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Genentech reaches for the stars
March 2012
by Lori Lesko  |  Email the author


CAMBRIDGE, Mass.—Gazing eastward toward the night sky, Genentech, a member of the Roche Group, has hitched its wagon to a star called Constellation Pharmaceuticals Inc., forging a major strategic agreement aimed at developing cancer treatments based on Constellation's epigenetics expertise.  
For this acumen, California-based Genentech has agreed to pay an unspecified upfront payment and $95 million in research funding over the course of three years. Constellation could also receive substantial milestone payments based on development and commercialization goals, as well as double-digit royalties on any commercial sales of products by Genentech that come from the agreement.  
Epigenetics is the study of certain types of proteins that affect chemical modifications on specific sites on DNA or chromosomal proteins. A key to the reading of these genetic changes is the substance chromatin, which is also a target of the research in the collaboration, the companies stated in a Jan. 17 news release.
Epigenetics research focuses on changes in gene expression that can be passed on to the next generation, but do not change underlying gene sequences. Chromatin is the combination of DNA and proteins in the nucleus of a cell.  
The agreement also calls for the companies to establish a research collaboration addressing multiple epigenetic target classes. Constellation will retain independent strategic direction, operational management and exclusive rights to programs outside of the collaboration scope, including its two most advanced programs that are focused on the development of inhibitors of the BET chromatin reader and EZH2 chromatin writer proteins.  
Genentech has a future option to acquire all outstanding shares of Constellation based on pre-negotiated terms, which include a significant initial acquisition payment plus contingent value rights payments based on the future successful development and commercialization of multiple products by Genentech. Genentech's option to acquire Constellation includes the BET and EZH2 programs as well as other programs outside the collaboration scope.
"Genentech is a global leader in the research and development of innovative medicines, and in combination with our class-leading product engine and deep expertise in chromatin biology, will create a powerhouse dedicated to bringing the greatest benefit to patients from drugs that modulate epigenetic pathways," states Dr. Mark A. Goldsmith, president and CEO of Constellation Pharmaceuticals. "This is a groundbreaking partnership in terms of the structure, breadth and potential future clinical impact of products created through our complementary capabilities. The committed revenue and post-collaboration economics should provide a highly attractive return for our investors."  
Dr. James Sabry, vice president of Genentech Partnering, adds, "We believe Constellation is a leading company in chromatin biology and epigenetics drug discovery and an excellent partner for Genentech in this area. With scientists committed to the collaboration at both Constellation and Genentech working together in a highly integrated way, our goal is to discover and ultimately bring to market promising new therapies for patients with unmet medical needs in oncology, and potentially other therapeutic areas."  
Sabry tells ddn that the deal "is one of the largest research collaborations we have done, and speaks to our interest in continuing to build first-in-class cancer drugs that will deliver true clinical value to patients, specifically in the rapidly evolving area of epigenetics and cancer."  
As it turns out, Constellation was never far from Genentech's radar.  
"We were both well aware of each other from the moment Constellation was formed," Sabry says. "We had been communicating for years prior to the collaboration being signed, and when the time was optimal for both companies, we moved ahead effectively to structure, negotiate and close the deal."  
Why epigenetics as opposed to more traditional modalities of researching and treating cancer?  
"Epigenetics describes a body of scientific mechanisms, targets and pathways that are involved in basic developmental and cellular biology," Sabry says. "Recently, a connection of this basic biology to the pathophysiology of cancer has been made by many laboratories. We believe that drugs that modulate epigenetic pathways may represent novel and highly effective therapies for a wide variety of cancers. This is one of a handful of promising new areas for the treatment of cancer."
Drug development in the field of epigenetics is directed towards the identification of small molecules that inhibit the activities of proteins that add, remove or recognize various chemical modifications to specific sites on DNA or chromosomal proteins.  These marks play a key role in determining whether a gene is on or off. Epigenetic regulators are often referred to as writers, erasers and readers. Research at Constellation and by others has shown that abnormal epigenetic regulation contributes to many different diseases.
In a study of chromatin readers that appeared recently in the Proceedings of the National Academy of Sciences, Constellation scientists demonstrated that transcription of the MYC oncogene can be suppressed using small-molecule inhibitors of the BET family of chromatin adapters. MYC is a master regulator of diverse cellular functions and has long been considered a compelling therapeutic target because of its role in many human malignancies including hematologic and solid tumors. Also, continued research by Constellation on chromatin modifying enzymes has resulted in significant progress towards developing small molecule inhibitors of the histone lysine methyltransferase EZH2. This enzyme functions as part of a chromatin-associated protein complex implicated in the repression of gene expression.
Recent cancer genomic sequencing studies have identified recurrent mutations in the EZH2 encoding genomic locus in a subset of human cancers. In addition, numerous epidemiological data sets linking increased EZH2 expression to late stage disease with poor prognosis suggest a prominent role for EZH2 in human malignancies.
Sabry declines to speculate on the specific types of cancer to be addressed.  
"Our goal is to … deliver meaningful clinical value to patients with a wide variety of cancer," Sabry says. "We have already begun our research collaboration and our scientists are working closely with colleagues at Constellation to identify promising new approaches and drug candidates in the field of epigenetics."
Code: E031217



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