The program aired April 29, 2004 - 19:00 ET, a transcript of the program can be seen at: http://www.cnn.com/TRANSCRIPTS/0404/29/acd.00.html

The segment began as follows:
ELIZABETH COHEN, CNN MEDICAL CORRESPONDENT (voice-over): Karen Bowers says after failing on all sort of diets an experimental pill helped her go from 190 to 145 pounds in about a year.
KAREN BOWERS, TRYING TO LOSE WEIGHT: And I lost 45 pounds and I didn't -- that was without effort, without pain. It just melted away.

The drug that Karen Bowers took was Sanofi-Synthelabo’s (SNY) Rimonabant. That a person who had failed on all previous diet was able to go from 190 to 145 pounds “without effort” was not the focus of the news story. Rather, the remainder of the segment scolded America for seeking a pill as a “fix” for obesity. Mr. Anderson and his guest, an osteopath, Dr. Howard Shapiro, author of "Dr. Shapiro's Picture Perfect Weight Loss, 30-day Plan." Went on to deride those such as Karen Bowers who want the pharmaceutical industry to solve their weight problems

After pointing out that: “Most of the people who took the drug weren't nearly as lucky as Karen. They were for the most part obese and when they took the pill called Rimonabant and dieted for a year they lost just 19 pounds.” “And the pill can have side effects.” “No one knows the long term side effects of most diet drugs because studies haven't been done yet but that doesn't bother Karen Bowers. She gained back nearly half her weight when she went off Rimonabant and so she says she wants to go back on it and stay on it for life.”

Elizabeth Cohen, CNN, Atlanta., the videotape ended and Anderson Cooper introduced Howard Shapiro.
COOPER: Well, the question, of course, can a pill really make you thin? Joining me now Dr. Howard Shapiro, author of "Dr. Shapiro's Picture Perfect Weight Loss, 30-day Plan." More than 100 obesity drugs -- good to see you. Thanks for being with us.
DR. HOWARD SHAPIRO, WEIGHT LOSS SPECIALIST: It's my pleasure.
COOPER: I was amazed to hear more than 100 obesity drugs are being developed right now. Everyone seems to be looking for this quick fix, that woman saying she wants to be on those pills for the rest of her life.

Cooper and Shapiro were not at all impressed by the fact that a person who had failed on all previous diet was able to go from 190 to 145 pounds “without effort”. They apparently considered that a bad thing. The pills would prevent people from following the regimen recommended by Shapiro’s books and clinic (which previously have worked so well form people such as Karen Bowers)

This exchange sums it up:
COOPER: Well, I mean I'm not a doctor. I find it alarming hearing that woman saying she wants to be on that pill the rest of her life. It doesn't seem like that's the way these pills are supposed to be used.
SHAPIRO: People will do anything to lose weight and they really don't care if it harms them or not. They take pills that have side effects. You have to be careful. You've got to understand that they want the magic fix. Nobody really wants to do what they have to do to lose weight and people want the easiest way out. Give me a pill so I don't have to think about it.
COOPER: So, where does the fault lie? Does it lie with the patient? Does it lie with the doctor or somewhere in between?
SHAPIRO: I think it lies everywhere. I think it lies with the patient because the patient demands it. It lies with the drug companies because it's a $40 billion business for them possibly if they come up with the right pill and they're going to market the public.

It appears that as far as Cooper and Shapiro are concerned, the “war on drugs” should be expended to include a new front to combat the “threat” of anti-obesity drugs.

The fallacy behind Cooper and Shapiro’s thinking stems from their view of obesity as a disease, as opposed to. the symptom of diseases. This is a subtle but crucial distinction. Fever, coughing and pain are not diseases but are symptoms of disease(s) that could result from various causes, such as infection, genetic defects, or environmental stress.

Obesity is the symptom of diseases. The problem is that today we usually do not know which disease that an obese individual may have. We are just beginning to identify the specific causes of obesity. We now know that in most cases obesity is the result of either an excess or a deficiency in the amount of specific proteins that are expressed by our genes.

We know there are many people who can eat whatever they want and never become obese. The difference between those slim individuals and people such as Karen Bowers is the Karen Bowers genetic makeup is such that a certain protein is either over expressed or under expressed. The problem is that we do not know which protein. However we are learning.

The reporter on ANDERSON COOPER 360 DEGREES noted that the average weight-loss on Rimonabant was only 19 pounds as compared to the 45 pounds lost by Karen Bowers. This suggests that Rimonabant corrects the defect in gene expression that causes Karen Bowers obesity but that many of the other participants in the drug trial had obesity caused by other factors.

We also know that a significant increase of adiponectin level from baseline was found in the patients such as Karen Bowers who took Rimonabant. Adiponectin [also known as adipocyte complement-related protein (ACRP-30), AdipoQ, etc.] has been shown to cause significant weight loss in mice. Normal mice who were made obese by being fed a high-fat diet lost on average 8 percent of their body weight after 16 days of ACRP-30 injections without any reduction in food intake.

Adiponectin is a protein that affects lipolysis, the hydrolysis of fat. Some people’s genes express more adiponectin than others. They more readily metabolize fat. There is a very significant negative correlation between adiponectin levels the percentage of body fat on an individual.

It is likely that people whose genes express too little adiponectin (possibly Karen Bowers) would show good results from a drug like Rimonabant which increase adiponectin levels and thus increase lipolysis . Those who are obese for other reasons might not good results from Rimonabant, thus bringing down the average weight loss shown by all of those who tried Rimonabant.

We are finding more and more examples of specific genes which express proteins which affect obesity. For example: Lexicon Genetics Inc. (LEXG) identified an enzyme they named LG653, that plays an important role in regulating the amount of body fat. Lexicon identified the genes that express LG653. They were able to “knock-out” the genes that express LG653. Lexicon scientists discovered that when LG653 was knocked out, mice were significantly leaner with a 30% to 44% reduction in body fat, despite consuming 19% more food. Importantly, the mice had normal muscle mass, lean body mass and bone mineral density and displayed no adverse side effects.

Lexicon has been screening for small molecule drugs against LG653. They have identified at least two molecules, which appear efficacious in blocking at least 50% of LG653. It is reasonable to assume that there are some people who obesity is caused by genes that express too much LG653. Such people probably would not necessarily respond well to Rimonabant. However, they would lose weight in response to a drug that could block LG653. Likewise, people whose genes express too little adiponectin (possibly Karen Bowers) might not good results from a drug that could block LG653.

Axokine, an anti-obesity drug from Regeneron Pharmaceuticals, Inc. (REGN), had overall mediocre results in phase III trials. However, 10% of those in the trials experienced very large weight loss. Again, this suggests that for some of those taking the drug, their obesity was caused by proteins that are involved with weight balance signals. Axokine is believed to bind to specific receptors and activate key signaling pathways in the hypothalamus that suppress appetite and subsequently lead to reduction in body weight. Those whose obesity might have been caused by genes which do not express enough adiponectin or express too much LG653 would not be expected to benefit from Axokine.

In the not too distant future we will be able to identify the specific causes of an individuals’ obesity. Until then trial and error involving drugs like Rimonabant and Axokine may be the best way for progress to be made against the scourge of obesity. Those involved in such trials should be encouraged, not derided.

Stock in the Spotlight: Lexicon Genetics (LEXG)

Lexicon Genetics (Nasdaq: LEXG) announced that the Company has begun screening for small molecule drugs against LG653, an enzyme that plays an important role in regulating the amount of body fat. Lexicon scientists discovered that when LG653 was knocked out, mice were significantly leaner with a 30% to 44% reduction in body fat, despite consuming 19% more food. Importantly, the mice had normal muscle mass, lean body mass and bone mineral density and displayed no adverse side effects. Therapeutics inhibiting LG653 could have significant potential for treating obesity and might also have an impact in associated diseases such as diabetes, heart disease and stroke.

PICTURES FROM LEXG PRESENTATION ILLUSTRATING THE RESULTS OF LG653

Latest addition
January 8, 2004
SNY: (NYSE ADR) Sanofi-Synthelabo SA
52-Week High (01/05/04) 38.50
52-Week Low (02/13/03) 22.53
Shares (Millions) 1,465.696
Market Cap (Millions) 54,333.360
Last Dividend Reported 0.416 Regular Cash

Anecdotal evidence (published in Reader’s Digest) suggests Sanofi-Synthelabo’s drug rimonabant is very effective. In an article about weight loss, it was mentioned that a patient participating in phase III trials had lost 75 pounds after failing on many diets previously. It quoted the director of the trial program as saying that he was bound by a non-disclosure agreement and could not give details on the drug that was being investigated. However, it was possible to determine that the drug being investigated was rimonabant.

Under development by Sanofi-Synthelabo, rimonabant is a selective CB1 endocannabinoid receptor antagonist indicated for the treatment of obesity. The drug, which has progressed to phase III development, works by blocking endogenous cannabinoid binding to neuronal CB1 receptors. Activation of these receptors by endogenous cannabinoids, such as anadamide, increases appetite. It is the only endocannabinoid receptor antagonist in clinical development and thus offers a unique therapeutic approach to appetite control and weight reduction.

Sanofi-Synthelabo worked on the premise that if cannabinoids stimulate appetite, blocking cannabinoid receptors in the brain might reduce appetite.

The central cannabinoid (CB1) receptors are believed to play a role in controlling food consumption and the phenomena of dependence/habituation. To develop suitable drugs against this target, the human cannabinoid receptor was first cloned and then expressed in cells. Compounds with potential inhibitory activity against this receptor were then screened for inhibitory activity. Rimonabant emerged from this screening process as a potent CB1 receptor antagonist. Preclinical animal studies subsequently showed that it could reduce consumption of fats and sugars, which contribute to weight gain.

CLINICAL TRIALS POINT TO GOOD EFFICACY AND SAFETY WITH RIMONABANT The promising preclinical findings with rimonabant have been confirmed in studies in man. Results from a 16-week phase II trial showed that treatment with rimonabant produced significant weight loss in obese patients and was well tolerated. There was evidence of a dose-response relationship in that weight loss was greatest in the higher dosage groups. Decreases of around 4kg were observed at the end of the trial in subjects receiving the highest dose of rimonabant. These reductions appear similar to the levels of weight loss achieved with existing antiobesity drugs.

Phase III trials involving 6,180 obese subjects are now ongoing in both the US and Europe. These trials will compare rimonabant at doses of 5mg and 20mg with placebo with respect to weight reduction and prevention of weight gain. Two additional trials involving about 1,000 patients each will assess the efficacy and safety of rimonabant in obese patients with concomitant type 2 diabetes and dyslipidaemia.

The basis for rimonabant is that Sanofi's researchers found a synthetic compound called a cannabinoid receptor antagonist that caps off the receptors, preventing cannabinoids from locking on and sending the "feed-me" message.

The article below indicates that rimonabant, also known as SR141716 also seems to increase Acrp30 also called Famoxin, which has been shown to cause significant weight loss in mice. Normal mice who were made obese by being fed a high-fat diet lost on average 8 percent of their body weight after 16 days of ACRP-30 injections without any reduction in food intake. Unlike appetite suppressants and other obesity drugs, ACRP-30 appears to burn fatty acids in muscles, not by activating the central nervous system.(see our discussion of CRGN earlier)
(Abtract)The cannabinoid CB1 receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells.

Bensaid M, Gary-Bobo M, Esclangon A, Maffrand JP, Le Fur G, Oury-Donat F, Soubrie P. CNS Research Department, Sanofi-Synthelabo Recherche, Montpellier, France. mohammed.bensaid@sanofi-synthelabo.com

This study investigates the effects of SR141716, a selective CB(1) receptor antagonist that reduces food intake and body weight of rodents, on Acrp30 mRNA expression in adipose tissue. Acrp30, a plasma protein exclusively expressed and secreted by adipose tissue, has been shown to induce free fatty acid oxidation, hyperglycemia and hyperinsulinemia decrease, and body weight reduction. We report that N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716) treatment once daily (10 mg/kg/d, i.p.) from 2 to 14 days reduced body weight and stimulated Acrp30 mRNA expression in adipose tissue of obese Zucker (fa/fa) rats. In parallel, the hyperinsulinemia associated with this animal model was reduced by SR141716 treatment. In cultured mouse adipocytes (3T3 F442A), SR141716 (25 to 100 nM) also induced an overexpression of Acrp30 mRNA and protein. In addition, in adipose tissue of CB(1)-receptor knockout mice, SR141716 had no effect on Acrp30 mRNA expression, demonstrating a CB(1) receptor mediating effect. Furthermore, RT-PCR analysis revealed that rat adipose tissue and 3T3 F442A adipocytes expressed CB(1) receptor mRNA. Relative quantification of this expression revealed an up-regulation (3- to 4-fold) of CB(1) receptor mRNA expression in adipose tissue of obese (fa/fa) rats and in differentiated 3T3 F442A adipocytes compared with lean rats and undifferentiated adipocytes, respectively. Western blot analysis revealed the presence of CB(1) receptors in 3T3 F442A adipocytes, and their expression was up-regulated in differentiated cells. These results show that SR141716 stimulated Acrp30 mRNA expression in adipose tissue by an effect on adipocytes, and reduced hyperinsulinemia in obese (fa/fa) rats. These hormonal regulations may participate in the body weight reduction induced by SR141716 and suggest a role of metabolic regulation in the antiobesity effect of SR141716.

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Update on Stocks in Our Model Portfolio

MBP:AU Metabolic Pharmaceuticals Ltd.
52-Week High (08/26/03) 1.510 .
52-Week Low (05/12/03) 0.500.
Shares (Millions)216.464.
Market Cap (AUD) (Millions)242.440.
Note that all figures above are in Australian Dollars which are now about $.70 US. The shares of Metabolic Pharmaceuticals Ltd. also trade over the counter in the USA with the symbol MBLPF.
In US Currency the recent price of MBLPF was $.82
52-Week High (09/15/03) 0.93
52-Week Low (05/27/03) 0.36

Metabolic Pharmaceuticals is working on a drug that has the promise of allowing people to lose weight without dieting. That, of course, is the Holy Grail of anti-obesity medication.
By isolating the fragment of the human growth hormone( hgh) that reduces fat and increases muscle, the drug seeks to provide the fat reducing benefits of hgh without the dangerous side-effects.
Phase 2b clinical trial on AOD9604 will soon begin and the first patient is expected to commence treatment in October 2003.

AOD9604 Obesity Drug - Background Metabolic’s candidate obesity drug, AOD9604, invented at Monash University, acts specifically on the body’s fat cells to enhance the breakdown of stored fats and inhibit the synthesis of new fat. This result is biochemically similar to the slimming effects of physical exercise. AOD9604 has proven to be effective in reducing obesity in laboratory animals through once daily oral administration, with no effect on food intake. The drug is modelled on the active fat reducing portion of the human Growth Hormone (hGH) molecule. hGH occurs naturally in the body and is involved in promoting growth. In addition it has pronounced effects on body fat. Scientists at Monash University have shown that, when dosed to animals, AOD9604 has the fat-reducing effects of the intact growth hormone without its other unwanted effects having been observed.

The drug is modelled on the active fat reducing portion of the human growth hormone molecule. Growth hormone occurs naturally in the body and is involved in promoting growth. However it also has pronounced effects on body fat. Scientists at Monash University have shown that, when dosed to animals, AOD9604 has the fat-reducing effects of the intact growth hormone without its other unwanted effects having been observed. A Phase 1 safety study conducted in 2001 in healthy non-obese volunteers showed that the drug was well tolerated after single intravenous doses and there were observations suggesting dose dependent activity on fat metabolism

Phase 2A human clinical trial of obesity drug AOD9604 by single-dose oral administration, showed positive results. Increased average fat breakdown compared to placebo was observed at all dose levels of AOD9604 (9, 27 and 54 mg) lasting several hours after administration, reaching statistical significance at 27 mg. Fat breakdown, a signal of drug activity, is followed in the blood by measuring levels of non-esterified fatty acids (NEFA). NEFA is a marker, evident after a single dose, of fat metabolic changes that are expected to result in weight loss after extended daily dosing.

In animal studies

Obese and lean mice were treated with hGH(human growth hormone), AOD or saline for 14 days using mini-osmotic pumps. Body weight, caloric intake, resting energy expenditure, fat oxidation, glucose oxidation, and plasma glucose, insulin and glycerol were measured before and after treatment. BaF-BO3 cells transfected with the hGH receptor were used to measure in vitro 125I-hGH receptor binding and cell proliferation. RESULTS: Both hGH and AOD significantly reduced body weight gain in obese mice. This was associated with increased in vivo fat oxidation and increased plasma glycerol levels (an index of lipolysis). Unlike hGH, however, AOD9604 did not induce hyperglycaemia or reduce insulin secretion. AOD9604 does not compete for the hGH receptor and nor does it induce cell proliferation, unlike hGH. CONCLUSIONS: Both hGH and its C-terminal fragment reduce body weight gain, increase fat oxidation, and stimulate lipolysis in obese mice, yet AOD9604 does not interact with the hGH receptor. Thus, the concept of hGH behaving as a pro-hormone is further confirmed. This data shows that fragments of hGH can act in a manner novel to traditional hGH-stimulated pathways.

A synthetic analogue (AOD9604) of the lipolytic domain of human growth hormone (hGH) has been studied for its metabolic actions in obese Zucker rats. Daily treatment with an oral dose of AOD9604 of 500 microg/kg body weight for 19 days reduced over 50% (15.8 +/- 0.6 vs. 35.6 +/- 0.8 g) body weight gain of the animals in comparison with the control. The adipose tissues of the AOD9604--treated animals were found to have an increase in lipolytic activity. In contrast to chronic treatment with intact hGH, chronic treatment with AOD9604 showed no adverse effect on insulin sensitivity of the animals, as demonstrated with euglycemic clamp techniques.

REGN: Regeneron Pharmaceuticals Inc.
Price 17.920 - 52-Week High (11/25/02) 22.85 - 52-Week Low (04/22/03) 5.77
Shares Outstanding (Millions) 52.118 - Market Cap (Millions) 928.214
Anti-obesity drug Axokine has run into problems. Phase III trials were somewhat disappointing. However, commercialization of Axokine is still possible and REGN is conducting new trials. More significant is the Aventis deal on the VEGF trap, which is a promising anti-cancer drug that works by cutting-off the blood supply to tumors (anti-angiogenesis). The two companies will share equally promotion rights and profits globally. Aventis will also pay Regeneron up to $360 million at identified milestones related to the receipt of marketing approvals for up to eight indications in Europe and the United States. Aventis will also fund development costs. It is now in Phase I trials. Sometimes, it is better to be lucky than smart. On the negative side, for its IL-1 Trap Phase II Study of efficacy and safety in patients with rheumatoid arthritis (RA) the primary endpoints were not met. It is possible that higher dose levels will give the desired results in the future as some efficacy was demonstrated at the highest dose in the study.


LEXG: Lexicon Genetics Inc.
Price 5.500 - 52-Week High (07/01/03) 7.45 - 52-Week Low (10/07/02) 2.97
Shares (Millions) 62.539 - Market Cap (Millions) 347.716
Company has been screening for small molecule drugs against LG653, an enzyme that plays an important role in regulating the amount of body fat. LEXG says that they have identified at least two molecules, which appear efficacious in blocking at least 50% of LG653.
Lexicon scientists discovered that when LG653 was knocked out, mice were significantly leaner with a 30% to 44% reduction in body fat, despite consuming 19% more food. Importantly, the mice had normal muscle mass, lean body mass and bone mineral density and displayed no adverse side effects.
LEXG: Lexicon Genetics Inc.
CRGN: CuraGen Corp.
Price 5.500 - 52-Week High (06/09/03) 7.04 - 52-Week Low (03/12/03) 3.02
Shares (Millions) 50.796 - Market Cap (Millions) 255.505
No new news on Adiponectin [also known as adipocyte complement-related protein (ACRP-30), AdipoQ, etc.] also called Famoxin, has been shown to cause significant weight loss in mice. Normal mice who were made obese by being fed a high-fat diet lost on average 8 percent of their body weight after 16 days of ACRP-30 injections without any reduction in food intake. CRGN isolated a novel variant of the human adiponectin gene with 54% homology at the amino acid level to the parent form. However, the company now notes that it has 9 small molecule projects to treat obesity and diabetes, in collaboration with Bayer, which are beyond high throughput screening.
In non-obesity areas: the results of a study on CG53135, the Company's leading protein therapeutic in Phase I clinical development, were published in the August 2003 edition of Clinical Cancer Research. The study demonstrates the protein's activity in two animal models of oral mucositis, a debilitating condition experienced by cancer patients undergoing chemotherapy or radiation therapy.
Also, the results of a study on CR002, the Company's leading fully human preclinical antibody, were published in the September 2003 edition of the Journal of the American Society of Nephrology. The study results, which were presented at the World Congress of Nephrology meeting, demonstrated the antibody's activity in an animal model of nephritis, or kidney inflammation.

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The Choices You Will Face

The primary purpose of this Newsletter is to prepare you for the choices and decisions that coming breakthroughs in obesity treatment will confront you with. Some of you are reading this Newsletter because you hope to get "Rich", while others are more interested in the "Thin" aspect of the newsletter. I suspect that many of you are like myself; interested in both the "Rich" and "Thin" aspects of the breakthroughs in the obesity field.

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Some knowledge and understanding of the science behind the revolution in obesity treatment (the "Thin" part of the newsletter), will be required of those who hope to become rich via investments in this area. An interest in the economic and financial consequences in the breakthroughs in obesity research is not required of those readers of this Newsletter wanting to be thin. However, many of you will be interested in the hows, whys and whens, of the timing of the introductions of the new anti-obesity products. In many cases, financial and commercial considerations will be the determining factor.



The investment related decisions that those of you seeking riches make will be important. However, those of you not inclined to involve themselves in such investments, can choose not to do so. An investor is free to ignore any potential investment or category of investments. Those of you hoping to be thin, cannot so easily avoid concerning themselves with the advances in anti-obesity field. The choice to ignore these breakthroughs can have serious consequences. Almost every obese person will have to decide if he or she wants to be among the early beneficiaries of the discoveries. For many it will not be an easy choice one way or the other.

OPPORTUNITY COSTS

In investment terminology "opportunity cost" refers to the foregone return from not making a particular investment or using the money in one investment as opposed to an alternative investment. For example, if you leave a particular sum in a non-interest bearing checking account, the opportunity cost could be considered the interest or dividends you could have earned on an alternative investment. Likewise, if you buy a stock that pays no dividends, and sell it ten years later for exactly what you paid for it, your opportunity cost could be considered what you would have made on an alternative investment. The opportunity cost concept also applies to personal health decisions. Not pursuing a certain treatment or course of action, could be said to entail an "opportunity cost" in the sense that the potential positive outcome that may have resulted from the treatment is foregone.

Stocks in companies that are developing the new cutting-edge weight loss medications

Stock in the Spotlight: CuraGen Corporation (Nasdaq: CRGN)

February 21, 2003 CuraGen is working on a drug that has the promise of allowing people to lose weight without dieting. That, of course, is the Holy Grail of anti-obesity medication. Adiponectin [also known as adipocyte complement-related protein (ACRP-30), AdipoQ, etc.] also called Famoxin, has been shown to cause significant weight loss in mice. Normal mice who were made obese by being fed a high-fat diet lost on average 8 percent of their body weight after 16 days of ACRP-30 injections without any reduction in food intake. Unlike appetite suppressants and other obesity drugs, ACRP-30 appears to burn fatty acids in muscles, not by activating the central nervous system. Scientists believe the isolated mechanism accounts for the lack of any visible changes in the mice's livers, hearts or dietary habits.

Famoxin was developed by Genset which was recently acquired by SERONO S.A. (NYSE:SRA), human trial have been delayed by an inability of Genset to manufacture sufficient quantities of Famoxin. However, CuraGen utilizing proprietary genomic technologies and databases discovered and initiated development of a novel adiponectin-like protein with potential for the treatment of obesity and diabetes. Employing proprietary genomic technologies they mined the human genome for potential novel genes related to adiponectin. They isolated a novel variant of the human adiponectin gene with 54% homology at the amino acid level to the parent form.

CRGN has been recently trading at abou $3 1/2 down from a high of $244 3/4 in March 2000. CuraGen's net loss for the year ended December 31, 2002, was $90.4 million or $1.85 per share. Cash per share is $8.76 and book value per share is $6.07, so at their present cash-burn rate they should be able to see the drug through to clinical trials.

Also significant is:

• see article: Genomic strategies to identify novel protein therapeutics for obesity and diabetes. Mark E Rothenberg, Esha A Gangolli, Constance A Berghs, Vincent A DiPippo, Karen Ellerman, Tatiana Ort, Michele Agee, Steven Spaderna, Andrew Eisen Internal Discovery, CuraGen Corp, Branford, CT. ENDO 2002
• (from CRGN press release): CuraGen scientists are developing a pipeline of products in the areas of obesity and diabetes, cancer, inflammatory disease, and central nervous system (CNS) disorders. This pipeline includes a portfolio of potential protein, antibody, and small molecule therapeutics to treat previously unmet medical needs. As a result of recent corporate restructuring, this pipeline has been re-prioritized to maximize output through focusing resources on those projects believed to have the highest potential for return on investment and shortest development time. CuraGen scientists have elected approximately 60 potential protein therapeutic projects and are now focused on the 20 with the highest priority. Five of these proteins have been validated in relevant cellular assays, and one of these, CG53135 (or FGF20), is anticipated to be advanced into the clinic during the first half of 2003.
• (from CRGN press release): Within one year of signing their $1.4 billion drug development and commercialization alliance, CuraGen and Bayer had elected 31 small molecule targets associated with obesity and diabetes and had completed screening against four of these targets. As a result of these accomplishments, CuraGen's targets were given high priority for screening at Bayer Corporation.

Stock in the Spotlight: Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN)

Update on Axokine. The results of the phase III trials should be released in March. However, a post on a message board by what appears to be a participant in the trials may give us a clue.

"I injected myself daily, under the skin. It didn't hurt. I agree with gotta, Axokine will save lives. Look at what people do to lose weight: stomach stapling, fasting.
I knew when I receive a placebo because there was no redness around the injection site. The months I received Axokine I wasn't hungry and had to remember to eat.
I'm losing about 7-10 pounds a month now I'm receiving Axokine"

HIGHLIGHTS

November 5, 2002
• Obese patients treated with AXOKINE showed medically meaningful and statistically significant weight loss compared to those receiving a placebo.
  
  
• Patients who were followed for another twelve weeks after their final AXOKINE treatment shows that they maintained their average weight loss during post-treatment follow-up period.
  
  
• In animal studies, weight loss was almost exclusively related to loss of fat, as opposed to lean body mass.
  
  
• U.S. Patent and Trademark Office has granted Regeneron U.S. Patent No. 6,472,178 covering an isolated nucleic acid molecule that encodes AXOKINE“, an expression vector containing this molecule, and methods of production of the molecule.
  
  
• Regeneron has initiated a Phase III program for AXOKINE for the treatment of obesity that is expected to include a total of approximately 4,000 subjects.
  
  
• AXOKINE is believed to bind to specific receptors and activate key signaling pathways in the hypothalamus that suppress appetite and subsequently lead to reduction in body weight.
  
  
• The initial pivotal trial, which enrolled approximately 2,000 subjects, includes a twelve-month treatment period which is expected to be completed in January 2003.

  Details of Phase II Trials

The Phase II trial was a randomized, double-blind, placebo-controlled, out-patient study conducted at seven clinical sites in the United States. Patients participating in the study were severely or morbidly obese, with an average baseline weight of 240 pounds and a body mass index (BMI) between 35 and 50 kg/m2. Following an initial two-week “run-in period” in which all subjects received a placebo, 170 patients were randomized into five groups who received 12 weeks of daily treatment, administered under the skin by patient self-injection. Four of the groups were part of the pre-specified primary analyses and consisted of a group receiving placebo, a second group receiving a daily dose of 0.3 micrograms (mcg) per kilogram (kg) of AXOKINE, a third group receiving a daily dose of 1.0 mcg/kg, and a fourth group receiving a daily dose of 2.0 mcg/kg. The fifth group consisted of patients who received a daily dose of 1.0 mcg/kg for eight weeks, followed by a blinded withdrawal period in which they received placebo for four weeks.

The pre-specified co-primary endpoints of the study were change in weight for the patients who completed the full 12 weeks of treatment (“Completer Analysis”), as well as change in weight for all patients, whether or not they completed the full 12 weeks of treatment (“Last Observed Value Analysis”). All AXOKINE-treated groups showed statistically significant weight loss compared to placebo, as summarized below:

Completer Analysis (Co-primary endpoint, trend analysis, p value < 0.0001) Mean Weight Change from Baseline (pounds) p value (relative to placebo) Placebo (n=19) +1.3 --- 0.3 mcg/kg (n=23) -3.4 p = 0.01 1.0 mcg/kg (n=26) -8.9 p <0.0001 2.0 mcg/kg (n=19) -7.5 p <0.0001

Last Observed Value Analysis (Co-primary endpoint, trend analysis, p value < 0.0001) Mean Weight Change from Baseline (pounds) p value (relative to placebo) Placebo (n=31) +0.6 --- 0.3 mcg/kg (n=31) -2.4 p = 0.04 1.0 mcg/kg (n=37) -7.5 p <0.0001 2.0 mcg/kg (n=33) -5.8 p <0.0001 Patients in the fifth group who received 1 mcg/kg of daily AXOKINE for eight weeks, followed by the four week blinded withdrawal period, lost weight during the treatment period and did not appear to regain weight while taking placebo. Safety and Tolerability No serious adverse events associated with the drug were reported during the trial. The most common side effect was dose-dependent injection site reactions (skin redness), which occurred in all patient groups, including placebo, and were generally mild. Other side effects associated with the drug included cough, which was notable only in the highest dose group, and nausea, which occurred most frequently in the highest dose group. There was no increase compared to placebo in the incidence of herpes simplex virus infections in patients taking AXOKINE. Neutralizing antibodies, based on a laboratory test, were not dose-related and occurred in less than 10% of all patients receiving AXOKINE. Further evidence of the tolerability of the drug was demonstrated by the ratio of patients in each dose group completing the full 12 weeks of treatment: placebo, 61%; 0.3 mcg/kg, 74%; 1.0 mcg/kg, 70%; and 2.0 mcg/kg, 58%.

Stock in the Spotlight: Lexicon Genetics (LEXG)

Lexicon Genetics (Nasdaq: LEXG) announced that the Company has begun screening for small molecule drugs against LG653, an enzyme that plays an important role in regulating the amount of body fat. Lexicon scientists discovered that when LG653 was knocked out, mice were significantly leaner with a 30% to 44% reduction in body fat, despite consuming 19% more food. Importantly, the mice had normal muscle mass, lean body mass and bone mineral density and displayed no adverse side effects. Therapeutics inhibiting LG653 could have significant potential for treating obesity and might also have an impact in associated diseases such as diabetes, heart disease and stroke.

Quote from the Company's President

"An ideal therapeutic for obesity would allow one to lose fat without altering diet," said Arthur T. Sands, M.D., Ph.D., President and Chief Executive Officer of Lexicon. "We believe the ability to reduce fat without curbing appetite or incurring undesirable side effects would have a tremendous impact in the treatment of obesity and related diseases. These are key criteria for our work as we advance LG653 to the lead compound stage."

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