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

Abstract

Glatiramer acetate (GA), the active ingredient in Copaxone 1 , 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.

Glatiramoids

“…As described below, TV-5010 showed severe toxicity in long-term preclinical studies that was never seen with GA (Ramot et al 2012).…”

“…Like other NBCDs, GA does not have a homo-molecular structure, and the GA in Copaxone ® is defined in large part by its well-controlled manufacturing process, which was developed and has been optimized by the manufacturer (Teva Pharmaceutical Industries, Ltd.) over the last few decades (Duncan and Gaspar 2011;Nicholas 2012;Schellekens et al 2011;Varkony et al 2009). The importance of the stringent manufacturing method used to create GA is exemplified by development of a second generation GA glatiramoid known as TV-5010 that the same manufacturer prepared by making slight changes to the GA manufacturing process conditions at downstream stages (Ramot et al 2012). The product had the same molar ratio of AA as GA but a higher average molecular weight (MW).…”

“…This is supported by experience with TV-5010 that suggests it is impossible to predict the safety or efficacy of a glatiramoid mixture in the absence of clinical testing in MS patients. TV-5010 was synthesized by the originator of Copaxone ® (Teva Pharmaceutical Industries, Inc.) by introducing small changes in the Copaxone ® manufacturing process (Ramot et al 2012;Varkony et al 2009). The product was similar to Copaxone ® in AA ratio and in physical properties.…”

“…Good safety and tolerability was shown in RRMS patients in two small 9-months clinical trials (De Stefano et al 2009). However, long-term toxicity studies in monkey (52 weeks) and rats (26 weeks) unexpectedly revealed an unfavorable long-term toxicity profile, including, but not limited to, fibrosis in rats and eosinophilia in monkeys (Ramot et al 2012;Varkony et al 2009). Development of TV-5010 was halted.…”

Complexity in the making: non-biological complex drugs (NBCDs) and the pharmacopoeias

“…In fact, by slight alteration of the manufacturing process, Teva had produced a glatiramoid (TV-5010) that was similar in terms of amino acid ratio and physical properties [13] to Copaxone ® . While good safety and tolerability in patients treated with TV-5010 was shown, long-term toxicity studies in rats and monkeys revealed the occurrence of fi brosis in rats and eosinophilia in monkeys.…”