Assessment of Biomarker Response to Clinical Administration of Adakveo in a “Real World” Clinical Setting: A Model for Therapeutic Monitoring in Sickle Cell Disease (SCD)

Abstract

Background Sickle cell disease (SCD) is characterized by frequent and unpredictable vaso-occlusive episodes (VOEs) often associated with microvascular blood cell adhesion. P-selectin adhesion has been shown to be a mediator of pathologic adhesive interactions involved in VOEs and is a therapeutic target for SCD-modifying therapies. Adakveo is an FDA-approved (2019) P-selectin monoclonal antibody (mAB) therapy shown to reduce the annualized frequency of VOEs in patients with SCD. Due to the lack of clinically available blood-based biomarkers to define an individual's cellular-level response to therapeutic p-selectin inhibition, providers often rely on the clinical assessment of VOE frequency and intensity to assess an individual's response to anti-p-selectin therapy. This may have contributed to the recently failed Phase 3 clinical trial. In this report, we monitored the cellular-level response to therapeutic p-selectin inhibition by Adakveo administered in a real-world clinical setting using the flow adhesion of whole blood to P-selectin (FA-WB-Psel) assay. Methods This study was a retrospective assessment of FA-WB-Psel biomarker levels before and after clinical administration of Adakveo between January 2019 through June 2022. Flow adhesion of whole blood to p-selectin (FA-WB-Psel ) assays were performed using pulsatile, shear flow (1.67Hz, 1.0 dyne/cm2). SCD patients that received at least 3 biomarker evaluations within 1-year pre-Adakveo and up to 1-year post-Adakveo treatment were included in this analysis. Clinical site received an IRB waiver to confirm therapy start/stop dates. The non-parametric Wilcoxon matched pairs signed rank test was used to test the statistical differences between groups. Data are presented as mean ± standard error of mean. A p-value < 0.05 was considered statistically significant. Results There were 15 patients that met the study criteria described above. All patients included were African American with a confirmed HbSS genotype and mean age of 31 years (93% female and 7% male). Of 475 biomarker evaluations, 169 were obtained pre-Adakveo administration, 247 obtained 1-year post-adakveo, and 59 obtained 2-years post-adakveo. Most patients (87%) had FA-WB-Psel biomarker levels above the critical threshold (46 cells/mm 2). Adakveo significantly reduced and stabilized P-selectin activity (FA-WB-PSEL) 12-months (mean pre=84.32 ± 8.44 cells/mm 2, mean post=48.02 ± 4.54 cells/mm2, p=0.001) and up to 24-months (p=0.0003) following Adakveo initiation. Higher pre-Adakveo FA-WB-Psel levels correlate with greater inhibition of cellular-level response to clinically administered Adakveo (r 2=0.4133). Discussion This study provides the first report of FA-WB-Psel adhesion levels in a real-world SCD population initiated on Adakveo therapy. We observed a statistically significant decrease in FA-WB-Psel following Adakveo initiation, suggesting that FA-WB-Psel may be an effective monitoring biomarker for anti-p-selectin therapy in clinical trials and clinical therapy. Patients with low pre-Adakveo FA-WB-Psel levels may be less likely to experience therapeutic p-selectin inhibition, and in fact may be at risk for increased FA-WB-Psel. Studies are underway to assess a potential role for FA-WB-Psel as a predictive biomarker to identify potential Adakveo responders, a monitoring biomarker to serially assess the pharmaco-dynamic response to Adakveo, and a potential surrogate endpoint for therapeutic p-selectin inhibition.