Subcutaneous Injection of IHP-102 Attenuates Lung Vaso-Occlusion in Sickle Cell Disease Mice

Sickle Cell Disease (SCD) is an autosomal-recessive-genetic disorder that affects ~100,000 Americans and over 3 million people world-wide. Acute systemic painful vaso-occlusive episode (VOE) is the primary reason for hospitalization of SCD patients and serves as an antecedent to acute chest syndrome (ACS), a type of acute lung injury and one of the primary reasons for mortality among SCD patients. Intravenous (IV) injection of P-selectin monoclonal antibodies have been shown to attenuate lung vaso-occlusion by neutrophil-platelet-erythrocyte aggregates in transgenic-humanized SCD mice and reduce frequency of VOE in SCD patients. However, IV route of administration requires at least an out-patient visit to the clinic, thus highlighting the need for therapies that can cut-down the health care cost by enabling self-administration (such as sub-cutaneous) by SCD patients at home during the prodromal phase of a VOE. Importantly, P-selectin dependent neutrophil-platelet aggregation and the complement pathway activation contribute to the vaso-occlusive pathophysiology in SCD. IHP-102 is a novel compound, which serves as a dual-inhibitor of both P-selectin and the complement pathway. Our initial pharmacodynamic findings in rodents revealed that P-selectin-inhibition activity of IHP-102 was detectable in the serum within 30 min following sub-cutaneous administration of 30 mg/kg IHP-102. Next, quantitative fluorescence intravital lung microscopy (qFILM) was conducted to assess the efficacy of IHP-102 in attenuating intravenous 10 μmole/kg oxy-hemoglobin (IV oxy-Hb) triggered lung vaso-occlusion in Townes SCD mice. Remarkably, and despite the described vasculopathy that would impair systemic delivery in this model, sub-cutaneous administration of either 10 or 30 mg/kg IHP-102 led to significant attenuation of lung vaso-occlusion by neutrophil-platelet aggregates in Townes SCD mice administered IV oxy-Hb. These findings are the first to highlight the therapeutic potential of a subcutaneously administrable therapy (IHP-102) in preventing VOE and ACS in SCD.

Njikang:IHP Therapeutics: Current Employment. Paderi:IHP Therapeutics: Current Employment. Sundd:IHP Therapeutics: Research Funding; Novartis corporation: Research Funding; Bayer Hemophilia Award Program: Research Funding; CSL Behring Inc: Research Funding.