Discussion
PD
Inclacumab is a fully human IgG4 mAb directed against P-selectin being developed for treatment of patients with SCD [Inclacumab PK parameters (In this study, a single IV dose of inclacumab resulted in nearly complete SPR P-selectin inhibition (> 90%) up to 12 weeks post-dose in most participants in both dose cohorts. The SPR assay is an ex vivo assay that measures the inhibition of the interaction between P-selectin and its ligand PSGL-1 by inclacumab [To allow modulation of PLA formation by inclacumab to be observed in healthy participants, ex vivo TRAP activation was used to promote formation of PLA. Reductions in TRAP-activated PLA formation by inclacumab were sustained through approximately 23 weeks for both dose cohorts, supporting a 12-week dosing interval for future development. The mean TRAP-activated PLA formation started to return to baseline values after week 23 but did not fully return to baseline values by 29 weeks post-dose. Similar to SPR P-selectin inhibition, ex vivo inhibition of PLA formation may not directly correlate with the in vivo biology of inclacumab. However, because this marker directly interrogates cell-cell interactions, TRAP-activated PLA formation may be a better biomarker for the pharmacodynamic activity of P-selectin inhibitors in patients with SCD.Soluble P-selectin is derived either through shedding from the cell surface or from an alternatively spliced mRNA [Administration of a single IV dose of inclacumab caused a rapid decrease of the free to total soluble P-selectin ratio, indicating target engagement. After the initial rapid decrease, the free to total soluble P-selectin ratio steadily increased over the study period to approximately 78% of baseline by week 29, indicating some degree of sustained target engagement for at least 7 months.ADAs were detected in 13% of participants in this study but were not associated with a safety risk and did not appear to affect the PK or PD. In prior inclacumab studies with healthy participants, ADA incidence ranged from 4 to 10% across populations and dosing regimens [