Investigation of the effect of an analogue of oxyntomodulin on appetite and energy intake

Obesity is a major cause of ill-health and death in the UK and costs the NHS #500 million pounds annually. Currently available treatments are limited in their effectiveness and often cause significant side effects.

We now know that after a meal, the gut naturally produces hormones which act on the appetite centres of the brain to switch off appetite and make a person feel full. Using this effect of gut hormones has the advantage of mimicking the way in which the body normally controls food intake, and so has less potential for side effects than some other treatments. We have recently shown that injections three times a day (before meals) of the gut hormone oxyntomodulin helped obese volunteers lose more weight than volunteers receiving a placebo. Oxyntomodulin, however, is broken down rapidly in the blood, meaning it has to be injected frequently and its effects are short-lasting.

We have altered the structure of the hormone in order to make it more resistant to the mechanisms by which it is broken down in the body. We now propose to test this analogue of oxyntomodulin in volunteers, to test it efectiveness.

We shall firstly start by injecting the analogue at very low doses into volunteers, and then giving them a standard meal to eat. The effect of the analogue on the amount that they eat at this meal will be measured. We will gradually increase the dose until we find a dose that causes a 20% reducition in the amount eaten at a test meal compared with when the volunteers have no analogue injected.

We will then proceed formally to compare the analogue against a placebo, and record the amount eaten at a test meal as well as at subsequent meals for 24 hours afterwards. We will also take blood smaples from the volunteers to measure levels of the analogu inthe blood, to confirm that it is longer-lasting that oxyntomodulin itself, as well as measure other hormone levels and glucose levels.

This research is being conducted by the Department of Metabolic Medicine, Hammersmith Hospital, Imperial College, London. The department has a long-standing interest in gut hormones and appetite regulation and has conducted and published work in the field over the last 3 decades.

It is hoped that, if the results of this study are promising, it might be possible to develop an effective treatment for obesity based on oxyntomodulin.

Obesity is a major cause of death. Currently available therapies have major shortcomings and serious side effects. Gut hormones are physiological regulators of appetite, and their role in the regulation of energy balance makes them candidates for the development of an effective therapy for obesity.

We have recently shown that subcutaneous preprandial administration of the anorexigenic gut hormone oxyntomodulin to obese subjects results in weight loss over 4 weeks. Oxyntomodulin s short half life in the circulation limits its applicability. We have therefore developed degradation-resistant analogues by alterations to the ammino acid sequence of oxyntomodulin which we have tested in rodents. One such analogue reduces food intake in mice by 3 times as much as oxyntomodulin at a dose that is 2 times lower, and the hypophagia lasts for 4 times longer, with no apparent ill effects. If effective in humans, this analogue could form the basis of an effective therapy for obesity.

We hypothesise that administration of this analogue to humans will reduce food intake and increase the intermeal period compared with controls. We predict the analogue will have a longer half-life than native oxyntomodulin.

We propose to perform a single-blind dose-escalation study in which volunteers will undergo a 90-minute intravenous infusion of the analogue followed by a test meal. Energy intake at the test meal will be measured and compared with a baseline obtained in the same volunteer following infusion of saline. The dose of analogue will initially be 0.003pmol/kg/min (3 orders of magnitude lower than the effective dose of oxyntomodulin), and the dose will be increased gradually until reliable inhibition of food intake by 20% is achieved.

We will then progress to a double-blind, randomised placebo-controlled crossover study, in which subjects will receive the oxyntomodulin analogue or saline intravenously for 90 minutes, followed by a test meal. They will be permitted to ask for a further meal later that day. The energy intake at both meals and the delay in asking for the second meal will be measured. Measurements of plasma analogue levels will be perfomed on blood samples taken throughout the day, using an in-house radio-immunoassay, in order to establish the half-life of the analogue in human plasma.