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Landmark studies assess risk of exposure to elevated levels of EMS confirm clear toxicity threshold

August 05, 2008

New data from studies presented at the XVII International AIDS Conference in Mexico City have provided unprecedented insight into the toxicity of an impurity called ethyl methanesulfonate (EMS). The formation of the EMS impurity is a potential by-product of the manufacturing of mesylate salts, which are contained in over 40 drugs currently available worldwide.

The studies were designed to determine the impact of elevated EMS levels in some batches of Roche's Viracept® (nelfinavir mesylate) and demonstrated a clear threshold response at which DNA damage, the underlying mechanism for the carcinogenesis of EMS, occurs. The results of these animal studies, which can be translated to humans with high confidence, confirm that Viracept patients exposed to the EMS impurity at levels well below this threshold are not at an increased risk of cancer.

"These data provide unprecedented insight into the toxicity of EMS for humans. They will change the long held perceptions of the hazards posed by low doses of some genotoxic carcinogens", said Professor David Tweats, Department of Medicine and Genetics, University of Wales Swansea, UK.

EMS is a known DNA-damaging agent capable of inducing gene mutations and chromosomal aberrations. Although existing in vitro data indicated that there was a threshold response at lower doses of EMSi at which no DNA damage was observed, the total body of literature about EMS at low doses was limited. Consequently, available data did not permit an adequate risk assessment for patients exposed to EMS in Viracept. Roche -- in agreement with the European regulatory agency -- undertook the largest and most comprehensive toxicology evaluation of EMS to-date.

Scientists investigated the genetic toxicity of EMS using the following sets of studies:

* Measurement of chromosomal damage in mice

* Quantification of gene mutations in the transgenic MutaMouse model - the largest study of its kind ever conducted

* Modelling of exposure and metabolism of EMS in humans based on experimental animal data

The first study clearly demonstrated a threshold-dose response with no chromosomal damage at EMS doses up to and including, 80 mg/kg/day. The second set of studies, the transgenic MutaMouse studies, also showed a clear threshold effect for mutations above 25 mg/kg/day, under chronic conditions. Effects were also shown not to be cumulative over time. This threshold is far above 0.055 mg/kg/day -- the highest estimated levels to which Viracept patients were exposed for no longer than 3-6 months.

The research team used these results to predict human exposure to EMS. They predicted that even at a maximal exposure level 370-fold higher than that calculated for affected Viracept patients, the damage potentially incurred by EMS can still effectively be dealt with by ubiquitous DNA repair mechanisms. As chromosome damage and mutations are the underlying molecular events for birth defects and cancer, the results of these studies can be used to reassure patients exposed to elevated levels of EMS, and their healthcare providers, that they are not at increased risk for developing cancer.

Ketchum