National Editor

Still sifting data from a Phase III study of its obesity drug Axokine, Regeneron Pharmaceuticals Inc. disclosed preliminary results from a Phase II trial in which the treatment yielded statistically significant weight loss in obese people with diabetes.

"What keeps mounting up is evidence we can produce weight loss and we can do it in a lot of settings," said Leonard Schleifer, president and CEO of Tarrytown, N.Y.-based Regeneron.

But Michael King, analyst with Banc of America Securities in New York, told BioWorld Today that additional positive data will be needed to keep the drug out of the "niche" category.

Regeneron's stock (NASDAQ:REGN) closed Monday at $6.37, up 22 cents.

The Phase II figures show subjects treated with Axokine, a modified form of ciliary neutrophic factor, at 1 mcg/kg/day plus dietary counseling lost 6.5 pounds on average, while those treated with placebo and dietary counseling lost only 2.5 pounds (p<0.01). Nineteen percent of patients lost more than 5 percent of their initial body weight.

About one-third of patients in the 1-mcg/kg group developed neutralizing antibodies by the 12th week, compared to about half of those in the Phase III trial who developed antibodies at that point. About 90 percent of patients completed the Phase II study. (See BioWorld Today, April 1, 2003.)

The lower incidence of antibodies observed in the Phase II study will be explored in a larger Phase III study in the diabetic population.

Schleifer told BioWorld Today "the market wants instant answers, but we haven't had a chance to think about this and discuss it with the FDA."

All the data must be assembled before talks with the agency, he said.

"It's not like we're filing a [biologics license application]," Schleifer said, but the process will take time. He said he expects the FDA package to be ready "in the near future. I hope it will be accomplished in a matter of months, not a matter of quarters."

King said the burden is on Regeneron to develop a dosing regimen that decreases neutralizing antibodies, and/or to develop a test that will select those patients least likely to develop them.

He added in a research note that "development costs will have to be streamlined, since a substantial cost-offsetting collaboration may be difficult to sign."

In the Phase II study, after a 14-day "run-in" period, participants were randomly assigned to receive daily subcutaneous injections of 0.5 mcg/kg, 1.0 mcg/kg or placebo, along with dietary counseling for a moderately reduced caloric intake. The first 12-week phase of the trial is being followed by a 12-week, open-label extension phase, still ongoing.

Although the Phase II study was relatively small (157 subjects) and short-term (12 weeks), Regeneron said trends also were noted toward improvement in blood glucose and other metabolic parameters. The drug was generally well tolerated, with no serious adverse events.

The 1-mcg/kg dose administered in the Phase II trial is the same as the dose in the ongoing Phase III Axokine program for non-diabetics, which so far has included more than 2,500 overweight and obese people. At the start of this month, Regeneron reported mixed preliminary Phase III data with Axokine, with bad news about the antibodies causing its stock to nosedive 56.6 percent.

Specifically, the Phase II double-blind, randomized, placebo-controlled trial was designed to measure safety and efficacy of Axokine compared to placebo for weight loss in overweight and obese individuals with Type II diabetes and a body mass index of 27 to 50 kg/m2.

Body mass index is a ratio of height to weight, calculated as the weight in kilograms divided by the square of the height in meters. Normal weight is in the range of 18.5 to 24.9 body mass index; overweight is 25 to 29.9; and obesity is 30 and above.

Average baseline weight for all participants at 24 sites in the U.S. was about 233 pounds.

"Diabetics do tend to be different," Schleifer said of the differing results of the Phase II and Phase III trials, "but we just don't know" if that difference will provide the window of benefit Regeneron needs for approval.

He said the company will be exploring two options. One is to target Axokine more effectively, as King proposed. The other is to change the Axokine molecule so that the antibody problem is lessened.

"Obviously if we could do that we'd be in terrific shape," Schleifer said.