A first-in-human phase 1 clinical study in healthy volunteers to assess the safety, tolerability and pharmacokinetics of EDI048, a novel promising agent to treat enteric cryptosporidiosis.

Abstract

Cryptosporidiosis is a major diarrheal disease with significant morbidity and mortality in young and malnourished children from low- and middle-income countries. EDI048 is a novel Cryptosporidium PI(4)K inhibitor, designed to be active in the gastrointestinal tract and undergo rapid hepatic metabolism to minimize systemic exposure. This study evaluated the safety, tolerability, pharmacokinetics (PK) and effect of food on PK of EDI048 and its metabolites in healthy adult volunteers. In a randomized, placebo-controlled, single and multiple ascending dose trial, healthy adults received EDI048 at 45, 180 and 400 mg doses while fasting and a single 400 mg dose under both fasted and fed states to evaluate safety and tolerability. Plasma PK analysis was performed for EDI048 and two inactive metabolites QPL621 and FRK011. Fifty-six participants were enrolled (SAD: n=24; MAD: n=24; Food Effect (FE): n=8). EDI048 was well tolerated up to 400 mg BID for 5.5 days. Few treatment-emergent adverse events occurred, with most events mild and unrelated to study drug. No deaths or drug-related serious adverse events occurred. PK analysis showed dose-proportional exposure for EDI048, QPL621, and FRK011. The AUC0-inf ratio of QPL621/EDI048 was 54.4 after a single 400 mg dose, suggesting substantial conversion of EDI048 to QPL621. No significant accumulation was observed after multiple dosing. Food intake marginally increased EDI048 exposure (Cmax by ∼2-fold; AUC by ∼1.6-fold). No clinically significant changes in ECG, laboratory, or vital sign parameters were observed. EDI048 had a tolerable safety profile at all doses tested, up to 400 mg orally administered BID for 5.5 days. Pharmacokinetic analysis showed minimal systemic exposure of EDI048 in healthy adults. These results support further clinical development for cryptosporidiosis.