My antisense is tingling

Strategic alliance between AstraZeneca and Isis aims to develop next-generation RNA therapeutics

Jim Cirigliano
LONDON—AstraZeneca PLC and Isis Pharmaceuticals Inc. haveannounced a strategic alliance focused on discovering and developingnext-generation antisense therapeutics against five cancer targets. As a keyelement of the alliance agreement, AstraZeneca will be granted an exclusivelicense to develop and commercialize ISIS-STAT3Rx, Isis' promising new productcurrently in early clinical trials in patients with advanced lymphomas. 
 
 
Under the terms of the agreement, Isis will receive fromAstraZeneca $25 million on signing, plus a $6 million payment in the secondquarter of 2013 as long as the research program persists at that time. Inexchange, Isis has granted AstraZeneca an exclusive license to develop andcommercialize ISIS-STAT3Rx and a preclinical program, as well as an option tolicense products developed under a separate research program.
 
 
AstraZeneca will be responsible for all further developmentand commercialization of ISIS-STAT3Rx apart from the ongoing clinical trial,which Isis will complete. Isis is eligible to receive additional milestonepayments subject to achieving predefined clinical success criteria forISIS-STAT3Rx and preclinical milestones for the other programs. Isis is alsoeligible to receive downstream development and approval milestone payments,license fees for research program targets and royalties on sales from productsthat are successfully commercialized.
 
 
The agreement also includes a research component; there arethree undisclosed research targets that the agreement allows AstraZeneca theoption to license at a later time.
ISIS-STAT3 is designed to inhibit the production of aprotein called "signal transducer and activator of transcription 3" (STAT3),which is implicated in a number of different cancers and appears to play acritical role in tumor growth and survival. The new drug uses Isis' mostcurrent technology and next-generation chemistry (dubbed Generation 2.5) toproduce potent new therapeutics that will initially be examined for theirapplication against lymphoma, including diffuse large B cell lymphoma, which isan area of high unmet need in the medical community. Other oncologyapplications will be explored.
 
 
"AstraZeneca has evaluated ISIS Generation 2.5 antisensetechnology in-house for oncology, and the data generated was very compellingwith improved potency compared with earlier antisense chemistry," says SusanGalbraith, head of AstraZeneca's Oncology Innovative Medicines unit.
 
 
Isis became interested in a large pharmaceutical partnerwhen it became clear that its new drug could have broad-ranging implications.The company sought to license their product to an organization that had thewherewithal to conduct broad evaluations of the drug's efficacy and potentialapplications, and the ability to move the drug swiftly forward through thedevelopment process.
 
 
The STAT3 protein is widely viewed as a promising target fortreatment of numerous diseases. It has been shown to be hyperactive in avariety of cancers, including brain, lung, breast, head and neck, bone, liver,myeloma and lymphoma.
 
 
"We feel AstraZeneca brings significant experience inoncology, and our partnership will serve to enhance our oncology franchise,which will lead to innovative new drugs and seeing STAT3 evaluated in a broaderclinical 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 ourdrug in hematologic malignancies, such as lymphoma," Dr. Brett Monia, seniorvice president of antisense drug discovery at Isis, said of the trials in anews release. "We have worked closely with AstraZeneca to design a rapid pathto the market for ISIS-STAT3Rx in these patient populations."
 
 
In early clinical trials, two patients with diffuse large Bcell lymphoma showed evidence of tumor shrinkage, suggesting that ISIS-STAT3 ispotent enough to achieve reduction of the STAT3 protein in tumor tissue.
 
"No company to date has marketed a drug targeting atranscription factor, and direct STAT3 competitors lack specificity andpotency," says Galbraith.
 
 
Beyond the promising ISIS-STAT3 product, the partnership isdesigned to be an alliance for the discovery and development of antisensetherapeutics against several cancer targets. Antisense therapies target theproteins involved in disease processes by destroying the RNA involved increating these proteins. Successful antisense technology can alter a gene,functionally silencing a mutation, or activating a gene to compensate for agenetic defect.
 
 
"When the genetic sequence of a gene is known to cause adisease, it is possible to synthesize a strand of nucleic acid—DNA, RNA or achemical analogue—that binds to the messenger RNA produced by that gene andeffectively turning that gene 'off,'" says Galbraith. "The Isis discoveryplatform develops specific therapies that bind to mRNA and inhibit theproduction of disease-causing proteins."
 
 
"We've structured a deal that will enable us to enhance ouroncology franchise and work with a partner that is knowledgeable andexperienced with taking oncology products to market," says Blackley.
 
 
"The deal adds an additional innovative technology platformto AstraZeneca for drug discovery," says Galbraith. "The collaboration alsostrengthens AstraZeneca's early-stage clinical and preclinical pipeline in corestrategic areas of oncology."
 
 
 

Jim Cirigliano

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