Phospholipase A2 Inhibitor Safety Trial

Children'S Hospital & Res Ctr At Oakland, Oakland CA

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Abstract

Acute chest syndrome (ACS) is the leading cause of death in sickle cell disease (SCD). The etiology of ACS includes infectious and non-infectious causes. ACS is commonly associated with vaso-occlusive crisis (VOC) which results in the intravascular release of bone marrow fat which in turn leads to pulmonary fat embolism (PFE). The pathophysiology of PFE in not completely understood but fatty acids liberated from embolized fat result in significant lung injury. Secretory phospholipase A2 (sPLA2) cleaves phospholipids, generating fatty acids and other lipid mediators. We demonstrated that sPLA2 is elevated in ACS and rising sPLA2 levels predict impending ACS. Because ACS often results from PFE and sPLA2 produces the fatty acids and lipid mediators responsible for PFE, sPLA2 likely plays an important role in the pathophysiology of lung injury in ACS. Inhibition of sPLA2 function, therefore, could ameliorate the course of ACS, especially if given before ACS develops. LY315920 is a sPLA2 inhibitor which has been used in a number of clinical trials including a phase II study in sepsis patients. Results in patients with sepsis show that LY315920 can reduce mortality if given early and toxicity is minimal. The objectives of our proposal are as follows: 1)To initiate a blinded, randomized, controlled phase IIa, dose-escalation trial to determine if LY315920 is safe in SCD patients with impending ACS as indicated by an elevated sPLA2, 2) To characterize the mechanisms by which LY315920 prevents endothelial damage and inflammation in SCD. Successful completion of the clinical trial and the accompanying in vitro investigations will substantially increase our knowledge about the potential efficacy of LY315920 in sickle cell disease. Evaluation of pharmacokinetics with different doses along with accompanying safety data will provide us with valuable information for subsequent phase III investigations.