LONDON - Vanguard Medica Ltd. has taken over development of Ro61-1790, an endothelin antagonist, from F. Hoffmann-La Roche, of Basel, Switzerland. Vanguard will usher the compound, renamed VML 588, into Phase II trials in two indications: acute renal failure prevention and sub-arachnoid hemorrhage.

Robert Mansfield, CEO of Vanguard, based in Guildford, U.K., told BioWorld International that Roche has started Phase I trials, and Vanguard expects to begin Phase II in the second quarter of next year.

“Obviously, we hope to get to the end of Phase III because it will then be worth more to us when we license it back,“ he said. “But that would represent greater risk as we are investing our own money, so we would also be happy to be able to license it at the end of Phase II.“

Although Vanguard describes the agreement as a collaboration, Roche will not be paying any fees, and Vanguard will do the work by itself. Roche has the right to take back VML 588 for commercialization at the end of either Phase II or Phase III. In exercising either of these rights, Roche would pay milestones and sales royalties. If Roche does not elect to take back the compound, Vanguard will have worldwide marketing rights, and Roche will be entitled to milestones and royalties.

Vanguard has no discovery program, but relies on its core expertise to identify and license early-stage compounds for further development.

Roche and Vanguard selected the two indications together. Other companies are investigating endothelin agonists in acute heart failure, but Mansfield said Vanguard “will be looking at a totally new set of indications, and we will be looking at prevention rather than treatment.“ Roche has already completed preclinical development, and a Phase I study of the compound, which is administered by injection, showed it to be well tolerated in humans.

VML 588 selectively blocks endothelin A receptors, reversing the vasoconstricting effects of the peptide endothelin, which is released by blood vessels in response to injury. Vanguard anticipates that it could prevent acute renal failure in at-risk patients, such as the elderly and diabetes patients, undergoing surgery. Acute renal failure is caused by reduction in the flow of blood to the kidneys during surgery. Mansfield estimated it could be used in 1.25 million operations per year in the U.S. and Europe, and that if its credentials are established the drug would be administered routinely.

In brain hemorrhages, the rupture of a blood vessel provokes the release of endothelin, which constricts cerebral blood vessels and increases the risk of brain damage in patients who survive the initial hemorrhage. Endothelin antagonists have been shown to reverse the constriction of the cerebral blood vessels in animal models.

Shares in Vanguard Medica rose by 50 percent in the second half of last week, from £2.07 (US$3.46) to £3.11. Mansfield said that this was not as a result of the deal with Roche, but because the market picked up on favorable comments by clinicians about its migraine treatment, frovatriptan, at a medical conference in the U.K. last week.

Vanguard licensed this compound, a serotonin (5-HT) antagonist, from SmithKline Beecham plc, of London, in 1994. But in May this year SmithKline declined to license it back, despite positive Phase III results, and agreed with Vanguard that the data would support a new drug application to be filed by the end of this year. Vanguard is trying to find another partner. “It is now three and a half months since SmithKline pulled out, and I am very pleased with the progress of negotiations,“ Mansfield said. *