Epizyme, a company targeting the nascent field of epigenetics, officially emerged from stealth mode March 23, unveiling a cracker-jack management team and an experienced scientific advisory board.

Although details have not been disclosed, Epizyme will focus first on developing therapies targeting cancer, where the link between epigenetic regulation and disease is strongest. The company is developing drugs aimed at a particular class of molecules called histone methyl transferases. The goals and structure of the company are outlined on a newly unveiled ¹ Web site.

In an interview, Kazumi Shiosaki, CEO of Epizyme, declined to reveal the biotech's financial status. However, the amassing of a modest Series A fund, between $12 million and $20 million, appears to be a reasonable ballpark of financing. The company was founded in 2007 with backing from MPM Capital and Kleiner Perkins Caufield & Byers.

In a year when scientists and scholars are marking the 200 anniversary of Charles Darwin's birth and 150 anniversary of his seminal work "On the Origin of Species," there's a certain irony in the increasing recognition that DNA-coding sequences only tell part of the story and new fields such as epigenetics are under investigation.

Scientists now believe that a second layer of genetic information -the epigenome - plays a critical role in normal cellular activity. Through subtle molecular modifications that affect the packaging of DNA into chromosomes, epigenetics allows individual cells to dial up, or down, activities of different genes in a highly specific and heritable manner. By activating certain genes and suppressing others, the end result is a breast cell. Turn on a different set of genes and a liver cell results.

It's not a great leap to recognize that misregulation of these chemical tags results in disease. "Every place we look, epigenetics is becoming key," said Nobel laureate H. Robert Horvitz, a Howard Hughes Medical Institute Investigator and biologist at the Massachusetts Institute of Technology. Horvitz is a scientific co-founder of Epizyme.

Epizyme isn't the only biotech with A-list backers, top scientific talent, and significant money aiming to develop epigenetic therapies, however.

In April 2008, Constellation Pharmaceuticals, Epizyme's competitor in the epigenetics vanguard, threw its hat in the ring with a $32 million Series A from venture backers Third Rock Ventures, The Column Group, and Venrock Associates. Like Epizyme, Constellation also is working on drugs that affect HMTs, as well as another class of proteins called histone demethylases (HDMs).

An epigenetics primer

Under normal circumstances, a cell's DNA is wrapped tightly around a complex of eight histone proteins called a nucleosome, much the way thread is wrapped around a spool. Together, this DNA-histone complex, known in the scientific literature as chromatin, makes it possible for the cell to pack two meters worth of genetic material into the nucleus of the cell. But that tight coiling creates a separate problem: In the same way that thread close to the heart of the spool is impossible to access, DNA at the center of the chromatin can't be activated either.

That's where the epigenetic modifications - methyl, acetyl, phosphoryl, or ubiquitin tags - become critical. The addition of these marks to either the DNA sequence or the histones regulates how loosely or tightly the DNA is wrapped around the nucleosome spool.

In recent years, biologists have amassed evidence that improper placement of these chemical tags results in diseases ranging from diabetes to cancer. In several types of cancer, for instance, it's known now that tumor-suppressor genes are inappropriately deactivated not by mutational changes to the DNA code, but by the incorrect placement of acetyl groups on histone proteins.

Early epigenetic therapies have targeted a specific family of enzymes called histone deacetylases. But because these inhibitors are notoriously non-specific, off-target side effects have shelved many potential HDAC inhibitors in development. Indeed, despite considerable investment in the space, Merck's Zolinza (vorinostat), approved in 2006, remains the only HDAC inhibitor currently on the market (² Also see "Merck Re-Enters Oncology With Zolinza Approval For Rare Skin Cancer" - Pink Sheet, 16 October, 2006., p.3).

If HDAC inhibitors haven't panned out in the clinic yet, they have paved the way for next-generation therapies with better specificity, say backers of Epizyme. HDAC inhibitors provided the business proof of concept, said Robert Gould, a former Merck scientist who now works at The Broad Institute and serves on Epizyme's scientific advisory board.

"There's clear evidence that modifying the chromatin through HDACs is important. Companies like Epizyme are poised to take advantage of that prior knowledge but move it to the next level," he said in a recent interview.

The HMT company

Epizyme was formed after MPM Capital's scientific advisory board, chaired by Horvitz, decided to invite University of North Carolina-Chapel Hill professor Yi Zhang to give a presentation at a board retreat. Zhang, a former post-doctoral fellow in the lab of Danny Reinberg, the scientific co-founder of Constellation, identified many of the proteins directly implicated in modifying histones and reportedly was interested in starting a company.

Zhang's presentation struck a chord with MPM, according to partner Ashley Dombkowski, who said "the company moved quickly from a white sheet of paper to reality" of forming a company, with Zhang as scientific founder.

Epizyme has gone to great lengths to assemble a team of aces, at both the managerial and advisory levels. Moreover, noted Dombkowski, the company is pulling in people with real-world drug discovery and commercial experience, from Shiosaki, a former Millennium biochemist, to chief scientific officer Robert Copeland, an enzymologist and former VP in the biology/oncology group at GlaxoSmithKline, to VP Biology Victoria Richon, who discovered Zolinza and developed the molecule through regulatory approval and commercial launch for Merck.

Others joining the company include patent attorney Robert Millman, who will serve as chief IP strategist. He is well known as the architect for the IP strategies of Human Genome Sciences, Millennium and, more recently, Alnylam.

A platform of targets

The company's leadership does not want Epizyme to be branded "the epigenetics company." As part of its mission to translate the principles of epigenetics into actual therapies, Epizyme's goal is to become the go-to experts in histone methyl transferase biology and drug development. "We are approaching the HMTs as a broad protein class," Shiosaki said.

Her goal is to use strategic mapping of the so-called "HMT-ome" to develop a pipeline of small molecules aimed at the individual family members. "That kind of approach will allow us to be creative and strategic around partnerships," Shiosaki predicts.

According to Millman, the company is taking a straightforward approach to carving out its intellectual property, filing composition of matter patents on chemical structures arising from high-throughput chemistry screens, while simultaneously pursuing target IP based on work performed by one of its scientific founders.

He says the company already has "had positive developments in two separate patent applications" covering two potential targets. While Millman declined to name the targets specifically, a search of pending applications with the U.S. Patent & Trademark Office associated with scientific founder Zhang revealed that one likely enzyme of interest is the DOT1 enzyme, a histone methyl transferase that may play a role in the development of certain leukemias.

This platform-based approach to a group of related targets has become increasingly popular in the start-up world. In November 2008, the Cambridge, Mass.-based Zafgen pulled in a $14 million Series B to develop a platform of products built around the links between blood vasculature and adipose tissue growth (³ Also see "Obesity-Focused Zafgen Raises Zaftig Series B" - Pink Sheet, 18 November, 2008.).

Like Zafgen, Epizyme's execs hope to translate their specific biological knowledge into a lucrative business development deal, much the way Sirtris Pharmaceuticals, developer of drugs aimed at the seven-member family of sirtuin enzymes, brokered a $720 million acquisition with GSK last April (⁴ Also see "GSK Gobbles Up Sirtris For $720 Million, But Still Prefers Alliances To Big Buys" - Pink Sheet, 28 April, 2008., p. 3).

-Ellen Foster Licking (e.licking@elsevier.com)

Epizyme Emerges From Stealth Mode

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