstr 9977 [www.page-meeting.org/?abstract=9977]
Poster: Drug/Disease Modelling - Other Topics