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With Celgene Partnership Epizyme Hopes to Accelerate Personalized Epigenetic Drug Development

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Epizyme is hoping that its new partnership with Celgene International Sarl will bolster the development and commercialization of its pipeline of personalized treatments that inhibit histone methyltransferase enzymes associated with specific genetic alterations.

In an arrangement the companies announced last month, Epizyme gave Celgene the exclusive option to license ex-US rights for any of the HMT inhibitor programs it has not yet licensed to other pharmaceutical companies. Specifically, under the terms of their agreement, Celgene gains ex-US rights to Epizyme's program on DOT1L, an oncogenic driver gene in a subtype of acute leukemias called Mixed Lineage Leukemia.

According to Epizyme's president and CEO Robert Gould and chief scientific officer Bob Copeland, several of the company's HMT inhibitor programs have already been partnered out with other drug firms, including its work with the enzyme EZH2, which was the subject of a March 2011 agreement with Japanese company Eisai, as well as a number of undisclosed programs that have been shared with GlaxoSmithKline.

Copeland told PGx Reporter that Epizyme's work is based on identifying enzymes from the 96-member HMT class whose oncogenic influence is associated with specific genetic alterations and resulting subgroups of patients.

"[This means] that if we come in with a small molecule inhibitor of that enzyme in a selective way, its going to have an anti-proliferative phenotype in the cancer but not in normal cells or cells that don't have that genetic alteration," he explained.

"The idea is that these are going to be personalized therapeutics. For many of these targets there will be multiple indications, but the unifying theme of these indications will always be a genetic alteration either in the enzyme or in other proteins that then drive the dependency on that enzyme activity," Copeland said.

"We believe that that’s really the future of cancer clinical treatment— that you'll have an armamentarium of personalized drugs and combine those in clever ways in the clinic."

In announcing its partnership with Celgene, Epizyme said the companies' collaboration will include its DOT1L HMT inhibitor program as the first for which Celgene has licensed the ex-US rights.

While Gould and Copeland declined to discuss additional programs, they said there are several others Celgene has interest in. DOT1L and EZH2 are the only targets Epizyme has made public from among its pipeline. However, Gould said, among the 96- member HMT class, about 20 enzymes already have existing genomic data suggesting "strong gene-disease associations — translocations, point mutations, over expression — that implicate them as being critically important drivers in oncogenic transformation."

"To date we are talking publicly about DOT1L and EZH2, but really they are the tip of the iceberg," Copeland said. "We see this as a very large target pool for development of personalized medicines … and Celgene [is] interested in a number of other targets."

Celgene and Epizyme will work together to prioritize development of drugs already in Epizyme's pipeline and eventually co-fund their development. "It’s true joint decision making from what targets we work on through clinical development strategy," Copeland said.

According to Epizyme, the agreement allows it to retain all US rights to the collaboration programs and includes a $90 million upfront payment. For each HMT inhibitor that Celgene licenses, Epizyme is eligible to earn more than $160 million in milestone payments and up to double-digit royalties on drug sales outside of the US, the company announced.

Epizyme's program on DOT1L is targeted to a subset of acute leukemias called MLL-rearranged leukemias, defined by a chromosomal translocation involving chromosome 11. This translocation results in the formation of a fusion of the MLL protein with a variety of partner molecules, Copland explained.

In the context of the fusions, he said, "MLL localizes to specific gene locations and the partner proteins recruit the enzyme DOT1L to those gene locations. As a result, you have the DOT1L enzyme activity localized to aberrant gene locations."

DOT1L then catalyzes methylation at those aberrant locations, which results in transcriptional activation of leukemigenic genes. "The enzyme itself is not genetically altered, but the enzyme activity becomes uniquely required for proliferation because of the association of the enzyme with that chromosomal translocation," he explained.

EZH2, the only other program Epizyme has made public, involves a more direct genetic influence, according to Copeland. With EZH2, "specific point mutations in the enzyme are associated with a subset of non-Hodgkin's lymphoma patients," he explained.

Mutations in EZH2 were originally identified in lymphoma in 2010, by a research team from Vancouver, Canada and published in Nature Genetics.

Copeland said the Vancouver group found that "all the patients that were identified with those mutations were heterozygous for the mutation, and at the message and protein level, they had equal amounts of wild type and mutant enzyme."

Initially, the researchers defined the mutations as loss-of-function alterations, but Copeland said Epizyme scientists later showed in a paper in the Proceedings of the National Academy of Sciences that instead of causing the enzyme to lose function, the mutations actually caused a "change of function" in EZH2.

According to Copeland, the tumorigenic activity of EZH2 involves a triple-methylation of the amino acid lysine. Normal EZH2 is only effective at adding one or two methyl groups to a lysine, while mutated EZH2 is lousy at adding a first methyl group, but much better at adding a second and then a third.

"So in order to get disease you need to have both the wild type and the mutant enzyme," Copeland said.

For Epizyme's purposes, he said, this gave a "very clear path to treating non-Hodgkin's lymphoma patients." The company has created an inhibitor targeting the EZH2 enzyme that appears "potent" at destroying lymphoma cells bearing those mutations," he said.

DOT1L and EZH2 are the furthest along among Epizyme's drug programs and are both in pre-clinical development. Gould said he expects both agents to move into the clinical stage soon.

For drugs the company is developing on its own and through three major partnerships, Copeland noted that Epizyme will likely pursue a variety of personalized treatment strategies to identify best responders.

"In order for patients to benefit from these types of therapies, they have to be defined by their genetic alterations," he said. "In some cases that means the development of a companion diagnostic test, but in some cases like DOT1L there already exist clinical tests — cytogenetic tests — that are sufficient to identify those patients."

Copeland believes that existing split-gene, FISH-based assay platforms will appropriately identify patients with chromosomal translocations necessary to respond to DOT1L. "In other cases we would likely commit to partnering with a diagnostic company to develop tests as they are needed," he said.

Gould added that Epizyme believes its deals with three major pharmaceutical companies have added a lot of credibility to the focus on HMT inhibitors as a drug class.

Unlike other epigenetic mechanisms like DNA methyltransferases, he said, "I think what distinguishes what we're doing from those earlier efforts is this idea of identifying specific enzymes for which there are genetic alterations that are drivers of cancer."

According to Gould, recent successes of drugs like Roche/Plexxikon's BRAF inhibitor Zelboraf and Pfizer's ALK inhibitor Xalkori have been a step in the right direction.

"What they've done is really shown that understanding patients with a specific genetic change who will respond [to a therapy] … is a real driver for benefit for those patients," he said.

"At the same time, cancer genome sequencing activities going on around the world, especially the Cancer Genome Atlas project, have really highlighted these HMTs as having strong genetic disease associations," Copeland continued.

"It's a paradigm shift from treating patients with drugs that affect key pathways and hoping we can identify the ones that respond, to moving toward using genome data to identify patients that are going to respond and then making the drugs for those patients."

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