Jeannine S. McCune: No relevant disclosure to display
Objectives: Vaso-occlusive crisis (VOC) is the primary reason for hospitalization for patients with sickle cell disease (SCD). Experiments in sickle cell mice show that free heme and depletion of hemopexin, the endogenous plasma protein that neutralizes heme, contribute to vaso-occlusion. In sickle cell mice with vaso-occlusion triggered in various ways, supplementing hemopexin levels through intravenous (IV) administration of hemopexin restores blood flow (Gentinetta et al., 2022). The phase 1 study [NCT04285827] explored the safety and pharmacokinetics (PK) of single IV doses of hemopexin purified from human plasma (CSL889) in adults with SCD. The goal of this work was to use pharmacometric modeling to inform the phase 2 doses of CSL889 for patients with VOC.
Methods: The observed PK data in serum from the phase 1 clinical study evaluating CSL889 in patients with SCD was used to build the population PK model describing the PK of total hemopexin, which includes all endogenous and exogenous hemopexin in both bound and unbound forms, The data included single IV doses in 24 patients with stable (no VOC) SCD and an intermediate dose in 4 patients with SCD in VOC. All population PK analyses were performed using the non-linear mixed-effects modeling software NONMEM version 7.3, employing first-order conditional estimation with interaction.
Results: The analysis dataset included 492 PK observations from 28 SCD patients. A two-compartment base model with first-order elimination with an endogenous synthesis rate best described the PK of total hemopexin in the serum. Inter-individual variability (IIV) parameters were estimated on CL, and V1. Correlations between IIV parameters and covariates were assessed. The model included the effect of body weight on CL and V1—with exponents fixed to a value of 0.75 and 1, respectively. Although it did not meet conventional criteria for inclusion, body weight was included because the phase 2 patient population is anticipated to have a larger weight range compared to that in the phase 1 study. The final model was evaluated based on objective function value, goodness of fit plots–including prediction corrected visual predictive checks–and relative standard error on parameter estimates. The population PK model was used to simulate the plasma PK of different dose levels with variability and to calculate exposures. The RP2D included either no loading dose or a loading dose, which was to test the working hypothesis that rapid heme scavenging is therapeutically beneficial, followed by maintenance doses. All regimens are scheduled for a maximum of 5 doses.
Conclusions: The model adequately described the PK data after CSL889 administration, enabling simulations to guide RP2D. Simulations confirmed that < 1% of samples would be above the maximum hemopexin concentration and < 1% of doses would be above the maximum hemopexin AUC observed in the phase 1 patient population.
Citations: [1]. Gentinetta T, et al. Plasma-Derived Hemopexin as a Candidate Therapeutic Agent for Acute Vaso-Occlusion in Sickle Cell Disease: Preclinical Evidence. J Clin Med. 2022;11(3):630.
