PROJECT SUMMARY/ABSTRACT Current therapies for sickle cell disease largely fail to meet patient needs, particularly for the management of acute pain crisis associated with this devastating disease. Healthcare systems are largely ill-equipped for managing patients in the midst of these extremely painful and life-threatening events, leaving patients with medical distrust and no effective treatment option. We are therefore developing IHP-100 for at-home self- management of pain crisis, thus empowering patients and providing significant freedom from disease. IHP-100 is a novel P-selectin and complement inhibitor that is administered by subcutaneous injection at the onset of early symptoms of pain crisis. This is a major paradigm shift in care that builds on our recent understanding of sickle cell pathology and incorporates direct patient feedback to provide a truly effective treatment. IHP-100 is a novel glycan-based therapeutic, designed to target the key underlying pathology of vaso-occlusive crisis (VOC). VOC is multi-factorial and includes both cellular adhesion via selectins as well as complement activation. Glycans are a prime drug class for such complex pathologies given their pleiotropic activities. We have therefore engineered IHP-100 as a single agent that potently inhibits P-selectin as well as complement. IHP-100 is therefore highly differentiated both in its biological activity and in its treatment paradigm at the earliest symptom of pain crisis. We have shown that IHP-100 inhibits P-selectin mediated cell binding to inflamed endothelium, inhibits complement-mediated cell lysis, and reduces vaso-occlusions in the Townes sickle cell disease mouse model of VOC. In the proposed work, we will optimize the dose level for in vivo efficacy, transfer manufacturing and analytical testing to a GMP facility, and complete non-clinical IND enabling dose-range finding studies. We will also further investigate mechanisms of IHP-100 in a P-selectin-deficient Townes sickle cell mouse model, and establish an adhesion-based biomarker strategy for clinical development.

PROJECT NARRATIVE Current therapies for sickle cell disease largely fail to meet patient needs, particularly for the management of acute pain crisis associated with this devastating disease. Healthcare systems are largely ill-equipped for managing patients in the midst of these extremely painful and life-threatening events, leaving patients with medical distrust and no effective treatment option. We are therefore developing IHP-100, a novel P-selectin and complement inhibitor, for at-home self-management of pain crisis, which would represent a major paradigm shift in SCD treatment that empowers patients and provide significant freedom from disease.