Pozen Inc. announced that the results of a two-year rat carcinogenicity study provided no evidence that the concomitant administration of maximum tolerated doses of metoclopramide and naproxen, the two active components in MT 100, produced any statistically significant differences in findings from those seen with metoclopramide alone. None of the tumours observed in the study were considered to be directly related to the administration of metoclopramide or naproxen; all were considered to be secondary to metoclopramide-induced increases in the levels of the hormone prolactin in the affected rats.

The study report was submitted yesterday to the US FDA and completes the MT 100 New Drug Application submission made by Pozen in July 2003, which was accepted for filing by the FDA in October 2003 and is currently in review. MT 100 is being developed as an oral first-line therapy for the acute treatment of migraine.

The study evaluated the occurrence of tumours among six groups of male and female Wistar han rats that received daily oral doses of metoclopramide and/or naproxen. One group received metoclopramide alone at its maximum tolerated dose (MTD). Another group received naproxen alone at its MTD. Three groups received naproxen at its MTD combined with metoclopramide at either a low or medium dose or at its MTD. A control group received placebo.

The data showed that there were no statistically significant differences in findings between the rats that received the MTD of metoclopramide in combination with naproxen and the rats that received metoclopramide alone at its MTD.

The study results are consistent with previous findings reported in rodents with chronically increased prolactin levels. As expected, metoclopramide, alone and in combination with naproxen, produced significant increases in serum prolactin levels compared to the control group, an effect thought to be due to the pharmacologic action of metoclopramide as a dopamine antagonist. Also as expected, increases in rates of prolactin-mediated tumours occurred in prolactin sensitive endocrine glands in rats that received metoclopramide, alone and in combination with naproxen, compared to the control group. Examples of drugs marketed in the US that elevate prolactin hormone levels in rodents include aripiprazole, risperidone, ziprasidone, olanzapine, pimozide, and quetiapine.

The data also showed no evidence that naproxen augmented the demonstrated endocrine effects of metoclopramide in the combination. There were also no statistically significant differences in findings between the rats that received naproxen alone and the rats in the control group, confirming results of previous studies with this drug in which there was no evidence of carcinogenicity. Metoclopramide and naproxen are commercially available drugs and have been on the market for more than 20 years.

"We are very pleased with the outcome of the study and we are grateful to the FDA for allowing us to submit these data during the NDA review process without affecting the date by which the FDA should complete its review of the NDA, May 31, 2004," said John Plachetka, chairman, president and chief executive officer of Pozen.

Pozen previously completed a six-month oral carcinogenicity study in p53 transgenic mice and submitted the report to the FDA in early 2002. The results of that study indicated that MT 100 was not carcinogenic in the p53 transgenic mouse model.