Washington Editor

In a new joint research venture worth up to $100 million, MethylGene Inc. and Pharmion are developing novel small-molecule inhibitors targeting sirtuins, a distinct member of the histone deacetylase enzyme class implicated in cell survival and death.

Sirtuins, including SIRT1, have been shown to deacetylate histone proteins and numerous transcription factors, leading to promotion of normal cell survival and aberrant gene silencing in cancer cells.

Most study of sirtuins has been in the area of proliferation of cell growth, or the agonist approach, the most well known of which is the agonist effects of resveratrol, a natural agent found in grapes and red wine, on sirtuins, said Pharmion Chief Medical Officer Andrew R. Allen.

Sirtris Pharmaceuticals and Elixir Pharmaceuticals, both of Cambridge, Mass., are two companies competing in developing drugs for disease treatment and longevity based on the agonist approach of sirtuins, Allen noted.

But MethylGene, of Montreal, and Pharmion, of Boulder, Colo., are taking the antagonist approach in studying sirtuins as the basis for potential agents to block growth of cancer cells, he said.

MethylGene and Pharmion are the first to publicly state that they are studying the antagonist approach of sirtuins, Allen said, adding that no companies have entered the clinical trial phase of development of a sirtuin inhibitor.

Inhibition of sirtuins allows re-expression of silenced tumor suppressor genes, leading to reduced growth of cancer cells, and anticancer effects have been observed with SIRT1 inhibitors in vitro and in vivo, the firms said.

While medical literature supports the antagonist approach of sirtuins in inhibiting cancer cell growth or promoting cancer cell death, the research in that area is still very early, said MethylGene's Chief Scientific Officer Jeffrey Besterman. Besterman and Allen said it will be 2010 before sirtuin inhibitors are studied in Phase I trials.

The sirtuin collaboration was a natural progression for MethylGene and Pharmion, Allen said, because those companies already have a collaborative project on a class I specific HDAC inhibitor, MGCD0103.

The sirtuin inhibitor research agreement expands the January 2006 license and collaboration agreement between MethylGene and Pharmion for the research, development and commercialization of MethylGene's oncology HDAC inhibitors, led by MGCD0103, which currently is in Phase II clinical trials.

Sirtuin inhibitors is the third epigenetic modality to be explored for anticancer activity by Pharmion and is the second in collaboration with MethylGene. The companies plan to study sirtuin inhibitors as monotherapy and combination therapy in the treatment of cancer once a clinical candidate is identified.

MethylGene said it already has identified a series of potent lead compounds. Pharmion said it expects to file an initial investigational new drug application within the next 24 to 30 months.

Two epigenetic therapy combinations already are under active investigation in Phase II studies combining Pharmion's Vidaza, a DNA hypomethylating agent, with MethylGene and Pharmion's HDAC inhibitor, MGCD0103.

The companies said they also intend to explore combinations with resulting anti-sirtuins.

MethylGene and Pharmion will share in the research, development and commercialization of the sirtuin inhibitor program, the companies stated. Pharmion is funding the preclinical research program, including about $5 million for personnel support to MethylGene over 18 months.

Once a development candidate is identified, the firms expect to share in development funding in accordance with an existing license and collaboration agreement: 40 percent for MethylGene and 60 percent for Pharmion.

Pharmion's milestone payments to MethylGene could reach about $22 million based on the achievement of development and regulatory goals, with the nearest-term milestone of $2 million to be paid on enrollment of the first patient in a Phase I trial, the companies said.

In addition, Pharmion could pay MethylGene up to approximately $79 million upon the achievement of sales milestones.

Under the terms of the deal, MethylGene will receive royalties on net sales in North America ranging from 10.5 percent to 21 percent and of 8.5 percent to 13 percent for all other licensed territories.

MethylGene will have an option, at its sole discretion as long as it continues to co-develop, to co-promote approved products in North America and, in lieu of receiving royalties, to share the resulting net profits equally with Pharmion.

Under an October 2003 agreement between MethylGene and Taiho Pharmaceutical, of Japan, Taiho has the exclusive right to develop and commercialize any resulting sirtuins cancer product in Japan, Korea, Taiwan and China in exchange for preclinical funding, royalties and milestones.