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HIGHLIGHTS:

• Adipotide starving fat cells.
• Weight loss in a study wita obese rhesus macaques.
• After four weeks of daily injections of adipotide and a four-week follow-up with no treatment — and without forced changes in diet or exercise — 10 obese female rhesus macaques lost an average of 11% of body weight and 39% of fat deposits.
• Adipotide as Cancer treatment

Obesity, defined as body mass index greater than 30, is a leading cause of morbidity and mortality and a financial burden worldwide. Despite significant efforts in the past decade, very few drugs have been successfully developed for the treatment of obese patients. Biological differences between rodents and primates are a major hurdle for translation of anti-obesity strategies either discovered or developed in rodents into effective human therapeutics. Here, we evaluate the ligand-directed peptidomimetic CKGGRAKDC-GG-_D(KLAKLAK)₂ (henceforth termed adipotide) in obese Old World monkeys. Treatment with adipotide induced targeted apoptosis within blood vessels of white adipose tissue and resulted in rapid weight loss and improved insulin resistance in obese monkeys. Magnetic resonance imaging and dual-energy x-ray absorptiometry confirmed a marked reduction in white adipose tissue. At experimentally determined optimal doses, monkeys from three different species displayed predictable and reversible changes in renal proximal tubule function. Together, these data in primates establish adipotide as a prototype in a new class of candidate drugs that may be useful for treating obesity in humans. [1]

We first used spontaneously obese rhesus macaques (Macaca mulatta), one of the most relevant primate models for human obesity and its associated comorbidities. In an initial dose-finding study, female rhesus macaques (n = 4) aged 9 to 13 years were selected for study entry on the basis of a history of spontaneous obesity, increased food consumption, and failure to maintain a high level of activity. All animals were defined as obese by a body mass index (BMI) ranging from 34 to 45 according to the equivalent formula for rhesus macaques (31). Body weights ranged from 10.0 to 11.7 kg, and the heaviest monkey had a morbidly obese body habitus (BMI = 45). All monkeys had the most clinically abundant abdominal fat in a central pattern relative to that of a large cohort of adult females (n = 350) in the breeding colony. Individual monkeys were euglycemic, with fasting serum glucose levels ranging from 65 to 71 mg/dl (normal range, <80 mg/dl) and serum insulin levels ranging from 21 to 52 μU/ml (normal range, <41 μU/ml). Adipotide was prepared under Good Manufacturing Practice (GMP) to our specifications by PolyPeptide Laboratories. Daily subcutaneous treatment with increasing doses of adipotide resulted in a dose-dependent decrease in body weight, BMI, and abdominal circumference relative to that of negative control monkeys receiving saline (Fig. 1, A to C). After dosing for 9 weeks, the body weight of the two treated monkeys in this initial cohort decreased by 1.8 kg (15.4%) and 2.1 kg (20.4%; Fig. 1A). Moreover, the BMI decreased from 45.0 to 37.3 (17.1%) in the morbidly obese monkey and from 38.8 to 30.9 (20.4%) in the second treated monkey (Fig. 1B). Finally, abdominal circumferences were reduced by 6.5 cm (13.1%) and 9.0 cm (14.2%) from baseline (pretreatment) measurements (Fig. 1C). During the same time period, the body weight, BMI, and abdominal circumference of the obese control monkeys receiving only saline did not change. [1]