Evotec Reports Phase I Safety Data from Tyramine Interaction Study with EVT 302
Evotec AG announced encouraging results of a Phase I safety study investigating the potential interaction of EVT 302, a reversible and highly selective inhibitor of monoamine oxidase B (MAO-B) in development for smoking cessation, with tyramine. The study was undertaken to determine potential safety advantages of EVT 302 versus non-selective MAO inhibitors and less selective MAO-B inhibitors already on the market. These MAO inhibitors are known to interact with tyramine, a natural constituent of some drinks or food such as red wine, cheese or chocolate. In extreme cases, the interaction can dangerously elevate blood pressure. As a result, some agents require patients to adhere to strict dietary restrictions to prevent the intake of food containing high levels of tyramine.
The study results showed that at the lowest dose tested, predicted to be at least twice the therapeutic dose, EVT 302, like placebo, did not increase the sensitivity to tyramine. Doses of EVT 302 for the current study were chosen based on the previously performed human PET imaging studies which showed that the lowest dose chosen for this study was already supramaximal for full inhibition of brain MAO-B. Selegiline was included as a control as it is a marketed MAO-B inhibitor with less subtype selectivity than EVT 302. At its recommended therapeutic dose selegiline does not require dietary restrictions, although it increases tyramine sensitivity slightly. Higher doses produce more dramatic increases in tyramine sensitivity. In this study, the therapeutic dose of selegiline did increase the sensitivity to tyramine compared to placebo. At the highest EVT 302 dose tested (>5 fold the expected therapeutic dose), a small increase in tyramine sensitivity was produced, which was within the range of that produced by the therapeutic dose of selegiline.
Tyramine when ingested with food is normally metabolized by MAO-A, and it is inhibition of this form of MAO by older generation MAO inhibitors which results in the potential for tyramine interaction. Such interaction with tyramine was not expected with EVT 302 since it is highly selective for MAO-B. Preclinical and clinical studies have demonstrated EVT 302 can achieve complete blockade of MAO-B without inhibition of MAO-A.
The study reported was performed double blind in 59 healthy young male subjects. The study assessed whether EVT 302 (administered at 3 different doses up to steady state) resulted in an increase in the sensitivity to tyramine in enhancing blood pressure. The study included selegiline, a marketed MAO-B inhibitor with less selectivity than EVT 302 over MAO-A, and as an active comparator.
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