Treatment of obesity by long acting analogues of peptide YY (PYY)

Obesity is a major cause of illness and death across the world and kills 80 people per day in the UK alone. At present, there is no safe and effective treatment for this disease. Gut bypass surgery does cause major weight loss but can be quite dangerous and has many side effects. Therefore, there is a need for a treatment that can mimic the effects of surgery without the dangerous surgery itself. In response to eating a meal the gut releases appetite inhibiting chemicals, known as gut hormones, which is why after eating you don?t feel hungry any more. These hormones influence parts of the brain to reduce appetite and so limit the amount of food we eat. It is thought that the bypass surgery works by causing an increased release of the satiety gut hormones, chronically reducing ones appetite and the intake of food. In this project, we are testing a modified version of the major satiety gut hormone, known as PYY, that we have successfully developed so that it lasts all day. We wish to show that it is effective at reducing weight, is easy to administer and doesn?t have unexpected side effects. We will also standardise its manufacture and develop a method to measure it accurately in man. At the end of the project we will use this information to get permission to test it in human volunteers, as a novel and potentially exciting treatment for obesity.

Obesity causes 600 premature deaths per week in the UK and is a serious risk factor for cancer, diabetes and cardiovascular disease. The two drugs available on the UK market are neither fully effective nor free of side effects. In contrast, gastrointestinal bypass surgery is very effective and works mainly by increasing the release of potent satiety gut hormones such as peptide YY 3-36NH2 (PYY3-36). Intravenous infusion of PYY3-36 significantly reduces food intake in humans. However, it is broken down by peptidases in vivo and has a limited circulatory half-life. Following a five year development programme, we have successfully designed several peptide analogues of PYY3-36 that are peptidase resistant, with a 24 hour profile of action after subcutaneous injection. They produce a powerful inhibition of food intake and significant weight loss in every animal model tested. While each selected analogue is highly efficacious, we now wish to confirm the superiority of the lead candidate in appropriate animal models of human obesity. With superiority confirmed, we will then undertake synthesis of the lead candidate, and perform the necessary preclinical safety work (GLP toxicology with pre-GMP standard peptide) to MHRA and FDA regulatory standards, in preparation for first-time-in-humans Phase 1 studies.