First-in-human phase 1 study of invariant NKT cell ligand OCH

Background: We have previously reported that OCH, a sphingosine‐truncated analog of alpha‐galactosylceramide (alphaGC), that selectively induces IL‐4 production from invariant NKT (iNKT) cells, would suppress the development of autoimmune disease models, including experimental autoimmune encephalomyelitis (EAE) (Miyamoto et al. Nature 2001). Objectives: Here we report on the results of the First‐in‐Human phase 1 study of OCH for healthy subjects, which we have recently conducted in the NCNP as an investigator initiated trial. The aim of the study was to evaluate safety and pharmacokinetics of a single oral administration of OCH, and investigate alterations in immunological parameters and gene expression profiles. Methods: Fifteen healthy subjects were enrolled and allocated to 1 of 5 cohorts and given escalating doses of OCH. We investigated lymphocyte subsets in peripheral blood with flow cytometer, and analyzed gene expressions of whole blood with DNA microarray. Results: Mild leukopenia occurred in two subjects, but recovered without any treatments. All other adverse events were grade 1. Plasma concentration of OCH was much higher than anticipated based on preclinical study, indicating the bioavailability of OCH may be higher than rodents and primates. Flow cytometer analysis of lymphocyte subsets revealed that GM‐CSF producing fractions in CD4+ memory T cells and CD8+ T cells were reduced after administration of OCH in all cohorts. IFN‐gamma producing fraction in CD4+ memory and CD8+ T cells were also reduced in lower dose cohorts. DNA microarray analysis revealed that expressions of some genes associated with autoimmune responses were decreased, and some immunoregulatory genes were increased. Conclusions: The results were potentially interesting and allowed us to start an early phase 2 study for patients with multiple sclerosis (MS). At April 2012, we have finished administration of OCH to two MS patients and analysis of immunological parameters.