BioWorld International Correspondent

Evotec AG discontinued development of its candidate for Alzheimer's disease, EVT.301, following indications of potential liver toxicity during a Phase I trial in healthy volunteers.

The Hamburg, Germany-based company had been testing the compound, an inhibitor of the mitochondrial enzyme monoamine oxidase B (MAO-B), in both elderly and young volunteers. Some time after the 28-day dosing period had ended, elevated liver function tests were observed in the elderly but not the young group. The effect was asymptomatic and resolved itself spontaneously.

"It's a finding which is quite surprising and which we cannot explain," said Evotec CEO Joern Aldag. "These findings had not at all been seen in animals."

Evotec licensed EVT.301 from Basel, Switzerland-based F. Hoffmann-La Roche Ltd., which had put the compound through five Phase I trials. All of those were of a shorter duration, however. It is related to a predecessor MAO-B inhibitor, which had failed a Phase III trial in Alzheimer's, the results of which were not published.

Although Evotec could have opted to pursue development of the compound by monitoring liver function during subsequent testing, it decided that the combination of scientific and commercial risk outweighed the potential gains.

"'Partnerability' actually is the word that is important," Aldag said.

The company also licensed a back-up MAO-B inhibitor, EVT.302, from Roche, which lags EVT.301 by 18 to 24 months.

"EVT.302 is a different chemistry. It has a different profile, a different half-life," Aldag said. The company continues to believe in the potential of MAO-B inhibition in Alzheimer's disease. The problems encountered with EVT.301 most likely are inherent to the compound rather than its mechanism of action, Aldag said.

However, it will evaluate several options before deciding whether to pursue development of EVT.302. The company raised €18.5 million (US$23.4 million) in a private placing earlier this year to fund clinical trials from its portfolio. (See BioWorld International, May 3, 2006.)

EVT.201, a positive allosteric modulator of the GABA A receptor complex, is in development for insomnia, and the company is using part of the proceeds of the fund raising to undertake trials that will support its differentiation.

EVT.101, a selective antagonist of NR2B subtype of the N-methyl-D-aspartate (NMDA) family of receptors has completed a Phase I trial. The compound has potential application in Alzheimer's disease and in neuropathic pain. "I would prefer to see more focus on EVT.101 in [a second] indication, because the mode of action is much more clear there," said Volker Braun, analyst at Frankfurt-based Equinet Institutional Services AG.

EVT.301 was the compound with the highest risk in Evotec's clinical portfolio, Braun said. That seems to have been reflected in the response to the news from investors.

Although Evotec's share price dropped from Sept. 13 close of €3.38 to €2.79 during early trading Sept. 14 - the news was released Sept. 13 after market close - it recovered to close the day at €3.20. "I think it reflects appropriately the value of the compound at that stage of development," Braun said.

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