Comparative Long-Term Preclinical Safety Evaluation of Two Glatiramoid Compounds (Glatiramer Acetate, Copaxone®, and TV-5010, Protiramer) in Rats and Monkeys

Yuval Ramot, Moti Rosenstock, Ety Klinger, Dizza Bursztyn, Abraham Nyska, Doron M. Shinar

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

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.

Original languageAmerican English
Pages (from-to)40-54
Number of pages15
JournalToxicologic Pathology
Volume40
Issue number1
DOIs
StatePublished - Jan 2012
Externally publishedYes

Bibliographical note

Funding Information:
This work was performed at Teva Pharmaceutical Industries, Ltd, Petach Tikva, Israel. Funds for this project were provided in part by Teva Pharmaceutical Industries, Ltd, Petach Tikva, Israel. Some of the authors are employees of Teva Pharmaceutical Industries, Ltd, Petach Tikva, Israel.

Keywords

  • glatiramer acetate
  • glatiramoids
  • injection site
  • protiramer
  • toxicity

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