HEM-001: Sickle Cell Crisis (P-selectin)

Vaso-Occlusive Crises: A Devastating Complication

Sickle cell disease (SCD) affects approximately 100,000 Americans and 20 million people globally, caused by a single point mutation in the β-globin gene. While the molecular defect is well understood, managing vaso-occlusive crises (VOCs)—acute episodes of microvascular obstruction causing excruciating pain, organ damage, and early mortality—remains a critical unmet need. VOCs account for 90% of SCD-related hospitalizations, costing the US healthcare system $1.5B annually, with individual crises lasting 7-10 days.

The pathophysiology is complex: deoxygenated sickle hemoglobin polymerizes, deforming erythrocytes into rigid, crescent shapes. These cells adhere abnormally to vascular endothelium through P-selectin-mediated interactions, triggering inflammatory cascades, platelet activation, and microvascular obstruction. Current therapies (hydroxyurea, L-glutamine, voxelotor) reduce crisis frequency by only 25-45%, and crizanlizumab, the only approved anti-P-selectin antibody, requires monthly IV infusions with limited real-world efficacy.

AI-Designed Oral P-selectin Inhibitor

Our AI platform designed a novel small molecule P-selectin inhibitor optimized for chronic oral prophylaxis. Using structure-based drug design, we identified compounds that selectively block the P-selectin binding site critical for sickle erythrocyte adhesion while preserving normal hemostatic function.

The lead candidate demonstrates high predicted oral bioavailability with rapid absorption kinetics, enabling once-daily dosing that maintains therapeutic P-selectin blockade throughout circadian peaks in endothelial activation. Computational modeling predicts significantly greater potency than current therapies while maintaining selectivity over related adhesion molecules.

Digital Patient Modeling

We built digital patient models of SCD pathophysiology incorporating diverse genotypes (HbSS, HbSC, HbS/β-thalassemia), fetal hemoglobin levels, and inflammatory states. Simulating our lead candidate across hundreds of these models predicts:

Substantial predicted reduction in VOC frequency with once-daily oral dosing, with efficacy maintained across SCD genotypes including HbSC patients who typically respond poorly to hydroxyurea.

An oral small molecule with these properties would address a significant unmet need—providing convenient, daily prophylaxis without the burden of monthly IV infusions required by current anti-adhesion therapies.