Early clinical experience with the novel proteasome inhibitor PS–519

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Abstract
The main objective of this study was to investigate the safety, tolerability and pharmacodynamics of the novel proteasome inhibitor PS-519 in young male volunteers. Many pro-inflammatory mediators such as cytokines and cell adhesion molecules that are responsible for the development of the cerebral infarct are under the control of the transcription factor Nuclear Factor kappa-B (NF-kappaB). The activity of NF-kappaB is itself tightly regulated through the multicatalytic enzyme known as the proteasome. PS-519 is a novel and highly selective small molecule that inhibits the proteasome. An ex vivo assay of 20S proteasome activity allows monitoring of the drug effect in blood. PS-519 is protective in multiple animal models of cerebral ischaemia over a range of doses that achieve 20S inhibition of 40%-80%. PS-519 has been administered to healthy male volunteers as single and repeated doses up to 1.6 mg m(-2). It was given as an intravenous bolus over 20-30 s in a double blind, randomized, placebo-controlled phase I study, examining vital signs, safety, tolerability and blood 20S proteasome inhibition. Thirty-nine subjects received single doses of 0.012 mg m-2-1.6 mg m(-2) and 28 subjects received doses of 0.5 mg m(-2)-1.6 mg m(-2) on three consecutive days. The drug was well tolerated. There was no clear treatment-emergent symptom or abnormality of laboratory tests. Proteasome inhibition in blood samples as measured by 20S assay achieved the intended maximum target level of 70-80% with 1.6 mg m(-2), and was reproducible with repeated dosing. This study has demonstrated that proteasome inhibition is well tolerated by healthy subjects at levels that are maximally neuroprotective in experimental conditions. Further clinical evaluation appears justified.