Abstract
Background/ObjectivesCholecystokinin (CCK) is a regulator of appetite and energy intake in man. The aim of this study was to determine the effect of NN9056, a long-acting CCK-1 receptor-selective CCK analogue, on food intake and body weight (BW) in obese Göttingen Minipigs.Subjects/MethodsTolerability of NN9056 and acute effects on food intake, pancreas histology, amylase and lipase levels were assessed in lean domestic pigs in doses up to 100 nmol/kg (n = 3–4). Subsequently, obese Göttingen Minipigs were treated subcutaneously (s.c.) once daily for 13 weeks with vehicle, NN9056 low dose (regulated from 5 to 2 nmol/kg) or NN9056 high dose (10 nmol/kg) (n = 7–8). Food intake was measured daily and BW twice weekly. At the end of the treatment period, an intravenous glucose tolerance test (IVGTT) and a 24-h exposure profile was obtained. Data are mean ± SD.ResultsThe acute studies in domestic pigs showed significant and dose-dependent effect of NN9056 on food intake, acceptable tolerability and no histopathological signs of pancreatitis. Sub-chronic treatment in obese Göttingen Minipigs was also well tolerated and accumulated food intake was significantly lower in both treated groups compared to vehicle, with no significant difference between the dose levels of NN9056 (41.8 ± 12.6, 51.5 ± 13.8 and 86.5 ± 19.5 kg in high-dose, low-dose and vehicle groups, respectively, p = 0.012 and p < 0.0001 for low and high dose vs. vehicle, respectively). Accordingly, there was a weight loss in both treated groups vs. a weight gain in the vehicle group (−7.2 ± 4.6%, −2.3 ± 3.2% and 12.3 ± 3.9% in the high-dose, low-dose and vehicle groups, respectively, p < 0.0001 for both vs. vehicle). IVGTT data were not significantly different between groups.ConclusionNN9056, a long-acting CCK-1 receptor-selective CCK analogue, significantly reduced food intake and BW in obese Göttingen Minipigs after once daily s.c. dosing for 13 weeks.
Highlights
Obesity is an increasing problem worldwide, with a great unmet medical need [1]
The aim of the present study was to evaluate the effect of NN9056, a novel long-acting and selective CCK-1 receptor agonist, on food intake and body weight (BW) in obese Göttingen Minipigs
The ISH analyses showed that the CCK-1 receptor messenger RNA expression level in the pancreatic acinar cells was species specific, with high expression observed in the mouse and rat, medium expression in the dog and low expression in the pig and human
Summary
The encouraging weight-modulating effects of subchronic CCK-1 receptor agonism observed pre-clinically [3, 16] have to date not been reproduced in the clinic. The small-molecule CCK-1 receptor agonist, GI181771X, was explored as an anti-obesity drug, but failed to induce weight loss in obese humans after 24 weeks of treatment [17]. Suboptimal exposure levels and lack of full-day coverage might explain the lack of efficacy. A peptide-based approach, with a half-life-extending acylation or PEGylation, could be more attractive compared to a small-molecule approach, due to better pharmacokinetic (PK) properties with continuous exposure. Higher specificity and fewer off-target effects would be expected with a peptide approach
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