Moving along with methyltransferase inhibitors

Epizyme earns $10- million milestone payment from GSK under inhibitor deal

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CAMBRIDGE, Mass.—Aimed at ultimately discovering and developing personal treatments for cancer patients, clinical-stage biopharmaceutical Epizyme Inc. has earned a $10-million milestone payment from GlaxoSmithKline (GSK), following GSK’s initiation of GLP toxicology studies for a first-in-class methyltransferase inhibitor discovered by Epizyme and licensed to GSK. The initial collaboration was announced six years ago, and the companies’ joint commitment has continued to thrive.
“We are pleased to achieve another milestone under our collaboration with GSK, further validating the strength of our epigenetic approach and drug discovery platform, as well our success in collaborating with industry leaders like GSK,” Susan Graf, chief business officer of Epizyme, stated in a May news release. “We are encouraged that this investigational medicine continues to advance toward the clinic.”
Under the terms of its license agreement, Epizyme granted GSK exclusive worldwide license rights to methyltransferase inhibitors directed to three targets. During the research term of the collaboration, which is now complete, Epizyme was primarily responsible for preclinical research; now, GSK is responsible for subsequent research, development and commercialization of the three programs, for which the pharma retains rights. 
To date, Epizyme has earned $69 million in upfront research and milestone payments, and may receive up to an additional $607 million from GSK if all milestones are met. Epizyme is eligible to receive up to double-digit royalties on worldwide net sales of collaboration products.
Using its proprietary drug discovery platform, Epizyme got the ball rolling after discovering and optimizing compounds targeting three methyltransferases.
The first methyltransferase inhibitor developed under the collaboration was the cancer treatment GSK3326595 (formerly EPZ015938), advanced to clinical studies in September 2016. The protein arginine methyltransferase 5 (PRMT 5) inhibitor is being developed for indications that include triple-negative breast cancer, bladder cancer, glioblastoma and p53 mutant and wild-type non-Hodgkin’s lymphoma, according to Epizyme.
“The introduction of this PRMT5 inhibitor into the clinic by GSK is an exciting scientific achievement for Epizyme,” states Robert A. Copeland, president of research and chief scientific officer at Epizyme. “This milestone reinforces the strength of our scientific capabilities, which have enabled us to expand our platform into new epigenetic target classes of potentially high importance in oncology.”
On Jan. 10, 2011, Epizyme first announced its “worldwide strategic alliance with GSK to discover, develop and market novel small molecule therapeutics targeting histone methyltransferases (HMTs), an important class of epigenetic enzymes, for the treatment of cancer and other diseases.” This alliance “leverages Epizyme’s unique HMT discovery platform, including its proprietary chemical library, expertise and intellectual property to discover and develop HMT therapeutics against the set of targets to be included in the collaboration,” Epizyme stated.
Under the terms of the agreement, Epizyme received an upfront payment of $20 million, as well as research funding, and is eligible to receive more than $630 million in total milestone payments if medicines are commercialized for all targets in the collaboration, the company said. 
Targeting specific HMTs with potent and selective small-molecule therapeutics offers the possibility of controlling pathways of gene expression that contribute to diseases. 
“Epizyme has pioneered the discovery and development of epigenetic therapies for the treatment of cancer, with three agents discovered by Epizyme now in clinical development,” stated Robert Bazemore, president and CEO of Epizyme. “Our collaboration with GSK represents an important part of our strategy of partnering with industry leaders to extend the breadth of our epigenetic therapies, while providing resources to help us accelerate our portfolio of assets.”
In an article published in Elsevier Journal in 2011, entitled “Protein methyltransferase inhibitors as personalized cancer therapeutics,” Copeland wrote: “The protein methyltransferases (PMTs) have emerged as a novel target class, especially for oncology indications where specific genetic alterations, affecting PMT activity, drive cancer tumorigenesis.” 
In conclusion, Copeland states, “The field of cancer therapeutics has undergone a continuous evolution of focus from early days of indiscriminant cytotoxics, such as mustard gas derivatives, to molecularly targeted agents, such as the various kinase inhibitors in clinical use, today.”
The concept of personally targeted therapeutics “resonates well in this current era of advanced genetic, proteomic, biochemical and biological understanding of cancer cells,” he says.
According to Copeland, personally targeted therapeutics can be operationally defined by three stages: “Identify the genetic alteration(s) that drive specific cancers; develop targeted therapeutics that selectively affect those genetic alterations; and define patient populations most probably to benefit from the therapy, based on the presence of the specific genetic alteration(s).”
Increasingly, oncologists are “moving away from descriptions of patient’s disease based solely on tissue of origin or site of lesion (e.g. breast cancer, prostate cancer and the like), and moving instead toward more genetic descriptors based on increased understanding of the alterations that drive individual cancers,” he says.

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