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Mar 1, 2005 (Vol. 25, No. 5)

Managing Cardiovascular Disease Risk Factors

Fighting Fat with New Medicine

  • With the increasing recognition that maintenance of overall metabolic health is critical to preventing heart disease, pharmaceutical and biotech companies are focusing on developing drugs that act to reduce overall heart disease risk or individual risk components.

    These include obesity, smoking, dyslipidemias, and diabetes, among others. While the statins have changed the outlook for individuals with dyslipidemia, other risk factors, particularly obesity, continue to be difficult to treat pharmacologically, and heart disease and other weight-related maladies remain major causes of morbidity and mortality.

    Despite the handful of anti-obesity drugs that have progressed to clinical trials and remain viable candidates for new drug approvals, the opportunity to develop new drugs remains compelling, as most obesity experts expect that more than one drug will be needed to control obesity.

    Efficient fat storage, the intricately controlled mechanism that helped mankind survive protracted food shortages, backfires in a well-fed, relatively sedentary society.

  • When Fat Becomes Fatal

    While diet and exercise successfully control weight for many individuals, clinicians increasingly recognize that safer, more effective drugs are needed in the war against the current obesity epidemic. According to the FDA, available drugs induce only modest weight loss15 kg relative to placebo, diet, and exercise.

    Upon drug discontinuation, 90% of individuals regain weight within 6 months and 95% within 23 years. Further, the emerging view of obesity as a chronic disease with complex pathophysiology likely to require long-term medication for adequate control imposes an additional safety burden on new drugs.

    Currently marketed drugs include Abbott's Meridia (sibutramine), which acts on the central nervous system (CNS) as a neurotransmitter reuptake inhibitor to suppress appetite, and Roche's Xenical (orlistat), which acts to prevent fat absorption.

    Both drugs produce side effects that discourage long-term use. Each of these represents a different approach to weight management: either a type of drug that acts directly on the brain to control appetite or one that acts locally at the gut.

  • New Anti-Obesity Medicine

    The need for chronically administered safe drug treatment, the FDA's commitment to support new drug development efforts, and the growing global market for anti-obesity drugs has fueled a surge in development of new anti-obesity drugs in the biotech and pharma industries.

    Part of the mandate for the FDA's Obesity Working Group, established in 2003, is to "make recommendations on ways to encourage development of new or enhanced therapeutics." This mandate includes revision of the 1996 guidelines intended to help drug makers develop new obesity products in a climate of great clarity and an improved review process.

    "The FDA agrees that obesity presents great problems both in the U.S. and elsewhere in the world," comments David Orloff, M.D., director of the FDA's division of metabolic and endocrine drug products.

    "We are fully supportive of the development of drugs to treat obesity and have been for years." However, he cautions, "At present, while there are many interesting possibilities for new drugs, it is important to understand that there are no miracles on the horizon and management of obesity and disease prevention requires not only the judicious use of therapeutics but lifestyle changes in order to be successful."

    A greater knowledge base now exists about the neuroendocrine pathways, hormones and/or neurotransmitters that impact appetite, fat storage, and metabolic rate. Drug developers are taking advantage of new drug targets to attack fat on a variety of fronts, with 200 novel drugs in development worldwide.

    Some targets for new drugs include hunger and satieity-signalling gastronintestinal peptides and/or their receptors, like ghrelin and Peptide Y (PYY), Glucagon-like peptide 1 (GLP-1), and colecystokinin (CCK). Other targets include CNS targets, like the hypothalamus and brain stem, involved in hunger and satiety feedback control mechanisms.

    The U.S. market alone for anti-obesity drugs is about $550 million, and Americans spend more than $33 billion annually on weight loss products and services.

    The emphasis on preventive healthcare and health maintenance by third-party healthcare payers favors a reimbursement climate in which weight-management drugs can potentially prosper.

    And, there's a lot of room for more than one novel obesity drug. According to obesity experts, it's likely that multiple drugs will be required. Arthur Frank, M.D., medical director of the George Washington University obesity program, says that because of rapid accumulation of more sophisticated knowledge about regulatory mechanisms impacting food intake, "Everything we are doing now will be obsolete in 10 years.

    "I am reasonably convinced that physiological eating control mechanisms have so many compensatory factors that no single medicine will be sufficient and medicines in combination will be needed for successful management."

  • Turning Off Your Fat Cells

    AdipoGenix, founded by a group of scientists from Boston Medical Center, believes that obesity can potentially be treated effectively and safely by either preventing the maturation of, or disabling those ultimate fat factoriesfat cells themselves.

    Company scientists grow human fat cells-adipocytes and their precursor cells in cell culture to identify drug targets and leads. Thus far, the company says it has found several molecular targets, which, if they can be modulated, will affect fat cell metabolism and dynamics. The company has already used high throughput assays based on this technology to identify potential drug candidates from combinatorial libraries.

    "What's distinctive about AdipoGenix is that it is really the only company screening the pathological tissue from the relevant organism for the desired result," explains AdipoGenix' CEO Edward Cannon.

    "We have shown that we can identify active compoundsour own and those of our collaborators, in this case Johnson & Johnsonby taking human pre-adipocytes (immature fat cells), differentiating them into mature cells in vitro, then screening for compounds that reduce their fat content.

    "We have found compounds that can prevent the preadipocytes from turning into mature fat cells, inhibit triglyceride synthesis, increase fat breakdown, and stimulate beta oxidation, or fat burning."

    AdipoGenix hopes to be in the clinic with their first anti-obesity compound in 18 months.

    Tuning Out Your Intestines

    One target for anti-obesity medicines is the gastro-intestinal tract, the site of nutrient absorption. Peptimmune (Cambridge, MA) seeks to prevent fat absorption through the gut, reducing caloric intake, by inhibiting the enzyme pancreatic lipase.

    Licensed from Genzyme, Peptimmune's GT389-255 combines pancreatic lipase inhibitor, a substance that blocks the fat-digesting enzyme from breaking down fats into trigylycerides with a fat-binding hydrogel polymer.

    The polymer component of the drug binds the undigested triglycerides and is thereby expected to ameliorate the side effects associated with other therapies that work through preventing absorption.

    Orlistat, the currently marketed pancreatic lipase inhibitor, is associated with oily incontinence. Peptimmune hopes its drug will circumvent unpleasant side effects because the enzyme inhibitor is conjugated to a fat-binding protein that binds to the undigested lipid.

  • Telling Your Brain That It's Full

    Nastech Pharmaceutical (Bothell, WA) has completed three Phase I trials with its anti-obesity drug, PYY3-36. Delivered intranasally, the drug consists of a 34 amino acid peptide fragment of PYY, a naturally occurring hormone produced by certain endocrine cells, L-cells, in the small intestine.

    Steven Quay, M.D., Ph.D., Nastech's CEO, explains that PYY is not released while food is in the stomach, but only in the intestine and shows up in the bloodstream about 40 minutes after food is ingested.

    "Once in the bloodstream, PYY is carried to the brain, specifically to the arcuate nucleus, and activates Y2 receptors. Receptor activation produces a satiety signal that says, You are full.' Interestingly, the amount of PYY releasedsome thirty to forty minutes after eatingis directly proportional to the calories consumed."

    Nastech's Phase I trials established the amount of peptide required in its delivery formulation to produce characteristic blood curves corresponding to specifically sized meals. "Our model of how to give this drug would be thirty to forty minutes prior to a meal to prevent overeating," Dr. Quay notes.

    Thus far, Dr. Quay pointed out, PYY3-36 has been safe and well tolerated over 900 doses in 60 obese individuals. "We are pleased because this is a natural peptide; if we keep dosages within the confines of normal physiological levels, we should have a fairly good safety profile."

    In September 2004, Nastech announced a co-development and co-promotion partnership with Merck & Co. (Whitehouse Station, NJ) for investigational PYY3-36 nasal spray for the treatment of obesity. Merck initiated a Phase I trial under its own IND, and Dr. Quay expects that they will move forward aggressively into clinical development with this compound.

  • Regulating Satiety

    Arena Pharmaceuticals (San Diego), began in December, a Phase II clinical trial of APD356, an orally administered small molecule designed to regulate satiety. The trial will enroll 400 obese patients and compare drug doses of 1, 5 and 15 mg of APD356 to the effects of a placebo on weight loss after one daily administration over 28 days.

    Arena expects to announce initial trial results in the second quarter of 2005. The compound works by selectively stimulating 5-HT2C serotonin receptors, concentrated in the hypothalamus, a brain area that regulates food intake and many aspects of metabolism.

    "We are in a Phase II study with this drug, comparing weight loss at 28 days at two different drug doses with placebo," says William Shanahan, Jr., M.D., vp and CMO of Arena. "There is precedent for getting determining efficacy from a 28-day study, so we will go on from there assuming we see some positive results."

    Neurogen (Branford, CT) is currently optimizing small molecule drug candidates that block the melanin-concentrating hormone receptor (MCH-1) in the hypothalamus.

    Neurogen scientists as well as those at academic institutions have shown that melanin concentrating hormone (MCH) stimulates food intake. Knockout mice lacking MCH receptors are obese and overeat when fed a high fat diet, while mice without MCH receptors are lean and do not overeat.

    While lower mammals, such as mice, have only the MCH-1 receptor, higher mammals, including dogs and humans, also have an MCH-2 receptor. Neurogen scientists recently showed that their MCH-1 antagonist drug candidate effectively reduced body weight and food intake in dogs when administered at two different doses.

    "These findings support further development of an MCH-1 receptor antagonist for obesity treatment," says company spokesperson Elaine Beckwith. "The big question with MCH compounds in animal models is whether your compound will make it to the next level and work in higher species with both MCH receptors. Ours did."

  • Conclusion

    "The complex biological-psychological-social nature of the disease, and the fact that it is chronic, has made the drug development pathway and regulatory environment difficult," according to William Green, M.D., a principal at MPM Capital, which has invested in Peptimmune. "For companies willing to take creative approaches there is a singular opportunity in obesity drug development."



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