Key clinical data set to come out this month for Isis Pharmaceuticals Inc.'s experimental lung cancer drug could be a litmus test for the novel field of drug development known as antisense, experts said.
Isis, based in Carlsbad, California, is a leader in the field of antisense -- an as yet unproven technology designed to work at the genetic level to block the formation of proteins that cause disease. Conventional drugs interact with already-created proteins.
Aspirin, for example, affects enzymes responsible for signaling proteins called prostaglandins that trigger nerve signals for pain and cause inflammation.
"People have learned to be skeptical ... but the antisense platform could be validated in less than a month," Elemer Piros, an analyst at Rodman & Renshaw.
So-called messenger RNA carries the codes that tell cells which proteins to make. They are called "sense" strands while synthetic DNA pieces designed to bind to them, and thus stop them from working, are called "antisense strands."
Affinitak, the Isis drug tested in lung cancer patients, is designed to block a specific gene from producing a protein believed to play a role in cancer cell development and growth.
Major drug firm Eli Lilly & Co.'s 2001 decision to co-develop the drug and commit $200 million in funding to Isis was seen as a long-awaited stamp of approval for the field.
But scientists have continued to debate whether antisense drugs can actually work by silencing gene activity.
"Antisense can work, but it seems to require more specialized sequences than RNA interference," said Lynne Maquat, professor of biochemistry and biophysics at the University of Rochester Medical Center in New York.
She was referring to a relatively new technique involving the use of tiny snippets of RNA to shut off specific genes.
Others are skeptical about Affinitak's particular mechanism of action. "Since the trial started in 1999 a lot of new things have been learned about lung cancer," said David Bouchey, an analyst at C.E. Unterberg, Towbin.
He said recent studies have shown that there are several versions of protein kinase C-alpha, the target of the Isis drug, which means tumors have backup mechanisms even if the antisense drug succeeds in knocking out its target.
Isis declined comment, citing a quiet period regarding Affinitak until the data is announced sometime this month.
"There is an incredible amount of talent at Isis. I just don't think this drug will work," Bouchey said. A more promising drug, he said, could be the company's antisense compound for Crohn's disease, for which a second round of Phase III results are expected early next year.
Lots of once-promising antisense drugs have failed, including experimental therapies from Isis for HIV and genital warts. Isis makes the world's only commercial antisense drug -- a treatment for a rare type of eye infection in AIDS patients.
In Phase II trials, Affinitak in combination with chemotherapy nearly doubled patient survival to just under 16 months compared with a life expectancy of 8 months to 9 months for patients given chemotherapy alone.
The critical Phase III trial compares a combination of Affinitak and chemotherapy to chemotherapy alone in more than 600 previously untreated lung cancer patients. The goal is to show a 33 percent or higher improvement in survival.
"If they get that, it's a home run," Piros said, adding that a single-digit improvement would probably spell the end of efforts to develop the drug, while 15 percent to 30 percent could still signal a future for Affinitak since other drugs used to treat lung cancer show similar efficacy.
If the drug is eventually approved by regulators, Piros estimated peak sales of $600 million to $800 million annually.
Genta Inc. of Berkeley Heights, New Jersey, which is also involved in antisense drug development, has a cancer drug in late stage trials called Genasense.