12:00 AM
Jan 23, 2012
 |  BioCentury  |  Strategy

Epigenetics land grab

Genentech joins rush into epigenetics space with Constellation deal

After about 20 years of academic research on epigenetics, large drug developers have decided the time is right to move in, making bets on biotechs that can provide platforms and compounds. Last week, Genentech Inc. threw its hat into the ring with $95 million in upfront payments and research funding to Constellation Pharmaceuticals Inc., the largest amount disclosed to date for an epigenetics deal, which includes a takeout option.

The Roche unit said epigenetics is ripe for investment because advances in biology have definitively linked targets to particular cancers. In addition, the last few years have also seen the publication of the first sets of small molecules that modify epigenetic proteins that are not already targeted by marketed drugs.

"The field is maturing so that we know what the molecular players are - and there are hundreds of them. And academic teams have started to link together the proteins with cancer phenotypes," James Sabry, VP of Genentech partnering, told BioCentury.

"Now there is a chance to develop drugs against these targets," he added. "This happens in every field: there is an explosion in research and then at a certain point companies like us are ready to jump in."

Including Genentech, at least five large companies have partnered with small biotechs that have epigenetic drug discovery capabilities.

The most active is GlaxoSmithKline plc, which has disclosed four deals worth at least $73.9 million in upfront payments and paid milestones, including ongoing projects with Cellzome AG, Chroma Therapeutics Ltd. and Epizyme Inc.

The pharma also has received undisclosed research and assets from one of the targets from a 2009 epigenetics deal with Astex Pharmaceuticals Inc., which partners terminated last week(see B3).

There are at least nine biotechs working on next-generation targets, three of which have no partners. All the programs are preclinical (see "Epigenetics Landscape").

Genentech chose Constellation because it believes the biotech has the best assays for validating a breadth of epigenetic targets and identifying small molecules that modulate them.

Details of Constellation's technologies have not been disclosed. However, the biotech might be the only company that does target discovery and screens for compounds that simultaneously modulate more than one epigenetic target across different families (see BioCentury, June 9, 2008).

Maturing science

Epigenetic enzymes regulate histones or DNA via chemical modifications such as methylation or acetylation without changing the DNA sequence. These modifications determine whether genes are turned on or off, and dysregulation of the processes often plays a central role in diseases such as cancer and immune disorders.

According to the Structural Genomics Consortium (SGC), there are 377 known epigenetic targets. But epigenetics has so far yielded only two target classes with approved drugs: HDACs and DNA methyltransferases, which together account for only 23 known proteins.

Over the past couple of years, papers have begun appearing that link cancer phenotypes to mutations in epigenetic proteins.

For example, in 2010, Epizyme published research in the Proceedings of the National Academy of Sciences showing that mutations in methyltransferase enhancer of zeste homolog 2 (EZH2) are required for a malignant B cell lymphoma phenotype (see SciBX: Science-Business eXchange, Dec. 9, 2010).

The last couple of years also have seen the first disclosures of small molecules targeting next-generation epigenetic proteins, enabled by the availability of protein X-ray crystal structures since about 2005.

In late 2010, two papers published independently in Nature described the identification of small molecule inhibitors of the...

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