Celgene Corp. is tapping San Francisco-based Nurix Inc. to discover and develop several new therapies targeting the ubiquitin proteasome system (UPS) for the treatment of cancer, inflammation and immune disorders. The deal includes a $150 million up-front payment for Nurix, plus an undisclosed equity investment, validating earlier seed and series B investments by Third Rock Ventures and the Column Group that established the company. (See BioWorld Today, May 23, 2014.)

Nurix is working exclusively with Celgene in the areas covered by the deal to advance new therapies that function through the UPS to modulate protein homeostasis, a fundamental cellular process controlling protein levels. Mutations in UPS genes are common drivers of many human cancers, the company said. In addition, certain UPS genes function in normal physiology encoding key checkpoints in the immune response.

From Nurix's first significant meeting with Celgene, held during January's J.P. Morgan Healthcare Conference in San Francisco, "there was a natural chemistry between our teams given their established presence in this field," with Celgene's Revlimid (lenalidomide), Pomalyst (pomalidomide) and Thalomid (thalidomide) all working in part by targeting cereblon, a ligase in the UPS, Nurix CEO Arthur Sands told BioWorld Today. "Since Celgene had a very mature scientific program in these ligases with their IMiD drugs, that set the stage for us to team up in this scientific collaboration," he said.

Nurix's platform is capable of producing small-molecule candidates that are activators or inhibitors of both E3 ubiquitin ligases – the last in a series of three enzymes that control the placement of ubiquitin onto a protein, making it a key regulator in determining proteins' fates – and E2 ubiquitin-conjugating enzymes, a capability that allows for them to disrupt or enhance protein-protein interactions.

The approach offers enormous opportunities, since each target has the potential to be a major regulatory node in the genome, but it will also face significant hurdles, Sands said. With some 600 E3 ligases or more in the genome, each with largely unknown biology and each a potential drug target under the collaboration, a very broad-based platform approach will be required to tackle the target class, he said.

As part of the agreement, Nurix maintains control and responsibility for all drug discovery and development activities through the end of phase I trials, a set-up that Sands said was extremely powerful. "It allows this culture of innovation and appropriate risk-taking for the biotech at the stages of discovery where we really need a scientist to take certain risks to really make breakthrough discoveries," he said.

There are three possible deal structures delineated in the agreement, Sands said. In the first, Summit, N.J.-based Celgene can license global development and commercialization rights to one program covered by the agreement in exchange for paying Nurix an option fee, potential clinical, regulatory and sales milestone payments totaling up to $405 million, as well as future tiered single-digit to low double-digit royalties on global sales. Celgene will have worldwide rights to collaboration products, with the exception of certain collaboration products for which Nurix retains U.S. development and commercialization rights. Those cases would be covered by one of two additional deal structures contemplated in the agreement. In one structure, Nurix would co-develop and co-commercialize products in the U.S., evenly splitting U.S. profits and losses with Celgene. Under that structure, Celgene would retain ex-U.S. rights and Nurix would be eligible to receive milestones and royalties on ex-U.S. sales. In the third and last possible structure, Nurix would retain all U.S. rights, Celgene would get all ex-U.S. rights, and Nurix could obtain milestones and royalties on ex-U.S. sales. For candidates not optioned by Celgene under the collaboration, Nurix would retain worldwide rights.

While the Celgene deal seems sizable enough to keep Nurix busy for quite some time, Sands said the company's platform gives it the ability to work in other therapeutic areas as well. Though he declined to indicate any current areas of interest for Nurix beyond those covered by the Celgene deal, he said attractive and well-known targets in which the UPS is involved include Parkinson's disease and other neurodegenerative diseases in which protein aggregation is a factor, such as Alzheimer's disease.

Interest in ubiquitin has been mounting since the approval of the first drug from the pathway, the proteasome inhibitor Velcade (bortezomib, Takeda Oncology Co. Ltd.), cleared by the FDA in 2008 for first-line multiple myeloma. Roche AG unit Genentech placed a big bet on the field in June with a new investment in Craigavon, UK-based Almac Discovery Inc. Alongside it, Malvern, Pa.-based Progenra Inc. and Hybrigenics SA, of Paris, are also working on early stage programs in the field. (See BioWorld Today, June 16, 2015.)

Celgene's shares (NASDAQ:CELG) fell 57 cents on Wednesday, closing at $123.78.

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