In part one of the Phase I trial, subjects took six different oral formulations/doses of the Company’s experimental medication while safety and tolerability were assessed. The formulations differed in dose and time release profile, which produced a range of PK outcomes. All formulations were generally well tolerated with no serious adverse events or safety issues leading to study withdrawal. Part two of the trial examined the effects of food on PK profiles produced by single oral doses of the medication. There were no safety concerns with these “food effect” studies and the medication was again well tolerated. Part three of the Phase I trial was a randomized, double blind-placebo controlled study design consisting of seven days of oral dosing of the study medication (or placebo) which demonstrated that the Company’s compound was safe and well tolerated.
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All active treatment parts of the Phase I trial were conducted with the healthy volunteers as inpatients in a clinical trial unit. Although the Company expects to have a final analysis at a later time, the conclusions from the clinical research organization conducting the studies were that there were no clinically significant changes in any safety assessments including clinical lab tests, vital signs and electrocardiograms (“ECGs”) in any of the parts of the Phase I trial.
Even though the Phase I trial was designed primarily for the assessment of safety, tolerability and PK, the PD report also covered data generated from the newly developed PD assay, as applied to two dosing regiments in Rock Creek’s Phase I trial. The PD assay examined the effect of the drug on inflammatory responses induced in blood samples taken from human volunteers. The blood samples were taken prior to ingestion of the drug and then taken at various times after ingestion. The blood samples were then stimulated with a bacterial inflammatory molecule called lipopolysaccharide (LPS) and two markers of inflammation were examined. These two inflammation markers are the transcription factors STAT 3 and NF-kB, which are widely known as key molecular drivers of inflammation, and are responsible for the production of a variety of inflammatory molecules such as TNF alpha, interleukin-1, interleukin-6 and COX-2, as examples.
In this study, it was observed that STAT 3 activity was shown to be significantly reduced in blood samples taken after drug administration compared to blood samples taken before drug administration, when activated STAT 3 values were appropriately normalized by the amount of a reference protein (GAPDH) that is unaffected by LPS stimulation in the blood samples.
Although observations for NF-kB activity were generally less consistent than the STAT 3 results, one of the oral dosing regimens within the study also showed NF-kB reduction, when data was normalized via this newly developed PD assay. This was attributed to the novel PD assay not being optimized for NF-kB, and that in future studies, the incubation period for the NF-kB samples should be changed to account for this finding. Analysis of the remaining regimens is ongoing.
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