Almost three years since Isis Pharmaceuticals Inc. and Eli Lilly and Co. embarked on a journey to find antisense therapeutics, the companies again tightened their bond with an extension that enables them to look for new cancer targets.

It's been a bumpy road for the two companies following a Phase III failure of their first partnered cancer product, Affinitak, in March 2003. But Carlsbad, Calif.-based Isis and Indianapolis-based Lilly have remained steadfast, first restructuring their agreement and now extending it.

Their original deal, signed in August 2001, focused on discovering antisense drugs for inflammatory and metabolic diseases. That agreement was broadened in June 2002 to include a focus on oncology.

And now it is growing again to include the exploration of new cancer drug targets using RNA-directed technologies.

"It's expanding to include additional work in different chemistries and different mechanisms of action," said Stanley Crooke, chairman and CEO of Isis.

The companies will continue to characterize and develop RNaseH, siRNA, and splicing modulating inhibitors for the treatment of cancer using second- and third-generation chemistries. However, they now will look for additional RNA-based cancer drug targets.

Crooke declined to give financial details of the extension, other than saying it is "meaningful" to the company. Financial terms of the oncology agreement also were never disclosed, but the original agreement was worth up to about $400 million. (See BioWorld Today, Aug. 23, 2001, and June 19, 2002.)

The extended agreement indicates the companies believe they are on the right drug development path. Isis and Lilly jointly have studied and selected LY2181308, a second-generation antisense agent directed at survivin, for clinical trials based on preclinical data showing antitumor activity. Cancer cells appear to need the help of survivin to grow. The molecule is abundant in cancers of the brain, colon, lung and skin, but rarely it is found in normal cells. As a result, Isis licensed to Lilly all RNA-directed drug discovery approaches to the survivin target, and Lilly plans to begin clinical trials of LY2181308 in various solid tumors this year.

"No validation is better than the fact that Lilly will take survivin into the clinic shortly," Crooke told BioWorld Today.

Isis' current clinical drug candidates and its second-generation drugs work through the RNase H mechanism. The drugs bind to their target RNA and activate a cellular enzyme called RNase H, which destroys the target RNA and inhibits production of a specific protein.

The RNAi antisense mechanism works the same way, but uses a different cellular enzyme to destroy the target RNA.

"I think the progress across the board in antisense is gratifying," Crooke said in a conference call Thursday. "Drugs are working in man and in animal. They're demonstrating antisense mechanism and adequate performance against the diseases that we're looking at."

A main area of interest is siRNA, but industry professionals should not ignore the potential of splicing, Crooke said.

"Splicing accounts for probably about 80 percent of your protein diversity, and so it will be a tremendously important topic in the coming years," he said.

In addition to LY2181308, the companies have identified a number of cancer drug leads and plan to exploit antisense mechanisms, such as siRNA and splicing, to identify more antisense cancer drugs.

Isis has one product on the market, the antisense drug Vitravene, which was approved in 1998 to treat cytomegalovirus retinitis in AIDS patients. The company also is working on 11 other antisense products to treat cancer, as well as metabolic, cardiovascular, inflammatory and viral diseases.

Results of Isis' lead drug candidate, Affinitak, which is in a Phase III program for non-small-cell lung cancer, are expected later this year. The company is testing Affinitak in combination with Gemzar and cisplatin. A similar Phase III trial that tested it with carboplatin and paclitaxel failed to meet its endpoint last year, causing the company to cut its staff and programs. (See BioWorld Today, March 18, 2003, and April 3, 2003.)

Lilly and Isis restructured their manufacturing agreement following the Phase III failure, with Lilly waiving the repayment of a $21 million loan used to build the Affinitak manufacturing facility. Isis agreed to let Lilly out of its Affinitak supply obligations. (See BioWorld Today, June 6, 2003.)

Isis also reported its first-quarter results on Thursday, showing revenues of $12.3 million and operating expenses of $31.4 million. The company's net loss for the quarter was $26.5 million, or 47 cents per share, compared with $24.5 million, or 44 cents per share, for the same period last year. As of March 31, the company had $180.9 million in cash and short-term investments.

"Our resources are more than adequate to fund our activities at least through the end of 2006," said Lynne Parshall, the company's executive vice president and chief financial officer.

Isis' stock (NASDAQ:ISIS) dropped 31 cents on Thursday, to close at $7.