October 2002 -- Obesity-news Drugs in Development Report Sample

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LETTER FROM THE EDITOR

Drug development is a very risky venture, with only one in several thousand compounds producing a marketable drug. A drug candidate can be shown to be ineffective or dangerous at any stage of development. Occasionally a compound will get all the way to the FDA approval stage and be rejected, as occurred in 1998 with Ergoset, a fast release version of bromocriptine. In fact, each year the universe of weight loss drugs in development changes substantially, with some candidates dropping out, and others taking their place.

From 1998 when we produced the first report below, to our fifth report, being published this fall, the numbers of drugs that are being developed has risen dramatically. In 2002, over 25 drug candidates are in phase I to phase III human testing compared to 4 in 1998. In addition, there are several drugs approved for other uses, which are now being tested on humans for weight loss, and several approved diabetes drugs with a positive effect on body weight. Obesity-news will review the data on about 10 of these drugs in this year's report. The progress in lead compounds and preclinical development skyrocketed with the completion of the Human Genome map and new drug discovery methods. There are dozens of lead compounds in preclinical development as well as hundreds of genes in early discovery. Obesity-news will present some of the most promising in Parts 2 and 3 of our report, in November and December.

In the five years since our first report, we have also greatly increased the depth with which we cover each candidate compound, both in our annual report, and in our newsletters (for an example, see our recent article on Xenical). To keep up the pace, our report has grown from the short update you see below to a five part report covering drugs in human testing, compounds in preclinical research, new gene discoveries, discontinued compounds, and an extensive drugs in development calendar covering 100 different companies. This calendar is updated continuously throughout the year.

Our Drugs in Development Report is included with a subscription to Obesity-news, a fantastic deal, considering that other much less complete reports cost thousands of dollars per year.

Obesity-news drug calendar	On the market in 1999. Drugs in human testing. Pipeline drugs.
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What it does. Stimulates dopamine type-2 receptors and antagonizes type-1 receptors in the hypothalamus and the neostriatum of the CNS.

Additional information. The Food and Drug Administration (FDA) endocrinologic and metabolic drugs advisory committee voted 9-0 against approving the new drug application (NDA) of Ergoset for type-2 diabetes. Ergo Sciences has submitted additional information to the FDA and expects to get a final decision next month. If the NDA for diabetes is rejected, it is expected that Ergo Sciences will abandon clinical trials on Ergoset for obesity.

Update. The Food and Drug Administration rejected Ergo Labs' NDA for Ergoset in late 1998. Ergo Labs discontinued its phase 1 trial of Ergoset for obesity shortly after the FDA decision.

What it does. Interferes with pancreatic lipase, one of the enzymes that breaks down fat, causing about thirty percent of fat eaten to pass undigested through the body.

Additional information. Roche withdrew its NDA in August 1997 after incidences of breast cancer were found in orlistat Phase III trial subjects. Later that fall an independent panel found that the breast cancer was not related to the orlistat, and Roche resubmitted its NDA in November of 1997. In March 1998, the FDA endocrinologic and metabolic drugs committee deadlocked 5-5 on approval of Xenical over the breast cancer issue, but in May Roche was granted a "letter of approvability". "Final approval is subject to certain conditions including submission of follow-up safety data from Xenical's ongoing clinical programs and agreement on final labeling. The company will continue to work closely with the FDA and expects to fulfill with these requirements during the first quarter of 1999." (Roche press release).

European Union approval. Meanwhile, Xenical was approved by the European Union on July 31, 1998 and is now available in Austria, Finland, France, Germany, Switzerland, and the United Kingdom. Xenical is also approved in New Zealand and several Latin American countries.

Update. Xenical was USFDA approved in 1998. The drug is currently under FDA review for the prevention of type-2 diabetes. Details of the XENDOS trials (XENical in the prevention of Diabetes in Obese Subjects) will be reported in the Obesity-news 2002 drugs in development report.

Additional information. P57 is derived from extracts of a plant native to South Africa. The drug produced appetite suppression in animal tests, but it is not known how it works. Phytopharm expects to discover the mode of action during Phase I testing.

In 1997 Phytopharm licensed the rights to P57 from the Council for Scientific and Industrial Research in South Africa. Only about 5 percent of the 250,000 plant species have been examined for medicinal purposes.

Additional information. Delayed gastric emptying limits food intake, stimulates insulin, and inhibits glucagon secretion after a meal. In diabetics this action reduces postprandial hypoglycemia, and may result in weight loss. GLP-1 may affect the "ileal brake mechanism", an important regulator of gastrointestinal function. Vagal activity may also contribute to the inhibitory effect of GLP-1 on gastric emptying.

Exendin-4 is similar to glucagon-like peptide-1, but "pharmaceutically more attractive" because of its longer duration of biological action. Exendin-4 was originally isolated from salivary secretions of the Gila monster, a lizard native to the Arizona deserts. In clinical trials the drug stimulated insulin secretion during periods of high blood sugar (hyperglycemia), but not during periods of low blood sugar (hypoglycemia). Exendin-4 also slowed gastric emptying. Chronic administration decreased food consumption in obese animals, and restored near normal glucose control in animal models of type-2 diabetes.

The good and the bad. Delaying gastric emptying is useful in treating diabetics, but it remains to be seen if it will produce weight loss. An oral version of GLP-1 is not available yet. Previous studies on humans were conducted using continuous infusion of GLP-1 because of the peptide's very short action. In a recent experiment, rodents became resistant to the appetite suppressing effects of GLP-1 within a few days.

Update. Amylin's Exendin-4 has advanced to Phase III, and a sustained release version of Exendin is currently in Phase II. Two other GLP-1 drugs are now in Phase I and Phase II testing, and several others are in the preclinical stage. Updates on those compounds will be contained in the 2002 report. Alizyme's drug AZM-134, which never moved past preclinical development, has been removed from the company pipeline.

What it does. Regulates body fat and produces weight loss through effects on metabolism and appetite.

Additional information. Amgen's injectable leptin is a recombinant form of the natural human protein produced by the obese (ob) gene. Early clinical trials demonstrated that leptin causes weight loss in humans. Two Phase II trials on leptin are underway, one on obesity and the other on type-2 diabetes. The studies are scheduled to treat more than 300 patients in total. Amgen has also started a Phase I pharmacokinetic trial with a second-generation leptin molecule which, it is hoped, will facilitate delivery of higher doses of the protein.

The good and the bad. Phase I studies showed a moderate weight loss in some subjects, but it is unknown why leptin works on some patients and not others. One theory is that non responders may be leptin resistant. A down-side to leptin is that it is currently available in injectable form only, making it unattractive to many patients.

Update. Research on recombinant leptin was discontinued in Phase II after it was shown that most obese patients do not lose weight when treated with leptin vs. placebo. Most studies on "leptin maintenance therapy" to prevent the decline of leptin after weight loss and the use of leptin in conjunction with other weight loss drugs, also showed no beneficial effect. The drug continues to be developed for the treatment of lipodystrophy. The only individuals who clearly benefit from leptin therapy are those who are leptin deficient, but there are only three known leptin deficient humans in the world. Those individuals have benefitted substantially from leptin therapy which reversed their obesity problems and other metabolic irregularities. While Amgen has discontinued its leptin program, the company continues to support research in "certain exploratory indications".

Additional information. RF 1051 is a human hormonal analog belonging to a class of steroids called etiocholanolones. Preclinical studies suggest that RF 1051 is involved in energy and glucose metabolism. Unlike thiazolidinediones which increase insulin sensitivity but result in weight gain, RF 1051 was found to be effective in promoting weight loss and increasing insulin sensitivity in obese animal models. Plasma levels of RF 1051 are significantly reduced in obesity, and are even lower in patients with Prader-Willi Syndrome. In Phase I human trials, subjects lost significantly more weight with RF 1051 than with placebo. Further, the weight loss was maintained for a period 10 weeks post medication. These results suggest that RF 1051 has a half-life, and may not need to be administered on a daily basis. There were no side effects during Phase I trials.

Supergen is now conducting Phase II trials on type-2 diabetes and obesity in multiple centers. RF 1051 has also been given orphan drug designation for the treatment of Prader-Willi Syndrome. Since Supergen is primarily involved in the development of oncology drugs, it plans to license RF 1051 to a company involved in the diabetes/obesity drug market.

Update. In the year 2001, RF 1051 disappeared from Supergen's late stage pipeline. However, according to the company's 2001 Form 10K, Supergen is seeking a strategic alliance or licensing agreement for the development of this drug. Supergen has also obtained the rights to a another compound, shown to prevent the onset on type-2 diabetes, and a diabetes/anti-obesity compound, both of which will be reviewed in the 2002 report.

What it does. Antagonizes the melanocortin-3 and melanocortin-4 receptors and causes obesity.

Additional information. AGRP is active primarily in the adrenal gland and the hypothalamus--regions that help regulate body weight. Researchers have found that mutant mice with high levels of AGRP were hungrier and 70 to 100 percent heavier than normal mice. A connection to leptin emerged when they discovered that leptin-deficient mice produced eight times more AGRP than normal rodents. These findings indicate that AGRP, which is downstream of leptin, may be useful in overcoming leptin resistance.

Gryphon Sciences has begun a pilot program on the agouti-related protein (AGRP) and its interactions with the melanocortin receptors (MCRs).

Update. Although AGRP remains a pipeline compound, many other drug companies are involved in its development. Recent patents and literature will be reviewed in the Obesity-news 2002 report.

What it does. Inhibits the breakdown of starch in the gut, reduces calorie intake from carbohydrate and normalizes blood glucose after a meal. Commonly known as a "starch blocker".

Additional information. Amylase is the enzyme that metabolizes starch. The major source of amylase is pancreatic secretions, although amylase is also present in saliva. Drugs inhibiting amylase slow down carbohydrate digestion.

In 1998 human study concluded that amylase inhibition delayed carbohydrate absorption and peak postprandial plasma glucose concentrations, but overall carbohydrate malabsorption was minimal.

The good and the bad. Amylase inhibitors reduce glucose levels and dietary carbohydrate absorption, making them useful agents in treating type-2 diabetes, but the effect on obesity is minimal.

Update. In its 1999 annual report, Alyzime announced that it discontinued its AZM-140 project,"for commercial and technical reasons."

What it does. Binds to the beta3-adrenergic receptor on fat cells increasing the amount of fat burned for energy.

Additional information. Stimulation of �-3 adrenoreceptors by selective agonists improves insulin action and stimulates energy metabolism in obese rodent models. Rodents have �-3 receptors in both brown adipose tissue (BAT) and white adipose tissue (WAT). However, human �-3 receptors are located primarily in BAT, which is present only in trace amounts in adults. Compounds used in previous studies have lacked selectivity for the human �-3 receptor, but recently more selective compounds have been developed. Research on rodents indicates that �-3 receptor stimulation may induce formation of brown adipocytes in white fat. If an effective human �-3 agonist is developed, drug tolerance should not be a problem. The �-3 receptor does not have phosphorylation sites, and at least in rodents, down relation does not occur. In fact, the �-3 receptor is up regulated by chronic stimulation. Selective �-3 agonists do not produce CNS stimulation, and unpleasant side effects like rapid heart beat (tachycardia) and hand tremors.

The compound CL 316,243 has been extensively tested on laboratory animals and humans. Although the drug is selective to the human �-3 adrenergic receptor, bioavailability is poor. More recently, Merck Research Laboratories has identified a new �-3AR agonist, L 755,507, that is both selective and potent. Early studies on humans have been somewhat encouraging, but L 755,507 has not yet been tested on humans.

The good and the bad. There is some reason to believe that humans can regenerate brown fat in white adipocytes. But finding a �-3 agonist that is both selective and bioavailable in humans has proved illusive. L 755,507 offers the best promise to date.

Update. While L-755,507 remains a pipeline compound, two other pharmaceutical companies have developed 3 selective β-3AR compounds which are all now in early human testing. Two of those compounds are new to Obesity-news this year and will be discussed in the 2002 report. Neither Oncor nor Pfizer has announced a lead compound to date. Oncor is primarily involved in cancer diagnostic and molecular biology products. It is not clear whether the company is still in business after a 1999 bankruptcy.

Additional information. Cholecystokinin is a brain/gut peptide. CCK-A in the gut induces the release of pancreatic enzymes and the contraction of the gallbladder. CCK-B is found predominantly in the brain, but its physiologic role is unclear. The CCK-B gene receptor is located in the same region as the mouse obesity mutation tubby (tub). Since CCK can function as a satiety factor when administered to rodents, localization of CCK-B receptor gene near the tub mutation identifies this receptor as a possible candidate gene for this obesity mutation.

Class A receptors have been implicated in the pathogenesis of feeding disorders. CCK-A receptor knockout mice are defective in gall bladder emptying, show increased prevalence of gall stone formation, and food intake is not inhibited by CCK-8. These results indicate that the CCK-A receptor mediates the feeding response to cholecystokinin peptides. However, CCK-A receptor knockout mice exhibit long term normal body weight regulation and do not become obese, indicating that systemic redundancies exist.

In the past, the drug companies above have been involved in research on CCK, but it appears that no current projects are in progress.

Update. GlaxoSmithKline (formerly GlaxoWellcome) has developed a CCK compound now in phase II testing. AstraZeneca (formerly Astra Arcus) has no late stage CCK compound in its portfolio, but has many preclinical collaborations on obesity and diabetes drug discovery some of which may include CCK.

What it does. Stimulates receptors in the leptin pathway that suppress food intake and lower body weight.

Additional information. Ciliary neurotrophic factor (CNTF) is a cytokine with strong neuroprotective effects and similarities to leptin. In studies on CNTF for amyotrophic lateral sclerosis (Lou Gehrig's disease) and Huntington's Disease, researchers found that weight loss was a side effect, possibly mediated by cross-reactivity between CNTF and other cytokine receptors, like leptin. Most people who are obese have high leptin levels, and possibly leptin resistance. An alternative to treating patients with leptin, may be to use a different molecule, such as CNTF, to activate the same signaling pathways, but circumvent leptin resistance.

The good and the bad. CNTF may be useful in overcoming leptin resistance, providing a viable alternative for patients who do not respond to leptin injections. But the jury is still out on whether or not CNTF will prove useful in the treatment of human obesity.

Update. Axokine is very likely to be the next antiobesity drug to hit the market. Regeneron is developing this drug on its own, after Procter & Gamble ended its collaboration during early clinical trials. P&G pulled out of the Axokine project after several subjects experienced a recurrence of herpes cold sores, and one subject contracted Bells Palsy. However, at the optimal dose of 1 mcg/kg there were no neurological effects during Phase II trials. Axokine is now in late stage Phase III development, with approximately 4,000 subjects at over 60 facilities across the United States. Regeneron has also developed a pegylated version of Axokine, which is now in Phase I clinical trials. Regeneron will have data from the first year of Phase III early next year, however subject retention to date has been very good. No accurate information on efficacy will become available until that time. Obesity-news has received many reports from individuals involved in the clinical trials. However, since none of the subjects know whether they are in the Axokine or placebo group, they can only guess as to whether their success is the result of Axokine therapy. In the 2002 report, Obesity-news will summarize data from Phase II and also late breaking information on side-effects. We will review the first year Phase III trial results when the data becomes available early next year.

What it does. Works on stress receptors in the brain to decrease appetite and regulate metabolism.

Additional information. Corticotropin releasing factor (CRF) functions as a neurotransmitter in the brain and plays a critical role in coordinating psychological and behavioral responses to stress, including eating behavior. Studies indicate that leptin modulates the secretion of CRF from the hypothalamus and that an imbalance between leptin and CRF may contribute to obesity. CRF, which decreases feeding, is found primarily in the paraventricular nucleus (PVN). CRF binding protein (CRF-BP) binds to and inactivates CRF. In preclinical studies, genetically altered obese rodents and obese rodents that were pharmacologically induced to overeat, normalized feeding and lost weight after treatment with a compound that selectively inhibits CRF binding to CRF-BP. The compound did this without inducing cardiovascular or endocrine side effects.

Update. CRF remains in preclinical testing for obesity, although Neurocrine does have a CRF drug in development of anxiety/depression. Other companies are also involved in the development of CRF antagonists for depression, and have CRF agonists in preclinical pipelines.

What it does. The antibodies destroy fat cells, effecting permanent weight loss.

Additional information. In preclinical studies, adult rats lost 10 percent of body weight after being injected. The weight loss was maintained for 3 months, even while the rats were being fed a high-fat, junk food diet of chocolate and peanuts. The company reports the effect of the drug should be permanent, because fat cells are destroyed.

The good and the bad. The concept of destroying fat cells is intriguing, and should produce permanent weight loss. But studies are very preliminary, with nothing in published literature at this time.

Update. This project disappeared from CAT's pipeline in 1999, with no explanation. CAT continues to develop human antibody drugs for rheumatoid arthritis, allergy and autoimmune diseases.

Additional information. Food intake is suppressed either by activation of the H-1 histamine receptor or inhibition of the H-3 receptor in the ventromedial hypothalamus. Histamine is a neurotransmitter that controls several central nervous system mechanisms including the sleep/wake cycle (circadian rhythm), arousal and body weight. Gliatech's selective H-3 histamine antagonists enhance histamine release in the brain and suppress food intake. The agents have been shown to suppress food intake in normal and genetically obese test animals.

Update. Gliatech never advanced its H-3 agonist for weight loss, and obesity was dropped as an indication for the drug after the company's 1998 annual report. However, Gliatech is currently conducting Phase II clinical trials on the compound for ADHD. While it appears that GT-2331 is no longer being looked at for the treatment of obesity, Gliatech and other companies have obtained patents on H-3 receptor compounds for the indication of obesity, among other conditions. So the H-3 receptor remains in the preclinical pipeline.

What it does. Increases lipolysis, decreases lipogenesis and raises resting energy expenditure.

Additional information. Human growth hormone causes body fat reduction, but also increases bone mass, decreases insulin sensitivity, and can lead to cardiovascular problems and acromegaly. The growth hormone fragment hGH 177-191 is specific to fat and has no effect on growth or insulin resistance. AOD 9604 is the most potent of the peptide variants of hGH 171-191. Rodent studies on the compound have been encouraging, and show an average weight reduction of 10 percent in 18 days without a modification of food consumption. In in vitro studies, AOD compounds are more potent on human tissue than rodent or pig fat tissue, and there were no toxic effects at 10 times the therapeutic dose.

The good and the bad. The preliminary studies look promising, but no research has been conducted on humans yet. Safety and efficacy is unknown.

Update. AOD-9604 has progressed through Phase IIa clinical trials, the results of which will be reviewed in the 2002 report. Phase I results were summarized in the 2001 drugs in development report, and preclinical results in January 2001.

Additional information. Ligand is developing two leptin "small molecule" drugs. The first uses the leptin promoter to increase leptin levels through control of gene expression. The switch, or "promoter" region of the gene regulates the production of leptin. In 1996, Ligand reported the discovery of C/EBPα, a cellular signaling molecule that increases expression of the obesity gene. Mutations in the region of the leptin promoter that bind C/EBPα decreases expression of leptin.

The good and the bad. A leptin promoter drug would have effects similar to leptin injections, but could be taken orally. However, leptin promoters would not surmount the problem of leptin resistance.

Additional information. Most obese people have high levels of leptin in their blood, but not in cerebral spinal fluid, prompting scientists to speculate that a cause of leptin resistance may be inefficient transport across the blood-brain barrier. Ligand's second "small molecule" drug in development would allow leptin to cross the blood-brain barrier via the JAK/STAT pathway.

Like other cytokines, leptin binds to a receptor to cross over into the brain. So far, at least five leptin receptors have been identified. Recently researchers found that the JAK/STAT pathway is activated by the full-length OB-receptor, found in the hypothalamus. JAK/STAT plays a major part in signal transduction of many different cytokine receptors besides leptin, including interferons and interleukins. JAK (for Janus kinase) is a family of protein tyrosine kinases that are capable of recruiting and activating different STATs. STAT (for Signal Transducer and Activator of Transcription) proteins regulate gene transcription. STATs are inactive until phosphorylated by receptor-activated JAKS.

Ligand researchers are developing a drug to mimic leptin's downstream effects, bind to the OB-receptor and hitch a ride across the blood-brain barrier via the JAK/STAT pathway.

The good and the bad. This drug offers promise to circumvent leptin resistance. Oral delivery should be possible, providing a significant advantage over injectable leptin.

Other leptin receptor research. In addition to the above, Amgen has obtained worldwide rights to develop and market products using Progenitor's leptin receptor technology. Progenitor, a division of Interneuron Pharmaceuticals, has retained the rights to leptin receptor technology using DNA anti-sense molecules and leptin receptor-specific antibodies.

Additional information. Alizyme has two drugs in development which are similar to Roche Pharmaceutical's Xenical. It is not clear how Alizyme's products differ from Roche's.

Update. Although neither of the candidates listed above progressed to human trials, Alizyme developed a third compound which is now in Phase II. Alizyme's compound is the only other lipase inhibitor in late stage development besides Hoffmann-LaRoche's Xenical, which was FDA approved in 1998. Preclinical results were reported in 2001. Phase I results will be covered in the 2002 report.

What it does. Hormone that works with leptin, and neuropeptide y to suppress appetite.

Additional information. Melanocortins are a group of pituitary peptide hormones that include adrenocorticotropin (ACTH) and the alpha, beta and gamma melanocyte stimulating hormones (MSH). Five melanocortin receptors have been identified to date, all of which are G-protein coupled receptors. Melanocortin stimulates certain hypothalamic neurons, via the melanocortin-4 receptor (MCR-4), inhibiting feeding behavior. A disruption of the MC-4 receptor in mice leads to an obesity syndrome similar to that seen in the agouti mouse, and coadministration of melanocortin antagonists prevents the obesity.

MC-4 receptor knockout mice have elevated levels of neuropeptide Y in certain areas of the hypothalamus, which results in hyperphagia and obesity. This effect is likely only part of the story of how melanocortins and their receptors contribute to regulation of body weight.

Trega withdrew its lead compound HP-228 for obesity, but announced in a May 26 press release that it had entered into an agreement with Novartis to develop orally-active small molecules for the treatment of certain diseases mediated by the melanocortin receptor pathway including obesity, Type II diabetes and Syndrome X.

Update. Of the five melanocortin receptors, only MCR-3 and MCR-4 are expressed in the brain. MCR-4 has the widest expression, but MCR-3 is more abundant in the hypothalamus, the satiety center of the brain. Unlike leptin, melanocortin mutations are known to cause obesity in humans, and up to 4% of human obesity is associated with defects in this receptor. Except for a pilot study on a nasal peptide and a non-selective MCR agonist, melanocortins remain in preclinical development for obesity. The MCR agonist MTII reduces appetite in humans, but also causes persistent and sometimes painful erections in men via the MC-4 receptor. This has reduced the probability that melanocortin agonists will be used for weight loss. However, the melanocortin peptides α-MSH, γ-MSH and peptide fragments, which have no effect on erections, are also being investigated. At the present time, many pharmaceutical companies are involved in preclinical research and patenting. A more in-depth update on melanocortins and related drug candidates will appear in the 2002 report.

What it does. Blocks neuropeptide y, an appetite stimulant that also signals the body to burn more sugar and less fat

Additional information. Neuropeptide Y (NPY) is the most abundant neuropeptide in the brain. It is a member of a family of proteins that include pancreatic polypeptide, peptide YY and seminalplasmin. NPY, a potent stimulator of feeding behavior, also plays a role in regulation of circadian rhythms, sexual function, anxiety responses and vascular resistance. Feeding in rodents decreases after injection with NPY antagonists. Studies also show that leptin inhibits NPY synthesis and release in the hypothalamus.

Although NPY is involved in control of food intake, other systems also control energy intake and expenditure. NPY deficient mice maintain normal body weight and responses to leptin. And when NPY knockout mice are mated with ob/ob mice, the resulting double mutants are less obese than ob/ob mice.

Neurogen and Pfizer collaborated on NG-95, an NPY antagonist, but Phase I trials were stopped in December 1997 when subjects in the NG-95 group experienced significant elevation of certain liver enzymes. At least for now, research on NG-95 has been abandoned, and the companies are looking at new NPY candidates, according to a May 1998 press release.

Update. Of the six NPY receptor subtypes, NPY-1 and NPY-5 have been shown to promote positive energy balance and increased body weight. In rodent experiments, central administration of selective NPY-1 or NPY-5 receptor agonists increased food intake, suggesting that activation of either receptor subtype causes hyperphagia. Therefore it would be expected that mice lacking either of the receptors would be anorexic and skinny. However, NPY-1 deficient mice only show slightly diminished feeding, becoming slightly obese as they age. And NPY-5 deficient mice have normal feeding and growth patterns. Later experiments found that both NPY-1 and NPY-5 deficiency is required to produce those skinny anorexic mice, showing that the two act together to regulate feeding. After the withdrawal of NG-95, no other NPY antagonist has advanced to human trials, but since 1998 many NPY-1 and NPY-5 antagonists have been developed with varying results. In the 2002 report, Obesity-news will report on some of the more promising compounds.

Additional information. An overexpression of PPARγ results in accelerated fat accumulation. Glucose sensitizing drugs, like troglitazone, activate PPARγ, resulting in weight gain. Consistent with this finding, mutations in PPARγ that result in overexpression of the gene, cause a form of severe obesity not associated with diabetes. Other PPARγ mutations result in higher plasma leptin levels. Increased PPARγ expression is also linked to breast cancer and rapid uptake of LDL cholesterol.

GlaxoWellcome was working on a PPARα antagonist GW409890 for treatment of obesity, but the compound was not on its most recent drug pipeline list from June 1998. The company confirmed that research on GW409890 has been discontinued, but would not say what the current status is on its PPAR project.

Update. Research on PPAR agonists for the treatment of obesity has concentrated on PPAR-α and dual PPAR-a/g agonists. While PPAR-γ causes increased fat accumulation, PPAR-α regulates the breakdown of lipids. It has been suggested that treatment with a dual agonist improves muscle insulin action without the increase in body fat associated with PPAR-γ agonist treatment. Since the withdrawal of GW409890 by GlaxoSmithKline (formerly GlaxoWellcome), several dual agonists have been developed, some of which are already in human testing. These compounds will be reviewed in the 2002 report.

What it does. The 5-HT2C receptor produces weight loss without the side effects of fenfluramine and dexfenfluramine.

Additional information. Fenfluramine and dexfenfluramine are non-specific serotonin ehancers and reuptake inhibitors associated with a number of serious conditions.

Recent research suggests that the 5-HT2C receptor subtype may play an important role in the control of food intake. Cerebrus is working on a compound based on 5-HT2C which will produce satiety and avoid the unwanted side effects of existing drugs. Researchers found that mice lacking the 5-HT2C receptor gene exhibited increased food intake and body weight gain compared with normal mice, because they took longer to feel satisfied. In a rodent experiment, researchers also found 5-HT2C mutant mice were significantly less sensitive to Redux. In a 1997 study, administration of the 5-HT2C receptor agonist m-chlorophenylpiperazine (mCPP) to 18 moderately obese patients, caused a small but significant reduction in body weight and in subjective ratings of hunger.

Cerebrus has synthesized a series of selective 5-HT2C agonists, which are being investigated as potential anti-obesity agents.

Update. Vernalis (formerly Cerebrus) developed a 5-HT2C agonist which was withdrawn after Phase 1 due to lack of efficacy. However, the company plans to advance other 5-HT2C candidates from its preclinical pipeline. In addition, a second company has developed a 5-HT2C drug which is now in early human testing. In the 2002 report, we will review current progress, recent literature and patenting.

The tubby gene was cloned and is expressed in nuclei of the hypothalamus responsible for feeding control. This finding indicates that this obesity phenotype may be a consequence of a neurodegenerative disorder. Unlike ob and db mice, which overeat, tub mice develop obesity despite consuming a normal amount of food for their size. As tub mice become obese they suffer from hyperinsulinemia and impaired glucose tolerance -- precursors to non-insulin dependent (adult-onset) diabetes. Tub mice also develop loss of sight and hearing at an early age. Recently, mutations in the human tubby like protein 1 gene (TULP1) have been linked to Retinitis pigmentosa, a human neurodegenerative disease.

Update. Tubby remains in preclinical testing, although Millennium has received many new patents on this gene since 1998. Some new theories have evolved on how the tub mutation causes obesity and how the gene is regulated. Some scientists beleive that the late-onset obesity observed in tubby mice is due to the loss of hypothalamic cells involved in body weight regulation. A more recent paper ties tubby to thyroid deficiency. These and other recent research will be discussed in the 2002 report.

What it does. A heat-generating protein that raises the metabolism and burns white adipose tissue.

Additional information. Uncoupling proteins (UCPs) stimulate thermogenesis through oxidative phosphorylation and ATP synthesis in mitochondria. UCP-1 is found primarily in brown adipose tissue (BAT), and therefore does not play a role in thermogenesis in humans, who have little brown fat. Brown fat plays an important role in temperature regulation (nonshivering thermogenesis) in small mammals. Large mammals, including humans, have brown fat when they are born, which disappears during the first year of life. In adult humans, skeletal muscle is the most important site of thermogenesis. Both UCP-2 and UCP-3 are found in muscle, making them candidates for obesity treatment.

UCP-2 and UCP-3 increase in both lean and obese individuals undergoing fasting, and there is no alteration of gene regulation in obese subjects. UCP-2 is found in BAT, WAT and skeletal muscle, whereas UCP-3 is found primarily in muscle.

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