By Brady Huggett

When considering Isis Pharmaceuticals Inc.¿s compound ISIS 2302, the old adage instructing thrown riders to get right back on the horse neatly applies.

Isis initiated a Phase III trial to evaluate ISIS 2302 (alicaforsen) in patients with Crohn¿s disease, after examining the failed Phase IIb trial in the same indication that threw the company in late 1999. Armed with a tweaked dosing scheme, Isis is again ready to test its product in a late-stage Crohn¿s trial.

¿On analysis of the previous study, it was clear that patients with a higher amount of [ISIS 2302] in their blood had a greater likelihood of responding, suggesting that a higher dose might be effective,¿ said Andrew Dorr, vice president and chief medical officer at Isis. ¿The dose in [the Phase IIb] trial was 2 mg/kg. If patients weighed more than 100 kilos, they still got the 200-mg dose. In the current trial, everyone who weighs 50 kilograms or more gets a 300-mg dose. Patients under 50 kilograms get a 200-mg dose.¿

The drug failed to demonstrate a statistically significant difference from placebo in the IIb trial. Isis¿ stock (NASDAQ:ISIP) the day the news was released dropped 64 percent, or $9.91, closing at $5.59. (See BioWorld Today, Dec. 16, 1999.)

Isis¿ stock rose 57 cents Thursday to close at $23.

Since the Phase IIb, Isis has conducted a 20-patient nonrandomized trial to evaluate the higher dose, just to reinforce what it believed had been gleaned from the Phase IIb analysis. That trial is still ongoing, but Isis saw what it wanted and moved ahead with Phase III plans.

The primary endpoint in the randomized trial is clinical remission as defined by a Crohn¿s disease activity index score of less than 150, with no increase in the use of medications and no need for surgery. The 150 patients, 100 of whom will receive the drug, will be evaluated at 12 weeks for determination of endpoint success, but will be followed beyond the 12-week marker for the secondary endpoint of remission duration.

That study is one of two Phase III trials Isis has planned for the compound. Endpoints will be the same for the second study.

Crohn¿s disease is characterized by a chronic inflammation of the gastrointestinal tract. Usually, inflammation occurs in the ileum as well as the large intestine, but can occur in other areas. ISIS 2302 is an antisense inhibitor of intercellular adhesion molecule-1, or ICAM-1, which is involved in ¿a variety of inflammatory processes,¿ Dorr said.

As with most trials, Dorr said, establishing a concrete timeline both for the release of data and for filing is difficult, but said the Phase III is ¿set up to go quickly.¿

The Phase IIb trial analysis revealed that patients who had adequate exposure to the drug reacted better, Dorr said, and therefore helped shape the Phase III design.

¿What we want to do is make sure everyone gets a higher dose,¿ he told BioWorld Today. ¿In the Phase III trial we are planning to use a fixed dose that will assure that virtually all the patients will get adequate exposure to drug.¿

Earlier this week, Isis, of Carlsbad, Calif., signed an agreement with OncoGenex Technologies Inc., of Vancouver, British Columbia, to collaborate on OGX-011, an antisense compound designed to inhibit clusterin and therefore help the effectiveness of anticancer agents. While that compound has yet to make its way into the clinic, the initiation of the Crohn¿s disease Phase III further fattens Isis¿ pipeline, particularly its late-stage products. Isis has two Phase III trials under way, including this study and a small-cell lung cancer study of ISIS 3521, and six other compounds in Phase II trials. (See BioWorld Today, Nov. 27, 2001.)

¿We now have two drugs in Phase III and one drug on the market [Vitravene, partnered with Novartis Ophthalmics],¿ Dorr said. ¿This means we have two opportunities for success in the future, and that, for us, is a big step forward. This increases our opportunity to bring antisense to practitioners and patients for common use.¿

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