Topiramate

Phentermine

2010 was supposed to be the year in which one or more new obesity drugs would be approved by the FDA and reach the market. Three new drugs developed by small California companies–Vivus Pharmaceuticals’ Qnexa, Orexigen Therapeutics’ Contrave, and Arena Therapeutics’ lorcaserin, were up for review by the FDA. This follows a long hiatus, since the FDA has approved no anti-obesity drug since 1999.

On July 15, 2010, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted against FDA approval of Vivus’ Qnexa (phentermine/topiramate), with six votes in favor and 10 against. The FDA usually follows the advice of its advisory panels, but does not always do so.

The advisory committee agreed that the drug caused significant weight loss, with patients who took the highest doses of the drug having lost over 10 percent of their weight in a year. But many panelists questioned the lack of long-term data on efficacy, since the real issue with weight loss regimens (whether diet and exercise alone or with drug treatments) is the inability of patients to keep weight off once it has been lost.

But above all, panelists had concerns about Qnexa’s safety. Major concerns included the potential for fetal exposure during pregnancy and birth defects, depression, cognitive issues, and increases in heart rate. Most panelists who voted no were not strongly against approval, but they had lingering concerns, especially since the drug if approved would be given to large numbers of essentially healthy people over a long period of time–perhaps a lifetime.

Vivus said that it would work with the FDA to address the panelists concerns. For example, the company expects to have longer-term safety data on the drug in the next several months.

Qnexa is a low-dose, controlled release formulation of two FDA-approved drugs: phentermine and topiramate. Qnexa is designed to both suppress appetite (phentermine) and promote satiety (topiramate). Phentermine, an amphetamine, is prescribed as a weight-loss aid that is used short-term. It was the “phen” half of the notorious “Fen-Phen” combination. The “fen” part, fenfluramine (Pondimin) or dexfenfluramine (Redux), were serotonin modulators that caused cardiovascular side-effects. Topiramate is an anticonvulsant. As separate agents, phentermine and topiramate have minimal effects on weight loss. However, according to Vivus’ studies, the two drugs appear to have a synergistic effect, even at low doses, that results in significant weight loss. Vivus’ studies also indicate that the two drugs mitigate each other’s side effects; the low does and controlled release is also designed to reduce side effects.

Side effects of phentermine may include increase in blood pressure and heart palpitations, as well as gastrointestinal side effects. Side effects of topirmate may include cognitive issues, lack of coordination, aggressiveness, changes in ability to taste food and loss of appetite, cardiovascular side effects, and others. The risk of birth defects with ether of these drugs is unknown. However, there is preliminary evidence that topiramate might cause birth defects.

Lorcaserin is up for FDA Advisory Panel review in September 2010 and Contrave is tentatively scheduled for review in December 2010. Lorcaserin is a selective serotonin receptor agonist, which is specific for the 5-HT2C receptor. This contrasts with the nonselective serotonin reuptake inhibitor and serotonin-releasing agents, fenfluramine and dexfenfluramine. Lorcaserin is thus designed to be a more selective agent that works by a similar mechanism to dexfenfluramine or fenfluramine. Since the anorectic effects of fenfluramine/dexfenfluramine is due to their activity on 5-HT2C, but the adverse effects of these agents appears to be due to their activity on 5-HT2B, lorcaserin may be a safer agent that fenfluramine/dexfenfluramine. But like fenfluramine and dexfenfluramine, the efficacy of lorcaserin appears to be minimal.

Contrave, like Qnexa, is a combination of long-acting formulations of two FDA-approved drugs–bupropion and naltrexone. Orexigen designed Contrave to have a dual effect on pathways within the hypothalamus of the brain that control energy balance–increasing anorexia and inhibiting the reward effects of food. The company also believes that Contrave may block the body’s compensation for weight loss–i.e., decreased energy use and increased feeding. (For additional details, see our 2008 book-length obesity report, published by Cambridge Healthtech Institute.)

The Endocrinologic and Metabolic Drugs Advisory Committee’s recommendation against Qnexa casts a cloud on the upcoming reviews by the same committee of the other two drugs. However, the jury is still out on lorcaserin and Contrave. And approval of Qnexa may (or may not) be reconsidered as Vivus presents additional data.

However, antiobesity drugs that work via the CNS to control appetite by modulating the activity of common neurotransmitter pathways have a generally poor record. First was the fenfluramine/dexfenfluramine/Fen-Phen debacle, in which fenfluramine and dexfenfluramine (Interneuron/Wyeth) were found in the postmarking period to cause heart valve damage, leading to market withdrawal in 1997 and a host of lawsuits. Sanofi Aventis’ rimonabant never reached the U.S. market–in 2007 the FDA rejected the drug due to neurologic and psychological adverse effects. Rimonabant was also suspended from use in Europe in 2008. A related Merck drug, taranabant, was never submitted to the FDA, since it had similar adverse effects to rimonabant. And despite a growing understanding of pathways (involving neurotransmitters and neuropeptides) in the hypothalamus that control appetite, and despite a large number of promising leads that emerged from that research, not one drug derived from this research has yet emerged from early clinical trials.

In many cases, drugs that were designed to address these pathways had unacceptable adverse effects, since the neurotransmitter or neuropeptide receptors that they addressed are also involved in other CNS and/or peripheral tissue pathways that do not control body weight or energy balance. This is also the problem with appetite control drugs that have reached the IND or post-marketing stage. Such drugs as fenfluramine/dexfenfluramine and sibutramine target receptors for such common neurotransmitters as serotonin and noradrenaline, which are involved in many pathways within the CNS and peripheral tissues. Rimonabant is an antagonist of the CB1 cannabinoid receptor, which is widely expressed in the brain and in other tissues and modulates multiple pathways.

Sibutramine (Abbott’s Meridia/ Reductil) is an approved and marketed appetite-control drug that works via the CNS. It is a serotonin–norepinephrine reuptake inhibitor. Sibutramine causes increases in blood pressure and heart rate. Therefore, the drug is contraindicated in patients with uncontrolled blood pressure and certain other conditions.

There is also concern that sibutramine may cause more serious cardiovascular conditions. Early in 2010, the FDA issued a warning that the drug posed an increased risk of heart attack and stroke in patients with a history of cardiovascular disease. This resulted in an additional contraindication on the drug’s label. And a few patients taking sibutramine may experience psychological adverse effects. Because of concerns about sibutramine’s safety, the drug has recently been suspended from use in the U.K. and the E.U. Sibutramine is also under continued review by the FDA.

Sibutramine and the other approved antiobesity drug, orlistat (Roche’s Xenical–also marketed as a low-dose over the counter formulation, GlaxoSmithKline’s alli) have only marginal efficacy. And orlistat, which works not in the CNS, but in the gut to block fat absorption, has unpleasant gastrointestinal adverse effects. Therefore there is a need for safer, more efficacious antiobesity drugs.

Nevertheless, the history of failure of antiobesity drugs, especially appetite-control drugs that work via the CNS and modulate neurotransmitter receptors that are involved in multiple pathways, continues, with the decision of the FDA Advisory Committee on Qnexa being the latest episode.

Perhaps companies will have more success developing antiobesity drugs that primarily address metabolic pathways involved in both obesity and diabetes, rather than being directed at appetite-control pathways in the CNS that involve common neurotransmitters. We discussed this strategy in two earlier articles on this blog, dated October 25, 2009 and January 28, 2010. These articles focused on the incretin mimetics, especially liraglutide (Novo Nordisk’s Victoza). Incretin mimetics [which also include exenatide (Amylin/Lilly’s Byetta)] trigger an increase in insulin secretion by the pancreas, and also reduces gastric emptying. The latter effect slows nutrient release into the bloodstream and appears to increase satiety and thus reduce food intake.

Part of the mechanisms of action of the natural incretin glucagon-like peptide-1 (GLP-1) and of incretin mimetics involves activity in the CNS. However, GLP-1 receptors in the brain appear to be more specific in their activity than receptors for common neurotransmitters like serotonin and norepinephrine. The main adverse effect that has been seen with the incretin mimetics exenatide and liraglutide is a transient nausea. Thus incretin mimetics do not appear to cause the psychological and neurological side effects seen with such drugs as sibutramine, rimonabant, and phentermine, and presumably Qnexa.

Nevertheless, acute pancreatitis has been seen in some patients taking exenatide (which resulted in a warning on the label that patients with a history of pancreatitis should not take the drug, and that the drug should be discontinued if symptoms suggesting pancreatitis should develop). Rodents receiving either exenatide or liraglutide have developed thyroid C-cell focal hyperplasia and C-cell tumors. There is no evidence that humans develop thyroid tumors as the result of taking ether drug, however. Nevertheless, the label for liraglutide carries a “back box” warning highlighting the thyroid tumor results in rodents, and including a contraindicating the use of the drug in patents with a history of medullary thyroid carcinoma.

Companies usually develop dual diabetes/obesity drugs first for diabetes, since the regulatory pathway for that disease is easier than for obesity. This has been the case for both exenatide and liraglutide. However, Novo Nordisk announced on June 22, 2010, that following the FDA approval of liraglutide for treatment of type 2 diabetes, it was restarting Phase III clinical trials of the drug in obesity.

As we noted in our October 25, 2009 article, there are at least several companies with early stage dual diabetes/obesity drugs, which they are developing for diabetes. Early-stage obesity drug development has been mainly on hold, awaiting the regulatory approval of Qnexa, Contrave, and/or lorcaserin. Now the results of the regulatory reviews of these three drugs are starting to come in. If none of the three is approved, than early-stage obesity drug development may remain on hold indefinitely.

While researching the material for the June 11 2010 article on obesity, I ran across the recent work of Katherine M. Flegal and her colleagues at the National Center for Health Statistics of the Centers for Disease Control and Prevention (CDC). Dr. Flegal has long been a leading obesity epidemiologist, and led the research that first identified the increased prevalence of obesity in the United States beginning in the 1980s.

Dr. Flegal’s recent work has been based in large part on the most recent data from the National Health and Nutrition Examination Survey (NHANES), and on long-term data from NHANES between 1960 and the early 2000s. In 2005, she and her colleagues published a report in the Journal of the American Medical Association (JAMA) on mortality as a function of Federally-defined weight class–underweight, normal weight, overweight, and obese. These categories were determined on the basis of the body mass index (BMI), with underweight at <18.5, normal weight at 18.5-24.9,  overweight at 25-29.9, and obesity at >30.  Subsequently, in 2007, Dr. Flegal and her colleagues published a report in the JAMA analyzing excess deaths in the underweight, overweight, and obese classes by cause (e.g., cardiovascular disease, diabetes, cancer, etc.).

Dr. Flegal has published other reports relevant to her analyses in these two papers between 2005 and 2010, and has lectured widely on her findings.  Her research was also discussed in a New York Times article in 2005, a 2007 article in the British newspaper The Independent, and in a January 2010 interview in the Association for Psychological Science Observer.

The surprising conclusion of Dr. Flegal’s research is that people in the overweight class have a lower risk of death than those in either the normal weight or the obese class. According to the 2005 study, obesity is associated with about 112,000 excess deaths per year (with most deaths [about 82,000 deaths] concentrated in the extreme obesity class, BMI >35), and underweight is associated with about 26,000 excess deaths per year, but overweight is associated with preventing 86,000 excess deaths per year. (“Excess deaths” refers to the number of deaths per year as compared to the normal weight class).

According to the 2007 study, underweight was associated with significantly increased mortality due to noncancer, non-cardiovascular disease (CVD) causes, but obesity was associated with associated with significantly increased mortality due to obesity-associated cancers, CVD, diabetes, and kidney disease. Thus excess deaths in the underweight and the obese classes vary by cause. Overweight was not associated with either increased or decreased deaths due to CVD, and overweight was not associated with excess deaths due to obesity-associated cancers. However, overweight was associated with a significantly reduced number of excess deaths due to noncancer, non-CVD causes.

Dr. Flegal and her colleagues found that the association of mortality with BMI appears to be much weaker in the most recent surveys as compared to earlier ones. In the most recent data, the association of overweight and mild obesity with risk of death appears to be weak and not statistically significant. This suggests that the association between mortality and weight has been decreasing with time, perhaps due to improvements in medical treatments and in public health. The results of other researchers confirm this hypothesis, and indicate that better management of the risk of death from CVD (e..g, the use of preventive measures such as blood pressure medications and statins, as well as better management of heart attacks via such procedures as angioplasty and stent placement) is responsible for the decreasing risk of obesity-associated death.

The other interesting issue is the risk of weight-related mortality and age. The association  of mortality with weight decreases in older people, especially for those over 70, with the overweight group again having a lower risk of death than the underweight and the obese. Since most people die when they are over 70, this may account, at least in part, for the reduced risk of death in the overweight group in Dr. Flegal’s studies.

Dr. Flegal’s analysis of population weight data over time leads her to dispute the term “obesity epidemic” that most researchers and commentators in the field (including me) have been using. The prevalence of obesity had been stable between 1960 and 1980, but then increased markedly between 1980 and 2000. This increase is what has been referred to as an “epidemic”, since it was expected to continue. However, the increase in prevalence of obesity appears to have diminished since 2000. Moreover, limited data going back to the Civil War suggests that weight in the American population has been increasing since that time, and increasing at a slower rate in recent decades than in the latter half of the 19th century. Dr. Flegal therefore sees obesity as endemic, rather than epidemic.

As might be expected, Dr. Flegal’s conclusions have generated a lot of controversy. Many researchers do not believe the findings, in some cases on the basis of their own earlier studies. Others are simply reluctant to go against the received wisdom that excess weight is a major health hazard, and perhaps the biggest public health problem facing the United States and many other countries. Many researchers note that Dr. Flegal’s studies measure only mortality, not the incidence of such diseases as diabetes and CVD. This is a valid criticism, calling for more epidemiological research. However, many epidemiologists note that Dr. Flegal’s methodology and data are solid, and that she and her colleagues are well respected in their field.

Dr. Flegal’s studies indicate that the designation of obesity and overweight as America’s biggest health problem, and the main cause cause of the rise in health care costs–as discussed in our June 11 2010 blog post–may be overblown. The emphasis for most overweight and moderately obese people may need to be exercise and diets that promote health, whether patients lose weight or not. Given the difficult that most overweight or obese people have in losing weight and keeping it off over the long term, this may be a more realistic approach.

What is a “diet that promotes health”? What is considered “healthy” changes over time, as the result of new research as well as other factors. It is not the purpose of this blog to prescribe or discuss different diets. There are many, many blogs–not to mention books, television programs and other media–that do that. A good place to start, however, might be the work of Walter Willett. (Dr. Willett has disputed the findings of Dr. Flegal’s research, which indicates the level of complexity and disagreement in the obesity field.) Diet and exercise issues should of course be discussed with one’s doctor, but informed patients will usually get better results than uninformed ones.

For those of us in the pharmaceutical and biotechnology industry, the controversies about weight and diet affect the enterprise of drug discovery and development, especially in the metabolic disease and CVD fields. Drugs for such conditions as diabetes and dyslipidemia, as well as antiobesity drugs, are indicated as “adjuncts to diet” or “adjuncts to diet and exercise”. Clinical studies do indicate that these drugs work best when combined with diet and exercise. However, which diet and exercise regimens might be best for various groups of patients, and which diet and exercise regimens might best potentate the efficacy of a drug for various groups of patients, is called into question by the results of Dr. Flegal’s research and the debate over them in the obesity research community. And if weight-associated mortally has been decreasing with time due to improvements in medical treatments, we need to keep up the good work, and develop improved treatments and preventives for such diseases as diabetes and its complications, and for CVD.  (It is the complications of diabetes that are responsible for the greatest level of mortality and disability due to diabetes, as well as the bulk of diabetes-related health care costs.) These new drugs should address unmet medical needs in the metabolic disease and CVD fields.

Health care policy makers should also stop blaming the overweight and the obese and their “lack of personal responsibility” for the woes of the health care system. As we discussed in our June 11 article, this is true whether Dr. Flegal’s conclusions are valid or not.

What causes obesity? To many people, the answer is obvious. Obesity is caused by eating too much food and/or not getting enough exercise. Obese and overweight people lack “personal responsibility” or have become addicted to food the same way that one becomes addicted to smoking. The alarming worldwide rise in obesity over the past several decades is due to an increasing lack of personal responsibility, perhaps as the result of the lure of bad eating habits and lack of exercise caused by increasing affluence.

This “common-sense view” of obesity is gaining increased currency, as the result of rising health care costs and health insurance premiums, and the drive to rein in these costs. Even some leaders of health insurance and health care providers blame the lack of personal responsibility of the obese for rising health care costs, and advocate using education, exhortation, and “economic incentives” (i.e., penalizing the obese, perhaps by raising their insurance rates) to combat obesity.

However, genetic and physiological research shows that obesity is a disease, not just the result of bad habits. This research has shown that weight is as heritable as height, and has uncovered a set of complex pathways that control energy balance. According to this “enlightened, science-based view”, the worldwide epidemic of obesity is mainly the result of the interaction between a set of social and economic factors (e.g., increased consumption of meals away from home, decreased prices for unhealthy versus healthy food, and decreased requirements for physical activity at work and for transportation) and genetic factors that make some people more susceptible to obesity than others. In the industrialized world, between 60%–70% of the variation in obesity-related phenotypes such as body mass index (BMI) and hip circumference appears to be heritable. People who undertake even the best systematic weight-loss programs are fighting a set of complex physiological pathways that have evolved to combat starvation. These pathways are only partially understood. Most people who manage to lose a significant amount of weight usually regain it over the medium to long term.

The “enlightened, science-based view” is discussed, for example, in our 2008 book-length report on obesity, and in our October 25, 2009 article on this blog. It is also the view of pharmaceutical and biotechnology companies that are developing antiobesity drugs, and the view of basic researchers who are endeavoring to understand pathways that control energy balance and may render individuals subject to obesity and its comorbidities.

Recent genetic studies provide an increasing amount of evidence that favors the  “enlightened, science-based view”. For example, researchers have recently identified associations between common variants in the fat mass and obesity-associated (FTO) geneand increases in BMI and waist circumference in several human populations. The FTO gene codes for a 2-oxoglutarate-dependent nucleic acid demethylase. It is expressed in the hypothalamus, a region of the brain that is involved in regulation of feeding and energy metabolism. Hypothalamic FTO appears to be involved in the regulation of energy intake, but not feeding reward. However, the mechanism of action of FTO in control of energy balance is not understood.

The findings on FTO adds to the large amount of evidence for the genetic determination of obesity, and thus for the “enlightened, science-based view” of this condition. Many academic and corporate researchers, including most of the recognized leaders in obesity research, believe that continued basic and translational research on the genetic and molecular basis of obesity will lead to new therapeutic strategies to control this disease.

Now comes a new research report that might result in a “game-changing view” of obesity, published in the 9 April issue of Science. Andrew Gewirtz (Emory University, Atlanta, GA) and his colleagues studied T5KO mice, which are genetically deficient in TLR5, a Toll-like receptor (TLR) that recognizes bacterial flagella as a ligand and is expressed on the surface of both intestinal epithelial cells and cells that mediate innate immunity. TLRs are receptors that recognize conserved molecules derived from bacteria or viruses, and activate immune responses, thus serving as a first line of defense against infection. Researchers hypothesize that TLR5 in gut mucosa may have a role in maintaining a harmonious relationship between the host and the complex population of intestinal microbes.

The researchers found that as compared to wild-type mice, T5KO mice showed increased fat mass and body weights 20% higher than wild-type mice, and features of the metabolic syndrome (insulin resistance, elevated serum cholesterol and triglycerides, and elevated blood pressure).  The adipose tissue of TK5KO mice exhibited higher production of the proinflammatory cytokines interferon-γ and interleukin-1β.  T5KO mice were also hyperphagic, eating 10% more than wild type mice. When the researchers restricted the food fed to T5KO mice to the amount eaten by wild type mice, they no longer exhibited increased fat mass or body weight, or abnormalities in blood glucose and lipids. However, they still were insulin resistant.

When both wild type and T5KO mice were fed a high-fat diet, both populations showed increases in fat mass and body weight, as well as elevated levels of blood lipids. However, unlike wild type mice, T5KO mice fed a high-fat diet has blood glucose levels of greater than 120 milligrams per deciliter, and thus were diabetic. The T5KO mice also showed inflammatory infiltrates in their pancreatic islets, and hepatic steatosis. Thus a high-fat diet exacerbated the metabolic syndrome shown by T5KO mice.

The researchers asked whether other mediators of the immune system were involved in the induction of metabolic syndrome shown by T5KO mice. Deletion of the Toll-like receptors TLR2 and/or TLR4 in T5KO mice had no effect on their metabolic syndrome.  Deletion of RAG1 (which is necessary for development of the T and B cells of the adaptive immune system) also had no effect. However, deletion of the intracellular protein MyD88 in T5KO mice resulted in normalization of the metabolic syndrome. Since MyD88 is necessary for signaling by all TLRs except for TLR3, and for signaling by receptors for interleukin-1β and interleukin-18, this suggests that another TLR and/or signaling by one or both of these two cytokines might be necessary, together with TLR5 knockout, for induction of the metabolic syndrome.

Since TLR5 is expressed in the gut mucosa and recognizes bacterial flagellin, the researchers tested the hypothesis that the metabolic syndrome seen in T5KO mice might be due to alterations in the population of gut microbes as the result of the loss of TLR5 function. When the researchers treated newly weaned T5KO mice with broad-spectrum antibiotics, the number of gut bacteria was reduced by 90%. This treatment eliminated the metabolic syndrome, hyperphagia, and obesity of the T5KO mice.  Conversely, when the researchers transplanted the gut microbiota of T5KO mice to the guts of wild type germ-free mice, the recipient mice exhibited hyperphagia, obesity, metabolic syndrome, and elevated levels of proinflammatory cytokines in their adipose tissue. Analysis of the gut microbiota of T5KO and wild type mice showed that the species composition of the gut bacteria of T5KO mice was significantly different from that found in wild type mice.

These results suggest that obesity and metabolic syndrome may be caused at least in part by genetically determined differences in interactions between the innate immune system of the gut mucosa and the intestinal flora. Obesity-prone individuals may develop a gut microbe population that interacts with the immune system in such a way as to promote obesity. Interactions between gut microbes and innate immunity that promote obesity might result in changes in proinflammatory cytokines and in adipokines in adipose tissue (and perhaps also in muscle and liver) that not only cause increased inflammation and metabolic syndrome, but also disrupt signals within the brain that promote appetite control and energy balance. They further suggest that treatments that target intestinal microbes may be effective therapies for obesity and its sequelae.

These conclusions are based on a mouse model, which may or may not have much to do with the pathogenesis of human obesity. However, there is evidence that the the composition of gut bacteria differs between obese and nonobese humans in similar ways to differences in gut flora between obese and nonobese mice. Colonization of germ-free mice with the gut microbiota of obese mice results in significantly greater increase in body fat than colonization with the gut microbiota of lean mice. Researchers obtained evidence that gut microbes from obese mice have an increased ability to harvest energy from food than do the gut bacteria of lean mice. They therefore hypothesize that this extra energy harvest may help promote obesity, in both mice and humans. But it is also possible that obesity-associated gut microbe populations might promote systemic low-grade inflammation that contributes to the pathogenesis of metabolic syndrome and obesity.

In addition to the research report itself, two commentaries on the report were published in April 2010–one by Darleen A Sandoval and Randy J Seeley (University of Cincinnati in Ohio) and the other by Ping Li and Gökhan Hotamisligil (Harvard School of Public Health, Boston MA). Drs. Sandoval and Seeley conclude that the new findings may allow researchers to develop means of preventing obesity by manipulating gut microbe-immune system interactions by such means as drugs, diet, or probiotics.  Drs.  Li and Hotamisligil take a more nuanced view. (Dr. Hotamisligil is a leader in the study of pathways involved in control of energy metabolism, and their relationship to inflammation and metabolic diseases.) They state that the results seen in T5KO mice were relatively mild, and thus probably cannot account for the full spectrum of metabolic dysfunction seen in obesity. They essentially see the gut microbiota/innate immunity interaction as one factor in the complex networks that determine obesity and metabolic syndrome. They call for more research into the gut microbe/immune system relationship, and believe that such research will lead to a better understanding of metabolic syndrome.

What if the gut microbiota/immune system interaction is a major factor in obesity, at least in a subpopulation of obese subjects? That would resemble the situation with peptic ulcers. Peptic ulcers were once considered a disease of “lifestyle”, due to the “type A personality”, “a stressful lifestyle”, and/or eating spicy foods. However, eventually Drs.  Barry J. Marshall and Robin Warren of Australia discovered that a high percentage of ulcers were caused by chronic inflammation due to infection with Helicobacter pylori. It is now accepted that this bacterium is responsible for 60% of gastric ulcers and up to 90% of duodenal ulcers. Treatment involves administration of combinations of antibiotics together with a proton pump inhibitor and sometimes a bismuth compound.

The majority of scientists and physicians resisted the idea that peptic ulcers were caused by a microbial infection for a long time. Dr. Marshall even had to do and publish a self-experiment, drinking a culture of bacteria from a patient, before the scientific community would accept his findings. Finally, In 2005, Drs. Marshall and Warren received the Nobel Prize in Physiology or Medicine for their [re]discovery of H. pylori and its role in gastritis and peptic ulcers.

The role of gut microbes in obesity and metabolic syndrome may not be simple as the role of H. pylori in gastric ulcers. Nevertheless, this hypothesis deserves intensive investigation, and it may lead to a game-changing view of metabolic disease and eventually important new treatments. In any event, it would be wise for the scientific, medical, and policy communities to take the advice of Dr. Jeffrey Friedman (Rockefeller University, New York, NY), who is arguably the founder of the “enlightened, science-based view” of obesity and metabolic syndrome, with his breakthrough discovery of the hormone leptin in 1994:  “A war on obesity, not the obese.”

On November 8, 2009, we posted an article entitled “Anti-aging biology: new basic research, drug development, and organizational strategy” on this blog. This article focused on new findings in anti-aging biology, their applications to drug discovery and development, and on how this field has affected the organizational strategy of GlaxoSmithKline (GSK).

GSK acquired Sirtris for $720 million in 2008. Later that year, GSK appointed Christoph Westphal, the CEO and co-founder of Sirtris, as the Senior Vice President of GSK’s Centre of Excellence in External Drug Discovery (CEEDD). The CEEDD works to develop external alliances with biotech companies, with the goal of acquiring promising new drug candidates for GSK’s pipeline. Michelle Dipp, who was the vice president of business development at Sirtris at the time of GSK’s appointment of Dr. Wesphal, became Vice President and the head of the US CEEDD at GSK. Thus GSK has been using its relationship with Sirtris to restructure its organizational strategy, attempting to become more “biotech-like” in order to improve its R&D performance.

Now we learn that several research groups and companies have been questioning whether resveratrol (a natural product derived from red wine which has been the basis of Sirtris’ sirtuin-activator platform), as well as Sirtris’ second-generation compounds, may not modulate the sirtuin SIRT1 at all. Thanks to Derek Lowe’s “In the Pipeline” blog for the information. This issue was also covered in a second post on the same blog. It was also covered by articles in the 15 January 2010 issue of New Scientist and in the January 26, 2010 issue of Forbes. Nature also covered this story in an online news article.

In a report published in December 2009, researchers at Amgen found evidence that the apparent in vitro activation of SIRT1 was an artifact of the experimental method used by Sirtris researchers. The Amgen group found that the fluorescent SIRT1 peptide substrate used in the Sirtris assay is a substrate for SIRT1, but in the absence of the covalently linked fluorophore, the peptide is not a SIRT1 substrate. Although resveratrol appears to be an activator of SIRT1 if the artificial fluorophore-conjugted substrate is used, resveratrol does not activate SIRT1 in vitro as determined by assays using two other non-fluorescently-labeled substrates.

More recently, researchers at Pfizer published a study of SIRT1 activation by resveratrol and three of Sirtris’ second-generation sirtuin activators (which the Pfizer researchers synthesized themselves, using published protocols). These researchers also found that although these compounds activated SIRT1 when a fluorophore-bearing peptide substrate was used, they were not SIRT1 activators in in vitro assays using native peptide or protein substrates. The Pfizer researchers also found that the Sirtris compounds interact directly with the fluorophore-conjugated peptide, but not with native peptide substrates.

Moreover, the Pfizer researchers were not able to replicate Sirtris’ in vivo studies of its compounds. Specifically, when the Pfizer researchers tested SRT1720 in a mouse model of obese diabetes, a 30 mg/kg dose of the compound failed to improve blood glucose levels, and the treated mice showed increased food intake and weight gain. A 100 mg/kg dose of SRT1720 was toxic, and resulted in the death of 3 out of 8 mice tested.

The Pfizer researchers also found that the Sirtris compounds interacted with an even greater number of cellular targets (including an assortment of receptors, enzymes, transporters, and ion channels) than resveratrol. For example, SRT1720 showed over 50% inhibition of 38 out of 100 targets tested, while resveratrol only inhibited 7 targets. Only one target, norepinephrine transporter, was inhibited by greater than 50% by all three Sirtris compounds and by resveratrol. Thus the Sirtris compounds have a different target selectivity profile than resveratrol, and all of these compounds exhibit promiscuous targeting.

Sirtris and GSK dispute the findings of the Amgen and Pfizer researchers. One issue raised by Sirtris is that the Sirtris compounds synthesized by Pfizer may have contained impurities, resulting in the toxicity and lack of specificity of the compounds in vivo. Researchers associated with Sirtris and GSK also contend that although the Sirtris compounds only work with fluorophore-conjugated peptides in vitro, they appear to increase the activity of SIRT1 in cells. However, other researchers assert that since resveratrol interacts with many targets in cells, the results of the cellular assays are difficult to interpret. In the Forbes article, GSK’s CEO Andrew Witty is quoted as calling the dispute over the activity of the Sirtris compounds “a bit of a storm in a teacup”. He says that the compounds that Pfizer tested in mice are not the same ones that Sirtris and GSK are currently testing in clinical trials for treatment of diabetes and cancer. (Sirtris’ compounds in clinical trials, discussed in the next paragraph, are in fact different from the ones tested by the Pfizer researchers.)

Currently, Sirtris is testing its proprietary formulation of resveratrol, SRT501, in a Phase IIa clinical trial in cancer. The company reports that SRT501 lowered blood glucose and improved insulin sensitivity in patients with type 2 diabetes in a Phase IIa trial. Sirtris is also testing a second-generation SIRT1 activator, SRT2104, in Phase IIa trials in patients with metabolic, inflammatory and cardiovascular diseases. SRT2104 was found to be safe and well tolerated in Phase I trials in healthy volunteers. Sirtris is also testing another second-generation SIRT1 activator, SRT2379, In Phase I trials. SRT2379 is structurally distinct from resveratrol and from SRT2104.

As we discussed in our original blog post, Elixir Pharmaceuticals is also developing various sirtuin inhibitors and activators for metabolic and neurodegenerative diseases and for cancer. One of Elixir’s products, the SIRT1 inhibitor EX-527, was in-licensed by Siena Biotech (Siena, Italy) in 2009, and was entered into Phase I clinical trials in January 2010. Siena Biotech is developing this compound for treatment of Huntington’s disease.

Despite the dispute over whether Sirtris’ compounds are real SIRT1 activators, the numerous studies on the biology of sirtuins are still valid. Companies with assays that use native peptide substrates and are amenable to high-throughput screening could use these assays to discover novel sirtuin activators. For example, Amgen published a report in 2008 describing such assays. The ability of companies such as Amgen and Pfizer to commercialize such novel sirtuin activators would depend on whether they could overcome the intellectual property position of Sirtris (and Elixir). Since Amgen and Pfizer are working in this area, this indicates that they believe that they can do so.

The efficacy of high doses of resveratrol in improving metabolic parameters of mice fed a high-calorie diet is also not invalidated by the Amgen and Pfizer studies. However these studies cast doubt on the mechanisms by which resveratrol exerts these effects. The apparent efficacy of SRT501 in improving metabolic parameters in patients with type 2 diabetes in a Sirtris Phase IIa trial is consistent with the mouse studies.

Finally, as we discussed in our November 8, 2009 blog post, longevity is controlled by numerous interacting pathways, which may provide at least several targets for drug discovery. Researchers are hard at work to gain additional understanding of these pathways, and some companies are working to discover and develop compounds that modulate these targets. For example, several companies are developing AMPK activators, as discussed in our original blog post. And numerous research groups are reportedly attempting to find drugs that act similarly to rapamycin in increasing lifespan in mice (the main focus of our November blog post), without rapamycin’s immunosuppressive effects.

On October 25, 2009, we posted an article on this blog that focused on liraglutide (Novo Nordisk’s Victoza) as a potential treatment for obesity. As we stated in the article, at that time liraglutide had recently been approved in Europe for treatment of type 2 diabetes. The drug was also awaiting FDA approval for that indication.

On January 26, 2010, after a 21-month review, the FDA approved liraglutide for treatment of type 2 diabetes. This followed the approval of the drug in Japan a week earlier.

The approval process for liraglutide in the United States had not been straightforward. In April 2009, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 6-6 (with one abstention) on approval versus disapproval of liraglutide, because of the finding of thyroid C-cell tumors in studies of the drug in rodents. There is no evidence, however, that liraglutide has ever caused thyroid tumors (or other types of cancer) in humans.

As a result, the drug’s label carries a black box warning of the risk for thyroid cancer, and requires a risk-mitigation strategy. However, as we discussed in our article, liraglutide has an advantage over most antidiabetic drugs in that it induces weight loss. It also has a low risk of triggering hypoglycemia, which is a problem with several antidiabetic drugs.

As we also discussed in our article, liraglutide belongs to a class of agents known as incretin mimetics. The first incretin mimetic to reach the market was exenatide (Amylin/Lilly’s Byetta). Exenatide, which is approved for type 2 diabetes, also induces weight loss. Physicians therefore sometimes prescribe exenatide off-label for treatment of obesity. However, exenatide has a relatively short half-life, and must be self-injected twice a day. In contrast, liraglutide has a longer half-life than exenatide, and is self-injected only once a day. Amylin and Lilly are developing a longer-acting, once-weekly formulation of exenatide (known as Exenatide Once Weekly) for treatment of type 2 diabetes. The new formulation is being developed in collaboration with Alkermes, which developed the long-acting drug-delivery technology. Amylin, Lilly, and Alkermes are awaiting FDA approval of the NDA for Exenatide Once Weekly.

Exenatide’s label carries no warning with respect to thyroid cancer. However, it does carry a warning concerning the risk of drug-associated pancreatitis. Moreover, the FDA Advisory Committee raised concerns that the risk of thyroid C-cell tumors may be a class effect of incretin mimetics. The FDA has mandated that Amylin conduct postmarketing studies to deal with this concern; depending on the results of the studies, a warning of a risk for thyroid cancer may (or may not) appear on the labels of Byetta and Exenatide Once Weekly.

Despite these safety concerns, the stocks of not only Novo Nordisk, but also Amylin and Alkermes, rose on the news that the FDA had approved Victoza. Stock analysts predicted that the approval of Victoza implied that the FDA was likely to approve Exenatide Once Weekly later in 2010.

Our October 2009 blog post discussed exenatide and liraglutide in the context of the obesity drug market, and specifically drugs that treat both type 2 diabetes and obesity. Neither exenatide not liraglutide is approved for treatment of obesity in any jurisdiction, however. As we discussed in our original article, Novo Nordisk has been developing liraglutide for obesity, but Amylin is developing other, earlier-stage drugs for that indication despite the weight loss benefits seen with exenatide. Novo Nordisk had been waiting for FDA approval of liraglutide for treatment of type 2 diabetes before proceeding with further development of the drug for obesity. Now that the company has obtained that approval, we expect that development of liraglutide for obesity will be restarted.