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

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.

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.

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.