Last week's blowup of Isis Pharmaceuticals Inc.'s antisense drug, Affinitak, in a Phase III trial for non-small-cell lung cancer placed a question mark above that category of therapeutics, but nobody is flying the white flag of surrender yet.
As Thomas Lynch, principal investigator in the 616-patient trial, put it during a conference call: "We cannot step away from the challenge." Affinitak combined with chemotherapy yielded no difference in a primary log-rank analysis of survival - the primary endpoint - as compared with chemotherapy only.
The company's stock dropped almost a third on the news, closing Monday at $2.83, down $1.33, or 31.9 percent.
Stanley Crooke, chairman and CEO of Isis, said the failure "will have an effect on our financial plans for the year. We think it will be modest, but we're just in the midst of analyzing all that." He added that revised projections will be disclosed in April.
Also still being analyzed are the data themselves. Patients given Affinitak plus carboplatin and paclitaxel experienced a median survival of 10 months, compared to 9.7 months for patients receiving chemotherapy alone. Ironically, the efficacy of the chemotherapy, while favoring patients, worked against Isis meeting its primary endpoint.
"We're way too early in the analysis to even begin to posit a possible reason for the survival of the control group," Crooke said.
On the upside for patients and Affinitak, an analysis that used predefined variables including duration of treatment showed survival of Affinitak-treated subjects was greater than that of control patients to a statistically significant degree (p=0.048).
What's more, a survival analysis of the 256 patients who made their way through the prescribed six cycles of treatment showed a median survival of 17.4 months for Affinitak patients vs. 14.3 months for patients receiving chemotherapy alone (p=0.054). Results also proved favorable across secondary endpoints in these subjects.
"It's a sad fact of our industry that the first Phase III trial is rarely perfectly designed," Crooke said, adding that "we will take advantage of the lessons we have learned with this trial" as a second Phase III study with Affinitak - this one sponsored by Isis partner Eli Lilly and Co. - continues.
The Lilly trial is expected to test 1,000 patients and yield data early next year. Andrew Gitkin, an analyst with UBS Warburg, told BioWorld Financial Watch that trying to get FDA clearance for changes in the trial protocol "may open a new jar of worms. I don't think Lilly will stop the trial, since it's half enrolled."
If anything, he said, enrollment in the Lilly trial might slow down, because ill patients could be reluctant to become involved with a drug that already has had one failure - since they are allowed to participate in only a limited number of trials.
In December, on the basis of talks with those involved in the Isis trial, Gitkin predicted that results might not be what the company was hoping for. Warburg, which makes a market in Isis and provides investment banking services, downgraded the company's stock from "buy" to "reduce" status at that time.
"I had a feeling that if the trial didn't work, the company should, and they did, look for a subset where [Affinitak] could work," Gitkin said, pointing to a strategy that is practically standard operating procedure in a failed trial.
Even the subset data are not "super compelling," however, and he said it's understandable that some investors are looking askance at antisense - although the time is too early to be giving up on the approach.
Next up is Genta Inc.'s antisense compound Genasense (oblimersen sodium), partnered with Aventis SA and being evaluated when combined with chemotherapy in multiple Phase III trials against cancer, including ones for malignant melanoma, multiple myeloma and chronic lymphocytic leukemia. Data are expected this summer.
Genasense is designed to inhibit production of the Bcl-2 protein believed to make cancer cells resistant to chemotherapy.
"Generally speaking, people tend to be more excited about this target," Gitkin said. "I think there's a greater chance of success for Genasense. Obviously it's 20-20 hindsight, to some extent, but if you would have asked me six months ago, I still probably would have said Genasense."
Affinitak selectively inhibits the production of protein kinase C-alpha. The issue of the viability of the target is one that remains unclear in the Phase III results disclosed by Isis, Gitkin said, noting that his firm also has placed Genta's stock in "hold" status.
"It's a little too unpredictable, even though we like the target," he said.
"There's this whole movement to be very specific, but the more specific you get, the higher premium you have to place on target selection," Gitkin said, pointing to a wider problem with the antisense approach. "If you're off by one epitope, you can lose all your efficacy. There has to be some dirty aspect,' in my opinion. You may not want to be a guided missile. You may want to be a regular rifle shot."
Until Lilly's experiments yield data, Isis will be poring over the results from its work. Crooke noted that "the gold standard for the FDA is the simple log-rank test," according to which Affinitak failed. But that test "doesn't do a very thorough job of dissection," and a more sophisticated, stratified study of the numbers will be deployed to investigate the apparently favorable results in some patients.
Lilly isn't backing down, either. Paolo Paoletti, the company's vice president of oncology products, said a decision won't be made about the further course of development for Affinitak until results from the second trial are available.
"The collaboration, from the scientific point of view, is still going on," he said.
Isis and Lilly entered the potential $400 million deal in August 2001, with Isis getting about $200 million in committed cash and another $200 million in milestones. Last fall, Lilly loaned Isis $21 million to build a manufacturing suite.
Crooke said there has been "no change in any of that" following the Phase III failure.
"The research is paid for by a $100 million loan, and we've drawn down not quite half of that loan," he said, adding that Lilly has seemed "extremely pleased with the progress we're making across a broad front." Crooke added that the $21 million loan made possible "the largest, most sophisticated antisense drug manufacturing plant in the world."
Still at issue is whether antisense drugs will be worth manufacturing. Gitkin said the Isis failure might at least help clarify the bigger picture regarding this area of therapy.
"If there's any lesson to be learned, it could be - and I stress the word could' - knowing whether the drug failed because of the target or the first-generation antisense technology," he said.
"If it comes to pass that [Lilly's] trial fails, too, then perhaps it is a first-generation problem," he added, but the situation for now is wait and see.
"I think we have to be careful not to jump to any conclusion," Gitkin said.