Next generation Y analogue for treatment of obesity

Obesity is a very common disease. Over 1 in 4 people in the UK are obese. Together, these diseases afflict 300 million people and cause an estimated 3 million premature deaths a year. We need a new, cheaper and adjustable treatment for obesity that acts to reduce appetite so that patients can lose weight.

Peptide YY (PYY) is a hormone that the bowels make in response to eating. PYY naturally suppresses appetite. We have developed a new medication called Y3394 based on PYY which can be injected under the skin in patients, and which acts to reduce appetite (and therefore weight).

In this project, we are aiming to study the safety of this drug in healthy volunteers, and to check how long the drug stays around in the blood stream. We will also make preliminary measurements to understand if this drug can cause these volunteers to lose weight. In this way we are developing Y3394 as a new treatment for obesity.

Peptide YY3-36 (PYY) is a naturally occurring gut satiety hormone. When infused intravenously to mimic postprandial levels of PYY, volunteers significantly reduced food intake. In an MRC funded Phase 1 trial, five weekly injections of a long-acting analogue of PYY, Y242, volunteers had significantly reduced weight and sustained food intake reduction. However, Y242 was subject to a dose-limiting burst release over the first 2 hours after injection, associated with temporary nausea and vomiting. There was also a dose dependent local skin irritation. We have therefore developed a related Y analogue, Y3394, which is 10 times more potent than Y242, and has a slow onset. This should completely prevent the side effects and allow higher relative dosage. We now propose to take Y3394 through pre-clinical development and a Phase 1 trial to confirm the safety and tolerability, acceptability and efficacy of Y3394 in man. A safe and effective drug, working through natural satiety mechanisms and additive with other agents, would have a massive market.

The ultimate beneficiaries of our research project will be patients with obesity. As obesity is highly prevalent in the UK (25% of the population and rising) and worldwide, our research will clearly have a massive impact outwith the academic community.

Application and exploitation pathways
At the end of the project, we expect to have developed the following:
1. An entirely new treatment for obesity, the Y3394 analogue.
2. Proof of the tolerability and safety of Y3394.
3. Pharmacokinetic and toxicological data.
4. Proof that Y3394 is capable to delivering a significant reduction in body weight when given for 78 days.

The pathways for exploitation of the technology to be developed in this research proposal are discussed in more detail in the DPFS/DCS Case for Support. However, in brief, we foresee that the technology will be taken forward in development in one of three ways:
1. Formation of a spin-out company to attract venture capital funding.
2. Licensing to an appropriate industrial partner for further development.
3. NIHR-funded development through an appropriate scheme, e.g. the Efficacy and Mechanism Evaluation scheme.

The project team and the Technology Transfer Office, Imperial Innovations, have deep experience in this arena. For example, Prof Bloom successfully developed another gut hormone analogue, TKS-1225, which formed the main product for a spin-out company, Thiakis. Thiakis was sold to Pfizer/Wyeth for £100 million (milestoned) in December 2008.

Communications and engagement
The Division of Diabetes, Endocrinology and Metabolism, Imperial College has a strong commitment to public engagement. The important implications of appetite and the obesity epidemic for society make lay education particularly pertinent.
a) The Division has a track record of drawing public attention to its scientific findings through both printed and broadcast media. See, for example, http://news.bbc.co.uk/1/hi/6262347.stm and http://www.independent.co.uk/life-style/health-and-families/health-news/antihunger-hormone-to-help-fight-against-obesity-432186.html.
b) In addition, we are involved in the Imperial College Outreach scheme which regularly organises science education events for pre-university students, their teachers and their parents or guardians, introducing them to the science of appetite regulation and obesity and discussing the Division's latest discoveries.
c) We also collaborate with the Dana Centre to promote public awareness of science. The Dana Centre is an organization and resource designed as a forum for non-scientists to take part in exciting, informative and innovative debates about contemporary science, technology and culture (http://www.danacentre.org.uk/events/2006/03/14/93 and http://www.danacentre.org.uk/events/2008/10/22).
d) The Division's research findings are also disseminated via the Internet using new media, e.g. Internet video (http://www.youtube.com/watch?v=t3oE-LRFgkY and http://www.youtube.com/watch?v=TWJyoVnBWKg).

The findings of this study are expected to have relevance not just to sufferers of obesity, but also to the wider public. We anticipate interest in our findings from press and broadcast media and we will handle enquiries via the Imperial College Press Office (http://www3.imperial.ac.uk/media).

Involvement of the project team in these activities
Prof Bloom and Dr Tan will be involved in the communications and engagement activities. With regards to the technology exploitation, this will be actively discussed and managed between the project team, Imperial Innovations and the MRC DCS Board.

Resources requested
No extra resources for these impact activities are requested.