Regulation of Appetite to Treat Obesity

Gilbert W Kim; Jieru E Lin; Michael A Valentino; Francheska Colon-Gonzalez; Scott A Waldman

Expert Rev Clin Pharmacol. 2011;4(2):243-259.

Five-year View

Anti-obesity pharmacotherapeutics, leveraging a variety of pathophysiological mechanisms, are in preclinical and clinical development, with several showing great promise to be superior alternatives to orlistat. In the context of the pandemic into which obesity has evolved, recent efforts have focused on the development of combination therapeutics for the treatment of obesity, and based on the positive results achieved with these agents and the effectiveness of combination drug therapy in treating a variety of other pathologies, new combinations of anti-obesity drugs can be expected. Agents that target gut, pancreatic and adipose hormone and neuropeptide signaling will also continue to be developed. Furthermore, new delivery methods, including oral, intranasal and transdermal formulations, will make these drugs more attractive to patients and physicians. In addition, a better understanding of how the body regulates appetite will probably result in the discovery of new therapeutic targets. For example, an obstacle such as obesity-related leptin resistance may be circumvented as we further define mechanisms by which central leptin resistance develops in obesity. Despite this progress, however, the aforementioned scientific, regulatory and economic hurdles must be overcome to permit the rapid entry of anti-obesity pharmacotherapeutics into mainstream clinical care.

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Financial & competing interests disclosure
Support was provided by NIH grants R01 CA75123, R01 CA95026, RC1 CA75123 and P30 CA56036 and from Targeted Diagnostic and Therapeutics, Inc. (Scott A Waldman). Michael A Valentino is the recipient of a predoctoral fellowship from the Pharmaceutical Research and Manufacturers of America Foundation. Francheska Colon-Gonzalez is the recipient of a post-doctoral fellowship from the Pharmaceutical Research and Manufacturers of America Foundation Foundation. Scott A Waldman is the Samuel MV Hamilton Endowed Professor. Scott A Waldman is also the Chair of the Data Safety Monitoring Board for the C-Cure Trial sponsored by Cardio3 Biosciences; and the Chair (uncompensated) of the Scientific Advisory Board to Targeted Diagnostics and Therapeutics, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

Cite this: Regulation of Appetite to Treat Obesity - Medscape - Mar 01, 2011.

Table 1. Therapeutic intervention targeting central appetite regulation signaling.
Drug	Company	Clinical trial status	Mechanism of action	Effects	Ref.
TTP-435	TransTech Pharma	Phase II	AgRP inhibitor, increasing MC3/4R signaling	Reduced food intake, bodyweight and insulin levels in animal models	[301,318]
RM-493	Rhythm	Preclinical	MC3/4R agonist, mimicking the effect of α-MSH	Reduced food intake, bodyweight and insulin resistance in preclinical studies	[319]
Spiegelmer® (NOX-B11)	Pfizer	Preclinical	Bind to and inhibit ghrelin	Reduced food intake and c-Fos induction in arcuate nucleus in rats and mice. However, other fasting-related signaling might mask the loss of the ghrelin effect	[201, 320]
GI 181771X	GlaxoSmithKine	Terminated	CCK-A agonist, mimicking the effect of CCK	Clinical trials failed	[82]
Sitagliptin (MK-0431)	Merck	Approved for diabetes	DDP-IV inhibitor, increasing GLP-1 signaling	Reduced weight gain and potentiated the secretion of insulin ^†Side effects include rare nausea, common cold-like symptoms and pancreatitis	[97,321]
Vildagliptin (LAF237)	Novartis	Phase III	DDP-IV inhibitor, increasing GLP-1 signaling	Reduced hyperglycemia ^†Skin lesions and kidney impairment in animal models. Additional safety data from clinical trials are required	[97,322]
Pramlintide	Amylin	Approved for diabetes	Amylin analog	Decreased blood glucose level and bodyweight ^†Side effects include nausea, hypoglycemia, vomiting, headache, abdominal pain and fatigue	[62,323]
Exenatide	Amylin/Eli Lilly	Approved for diabetes	GLP1R agonist, GLP-1 mimicking	Decreased blood glucose level and bodyweight ^†Side effects include gastrointestinal symptoms, acute pancreatitis, dizziness and headache. May increase risks of sulfonylurea-induced hypoglycemia and thryroid cancer	[97,98,100, 304,305,324]
Liraglutide (NN2211)	Novo Nordisk	Approved for diabetes	GLP1R agonist, GLP-1 mimicking	Maintained normal blood glucose and bodyweight ^†Side effects including increased risks of C-cell carcinoma and thyroid C-cell focal hyperplasia were observed in rats and mice	[97,303, 325–327]
NN9924	Novo Nordisk	Phase I	GLP1R agonist, GLP-1 mimicking	Variant of liraglutide	[328]
TKS1225	Thiakis/Wyeth/Pfizer	Phase I	GLP1R agonist, OXM mimicking	Reduced insulin resistance, appetite and bodyweight preclinical models	[329,330]
Histalean (Betahistine)	OBEcure Ltd.	Phase II	H1 receptor agonist H3 receptor antagonist	Weight loss and decreased appetite ^†Side effects include headache and nausea	[331,332]
SCH-497079	Schering–Plough	Phase II	Histamine receptor antagonist	No study results posted	[333,334]
Metreleptin	Amylin/Takeda	Phase III	Leptin receptor agonist	Weight loss ^†Side effects include nausea and injection site adverse events	[310,311,335]
BMS-830216	Bristol-Myers Squibb	Phase I/II	MCH receptor antagonist	The Phase I/II studies is anticipated to be completed in 2011. No study results posted	[302,336]
ALB-127158	AMRI	Phase I	MCH1 antagonist	The Phase I study is anticipated to be completed in 2011. No study results posted	[337]
Qnexa® (phentermine/topiramate)	Vivus	Phase III	Norepinephrine-releasing agent GABA receptor activator	Weight loss Currently under review for approval. Possible side effects include suicidal thoughts, heart palpitations, memory lapses and birth defects	[338]
Empatic™ (zonisamide SR/bupropion SR)	Orexigen	Phase II	Norepinephrine/dopamine reuptake inhibitor GABA receptor activator	Weight loss and reduced metabolic syndrome ^†Side effects include birth defects. Possible side effects in cognitive function, thoughts of suicide or depression were not significantly different from placebo	[339]
Contrave® (bupropion SR/naltrexone SR)	Orexigen	Rejected for approval in February 2011	Norepinephrine/dopamine reuptake inhibitor GABA receptor activator	Weight loss, decreased appetite and reduced metabolic syndrome ^†Side effects include headaches and constipation. Concerns are cardiovascular safety and psychological issues	[340,341]
Taranabant (MK-0364)	Merck	Phase III terminated	Cannabinoid receptor inverse agonist	Study stopped due to high level of control side effects, mainy depression and anxiety	[202,342]
Lorcaserin HCI	Eisai	Rejected for approval in October 2010	Selective 5HT2c receptor agonist	Limited weight loss efficiacy and possible increase in cancer risk ^†Side effects include headache, infection, sinusitis, nausea, depression, anxiety and suicidal thoughts. Possible concerns of cancer risk	[199,316,343]
Tesofensine (NS2330)	NeuroSearch	Phase III	Serotonin-norepinephrine/dopamine reuptake inhibitor	Weight loss ^†Side effects include dry mouth, headache, nausea, insomnia, diarrhea and constipation	[344,345]
TM30339	7TM Pharma	Phase I/II	Y4R agonist in DVC, Y2R agonist in arcuate nucleus	Weight loss and reduced metabolic syndrome. The study is ongoing and no study results posted	[309,346]
Obinepitide	7TM Pharma	Phase II	Y4R agonist in DVC, Y2R agonist in arcuate nucleus	Weight loss and reduced metabolic syndrome. No study results posted	[308,347]
PYY (3–36)	Merck	Phase II	Y4R agonist in DVC, Y2R agonist in arcuate nucleus	The Phase II trial does not meet weight loss end point	[42,94,112–118, 348]
MK-0557	Merck	Phase II	Y5 receptor antagonist, NPY blocker	No significant weight loss compared with placebo	[65,349]
Velneperit (S-2367)	Shionogi USA	Phase II	Y5 receptor antagonist, NPY blocker	Reduced bodyweight ^† Side effects include nasopharyngitis, upper respiratory infection, sinusitis and headache	[350,351]

^†Adverse effect(s) of the drug.
α-MSH: α-melanocyte stimulating hormone; AgRP: Agouti-related protein; CCK: Cholecystokinin; DPP-IV: Dipeptidyl peptidase IV; DVC: Dorsal vagal complex; GABA: γ-aminobutyric acid; GLP-1: Glucagon-like peptide 1; GPL1R: Glucagon-like peptide 1 receptor; MC3/4R: Melanocortin 3/4 receptor; MCH: Melanin-concentrating hormone; NPY: Neuropeptide Y; OXM: Oxyntomodulin; Y2R: Neuropeptide Y receptor subtype 2.

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Regulation of Appetite to Treat Obesity

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