By Randall Osborne
Editor
Neanderthals did not eat Big Macs, which is why their clothes fit them so well. But ours is a new world, where half of America is overweight, and half the overweight people are clinically obese, and about one-third of these, or 12 million, are severely obese.
Each of the obese is at risk for serious health problems that can go along with the condition, such as heart disease and diabetes. Now it seems that the hormone leptin, viewed just a few years ago as possibly the most potent fat buster of all, can't save them. But maybe ciliary neurotrophic factor, also known as CNTF, can.
Last week, Regeneron Pharmaceuticals Inc. reported strongly favorable results from a Phase II study of its CNTF drug, Axokine, which helped patients in the study lose an average of 10 pounds more than those given placebo.
Michael King, an analyst with Robertson Stephens, enthused that Axokine is a potential blockbuster drug, likely to take its place at least alongside and, more likely, ahead of the two main treatments for diet-related obesity: Meridia (sibutramine hydrochloride monohydrate) and Xenical (orlistat).
King is not alone. Steven Heymsfield, one of the leading obesity researchers in the U.S., is deputy director of the New York Obesity Center, which was one of the sites for the Axokine Phase II study, and professor of medicine at Columbia University's College of Physicians and Surgeons.
Heymsfield authored papers for the Journal of American Medical Association on leptin last year and on Xenical the year before, and told BioWorld Financial Watch he has "seen all of these drugs now, so I have a good sense of them."
"I don't want to oversell [Axokine], because it's a potent cytokine, but the side effects are much more encouraging than they were originally," Heymsfield said.
In September of last year, Procter & Gamble Co. returned Axokine rights to Regeneron after preliminary data showed that, although patients on the drug lost weight and reduced their food intake, some of those in the higher, single-dosage group had activation of their herpes simplex virus (HSV) infections, or cold sores.
But, in the Phase II study, researchers found no HSV increase in Axokine patients compared to those given placebo and the drug worked against obesity.
"It's certainly more effective than leptin," Heymsfield said. "That's easy."
Amgen Inc. licensed the ob gene, which expresses leptin, in March 1995 from Rockefeller University, where it was discovered. Obese mice had been shown to lose weight after leptin injections, and scientists concluded it was an appetite suppressant that not only signaled the brain to stop hunger, but also increased calorie burning.
Since then, clinical results with leptin have been lackluster.
Heymsfield said Axokine is "probably more effective than either Xenical or [Meridia], but that's not saying much, since none of these drugs is extremely potent."
So, pass the hot fudge.
Better yet, don't.
George Yancopoulos, chief scientific officer for Regeneron, acknowledged the often preventable nature of obesity, but the destiny of Americans is to face what Yancopoulos calls "high caloric challenges," the likes of which our ancestors never saw, and almost all organisms will succumb to such challenges.
"The easiest way to make any animal fat is to put it on a McDonalds-like, high-fat diet," Yancopoulos said. "Almost no animal can resist that."
Having failed to resist, the overweight animal (man or woman) finds itself in need of some way to interrupt or forestall the craving. Simply stopping food doesn't work, because "as soon as an obese animal goes on an enforced diet, the hypothalamus starts putting out these neuropeptides to eat," Yancopoulos said. "If you assay these in the critical brain region, the brain is literally screaming to eat."
Take the animals (the men, the women) off the forced diet, and "they got back to their set point," Yancopoulos said. "Their brain has a memory of all the calories they missed," and they make them up quickly packing on again the weight that was lost. This is the yo-yo effect, sadly well known to dieters everywhere.
Enter Axokine.
"When we don't put them on a forced diet, and make them lose weight with Axokine, they're actually not hungry," Yancopoulos said. "And when you stop the Axokine treatment, you've wiped out the memory of the missed calories. They don't immediately rebound, binge eat and regain their weight."
Yancopoulos, a member of the normally subdued sector of scientists, is unabashedly proud of Axokine.
"This is such a rare story," he said. "There are a million things in development for obesity, and a million claims of cure for cancer, but they rarely come to fruition, because the science is so hard to model in animals and get efficacy. Most of it's hype and promise.
"Axokine," he said, "has shown remarkable efficacy in animals, and already appears to be following up on this promise in humans."
Not bad, for an accident.
Regeneron came across CNTF, first recognized for its beneficial effects on motor neurons, in the course of investigating a treatment for amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease.
"We had a substantial, unexpected side effect, which was weight loss," Yancopoulos said. "That concerned us at the time. This is usually not a good thing.
"But we had no evidence to suggest the weight loss was reflected in a decrease in neuromuscular function. So, we said, 'Maybe they are not losing muscle. Maybe they are losing fat.'"
They were. And they were doing it without the usual cachexia or wasting. So, Regeneron synthesized a new, more potent version of CNTF, removing some immunogenic regions of the molecule. They called it Axokine.
"We're using one to two orders of magnitude less drug now," Yancopoulos said.
CNTF works similarly to leptin, but has key differences and those differences relate mainly to its effectiveness, he said.
Axokine works with "a similar receptor, similar pathway, similar region of the brain," he said, although it's "a different molecule that is a distant leptin relative."
The hormone leptin is a natural regulator of body weight and appetite that is released by fat stores, Yancopoulos said.
"When they've built up to a certain level, which is actually modest, it tells your brain they don't have to engage in food-seeking behavior," he said. "Rare genetic mutants don't make leptin, so their fat never signals back, and they engage in voracious eating behaviors. The only problem with leptin is, although it's a panacea, a magic bullet for the specific type of obesity that is due to a lack of leptin, only a handful of patients really have that kind of obesity."
Although for these patients, leptin is a "miracle drug," for the rest the ordinary overeaters leptin isn't going to help.
"If anything, they're making excess leptin already, because they have excess fat, and their body isn't getting the message," Yancopoulos said.
Axokine, or CNTF, gets the message to them. It seems to do that better and without the side effects of either Xenical, which generates $600 million per year in sales for Hoffmann-La Roche Inc., or Meridia, the other high-selling obesity drug, marketed by Knoll Pharmaceutical Co.
The real test is weight loss induced by drug as compared with placebo, Yancopoulos noted and, here, Axokine with its 10 pounds is particularly impressive by comparison to Xenical (6 pounds) and Meridia (8 pounds).
The critical question for Axokine has to do with side effects, he added, which is also where Xenical and Meridia fall down. Yancopoulos noted Axokine seems to lack the problems of Meridia, which brings cardiovascular concerns, and of Xenical, which causes unpleasant gastrointestinal events, such as "flatus with discharge" and "oil spotting," in about one-fourth of its users.
One of the more encouraging secondary findings in the Phase II trial involved a fifth treatment arm, in which patients got eight weeks of Axokine and gained no weight back during four weeks without it afterward.
Yancopoulos said the Phase III study, expected to begin by mid-2001, will involve a more extended follow-up period, to be determined in talks with the FDA. Although cautious, Heymsfield said Axokine looks better than anything else that has come down the pike in years.
"So far, the light is green," he said. *