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-- Waist circumference reduction of 9.1 cm (3.5 inches) in patients treated for a year (completers) with rimonabant 20 mg (p<0.001 vs. placebo).
-- Average increase of 23% in HDL-cholesterol in completers (p<0.001 vs. placebo).
-- Average reduction of 15% in triglycerides in completers (p<0.001 vs. placebo).
-- A positive shift in LDL particle size, with a reduction (p=0.002 vs. placebo) in the proportion of smaller dense atherogenic LDL particles, which are associated with cardiovascular risk, and an increase (p<0.001 vs. placebo) in the proportion of larger, less atherogenic LDL particles.
An extremely important result was that after one year of treatment, a significant increase of adiponectin level from baseline was found in the rimonabant 20 mg group vs. placebo (p=0.001).
Adiponectin has been shown to cause significant weight loss, even where food intake was not reduced. (See what we previously wrote on CRGN with regard to their analogue of Famoxin, which is a form of adiponectin.
Adiponectin, 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 adiponectin injections without any reduction in food intake.
Sanofi-Synthelabo's news of the significant weight loss and lipid profile results from Acomplia(TM)(Rimonabant) and the adiponectin increase announced March 11, 2004 received surprisingly little media attention. It appears the media instead picked-up a story about Nastech Pharmaceutical Company Inc. (NSTK) which announced the initiation of a phase I dose-range finding study in 12 overweight adult subjects using its investigational PYY3-36 Nasal Spray for obesity.
NSTK's small phase I study is much less significant than the initial results of SNY's massive phase III study that indicates Rimonabant's efficacy and safety.
Furthermore, it appears that there was some confusion due to the announcement by the US Government that obesity was overtaking tobacco as the number one preventable cause of death in America.
Apparently, because Rimonabant was shown to be effective in both weight loss and enabling smokers to quite, in two separate studies release simultaneously, some media outlets thought they had already reported the Rimonabant results because they had already the US Government announcement.
When the media that would normally carry (and hype) such an important obesity breakthrough does report Rimonabant results there might be a significant move in SNY.
January 8, 2004
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)
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.
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.
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.
(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
February 21, 2007 Changes to Our Model Portfolio - Manhattan Pharmaceuticals (MHA) Added; Metabolic Pharmaceuticals (MBLPF) and Curagen (CRGN) Removed. LEXG being reevaluated.
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.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.
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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.
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February 21, 2007 Changes to Our Model Portfolio - Manhattan Pharmaceuticals (MHA) Added; Metabolic Pharmaceuticals (MBLPF) and Curagen (CRGN) Removed. LEXG being reevaluated.
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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The Advertisements allow us to bring you this website and the Newsletter for free.
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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.
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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.
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Stocks in companies that are developing the new cutting-edge weight loss medications
Stock in the Spotlight: CuraGen Corporation (Nasdaq: CRGN)
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.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%.
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.
"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."
Stock in the Spotlight: Lexicon Genetics (LEXG)
Quote from the Company's President
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