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

Lead Research Organisation: Imperial College London
Department Name: Dept of Medicine

Abstract

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.

Technical Summary

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.

Publications

10 25 50
 
Description Led the pharmaceutical industry to develop analogues in this field
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in systematic reviews
Impact Indicated a new method for limiting weight.
 
Title Analogue of peptide YY 
Description Describes novel analogues of the gut hormone peptide YY. 
IP Reference WO2008003947 
Protection Patent application published
Year Protection Granted 2008
Licensed No
Impact The analogue is being developed for a Phase I trial (funded by the MRC DCS grant). This Phase I trial has commenced April 2012.
 
Title Analogue of peptide YY 
Description Analogue Y242 completed Phase I trial 2013 
Type Therapeutic Intervention - Drug
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2013
Development Status Under active development/distribution
Clinical Trial? Yes
Impact This drug is intended as a treatment for obesity, which afflicts 20-25% of the UK population. 
URL https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-003549-17
 
Company Name ZIHIPP LTD 
Description Zihipp is committed to transforming the lives of patients with diabetes and obesity by developing safe and effective weight loss therapies that deliver the benefits of gastrointestinal surgery without the need to have an operation. 
Year Established 2012 
Impact Company has only recently been funded no impact to date ongoing work.
Website https://www.zihipp.com
 
Description BBC Horizon 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Gave interview to BBC Horizon Programme
Year(s) Of Engagement Activity 2016
 
Description Bayliss-Starling Lecture 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact talk has been published in special themed issue of J Physiol

talk was well received
Year(s) Of Engagement Activity 2014
 
Description ITV The Tonight Programme 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Gave interview to ITV's 'The Tonight Programme' discussing current research.
Year(s) Of Engagement Activity 2015
URL http://www.itv.com/news/2015-10-21/xxl-britain-tonight/
 
Description Interview for BBC Persian World Service 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Interviewed for BBC Persian World Service programme.
Year(s) Of Engagement Activity 2015
 
Description Interview of BBC Documentary "The Truth About Obesity" 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Interviewed for BBC Documentary "The Truth About Obesity". Not yet broadcast.
Year(s) Of Engagement Activity 2018
 
Description Knighthood honour for 'outstanding' obesity expert 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact http://www.bbc.co.uk/news/health-16363464

Publicity regarding laboratory's work.
Year(s) Of Engagement Activity 2012
 
Description Plenary Lecture, Japan Endocrine Society 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Gave the Plenary Lecture at the Japan Endocrine Society entitled "Gut Hormones and the Brain". This disseminated the research so that a wide range of professionals could benefit.
Year(s) Of Engagement Activity 2019