Dose Selection Process for Younger Children Participating in a Phase 3 Study to Evaluate the Efficacy and Safety of Rivipansel (GMI-1070) in the Treatment of Vaso-Occlusive Crisis in Hospitalized Patients with Sickle Cell Disease

Abstract Background: Rivipansel is a pan-selectin inhibitor in development for the treatment of sickle cell disease (SCD) vaso-occlusive crisis (VOC). A single phase 3 study was planned to evaluate the efficacy and safety of rivipansel (GMI-1070) in the treatment of VOC in hospitalized patients with SCD. Selection of the dose to be used in this phase 3 study was based on the efficacy, safety, and pharmacokinetic (PK) results from the rivipansel phase 2 study. Modeling and Simulation (MS6:845-54) into the model for younger children (aged 6-11 years). Simulations from the model in the adult and pediatric population are presented in Figure 1. To confirm the predicted exposure in cohort 2, in particular their average concentration at steady-state (Cavg,ss), age- and weight-dependent cumulative distribution functions (CDFs) of parameters in the population PK model (eg, CL Vss) were derived for the first 6 actively treated children. During this blinded review, concentration time profiles for these children were generated and empirical Bayesian estimates (EBEs) for their corresponding Cavg,ss were derived. The percentiles in which the EBEs fell within the simulated CDFs from the model were used to guide decisions for a potential dose adjustment. This process is outlined in the flow chart in Figure 2 and in the percentile plot diagram shown in Figure 3. Results: The PK data from the Phase 2 study supported fixed flat dosing for patient aged 12 years and older. Pharmacokinetic M&S predicted that a loading dose of 1680 mg followed by a maintenance dose of 840 mg every 12 hours would result in exposures similar to those observed with the lower dose used in the Phase 2 study, such that a minimum plasma concentration >10 μg/mL would be maintained throughout the dosing interval. For patients in cohort 2, weight-based dosing was considered, as it is the most conservative approach, given that children in this age range have not been studied previously. For each dosing regimen tested, the simulated demographic target distribution in pediatric SCD patients was used to derive concentration-time profiles. A summary of the Cavg,ss distribution across different ages is shown in Figure 1. The simulations showed that for children aged 6-11 years, a 40-mg/kg loading dose (maximum 1680 mg) followed by 20 mg/kg every 12 hours (maximum 840 mg) would likely result in concentrations similar to those observed with the 20/10 mg/kg dosing used in adults in the Phase 2 study. To confirm the validity of the exposure predictions, PK assessments were performed in the Phase 3 study and a blinded interim analysis of pediatric exposures was conducted. Conclusions: A population PK model for rivipansel has been developed, applicable to the whole target SCD population of adults and children older than 12 years. Its applicability in children aged 6-11 years is under investigation as part of the ongoing Phase 3 study, and interim assessments of the PK exposure have been done in small cohorts of 6 patients. The corresponding decision framework has been implemented, exercised successfully, with the results of potential dose adaptations to be published once the Phase 3 study has been concluded. Download : Download high-res image (1MB) Download : Download full-size image Disclosures Tammara: Pfizer Inc.: Employment. Shafer: Pfizer Inc.: Employment. Harnisch: Pfizer Inc.: Employment.