Addressing the Unmet Medical Need for Safe and Effective Weight Loss Therapies

Abstract

Perspective

Addressing the Unmet Medical Need for Safe and Effective Weight Loss Therapies

Cynthia M. Arbeeny

Address correspondence to Cynthia M. Arbeeny, Genzyme Drug Discovery and Development, 153 Second Avenue, Waltham, MA 02451. E-mail: cynthia.arbeeny@genzyme.com

 

Obesity is a significant healthcare problem worldwide and increases the risk of developing debilitating diseases including type 2 diabetes, cardiovascular disease, and cancer. Although the health benefits of weight reduction are well-recognized, weight loss by diet and exercise fail in most patients, and the current marketed drugs have had limited success. It is clear that there is a significant unmet medical need for safe and effective weight-reducing agents. In this review, the current status of potential weight loss approaches that are in development by the pharmaceutical and biotechnology industry are discussed. This should lead to novel treatments that can be used long-term to effectively treat this serious metabolic disorder.

Key Words: weight loss • antiobesity • pharmacotherapy • drug development • metabolic syndrome

We are in the throes of a global obesity crisis, which currently afflicts over 300 million adults in both industrialized and developing countries (1) . Excessive body weight increases the risk of developing serious and life-threatening diseases including type 2 diabetes, cardiovascular disease, and some forms of cancer (2) (3) (4) . Obesity is the direct cause of the epidemic of type 2 diabetes that is rapidly escalating at an alarming rate, and obesity is projected to overtake cigarette smoking as the leading cause of preventable death. There is clearly a significant unmet medical need for safe and effective weight-reducing therapies to prevent the debilitating metabolic diseases and mortality that are associated with increasing adiposity.

Numerous studies have demonstrated the health risks associated with weight gain and the benefits of intentional weight loss. A weight gain of 1 kg increases cardiovascular risk by 3.1% (5) and diabetes risk by 4.5% to 9% (6) (7) . Intentional weight loss of 11% of body weight is associated with a 25% reduction in cardiovascular disease and diabetes mortality (8) , and a weight loss of 4 kg in overweight subjects with impaired glucose tolerance reduced the risk of developing diabetes by 58% (9) .

A weight loss of 5% to 10% has a significant impact on improving cardiovascular risk factors and the progression to type 2 diabetes (8) (9) (10) (11) . However, even this modest degree of weight loss has been difficult to achieve in the obese population. Diet and exercise fail in the vast majority of patients, whereas the marketed drugs have had limited success. Thus, there is an important need to treat obesity to prevent the progression toward additional disease states such as diabetes and cardiovascular disease. This has led to an intense effort to identify new targets for pharmacological intervention. A number of agents that are being developed by the pharmaceutical industry are directed at inhibiting caloric intake and/or increasing energy expenditure by unique mechanisms. The current status of drugs that are in preclinical and clinical development are shown in Tables 123 . (The information was obtained from corporate press releases, web sites, publications, and patent searches.)

In the comprehensive review that appears in this issue, Dr. Harold Bays discusses the limitations of the drugs that are on the market, the current status of investigational antiobesity agents that are in development, and the novel targets that hold promise for the future. Although there are many challenges to developing novel pharmaceuticals to treat obesity, the extensive research that is ongoing within the academic and pharmaceutical community should yield safe and effective long-term treatments, which can be used, either alone or in combination, to treat this serious metabolic disease.

Footnotes

According to U.S. code, all journals requesting payment of author page charges in order to defray the cost of publication are required to publish a disclaimer. This article must, therefore, be marked "advertisement" in compliance with U.S.C. Section 1734 solely to indicate this fact.

References

International Obesity Task Force The Global Epidemic http://www.iotf.org (Accessed June 2004) Mokdad, AH, Ford, ES, Bowman, BA, et al (2003) Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001 JAMA 289,76-79 U.S. Department of Health and Human Services (2000) Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: National Institutes of Health Publication Number 00-4084 U.S. Department of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute; North American Association for the Study of Obesity Rockville, MD. U.S. Department of Health and Human Services The Surgeon General’s Call to Action to Prevent and Decrease Overweight and Obesity 2001 http://www.surgeongeneral.gov/topics/obesity (Accessed June 2004) Willett, WC, Manson, JE, Stampfer, MJ, et al (1995) Weight, weight change and coronary heart disease in women JAMA 273,461-465 Ford, ES, Williamson, DF, Liu, S (1997) Weight change and diabetes incidence: findings from a national cohort of US adults A J Epidemiol 146,214-222 Mokdad, AH, Ford, ES, Bowman, BA, et al (2000) Diabetes trends in the U.S.: 1990-1998 Diabetes Care 23,1278-1283 Williamson, DF, Thompson, TJ, Thun, M, Flanders, D, Pamuk, E, Byers, T (2000) Intentional weight loss and mortality among overweight individuals with diabetes Diabetes Care 23,1499-1504 Tuomilehto, J, Lindstrom, J, Eriksson, JG, et al (2001) Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance N Engl J Med 344,1343-1350 Goldstein, DJ (1992) Beneficial health effects of modest weight loss Int J Obes 16,397-415 Blackburn, G (1995) Effect of degree of weight loss on health benefits Obes Res 3(Suppl 2),211-6s

Tables

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Table 1. Antiobesity therapeutics in development: appetite suppression via central nervous system action

Pharmacological Target Company Compound Development Status
Dopamine and norepinephrine reuptake inhibitor GSK Buproprion Marketed for depression and smoking cessation as Welbutrin
Phase III for obesity indication
Voltage-sensitive sodium channel and T-type calcium channel antagonist Dainippon Zonisamide Marketed for epilepsy as Excegran
Phase II for obesity indication
GABA receptor agonist/glutamate antagonist/sodium channel antagonist J&J Topiramate Marketed for epilepsy as Topamax
Discontinued for obesity indication
Modified ciliary neurotrophic factor, action on neural pathways Regeneron Axokine Phase III
Cannabinoid CB1 receptor antagonist Sanofi-Synthelabo Rimonabant/Acomplia Phase III
Solvay SR147778 Phase I
SLV319 Phase I
Natural product derived from a South-African plant, acts via an undisclosed mechanism Phytopharm P57 Phase II
Dopamine D2 receptor agonist PLIVA Bromocriptine (PLD165) Phase III for type 2 diabetes
Phase II discontinued for obesity
5HT2c serotonin receptor agonist Arena APD356 Phase I
Undisclosed target Shionogi S2367 Phase I
Undisclosed target Tularik T71 Phase I
Undisclosed target Biovitrum BVT.5182 Preclinical
Neuropeptide Y1 receptor antagonist GSK Preclinical
Neuropeptide Y5 receptor antagonist J&J Preclinical
Melanocortin 4 receptor agonist Several including GSK, Melacure, Merck, Neurocrine Research
Melanin-concentrating hormone receptor antagonist Several including Amgen, GSK, Lilly, Neurocrine, Neurogen, Takada Research
Histamine H3 receptor antagonist Abbott A331440 Research

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Table 2. Antiobesity therapeutics in development: gastrointestinal tract-signaling peptides, digestive enzyme targets

Pharmacological target Company Compound Development status
{alpha}-Glucosidase inhibitor, inhibits carbohydrate digestion and absorption Bayer/Pfizer (licensee, U.S.)/Sanofi-Synthelabo (licensee, European Union)/Sanwa Kagaku Kenkyusho (licensee, Japan) Miglitol Marketed for type 2 diabetes as Diastabol, Glyset, Miglibay, Plumarol
Phase II for obesity in patients with type 2 diabetes
Synthetic human amylin analog that acts as a gut-signaling peptide, prevents the abnormal rise in glucagon after meals, slows the rate of gastric emptying, and reduces postprandial glucose peaks Amylin Pharma Pramlintide/Symlin Preregistration for type 1 and type 2 diabetes
Phase II for obesity indication
Glucagon-like peptide peptide mimetic of GLP-17–36 amide, a peptide produced by the intestine, that stimulates insulin secretion in response to an increase in blood glucose, slows gastric emptying, and provides a satiety signal to the central nervous system Amylin Pharma/Lilly (licensee) Exenatide (AC2993) Phase III for type 2 diabetes
Preclinical for obesity
Exenatide-LAR (AC2993LAR) Phase II
NovoNordisk Liraglutide (NN2211) Phase II for type 2 diabetes
Preclinical for obesity indication
Biomeasure, Ipsen/Roche (licensee) BIM 51077 Phase II for type 2 diabetes
Zealand Pharma/Aventis (licensee) AVE0010 Phase II for type 2 diabetes
ConjuChem CJC-1131 Phase II for type 2 diabetes
Human Genome Sciences Albugon Preclinical
Theratechnologies TH0318 Preclinical
Genzyme GLP-1 gene therapy Research
Pancreatic lipase inhibitor, inhibits fat digestion and absorption Alizyme/Takeda (licensee for Japan) ATL962 Phase II
CCK-A agonist, provides a satiety signal to the central nervous system GSK 181771 Phase II
Sanofi-Synthelabo SR146131 Phase I
SR125180 Phase I
Undisclosed target, decreases gastric emptying, provides a satiety signal to the central nervous system Aventis Pharma HMR1426 Phase II
HMR1954 Phase I
Dipeptidyl peptidase IV inhibitor, prevents the inactivation of GLP-1, prolonging its action Novartis NVP LAF237 Phase III for type 2 diabetes
Merck MK431 Phase II for type 2 diabetes
Tanabe/GSK (licensee) T6666/815541A, 825964, 823093 Phase I for type 2 diabetes
BMS BMS 477119 Phase I for type 2 diabetes
Several including Ferring/J&J (licensee), Kyowa Haako, Sanofi-Synthelabo, PPD/Syrrx, Graffinity Pharma Preclinical
PYY3–36 receptor agonist, PYY3–36 is a naturally occurring intestinal peptide that provides a satiety signal to central nervous system Nastech PYY3–36 (intranasal) Phase I
Curis/Amylin Pharma (licensee) AC162352 Preclinical
Dual acting pancreatic lipase inhibitor and fat binding polymer, inhibits fat digestion and absorption without oil leakage Genzyme/Peptimmune (licensee) GT389-255 Phase I
Ghrelin antagonist, inhibits the action of ghrelin, a natural peptide hormone produced by the stomach that increases appetite Zenteris Preclinical

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Table 3. Antiobesity therapeutics in development: metabolic regulators

Pharmacological target Company Compound Development status
ß3-adrenergic receptor agonist, sympathomimetic, increases energy expenditure, inhibits intestinal motility Sanofi-Synthelabo SR58611A Phase III for depression
Phase IIa for obesity
Merck L796568 Phase II
GSK Solabegron (GW427353) Phase 1 for type 2 diabetes, discontinued for obesity
Nisshin-Kyorin N5984 Phase I
Modified leptin, decreases appetite and increases energy expenditure, useful in patients with lipodystrophy Arngen Metreleptin (recombinant methionyl human leptin) Phase II
An orally active peptide analog of a fragment of human growth hormone, hGH177–191, increases fat breakdown Metabolic Pharma AOD9604 Phase II
11ß-hydroxysteroid dehydrogenase type 1 (11-ß HSD-1) inhibitor, reduces tissue cortisol levels, results in an improvement in insulin sensitivity, metabolic risk factors, and body composition Biovitrum/Amgen (licensee) BVT.3498/AMG331 Phase II for type 2 diabetes and the metabolic syndrome
Acetyl CoA carboxylase 2 inhibitor, increases energy expenditure Pfizer Preclinical
Globular fragment of adiponectin, increases energy expenditure via adiponectin signaling pathway Serono Famoxin (gACRP30) Preclinical
Thyroid hormone receptorß agonist, increases energy expenditure Karo Preclinical
Fatty acid synthesis inhibitor and O-carnitine palmitoyltransferase-1 stimulator, decreases appetite via central nervous system action and increases peripheral fatty acid oxidation FASGen/P&G (licensee) C75 Preclinical
Stearoyl CoA desaturase-1 inhibitor, decreases fatty acid synthesis and increases fatty acid oxidation Xenon Genetics Preclinical

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