Common sense

CARLSBAD, Calif.—Seeking to further its concentration on the promising research area of rare and severe disease, London-based pharma GlaxoSmithKline PLC (GSK) announced in late March a blockbuster deal with Isis Pharmaceuticals, a drug developer known for its expertise in RNA-targeted therapeutics, that will apply Isis' antisense drug discovery platform to seek out and develop new therapeutics against targets for infectious diseases and some conditions causing blindness.

Under the terms of the agreement, which covers up to six programs, Isis will receive an upfront $35 million payment from GSK and is eligible to receive up to $20 million in milestones per program up to Phase II proof-of-concept (PoC). GSK will have the option to license compounds at PoC, and will be responsible for all further development and commercialization. Should all six programs be successfully developed for one or more indications and commercialized through to pre-agreed sales targets, Isis will be eligible to receive license fees and milestone payments totaling nearly $1.5 billion. In addition, Isis will receive up to double-digit royalties on sales from any product that is successfully commercialized.

Dr. Patrick Vallance, senior vice president and head of drug discovery at GSK, said in a statement released by the company that Isis' antisense approach offers an exciting opportunity to target certain severe diseases in a way that has not previously been possible. Antisense therapies target the proteins involved in disease processes through the RNA that is involved in building these proteins. Isis' discovery platform develops specific therapies that bind to messenger RNA (mRNA) and inhibit the production of disease-causing proteins.

"Isis Pharmaceuticals is a leader in antisense technology, and this new alliance will enhance our discovery platform in this promising research area," Vallance stated.

Dr. Stanley T. Crooke, Isis' chairman and CEO, notes that the alliance differs from most traditional pharma collaborations in that it allows Isis to accept a bit more risk and retain control of the discovery and early development of drugs while working with a high-quality partner who accepts a little less control to maximize the value of the drugs in late-stage development and commercialization.

"This alliance is exactly the type of deal we want to do," Crooke says. "It has benefits for both companies. It gives us cash now and puts us in the driver's seat in terms of drug discovery. When we get to Phase II, we have a partner who is ready to license the drugs, so there is no delay in moving forward. It also means that our partner knows what it wants and can move with the speed and efficiency of a smaller company."

Although Isis has never worked directly with GSK before, Regulus Therapeutics Inc., a developer of microRNA therapeutics jointly owned by Isis and Alnylam, has had several collaborations with the top pharma in recent years. Crooke points out that Isis' antisense drug discovery platform is so efficient, the company discovers more drugs than it can develop by itself. Because of that, Isis licenses its drugs to partners prior to late-phase development and commercialization, eliminating the costs associated with a sales and marketing force. Isis then benefits from upfront license fees, milestone payments and royalties.

Some of Isis' other many pharma partners include Genzyme, Bristol-Myers Squibb Co., Teva, OncoGenex and Novartis, Crooke notes. To date, Isis has generated more than $1.6 billion from the successful execution of its partnership strategy, and is the owner or exclusive licensee of more than 1,600 patents worldwide.

"If people are involved in RNA therapeutics, they generally end up dealing with us or one of our partners," Crooke says. "We're interested in moving more aggressively into some orphan diseases, as was GSK, so our common interests, Isis' position at the center of the world of RNA therapeutics and GSK's interest in seeking the type of deal we have done with other companies in the past led to productive conversations."

Isis' antisense technology has proved to work in multiple drugs in the clinic, Crooke adds, and the company has 22 drugs in development for cardiovascular, metabolic, neurodegenerative and inflammatory diseases as well as cancer. Recently, the company announced data from a Phase III trial in heterozygous familial hypercholesterolemia patients that demonstrated the therapeutic effect of the antisense approach.

RNA-targeted therapeutics, or antisense therapies such as oligonucleotides, represent an opportunity for a new drug class. Where most other medicines are small molecules or biologics that target a specific protein in a disease process, antisense therapies prevent protein synthesis by eliminating the mRNA, the template or pattern that guides the production of the protein.

"New mechanisms are emerging that we are quite excited about," Crooke says. "And there are risk-based mechanisms, such as research in the field of siRNA therapeutics, which are very exciting, but are going to require quite a bit more work to understand what kinds of molecules are going to be best to exploit."