Developmental Clinical Studies - Curing Obesity with the 'Medical Bypass'

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

Abstract

A quarter of the UK population is obese and unfortunately this number is still rising. Obesity is strongly associated with maturity onset diabetes. Obesity is also a major cause of cancer, heart attacks, strokes and other illnesses. There is no effective drug therapy for obesity. The only effective treatment is gastric bypass surgery which causes a large weight loss, cure of diabetes and a reduction of rates of cancer and heart attacks. Unfortunately surgery is a major undertaking, is expensive, is irreversible, is associated with complications, and is risky.

The benefits of this surgery are due to the much increased secretion of chemicals by the gut, called gut hormones. These are glucagon-like peptide-1, oxyntomodulin and peptide YY. We have developed two new drugs based on these gut hormones, made with natural amino acids, and combined them together to mimic the effect of bypass surgery in a single weekly injection through a fine needle. We call this the 'medical bypass' as it works by the same mechanism as the surgical bypass. This treatment will be as effective as bypass surgery but it will be less expensive and will be much less risky.

One of the components of the medical bypass, which we call Y242, is already being tested in trials this year. In the project here, we are going to develop the other component, which we call G3215. We will first test G3215 to make sure it is safe before testing it in human volunteers to check that it is well-tolerated. We will then mix the Y242 and G3215 together and test this in human volunteers, as well as in patients with diabetes, to prove that the medical bypass is effective in helping patients lose weight and control their blood sugar levels.

If our medical bypass is effective, this would be a great advance in the treatment of obesity and diabetes, and would help to save the many lives lost each year to the complications of these serious conditions.

Technical Summary

This project is divided into three Milestones. Note that the Y242 analogue is presently being developed in a separate DCS Project.

Milestone 1: Statutory pre-clinical studies prior to starting Phase 1 studies on G3215
- Peptide synthesis to support clinical trial material (CTM) formulation and toxicokinetic studies.
- GLP-standard bioanalysis method for G3215 for the human, rodent and dog plasma matrices.
- Good Laboratory Practice (GLP)-standard toxicokinetic programme in two animal species, four weeks.
- Synthesis of G3215 to Good Medical Practice (GMP) standard.
- Formulation, manufacturing and stability studies on G3215 CTM.
- Application to MHRA and a REC to allow Phase 1 studies to start.

Milestone 2: Phase 1 trials on G3215
This will utilize a combined single ascending dose (SAD) and multiple ascending dose (MAD) protocol. The SAD trial is a single-blind, placebo-controlled, randomised study to establish the safety, tolerability, PK and dose proportionality of single doses of G3215 in healthy males. This is followed by a double-blind, placebo-controlled, randomised MAD study to establish the safety, tolerability and PK of multiple doses of G3215. The MAD trial will also collect preliminary efficacy data in terms of food intake, body weight, and glucose tolerance.

Milestone 2: Statutory pre-clinical studies for combination of Y242/G3215 to enable Phase 1 studies
- A toxicokinetic study in one animal species of Y242/G3215.
- A study to ensure that both analogues are stable when mixed in a syringe.
- Application to the MHRA and a REC to allow the combination Phase 1 studies to start.

Milestone 3: Phase 1 trials on the Y242/G3215 fixed-ratio combination
A similar SAD/MAD Phase 1 protocol for the Y242/G3215 combination will be used to establish the safety, tolerability, PK and dose proportionality of single and multiple ascending doses of the fixed-ratio Y242/G3215 combination, as well as efficacy data.

Planned Impact

BENEFITS TO PATIENTS
The ultimate beneficiaries of our research project will be patients with obesity and type 2 diabetes. Obesity is highly prevalent in the UK (25% of the population and rising) and worldwide. Type 2 diabetes affects 1 in 20 of the population and is also rising in prevalence, driven by the obesity trend. Compared to the current medication, our new therapies produces greatly enhanced weight loss and improvement in diabetic control. This will ameliorate the co-morbidities of obesity (obstructive sleep apnoea, cardiovascular disease, cancer, osteoarthritis), and prevent many diabetic complications, thus reducing the burden of suffering from these health problems. Obesity is also widely considered a social disadvantage.

BENEFITS TO THE NHS AND OTHER HEALTHCARE SYSTEMS
The NHS spends approximately £9 billion/year on diabetes and £1 billion/year on obesity, with these costs set to rise sharply over the next 20 years (Wang et al, Lancet 378: p.815) . These direct costs do not account for the loss of productivity entailed by the co-morbidities and complications of obesity and diabetes. Therefore, our new treatments have the potential to reduce the costs to healthcare systems in the UK and in other countries of treating obesity, diabetes and their complications.

BENEFIT TO THE WEALTH OF THE NATION
The therapies to be developed in this project will be patented by the University. We anticipate that this will create an opportunity to license to interested pharmaceutical companies, or form the basis of a spin-out company to attract investment (e.g. from venture capital funds) for further development. This will benefit the UK in terms of attracting international investment and, later, licence fees.

Publications

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Choudhury SM (2016) Gastrointestinal hormones and their role in obesity. in Current opinion in endocrinology, diabetes, and obesity

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Law J (2018) Thermal Imaging Is a Noninvasive Alternative to PET/CT for Measurement of Brown Adipose Tissue Activity in Humans. in Journal of nuclear medicine : official publication, Society of Nuclear Medicine

 
Title Chronic subcutaneous infusion technique 
Description Established the length of time peptides were stable in a pump (8 hours) and therefore how often the pump needed changing to provide effective day time cover. 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2018 
Provided To Others? Yes  
Impact Allows testing in man of chronically elevated natural gut hormones. 
 
Title Analogue of oxyntomodulin 
Description Oxyntomodulin analogue for treatment of diabetes and obesity Supported by MRC DCS 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2014
Development Status Under active development/distribution
Impact N/A 
 
Title Combination gut hormones via subcutaneous infusion 
Description Combination of GLP-1, oxyntomodulin and peptide YY via subcutaneous pump. Proof of principle obtained (funded by MRC Experimental Medicine Challenge Grant). 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2018
Development Status Under active development/distribution
Impact Demonstrated that the GOP infusion is capable of reducing weight and ameliorating glucoswe 
 
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 Front page article in the Telegraph 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Front page article in the Telegraph Newspaper on 4th May 2019. Headline was: "The monthly hormone jab hailed as 'most exciting' weight-loss treatment ever"
Year(s) Of Engagement Activity 2018
URL https://www.telegraph.co.uk/science/2018/05/04/hormone-jab-mimics-gastric-band-hailed-exciting-obesi...
 
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 Multidisciplinary Endocrine Symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Annual Imperial Centre for Endocrinology Symposium
Day of presentations and talks.
Talk given: Obesity Surgery vs Medical Treatment: Who Gets What and what is to come?
Year(s) Of Engagement Activity 2018
URL http://www.imperialendo.com/thirteenm
 
Description Pharmaceutical Innovation "Treatment landscape for diabetes and obesity" for Financial Investors 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact A day of lectures and meetings organised by Goldman Sachs to better understand on-going innovation in drug development and how the treatment landscapes could evolve.
Spoke on the following:
Is obesity a disease? Thus, is it insurance reimbursable?
Why is the uptake of current oral anti-obesity agents so poor?
Why isn't bypass surgery not more popular?
Year(s) Of Engagement Activity 2018
 
Description Press release (GLP-1/glucagon food intake study) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach National
Primary Audience Health professionals
Results and Impact Paper presented at BES 2013 conference. Press release regarding this, see for example http://www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/newssummary/news_18-3-2013-17-37-33

Widespread interest in research world wide
Year(s) Of Engagement Activity 2013