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Taking aim at neurodegenerative diseases, MethylGene Inc. and EnVivo Pharmaceuticals Inc. entered a collaboration to develop the former's isotypic selective small-molecule histone deacetylase (HDAC) inhibitors.

Montreal-based MethylGene's stock (TSE:MYG) closed Tuesday at C$4.25 (US$3.20), unchanged.

MethylGene - fresh from pricing its initial public offering and private placement that netted C$20 million - gets, upon closure of the deal, an up-front license payment and contract research payments totaling $1.1 million, plus a milestone payment based on an early stage clinical achievement.

"They had the models so we could establish proof of concept," said Donald Corcoran, MethylGene's president and CEO. "It's not a lot a money up front, but it is moving out of cancer," a field in which MethylGene already has a pair of candidates undergoing trials.

EnVivo and MethylGene will jointly fund research, development and commercialization, sharing equally in profits, subject to opt-out provisions. The targets are such afflictions as Alzheimer's, Parkinson's and Huntington's disease.

Chemistry and functional genomics expertise for HDAC inhibitors come from the MethylGene side. Privately held EnVivo, of Watertown, Mass., brings to the table in vivo models and a Drosophila discovery platform. Vertebrate assays also help the push.

"We haven't said [when the deal will officially be concluded], but it will take the normal course of negotiations," Corcoran said.

It's part of MethylGene's bid to leverage HDACs in non-oncology indications by establishing proof of concept and intellectual property with partners, and then getting into the clinic as quickly as possible.

The company has two product candidates, MG98 (partnered in North America with MGI Pharma Inc., of Minneapolis) and MGCD0103 (partnered in certain Asian countries with Taiho Pharmaceuticals Inc., of Tokyo) in clinical trials. (See BioWorld Today, Oct. 21, 2003.)

MG98, which inhibits DNA methyltransferase, is in a Phase I dose-escalation monotherapy trial and is expected to enter a randomized two-step Phase II combination trial with interferon-alpha in metastatic renal-cell cancer this quarter.

"In cancer, specifically, [methyltransferase] silences tumor-suppressor genes," Corcoran said. By demethylating the genes, researchers hope to reactivate them against cancer.

MGCD0103, an HDAC inhibitor, is in two Phase I monotherapy trials against solid tumors. In one trial, the oral drug is given three times a week, and in the other trial, once daily.

Taiho, Corcoran said, is "one of the leaders in oncology in Japan. We gave them Japan, Korea, Taiwan and China." An especially sweet part of the deal was that the overseas firm contributed $13.5 million in funding for Phase I and Phase II trials, even though Taiho has no rights in the U.S.

"Our overall goal in the cancer franchise is to keep as much North American rights as possible," he said.

In infectious diseases, MethylGene has small-molecule beta-lactamase inhibitors being developed in collaboration with Merck-Frosst Canada & Co. that target antibiotic resistance by increasing the effectiveness of existing beta-lactam antibiotics.

"It's in late research," Corcoran told BioWorld Today. "We expect to identify a clinical candidate by the end of next year. Antibiotic trials are by nature large trials, and Merck is arguably an expert at developing these kinds of drugs. We'll hand it off to them and they'll develop it."

HDACs represent "a hot field," he noted. "People are just beginning to dive in, certainly in oncology, and we want to be early."

Among others in the space are Syrrx Inc., of San Diego, and Nutley, N.J.-based Hoffmann-La Roche Inc., which this spring entered a strategic partnership for cancer and diabetes treatments that could mean up to $178 million for Syrrx. Included are preclinical programs focused on an HDAC inhibitor and on 11-beta hydroxysteroid dehydrogenase-1, a metabolic target that reduces the production of cortisol, which is overexpressed in diabetics. (See BioWorld Today, May 13, 2004.)

Roche is the U.S. prescription drug unit of the Roche Group, of Basel, Switzerland. Among other signs of strong pharmaceutical interest in HDACs is the buyout earlier this year of Aton Pharma Inc., of Tarrytown, N.Y., by Whitehouse Station, N.J.-based Merck & Co. Inc. Merck wanted Aton's lead candidate HDAC inhibitor, suberoylanilide hydroxamic acid, or SAHA, which is in Phase II trials. Another HDAC inhibitor for cancer, pyroxamide, is in Phase I work. Novartis AG, of Basel, Switzerland, and Berlin-based Schering AG also are working on products in the HDAC class. (See BioWorld Today, Feb. 25, 2004.)

Several of the 11 known HDACs have been discovered to be involved in cancer.

"That begs the question, what are the other eight or so there for? There are potentially five or six other disease indications where HDACs may play a role," Corcoran said. "There are other areas that we're looking at - diabetes, cardiovascular, inflammatory diseases. Two of those we're going to keep to ourselves for a period of time, and then we'll seek partners." He declined to say which two.

MethylGene will be shooting for selective inhibitors rather than "pan" inhibitors, he said.

"The hallmark of the most competitive molecules is that they are pan inhibitors," Corcoran said, whereas MethylGene was able to be more specific by identifying the cancer-causing isoforms through biology.

"One could argue that a pan inhibitor in cancer might ultimately be successful because you can tolerate some of the side effects," he conceded, but a better-targeted drug has an obviously better chance in the clinic.

MethylGene ended last year with about C$35 million in cash, and Corcoran said the firm has "about 30 months of [funding]" now.

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