Progressive Reduction in Body Weight after Treatment with the Amylin Analog Pramlintide in Obese Subjects: A Phase 2, Randomized, Placebo-Controlled, Dose-Escalation Study

Aronne, Louis J.; Fujioka, Ken; Aroda, Vanita R.; Chen, Kim; Halseth, Amy E.; Kesty, Nicole C.; Burns, Colleen; Lush, Cameron W.; Weyer, Christian

doi:10.1210/jc.2006-2003

Cited by 157 publications

(137 citation statements)

References 25 publications

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“…For example, pramlintide significantly reduced body weight in patients with diabetes on insulin therapy, an intervention associated with weight gain. 26 Pramlintide also elicited significant weight loss in obese subjects in the absence of lifestyle intervention, 27,28 and produced greater initial weight loss compared with placebo and longer maintenance of weight loss when used in conjunction with lifestyle intervention. 29 Although the therapeutic potential of amylin receptor agonism to stimulate weight loss has been clearly demonstrated, pramlintide and amylin have a short half-life (rat t 1/2 ¼ 13 min, human t 1/2 ¼ 20-45 min) and low bioavailability, resulting in multiple daily dosing that impacts patient compliance and cost per day of therapy (for review, see Roth et al 30 ).…”

Section: Introductionmentioning

confidence: 97%

Davalintide (AC2307), a novel amylin-mimetic peptide: enhanced pharmacological properties over native amylin to reduce food intake and body weight

Mack¹,

Soares²,

Wilson³

et al. 2009

Int J Obes

105

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Objective: The current set of studies describe the in vivo metabolic actions of the novel amylin-mimetic peptide davalintide (AC2307) in rodents and compares these effects with those of the native peptide. Research design and methods: The anti-obesity effects of davalintide were examined after intraperitoneal injection or sustained peripheral infusion through subcutaneously implanted osmotic pumps. The effect of davalintide on food intake after lesioning of the area postrema (AP) and neuronal activation as measured by c-Fos, were also investigated. Results: Similar to amylin, davalintide bound with high affinity to amylin, calcitonin and calcitonin gene-related peptide receptors. Acutely, davalintide displayed greater suppression of dark-cycle feeding and an extended duration of action compared with amylin (23 versus 6 h). Davalintide had no effect on locomotor activity or kaolin consumption at doses that decreased food intake. Davalintide-induced weight loss through infusion was dose dependent, durable up to 8 weeks, fat-specific and lean-sparing, and was associated with a shift in food preference away from high-fat (palatable) chow. Metabolic rate was maintained during active weight loss. Both davalintide and amylin failed to suppress food intake after lesioning of the AP and activated similar brain nuclei, with davalintide displaying an extended duration of c-Fos expression compared with amylin (8 versus 2 h). Conclusion: Davalintide displayed enhanced in vivo metabolic activity over amylin while retaining the beneficial properties possessed by the native molecule. In vitro receptor binding, c-Fos expression and AP lesion studies suggest that the metabolic actions of davalintide and amylin occur through activation of similar neuronal pathways.

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Section: Introductionmentioning

confidence: 97%

Davalintide (AC2307), a novel amylin-mimetic peptide: enhanced pharmacological properties over native amylin to reduce food intake and body weight

Mack¹,

Soares²,

Wilson³

et al. 2009

Int J Obes

105

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“…10 The most common adverse event in these trials was nausea, which was primarily mild to moderate and transient in nature. 12,13 Phentermine and sibutramine are two monoaminergic antiobesity agents indicated for the short-and long-term management of obesity, respectively. Phentermine is a b-phenethylaminic derivative that acts through monoaminergic systems (noradrenaline and dopamine) to decrease food intake and body weight.…”

Section: Introductionmentioning

confidence: 99%

Antiobesity effects of the β-cell hormone amylin in combination with phentermine or sibutramine in diet-induced obese rats

Roth¹,

Trevaskis²,

Wilson³

et al. 2008

Int J Obes

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Objective: To characterize the interactive effects of amylin with phentermine or sibutramine on food intake, body weight/ composition and gene expression in diet-induced obese (DIO) rats. Design: DIO rats were intraperitoneally injected with a single dose of amylin (10 mg kg À1 ) and/or phentermine (1 mg kg À1 ) or chronically infused with amylin (100 mg kg À1 d À1 ) or vehicle with or without phentermine (0.5-10 mg kg À1 d À1 ) or sibutramine (3 mg kg À1 d À1 ) using two surgically implanted subcutaneous osmotic mini-pumps. Measurements: Twenty-four hour food intake, locomotor activity and components of meal microstructure (meal size, latency, duration and intermeal interval) were measured following acute administration (amylin, phentermine or amylin þ phentermine). Body weight and composition (for amylin and/or sibutramine or phentermine) and metabolism-related gene mRNA expression in the liver (fatty acid synthase, stearoyl-CoA desaturase-1 and carnitine palmitoyltransferase-1) and brown fat (b-adrenergic receptors and uncoupling protein-1) were measured (for amylin and/or phentermine) after sustained infusion (2 weeks). Results: Acute co-administration of amylin (10 mg kg À1 ) and phentermine (1 mg kg À1 ) reduced acute food intake (up to 19 h) more than either monotherapy. In two studies, sustained subcutaneous infusion of amylin for 2 weeks decreased cumulative food intake (22%) and vehicle-corrected body weight gain (B4-8%). Phentermine's anorexigenic (10-17%) and weightreducing effects (B0-5%) were only evident at the highest dose tested (10 mg kg À1 d À1 ). Combination of amylin (100 mg kg À1 d À1 ) and phentermine reduced food intake (30-43%), body weight (8-12%) and adiposity to a greater extent than either monotherapy. Amylin prevented phentermine-induced reductions in UCP-1 mRNA in brown adipose tissue. When amylin þ sibutramine were infused, mathematically additive decreases in food intake (up to 45%) and body weight (up to 12%) were evident. Similar to amylin þ phentermine treatment, amylin þ sibutramine mediated weight loss was attributable to significant reductions in fat mass. Conclusions: Combined treatment of DIO rats with the pancreatic b-cell hormone amylin and phentermine or sibutramine resulted in additive anorexigenic, weight-and fat-reducing effects.

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“…In obese humans, the amylin analog pramlintide elicited sustained reductions in food intake and body weight (13,14). Amylin-induced weight loss in DIO rats that was observed to be fat-specific with relative preservation of lean mass was associated with increased proopiomelanocortin (POMC) gene expression in the arcuate nucleus (ARC) and was not accompanied by a compensatory decline in metabolic rate (15, 16).…”

mentioning

confidence: 99%

Leptin responsiveness restored by amylin agonism in diet-induced obesity: Evidence from nonclinical and clinical studies

Roth¹,

Roland²,

Cole³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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392

383

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Body weight is regulated by complex neurohormonal interactions between endocrine signals of long-term adiposity (e.g., leptin, a hypothalamic signal) and short-term satiety (e.g., amylin, a hindbrain signal). We report that concurrent peripheral administration of amylin and leptin elicits synergistic, fat-specific weight loss in leptin-resistant, diet-induced obese rats. Weight loss synergy was specific to amylin treatment, compared with other anorexigenic peptides, and dissociable from amylin's effect on food intake. The addition of leptin after amylin pretreatment elicited further weight loss, compared with either monotherapy condition. In a 24-week randomized, double-blind, clinical proof-of-concept study in overweight/obese subjects, coadministration of recombinant human leptin and the amylin analog pramlintide elicited 12.7% mean weight loss, significantly more than was observed with either treatment alone (P < 0.01). In obese rats, amylin pretreatment partially restored hypothalamic leptin signaling (pSTAT3 immunoreactivity) within the ventromedial, but not the arcuate nucleus and up-regulated basal and leptin-stimulated signaling in the hindbrain area postrema. These findings provide both nonclinical and clinical evidence that amylin agonism restored leptin responsiveness in diet-induced obesity, suggesting that integrated neurohormonal approaches to obesity pharmacotherapy may facilitate greater weight loss by harnessing naturally occurring synergies.pramlintide ͉ metreleptin ͉ adiposity ͉ synergy ͉ leptin resistance T he discovery of leptin in 1994 (1) revolutionized our understanding of the biological basis of body-weight regulation and raised hopes that this adipokine could be a breakthrough treatment for obesity. Although leptin plays a pivotal role in regulating energy homeostasis in rodents and humans, its pharmaceutical development as a stand-alone antiobesity agent has proven unsuccessful (2). Although leptin replacement elicits profound weight loss in leptindeficient (Lep ob /Lep ob ) mice and humans (3, 4), even high pharmacological doses elicit only marginal weight loss in non-leptindeficient, diet-induced obese (DIO) rodents and humans (2, 5). The obese state is thus thought to be associated with ''leptin resistance,'' wherein overweight/obese individuals become insensitive to high circulating leptin concentrations (6). The mechanistic basis for leptin resistance is poorly understood, but rodent data implicate leptin transport saturation (7), leptin receptor down-regulation (8), and reduced hypothalamic postreceptor signaling (9, 10).Amylin, a 37-aa peptide hormone cosecreted with insulin from pancreatic ␤-cells (11), binds specific receptors in the hindbrain area postrema (AP) that activate multiple central nervous system (CNS) regions to regulate both glucose and energy homeostasis (12). In obese humans, the amylin analog pramlintide elicited sustained reductions in food intake and body weight (13,14). Amylin-induced weight loss in DIO rats that was observed to be fat-specific with relative...

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Progressive Reduction in Body Weight after Treatment with the Amylin Analog Pramlintide in Obese Subjects: A Phase 2, Randomized, Placebo-Controlled, Dose-Escalation Study

Abstract: These results support continued evaluation of pramlintide as a potential treatment for obesity.

Cited by 157 publications

References 25 publications

Davalintide (AC2307), a novel amylin-mimetic peptide: enhanced pharmacological properties over native amylin to reduce food intake and body weight

Davalintide (AC2307), a novel amylin-mimetic peptide: enhanced pharmacological properties over native amylin to reduce food intake and body weight

Antiobesity effects of the β-cell hormone amylin in combination with phentermine or sibutramine in diet-induced obese rats

Leptin responsiveness restored by amylin agonism in diet-induced obesity: Evidence from nonclinical and clinical studies

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