Epigenetics or bust

Roche and Oryzon partner to develop inhibitors of lysine-specific demethylase-1

Lloyd Dunlap
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BASEL, Switzerland—Roche and Barcelona, Spain-based Oryzon Genomics SA have entered into a worldwide collaboration to research, develop and commercialize inhibitors of lysine-specific demethylase-1 (LSD1), an epigenetic modulator that regulates gene expression. The agreement also includes an initial two-year collaborative research program between Oryzon and Roche’s New York-based Translational Clinical Research Center (TCRC), Roche’s hub for research and early development activities in North America, to better understand the potential of LSD1 inhibitors in oncology and hematology. This will be the first project to come online for TCRC’s Early Development Group, formed in January of this year.
 
In the absence of key executives due to the Easter holidays, DDNews was asked to attribute quotes to a Roche spokesperson. Explaining the decision to assign the ORY-1001 project to the TCRC, said spokesperson noted that, “This opportunity is an ideal fit for our Translational Clinical Research Center with its mandate to identify partnerships that drive innovation and source the next generation of successful pharmaceutical products driven by revolutionary science. TCRC comprises some 250 experienced drug developers with pharma expertise that spans the full development process. TCRC leverages its location at the Alexandria Life Sciences Center in New York City to access talent and technology, not only to advance Roche’s existing portfolio, but also by identifying collaborations ranging from very early discovery platforms through advanced-stage molecules.”  
 
The lead molecule in the Oryzon-Roche collaboration, ORY-1001, was granted orphan drug status by the European Medicines Agency in August 2013 and is currently in Phase 1/2a trials for acute myeloid leukemia. Roche will have sole responsibility for developing and commercializing the drug and/or its backup compounds. The agreement includes the licensing of two patent families that Oryzon has created in its pioneering research in LSD1 and includes options for other Oryzon programs to be incorporated in the future.
 
“ORY-1001 is potentially first in class, potentially best in class,” says Stefan Fring, Roche’s head of oncology partnering. “It’s an opportunity to really be one of the first companies out there.”
 
John Reed, Roche’s head of pharma research and early development, commented in a news release, “Oryzon is working at the leading edge of LSD1 inhibition, a technology with great potential to bring genuine patient benefit. Our TCRC in New York has been launched with a mandate to identify partnerships that drive innovation, providing an industry-leading conduit between sources of breakthrough science and the broader Roche organization. This collaboration on LSD1 inhibition with Oryzon fulfils that mandate perfectly.”
 
“We are excited to work with Roche in developing ORY-1001 to make a significant difference for patients with AML and, hopefully, for patients in other disease areas as well,” added Carlos Buesa, CEO of Oryzon. “Roche is the global leader in oncology and hematology, with a tremendous expertise in clinical development; this was the primary reason to prioritize this alliance. The collaboration is recognition of our cutting-edge science and our experience in epigenetics, an approach that we believe holds great promise for many patient groups.”
 
Under the terms of the agreement, Oryzon will receive an upfront payment and near-term milestones totaling $21 million, plus potential development, commercial and sales milestone payments across hematology, cancer and non-malignant indications that could exceed $500 million, together with tiered royalties on sales which range up to mid-double digits.
 
The Oryzon deal gives Roche its first drug in human testing in the field of epigenetics, a term used to describe functionally relevant changes to the genome that do not involve a change in the nucleotide sequence. Examples of epigenetic mechanisms include DNA methylation or histone modification, each of which alters how genes are expressed and consequently read or not read without altering the underlying DNA sequence. These epigenetic changes may last through cell divisions for the duration of the cell's life, and may also last for multiple generations even though they do not involve changes in the underlying DNA sequence. LSD1, which demethylates a histone, is an indispensible epigenetic governor involved in regulation of key cellular processes, including proliferation and differentiation.
 
LSD1 is also called an “eraser” because it removes signals in the histone, provoking changes in the reading context of the chromosome and turning off genes. Aberrant “erasing” activity may lead to disease. In mixed lineage leukemia, such as acute myeloid leukemia (AML) and acute lymphoblastic leukemia, LSD1 has been identified as playing a pivotal role. Drugs inhibiting LSD1 produce changes in gene expression leading to differentiation of leukemic blasts cells into normal differentiated cells, reducing proliferation and reducing viability of leukemic stem cells.
 
ORY-1001 is a highly selective and potent LSD1 inhibitor which can be orally administered to patients. ORY-1001 affects AML stem cells, a subpopulation of cancer cells that has been proposed to be responsible for frequent relapses of the disease. ORY-1001 also significantly reduces tumor cell load and increases survival time in mouse models of acute lymphoblastic leukemia. LSD1 has been also related with other malignancies, such as solid tumors and other hematological diseases.
 
Founded in 2000, Oryzon is a privately held, clinical-stage biotechnology company with a strong portfolio in the field of epigenetics. Its lysine-specific demethylase program is currently covered by 18 patent families. The company has a second program in LSD1 inhibition devoted to Alzheimer’s disease and Huntington’s disease that is expected to enter clinical trials in 2015.

Lloyd Dunlap

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