title: Comparative long-term preclinical safety evaluation of two glatiramoid compounds (glatiramer Acetate, Copaxone(R), and TV-5010, protiramer) in rats and monkeys.
abstract: Glatiramer acetate (GA), the active ingredient in Copaxone®, is a complex mixture of polypeptides used for the treatment of relapsing remitting multiple sclerosis. Glatiramoids are related mixtures that may differ in some characteristics of the prototype molecule. Our aim is to describe the long-term toxicity studies with protiramer (TV-5010), a new glatiramoid, in comparison with similar studies conducted with GA. The toxicity of twice-weekly subcutaneous injections of protiramer to Sprague-Dawley rats (twenty-six weeks) and cynomolgus monkeys (fifty-two weeks) was compared with similar studies done with daily subcutaneous injections of GA. Daily treatment with GA was safe and well tolerated, without systemic effects or death. Protiramer administration was not as well tolerated as GA and led to dose- and time-related mortalities, probably mediated through severe injection-site lesions both in rats and in monkeys. Bridging fibrosis in the liver and severe progressive nephropathy were seen in rats. A dose-related increase in eosinophils was observed in monkeys. The protiramer toxicity studies show that minor variations in the manufacturing of glatiramoids may lead to significant toxic effects. It is therefore essential that the safety of any new glatiramoid be studied in long-term preclinical studies before exposing humans.
authors.affiliation: Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Ramot
authors.forename: Moti
authors.initials: M
authors.lastname: Rosenstock
authors.forename: Ety
authors.initials: E
authors.lastname: Klinger
authors.forename: Dizza
authors.initials: D
authors.lastname: Bursztyn
authors.forename: Abraham
authors.initials: A
authors.lastname: Nyska
authors.forename: Doron M
authors.initials: DM
authors.lastname: Shinar
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001774:Blood Chemical Analysis; D001835:Body Weight / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005260:Female; D000068717:Glatiramer Acetate; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000633:toxicity; D007279:Injections, Subcutaneous; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D010455:Peptides / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D036401:Toxicity Tests, Chronic
chemical_list: D007166:Immunosuppressive Agents; D010455:Peptides; D000068717:Glatiramer Acetate