Preclinical Safety Assessment of Photochemically-Treated Platelets: No Toxicologically Relevant Effects with Large Multiples of the Clinical Exposure.

Background: The photochemical treatment of platelets employs Helinx™ technology, which uses the psoralen S-59 and UVA light in an ex vivo photochemical treatment (PCT) to inactivate viruses, bacteria, and leukocytes in platelet concentrates while retaining therapeutic function. After UVA and before transfusion, residual S-59 and free S-59 photoproduct levels are lowered by an S-59 compound adsorption device (CAD). A comprehensive preclinical safety program, including carcinogenicity, was conducted based on the broad strategy normally applied to a new pharmaceutical. Methods: Studies were performed by intravenous infusion of S-59 PCT formulations +/-CAD treatment and with unilluminated S-59, with doses that were multiples of potential clinical exposures. The studies completed were single dose and multiple dose (up to 13 weeks duration) toxicity, safety pharmacology (CNS, renal, and cardiovascular), reproductive toxicity, genotoxicity, p53 carcinogenicity, vein irritation, phototoxicity, and toxicokinetics (multiple dose pharmacokinetics). Results: No specific target organ toxicity (clinical or histologic pathology), reproductive toxicity, or carcinogenicity was observed. S-59 and/or PCT formulations demonstrated CNS, electrocardiographic (ECG), and phototoxicity at non-clinical doses. Based on the extremely large safety margins (>30,000-fold expected clinical exposures), the CNS and ECG observations are not considered to be of toxicological relevance. Additionally, after a complete assessment, the results of mutagenicity and phototoxicity studies are not considered to be relevant for the proposed use of the photochemically-treated platelets. Conclusion: The results of an extensive series of studies have thus demonstrated no toxicologically relevant effects of platelets treated with Helinx™ technology. The results of the toxicokinetic analyses from 3-month rat and dog studies with S-59 PCT formulations +/CAD treatment were compared with clinical data. These data indicate that the test articles used in the key toxicology studies provided large multiples of the clinical exposure to S-59, whether the comparison was based on dose, C[sub max], or AUC. [ABSTRACT FROM AUTHOR]