Genentech reaches for the stars

Company gains access to Constellation Pharmaceuticals’ epigenetics expertise with $95 million deal

Lori Lesko
CAMBRIDGE, Mass.—Gazing eastward toward the night sky,Genentech, a member of the Roche Group, has hitched its wagon to a star calledConstellation Pharmaceuticals Inc., forging a major strategic agreement aimedat developing cancer treatments based on Constellation's epigenetics expertise.
For this acumen, California-based Genentech has agreed topay an unspecified upfront payment and $95 million in research funding over thecourse of three years. Constellation could also receive substantial milestonepayments based on development and commercialization goals, as well as double-digitroyalties on any commercial sales of products by Genentech that come from theagreement.
Epigenetics is the study of certain types of proteins thataffect chemical modifications on specific sites on DNA or chromosomal proteins.A key to the reading of these genetic changes is the substance chromatin, whichis also a target of the research in the collaboration, the companies stated ina Jan. 17 news release.
Epigenetics research focuses on changes in gene expressionthat can be passed on to the next generation, but do not change underlying genesequences. Chromatin is the combination of DNA and proteins in the nucleus of acell.
The agreement also calls for the companies to establish aresearch collaboration addressing multiple epigenetic target classes.Constellation will retain independent strategic direction, operationalmanagement and exclusive rights to programs outside of the collaboration scope,including its two most advanced programs that are focused on the development ofinhibitors of the BET chromatin reader and EZH2 chromatin writer proteins.
Genentech has a future option to acquire all outstandingshares of Constellation based on pre-negotiated terms, which include asignificant initial acquisition payment plus contingent value rights paymentsbased on the future successful development and commercialization of multipleproducts by Genentech. Genentech's option to acquire Constellation includes theBET and EZH2 programs as well as other programs outside the collaborationscope.
"Genentech is a global leader in the research anddevelopment of innovative medicines, and in combination with our class-leadingproduct engine and deep expertise in chromatin biology, will create apowerhouse dedicated to bringing the greatest benefit to patients from drugsthat modulate epigenetic pathways," states Dr. Mark A. Goldsmith, president andCEO of Constellation Pharmaceuticals. "This is a groundbreaking partnership interms of the structure, breadth and potential future clinical impact ofproducts created through our complementary capabilities. The committed revenueand post-collaboration economics should provide a highly attractive return forour investors."
Dr. James Sabry, vice president of Genentech Partnering,adds, "We believe Constellation is a leading company in chromatin biology andepigenetics drug discovery and an excellent partner for Genentech in this area.With scientists committed to the collaboration at both Constellation andGenentech working together in a highly integrated way, our goal is to discoverand ultimately bring to market promising new therapies for patients with unmetmedical needs in oncology, and potentially other therapeutic areas."
Sabry tells ddn thatthe deal "is one of the largest research collaborations we have done, and speaksto our interest in continuing to build first-in-class cancer drugs that willdeliver true clinical value to patients, specifically in the rapidly evolving areaof epigenetics and cancer."
As it turns out, Constellation was never far fromGenentech's radar.
"We were both well aware of each other from the momentConstellation was formed," Sabry says. "We had been communicating for yearsprior to the collaboration being signed, and when the time was optimal for bothcompanies, we moved ahead effectively to structure, negotiate and close thedeal."
Why epigenetics as opposed to more traditional modalities ofresearching and treating cancer?
"Epigenetics describes a body of scientific mechanisms,targets and pathways that are involved in basic developmental and cellularbiology," Sabry says. "Recently, a connection of this basic biology to thepathophysiology of cancer has been made by many laboratories. We believe thatdrugs that modulate epigenetic pathways may represent novel and highlyeffective therapies for a wide variety of cancers. This is one of a handful ofpromising new areas for the treatment of cancer."
Drug development in the field of epigenetics is directedtowards the identification of small molecules that inhibit the activities ofproteins that add, remove or recognize various chemical modifications tospecific sites on DNA or chromosomal proteins.  These marks play a key role in determining whether a gene ison or off. Epigenetic regulators are often referred to as writers, erasers andreaders. Research at Constellation and by others has shown that abnormalepigenetic regulation contributes to many different diseases.
In a study of chromatin readers that appeared recently inthe Proceedings of the National Academy of Sciences, Constellation scientists demonstrated thattranscription of the MYC oncogene can be suppressed using small-moleculeinhibitors of the BET family of chromatin adapters. MYC is a master regulatorof diverse cellular functions and has long been considered a compelling therapeutictarget because of its role in many human malignancies including hematologic andsolid tumors. Also, continued research by Constellation on chromatin modifyingenzymes has resulted in significant progress towards developing small moleculeinhibitors of the histone lysine methyltransferase EZH2. This enzyme functionsas part of a chromatin-associated protein complex implicated in the repressionof gene expression.
Recent cancer genomic sequencing studies have identifiedrecurrent mutations in the EZH2 encoding genomic locus in a subset of humancancers. In addition, numerous epidemiological data sets linking increased EZH2expression to late stage disease with poor prognosis suggest a prominent rolefor EZH2 in human malignancies. 
Sabry declines to speculate on the specific types of cancerto be addressed.
"Our goal is to … deliver meaningful clinical value topatients with a wide variety of cancer," Sabry says. "We have already begun ourresearch collaboration and our scientists are working closely with colleaguesat Constellation to identify promising new approaches and drug candidates inthe field of epigenetics."

Lori Lesko

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