My antisense is tingling
February 2013
by Jim Cirigliano  |  Email the author


LONDON—AstraZeneca PLC and Isis Pharmaceuticals Inc. have announced a strategic alliance focused on discovering and developing next-generation antisense therapeutics against five cancer targets. As a key element of the alliance agreement, AstraZeneca will be granted an exclusive license to develop and commercialize ISIS-STAT3Rx, Isis' promising new product currently in early clinical trials in patients with advanced lymphomas.   
Under the terms of the agreement, Isis will receive from AstraZeneca $25 million on signing, plus a $6 million payment in the second quarter of 2013 as long as the research program persists at that time. In exchange, Isis has granted AstraZeneca an exclusive license to develop and commercialize ISIS-STAT3Rx and a preclinical program, as well as an option to license products developed under a separate research program.  
AstraZeneca will be responsible for all further development and commercialization of ISIS-STAT3Rx apart from the ongoing clinical trial, which Isis will complete. Isis is eligible to receive additional milestone payments subject to achieving predefined clinical success criteria for ISIS-STAT3Rx and preclinical milestones for the other programs. Isis is also eligible to receive downstream development and approval milestone payments, license fees for research program targets and royalties on sales from products that are successfully commercialized.  
The agreement also includes a research component; there are three undisclosed research targets that the agreement allows AstraZeneca the option to license at a later time. ISIS-STAT3 is designed to inhibit the production of a protein called "signal transducer and activator of transcription 3" (STAT3), which is implicated in a number of different cancers and appears to play a critical role in tumor growth and survival. The new drug uses Isis' most current technology and next-generation chemistry (dubbed Generation 2.5) to produce potent new therapeutics that will initially be examined for their application against lymphoma, including diffuse large B cell lymphoma, which is an area of high unmet need in the medical community. Other oncology applications will be explored.  
"AstraZeneca has evaluated ISIS Generation 2.5 antisense technology in-house for oncology, and the data generated was very compelling with improved potency compared with earlier antisense chemistry," says Susan Galbraith, head of AstraZeneca's Oncology Innovative Medicines unit.  
Isis became interested in a large pharmaceutical partner when it became clear that its new drug could have broad-ranging implications. The company sought to license their product to an organization that had the wherewithal to conduct broad evaluations of the drug's efficacy and potential applications, and the ability to move the drug swiftly forward through the development process.  
The STAT3 protein is widely viewed as a promising target for treatment of numerous diseases. It has been shown to be hyperactive in a variety of cancers, including brain, lung, breast, head and neck, bone, liver, myeloma and lymphoma.  
"We feel AstraZeneca brings significant experience in oncology, and our partnership will serve to enhance our oncology franchise, which will lead to innovative new drugs and seeing STAT3 evaluated in a broader clinical program than we could have done on our own," says Amy Blackley, associate director of corporate communications at Isis. "While STAT3 is implicated in a number of different cancers, the focus in our ongoing clinical study is to evaluate the effectiveness of our drug in hematologic malignancies, such as lymphoma," Dr. Brett Monia, senior vice president of antisense drug discovery at Isis, said of the trials in a news release. "We have worked closely with AstraZeneca to design a rapid path to the market for ISIS-STAT3Rx in these patient populations."  
In early clinical trials, two patients with diffuse large B cell lymphoma showed evidence of tumor shrinkage, suggesting that ISIS-STAT3 is potent enough to achieve reduction of the STAT3 protein in tumor tissue.
"No company to date has marketed a drug targeting a transcription factor, and direct STAT3 competitors lack specificity and potency," says Galbraith.  
Beyond the promising ISIS-STAT3 product, the partnership is designed to be an alliance for the discovery and development of antisense therapeutics against several cancer targets. Antisense therapies target the proteins involved in disease processes by destroying the RNA involved in creating these proteins. Successful antisense technology can alter a gene, functionally silencing a mutation, or activating a gene to compensate for a genetic defect.  
"When the genetic sequence of a gene is known to cause a disease, it is possible to synthesize a strand of nucleic acid—DNA, RNA or a chemical analogue—that binds to the messenger RNA produced by that gene and effectively turning that gene 'off,'" says Galbraith. "The Isis discovery platform develops specific therapies that bind to mRNA and inhibit the production of disease-causing proteins."  
"We've structured a deal that will enable us to enhance our oncology franchise and work with a partner that is knowledgeable and experienced with taking oncology products to market," says Blackley.  
"The deal adds an additional innovative technology platform to AstraZeneca for drug discovery," says Galbraith. "The collaboration also strengthens AstraZeneca's early-stage clinical and preclinical pipeline in core strategic areas of oncology."  
Code: E021317

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