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Improving immune response
February 2013
by Lori Lesko  |  Email the author
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LUDWIGSHAFEN, Germany—Aimed at providing an urgent unmet need for disorders such as rheumatoid arthritis, psoriasis and inflammatory bowel disease, Janssen Biotech Inc. and Phenex Pharmaceuticals AG have joined forces to discover compounds that target the nuclear hormone receptor RORγT in the treatment of chronic autoimmune and inflammatory disorders.
 
 
Under the terms of an agreement announced Dec. 17, Phenex will receive an upfront payment and milestone payments up to $135 million upon meeting specific goals. Phenex will also be eligible to receive tiered royalties and milestones on the global sales of products that arise from the collaboration.  
 
There is little doubt that a huge market exists for these disorders, which seem to come out of nowhere to disarm the body's immune system. Autoinflammatory diseases are a relatively new category of diseases that are different from autoimmune diseases, according to the U.S. National Institutes of Health. However, autoimmune and autoinflammatory diseases share common characteristics in that both groups of disorders result from the immune system attacking the body's own tissues, and also result in increased inflammation.  
 
The part of the immune system that orchestrates all of this develops as a person grows, and is known as the acquired immune system. It "remembers" foreign antigens, or proteins, so that it can fight them if they come back. It employs white blood cells called lymphocytes.  
 
In autoinflammatory diseases, the body's more primitive innate immune system causes inflammation for unknown reasons. Autoinflammatory disorders are characterized by intense episodes of inflammation, resulting in such symptoms as fever, rash or joint swelling. These diseases also carry the risk of amyloidosis, a potentially fatal build-up of a blood protein in vital organs.  
 
Researchers from Phenex and Janssen believe the solution is to work collaboratively to identify compounds that are active against RORγT and optimized for preclinical development. Janssen will then have sole responsibility for the continued development and worldwide commercialization of any compounds that arise from the collaboration. RORgamma(t), or RORγT, is a nuclear receptor that was recently identified as a key differentiation factor of Th-17 cells—immune cells that produce and secrete Interleukin-17 (IL-17), which is believed to be a key player in chronic autoimmune-related inflammation.  
 
The relevance of the IL-17 pathway has been highlighted by the fact that antibodies that target key cytokines in this pathway have demonstrated impressive efficacy in reducing symptoms in patients with plaque psoriasis.  
 
The effectiveness of inhibiting the IL-17 pathway through small-molecule RORγT inhibitors was recently demonstrated in animal models in two adjacent publications in Nature.  
 
"The upfront payment and near-term milestones that may be achieved through this collaboration are quite important for Phenex, as the funds received will make it possible for us to both collaborate with Janssen on RORγT and continue the clinical development of our proprietary FXR program through the next few years," says Thomas Hoffmann, Phenex's chief financial officer.  
 
Under the terms of this agreement, "Phenex will be able to fund its operations and does not expect to seek further equity financing," says Hoffman. "Phenex maintains a favorable and exciting position in its ability to both help the patients who could benefit from RORγT-based therapies and provide our shareholders with a satisfactory return on their investments."  
 
Murray McKinnon, vice president and head of Immunology Discovery at Janssen Research & Development, has been impressed with Phenex's particular expertise.
 
"We have been aware of Phenex's expertise in the nuclear hormone receptor field for some years and have followed their RORγT program with interest," McKinnon tells ddn.  "Phenex brings strong expertise and capabilities in nuclear receptor biology to the collaboration, as well as a strong portfolio of chemical modulators of RORγT function. We believe our combined scientific efforts increase our overall probability of success."
 
Even the latest, most sophisticated drugs do not help everyone, he notes.  
 
"Despite the successes of antibody-based therapeutics in rheumatoid arthritis, psoriasis and inflammatory bowel disease (Crohn's disease and ulcerative colitis), there remains unmet need in patients who exhibit an inadequate response, or who are non-responsive, to these therapeutics," McKinnon says. "Orally available molecules may have advantages in patient compliance for those who cannot tolerate—or are afraid of—injections."  
 
McKinnon defines "success" in this partnership as "a robust, mutually beneficial scientific collaboration founded on rigorous science that enables Janssen to test the hypothesis in the clinic and ultimately advance novel therapeutic options for patients." Successful external collaborations "continue to enhance our focus of driving strong science in the Immunology," McKinnon adds.  
 
"Ultimately, novel, new medicines will position the Janssen Immunology Therapeutic area for future success beyond our current portfolio of biologics in addressing unmet needs in autoimmune diseases, and satisfy patient and healthcare provider needs—while strengthening our industry-leading position," he says.  
 

 
Janssen, NGM Biopharmaceuticals target diabetes, metabolic diseases
 
SOUTH SAN FRANCISCO, Calif.—Janssen Pharmaceuticals Inc. also announced last month a worldwide agreement with NGM Biopharmaceuticals Inc. to discover and develop novel therapeutics for the potential treatment of type 2 diabetes and other metabolic diseases.   
 
NGM and Janssen will jointly conduct research on selected protein factors discovered by NGM using its diabetes discovery platform, with the goal of advancing drug candidates that mimic the potential glucoregulatory effects of bariatric surgery on diabetes patients. Janssen will receive an exclusive worldwide license to develop, manufacture and commercialize compounds resulting from the collaboration.  
 
Under the terms of the agreement, NGM will receive an upfront payment and research support for activities conducted in collaboration with Janssen. In addition, NGM is eligible to receive payments upon the achievement of certain research, development, regulatory and commercial milestones, as well as royalties on worldwide product sales.   
 
"NGM's commitment to drug discovery has resulted in a deep pipeline of novel targets that have a potentially profound effect on metabolic diseases," said Dr. Jin-Long Chen, founder, president and chief scientific officer of NGM. "We are pleased to be working with Janssen, who will bring world-class drug discovery and development expertise to the advancement of NGM's first-in-class therapies for the treatment of patients with diabetes."
 
Code: E021304

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