The wonderful world of obesity research seems to grow morecomplex with each passing week. And this week was no exception. Asomewhat arcane article on the biochemistry and function of proteinkinase A (PKA) published in Nature on Wednesday attractedenthusiastic media attention. One article describing the study,published in The Washington Post, ran under the headline "ScientistsKeep Mice Thin on High-Fat Diet" and came complete withphotographs of skinny mice sniffing their chubby cagemates.

According to the study, mutant mice missing one subunit of PKAhave elevated metabolic rates and body temperatures, protecting themfrom diet-induced obesity.

While the study is a nice demonstration of the fact that the foursubunits of PKA are not redundant but rather have specializedfunctions, its relevance for developing a near-term treatment forhuman obesity is doubtful at best. But the intense media interest inthis and other obesity-related studies, no matter how early-stage theresearch, demonstrate the powerful appeal of finding a treatment forthis prevalent disease. Biotechnology companies also have shownintense interest in this field: at least seven currently are in hot pursuitof potential therapies. (See the chart on p. 4.)

It's estimated that almost 34 million Americans are obese (defined asbeing more than 20 percent over ideal body weight) and the conditionbrings with it social stigmatization as well as a host of medicalproblems such as diabetes, high blood pressure and cardiovasculardisease. But the recent flood of research on obesity has left manypeople confused. Some researchers have taken to dismissing newgenetic discoveries as the "gene du jour" and one dubbed the ever-proliferating research on leptin "leptinomania."

Leptin is the hormone (named for the Greek word thin) that isproduced by the obese (ob) gene. In March 1995, Amgen Inc., ofThousand Oaks, Calif., paid $20 million to license the rights to the obgene from Rockefeller University, in New York, where it wasdiscovered in 1994. Amgen, which now is testing recombinant leptinin a Phase I clinical trial, has had to stand by quietly while acontinuous stream of sometimes contradictory research on leptin hasbeen published.

Since Rockefeller made its discovery, other research has shown thatobese humans, instead of being leptin-deficient as was originallythought, actually have high levels of the hormone. The strategy ofgiving them more leptin has thus been called into question. "Theleptin debate will be settled by the outcome of the clinical trials," saidBradford Lowell, an endocrinologist at Beth Israel Hospital andHarvard Medical School, in Boston, Mass. "We could have ananswer within a year. I personally am skeptical that recombinantleptin will be useful in treating human obesity."

But Lowell said, even if leptin doesn't prove effective as a treatmentfor obesity, it nevertheless represents "the biggest discovery in theobesity field ever." Further, in Type II (adult onset) diabetes _ wherepatients with high levels of insulin suffer from insulin-resistance _giving them more insulin works. "It could be that obese people areleptin-resistant," Lowell told BioWorld Today. "Or it could be thatleptin just doesn't do anything at high levels. It's pure speculation atthis point."

Indeed, the research on obesity in recent months has been confusing,even to experts. "I think what the stream of new data tells us is thatthere is more than one biochemical mechanism involved in obesityand that it is a multifactorial disorder," said Adele Haley, a lifesciences technology analyst at Kaufman Bros., L.P. in New York."Science is slowly unraveling the discrete molecular biology ofeating and appetite control and it may be that this disease requiresseveral approaches just as we see in cardiovascular disease."

Haley said that Interneuron Pharmaceuticals Inc., of Lexington,Mass., has opened the door for obesity drugs with its recentlyapproved product, Redux (dexfenfluramine). Redux, being marketedby Radnor, Pa.-based Wyeth-Ayerst Laboratories (a subsidiary ofAmerican Home Products Corp.), has enjoyed "phenomenal earlyacceptance," according to Haley.

Mike King, an analyst at Vector Securities International in Deerfield,Ill., said he expects Redux to generate $152 million in sales in 1997,its first full year on the market. In five years, he's projecting the drugwill generate $1 billion. Interneuron gets a royalty rate from Wyeth-Ayerst that slides between 5 percent and 12 percent, depending onthe level of sales and the classification of the drug, according toInterneuron spokesman William Boni.

Neurogen Corp., which is right on Amgen's heels with a Phase I trialof its drug, NGD-95-1, appears to be at the head of the pack ofcompanies using neuropeptide Y (NPY) receptors as the basis fornew therapies. "We believe Neurogen's strategy and compound likelyis to represent the next generation of treatment in the battle of thebulge," said Haley. Synaptic Pharmaceutical Corp. of Paramus, N.J.,and Allelix Biopharmaceuticals Inc., of Mississauga, Canada also areworking on NPY receptors. n

-- Lisa Piercey Special To BioWorld Today

(c) 1997 American Health Consultants. All rights reserved.