Isis, Zeneca Establish Antisense Collaboration For Cancer

Even as it heads into its corporate merger with Astra (see: Astra, Zeneca To Merge), Zeneca Pharmaceuticals (London, UK) continues to ink R&D collaborations with U.S. biotech companies (see: Incyte And Zeneca Partner On Agrigenomics). On Dec. 21 Zeneca and Isis Pharmaceuticals (Carlsbad, CA) established a three-year, worldwide research collaboration focusing on development and commercialization of novel antisense-based cancer drugs.

Like many such deals, this one teams a drug maker with very significant manufacturing and marketing capability (Zeneca) with a much smaller biotech discovery partner (Isis). Under terms of the agreement Isis will create and, with Zeneca, screen antisense-based candidates for undisclosed targets on an exclusive basis. Zeneca will be responsible for developing any potential drug candidates. Zeneca will pay Isis a technology access fee, annual research funding, and milestone payments for any drugs progressing into clinical development. In addition, Isis will receive royalties on the sales of any marketed drug arising out of the collaboration. Zeneca will have exclusive worldwide rights to develop and commercialize drug candidates emerging from this collaboration.

All told, the deal could bring Isis more than $40 million, plus royalties upon commercialization. This value assumes the completed development of compounds, based on leads already identified by Isis—some of which are already in early preclinical research.

While the initial focus of this collaboration is on a limited number of cancer targets, Zeneca and Isis can also pursue additional targets in cancer and expand to targets in other therapeutic areas. The collaboration is extendable beyond its initial 3-year term.

Closing the Discovery Gap—The Lure of Antisense

By closing this deal Zeneca fills an important gap in its drug discovery activities, i.e. antisense. The firm has kept a close watch on the development of antisense, particularly for cancer therapeutics. According to Richard Auty, director of Development at Zeneca, his company's "eyes" have followed Isis and its approach to antisense. "We have been very impressed with the recent progress and achievements of Isis in this area and are delighted to enter into this collaboration with them," Auty said.

During transcription of information from DNA into mRNA, the two complementary strands of the DNA partly uncoil. The "sense" strand separates from the "antisense" strand, which serves as a template for transcribing enzymes which assemble mRNA—a process known as transcription. mRNA then migrates into the cell where other cellular structures (ribosomes) read the encoded information, its mRNA's base sequence, and in so doing, string together amino acids to form a specific protein. This process is called "translation."

Antisense drugs are nothing more than complementary strands of small segments of mRNA. To create antisense drugs, nucleotides are linked together in such a way as to bind to specific sequences of nucleotides in its mRNA target, thereby inhibiting production of proteins. By acting at this earlier stage in the disease-causing process to prevent the production of a disease-causing protein, antisense drugs have the potential to provide greater therapeutic benefit than traditional drugs that do not act until the disease-causing protein has already been produced.

Antisense drugs have the potential to be much more selective and specific than traditional drugs, and therefore more effective, because they bind to mRNA targets at multiple points of interaction at a single receptor site. Traditional drugs usually bind at only two points of interaction.

The design of antisense compounds also has the advantage of being less complex, more rapid, and more efficient than traditional drug design directed at protein targets. Rational drug design usually begins by characterizing the three-dimensional structure of the protein target in order to design a prototype drug to interact with the target. Proteins, however, are complex molecules whose structure is difficult to predict. In contrast, antisense compounds are designed to bind to simpler two-dimensional mRNA whose structures are more easily understood and predicted. Once the receptor sequence on the mRNA is identified, the three-dimensional structure of the receptor site can be defined, and the prototype antisense drugs can be designed.

On paper antisense sounds like it could cure almost any disease, and if it worked it probably would. That's the incentive for getting into antisense. Making antisense drugs go to the right compartments within cells (or into cells at all) has been the single most important hurdle, however.

Isis Clinical Pipeline

Isis has six compounds in human clinical trials:

• Vitravene (fomivirsen), to treat CMV-induced retinitis in AIDS patients, has been approved for marketing by the FDA and is currently undergoing regulatory review in Europe
• ISIS 2302, an inhibitor of ICAM-1, is in a quality trial for Crohn's disease, as well as in Phase II clinical trials for renal transplant rejection, rheumatoid arthritis and ulcerative colitis, and is being explored as a topical administration for psoriasis and an aerosol administration for asthma
• ISIS 3521 and ISIS 5132 are in Phase II cancer trials
• ISIS 2503 is in Phase I trials for cancer
• ISIS 13312 is in Phase I/II clinical trials for the treatment of CMV retinitis in AIDS patients

The company also has several additional compounds in preclinical development. Isis' broad medicinal chemistry and biology research programs support efforts in both antisense and small molecule drug discovery.

For more information: Stephen James, VP of Business Development, Isis Pharmaceuticals, Inc., Carlsbad Research Center, 2292 Faraday Ave. Carlsbad, CA 92008. Tel: 760-931-9200.