West Coast Editor
The second Phase III failure of an antisense drug in a week - this time, Isis Pharmaceuticals Inc.'s first-generation alicaforsen for Crohn's disease - might have cast some doubt on the once-ballyhooed field, but Isis is sticking with the compound for ulcerative colitis on the basis of success in three Phase II studies.
Wall Street took to the news. Isis' stock (NASDAQ:ISIS) closed Thursday at $6.01, up $1.09, or 22.2 percent.
"We'd probably been fully discounted for Crohn's and a lot of people were waiting for us to get that behind us," said Stanley Crooke, chairman and CEO of Carlsbad, Calif.-based Isis. Crooke said he was disappointed but "we knew it was risky" and, on the basis of Phase II data, the company had to try.
In a pair of identically designed Phase III trials, alicaforsen failed to hit statistical significance in causing remission compared to placebo, and Isis said it will not pursue the drug for Crohn's disease.
But, alicaforsen, an inhibitor of ICAM-1 (which influences lymphocyte function), did show important results when delivered to ulcerative colitis patients by way of an enema, reaching significance as measured by changes in the Disease Activity Index (DAI).
First, the details of the bad news. Isis carried out two Phase III studies in patients with active moderate to severe Crohn's disease. The first, in North America, enrolled 151 patients. The second, in Europe and Israel, enrolled 180 patients.
Patients got either placebo or 300 mg of alicaforsen by intravenous infusion three times a week for four weeks, and were followed for six months, with alicaforsen-treated patients who achieved remission followed for up to one year. The primary endpoint for both trials was clinical remission (defined as a Crohn's DAI score of 150 or less) by week 12. Alicaforsen missed in both trials.
The good news involved a trio of Phase II trials. One was a placebo-controlled study involving once-nightly dosing of 240-mg alicaforsen enema for six weeks, and yielded greater and more durable responses, as measured by the DAI, than placebo. Alicaforsen patients had improved mucosal healing, decreased rectal bleeding and decreased stool frequency. Based on an intent-to-treat analysis, 59 percent (13 of 22) alicaforsen patients achieved a response, as measured by DAI. Six months later, at the end of the study, 77 percent (10 of 13) continued to respond.
Another Phase II trial compared alicaforsen with mesalamine enema. Patients treated with 240-mg alicaforsen enema nightly for six weeks gained improvements in disease equal to or better than patients treated with mesalamine enema, with responses "substantially more durable," Isis said. Specifically, acute response was comparable to mesalamine, and many treated with alicaforsen enema who achieved a response maintained their response for six months or longer, compared to an average of less than three months for mesalamine patients.
Cincinnati-based Procter & Gamble Co. markets the anti-inflammatory mesalamine, the leading therapy for mild to moderate ulcerative colitis, under the brand name Asacol.
Isis' third Phase II study examined pharmacokinetics. Patients who got once-nightly doses of 240-mg alicaforsen enema for six weeks gained significant improvements in DAI, with little to no systemic absorption of the drug, and achieved mucosal healing by the end of the trial.
In all three ulcerative colitis studies, alicaforsen was well tolerated with no discontinuations due to side effects and no notable difference in the overall rate of side effects between the alicaforsen, placebo and mesalamine treatment groups.
Isis has settled on the dose of 240 mg nightly for Phase III trials.
"We have to sit down with the FDA" and decide on the design of those trials, Crooke said, but declined to predict when they might begin.
Lately antisense as a method of gene silencing has been overshadowed by RNA interference. While some antisense companies might try to equate the approaches - dodging the stigma of one while partaking of the other's apparent promise - they are not quite identical.
Antisense drugs are single-stranded RNA molecules that bear regions matching the messenger RNA to be silenced, and thus hybridize with the mRNA to block protein translation. Short interfering RNA, on the other hand, consists of double strands of RNA that hybridize with the mRNA of the targeted gene.
Second Generation's Potency Hailed
Crooke bristled at any suggestion by observers that Isis might be one of those companies trying to hitch its wagon to RNAi.
"I would say they're either stupid or liars," he said, adding that Isis "pioneered this technology," gaining 1,400 issued patents during 15 years of research, including some by Crooke himself, on RNAi's mechanism of action.
"I didn't know to call it RNAi when I did the work because [the term] hadn't been invented," Crooke said. "One of our central failures is that we haven't been very good at coining exciting terms," he added dryly.
What the company has been good at, though, is nailing down intellectual property that others working in antisense must contend with. Does Crooke expect court battles down the road?
"Not at all," he told BioWorld Today. "I think the fights are over with." The focus instead has been on establishing relationships such as the one with RNAi-focused Alnylam Pharmaceuticals Inc., of Cambridge, Mass., entered this spring. Isis licensed to Alnylam its patents relating to antisense mechanisms and oligonucleotide chemistry for double-stranded RNAi therapeutics in exchange for a $5 million technology access fee, along with participation in fees related to Alnylam's partnering programs, and downstream milestone and royalty payments. (See BioWorld Today, March 15, 2004.)
"We always thought that double-strand [RNA work] ought to be more interesting, but we felt we had to understand all the mechanisms," Crooke said.
Another Isis deal is with Indianapolis-based Eli Lilly and Co., and last month the first second-generation antisense drug to emerge from that deal entered Phase I trials in cancer patients.
Kate Winkler, vice president of equity research for Merriman Curhan Ford & Co. in San Francisco, doesn't cover Isis but has done "a lot of work in antisense," and finds promise in the follow-on lineup.
"I think the second generation solves a lot of problems the first generation had," she said. "It was also much more difficult to get the effect, in terms of the delivery." Those issues may be less troublesome thanks to differing chemistry and more stable formulations.
Crooke noted the problem with first-generation antisense has not been toxicity.
"People keep talking about that as though it's fact," he said. "We have the largest clinical database in the world, with almost 4,000 patients [given] first-generation antisense," which he called "extremely well tolerated," referring specifically to ISIS 2302, for which Isis recently reported data from a Phase II trial in pouchitis patients.
"Even if you looked at the Genta drug, the side effects are not bad for cancer," Crooke added. Berkeley Heights, N.J.-based Genta Inc. is the other antisense company that made news this week with a failure, when its chemotherapy booster Genasense (oblimersen sodium) didn't reach statistical significance against advanced multiple myeloma. (See BioWorld Today, Nov. 30, 2004.)
"The focus is on second-generation drugs because they're turning out to be as much as 20 times more potent in man - at least 10 times, maybe more," Crooke said. That means dosing could be "not every other day but maybe once per month. That frees us up to look at a lot of diseases that are easier to measure" than, for example, Crohn's disease, he said.
Dosing might even be less frequent. "With the cholesterol-lowering data we showed, it may be once a quarter," Crooke said.
In August, preliminary Phase I results with ISIS 301012 showed reduction of its target, ApoB-100, by up to 55 percent, along with reduction in low-density lipoprotein, very-low-density lipoprotein and total cholesterol levels in normal volunteers with borderline elevated cholesterol. The findings stem from 19 patients. The dose-escalation study is expected to enroll about 40 volunteers.
Generally, Crooke said, "the more interest in RNA-based therapeutics, the better for the field and better for us. We own it."