Natural hormone inspires obesity drug
hormone in the gut that tells our bodies when we are full.
Professor Steve Bloom is head of a research team at Imperial College London's Hammersmith Hospital campus that discovered pancreatic peptide (PP) is secreted after every meal and signals to the brain to stop eating.
Around a third of the world's population is overweight with obesity causing 1,000 deaths a day in the US and over 30,000 a year in the UK. Obesity has been linked with higher levels of depression and stress and causes serious secondary problems such as diabetes, heart problems, stroke and gall bladder disease. There is currently a lack of effective, safe drugs to treat a problem that is only getting worse with time.
"Developing a treatment based on natural appetite suppression, mimicking our body's response to being full, has the potential to be safe and effective, " said Prof Bloom, explaining that other drugs target the brain and so are much less safe.
"We believe that pancreatic polypeptide may be the answer."
Indeed, people with benign PP-secreting tumours have elevated levels of the hormone and although chronically thin, show no other side effects. In fact, according to Prof Bloom, the patients are not even aware they have a suppressed appetite: the tumour is always discovered by accident after the patient sees a doctor with a different complaint.
"These people may have had high levels of PP for 10 or 15 years without showing side effects," Prof Bloom explained. "In that sense, they have provided us with a natural experiment that suggests that excess levels of PP over a long period are safe. It does not appear to raise blood pressure or heart rate, or any other obvious side effects."
When the tumours are removed, the patients gain weight.
The first infusion of PP was given to humans around 20 years ago with Prof Bloom so confident in its safety that he agreed to be given the treatment himself.
However, PP isn't the perfect solution yet. Its appetite suppression effects only last up to 24 hours so it currently needs to be administered daily.
Prof Bloom said: "We need to be hungry before our next meal, so it doesn't last very long."
This explains why, if we eat a large meal, we're often not so hungry the next day. Prof Bloom also explained that is possible that obese people could have naturally elevated levels of PP. In human trials of overweight yet otherwise healthy volunteers, administration of PP lowered appetite in all patients to varying degrees but an average reduction of around 15 to 25 per cent.
Prof Bloom and his team have been awarded £2.3m (€3.5m) by the Wellcome Trust as one the three inaugural grants from their Seeding Drug Discovery initiative. The £91m scheme aims to bridge the funding gap in early-stage drug discovery and is a charitable endeavour and so is not restricted by commercial interests: it can be guided by science alone.
"Our funding is designed to take the research forward to a point that makes it more attractive to venture capital firms, industry and public-private partnerships," said Dr Ted Bianco, director of Technology Transfer at the Welcome Trust.
"We want to put flesh on the bones of great ideas from the lab."
Prof Bloom and his team will use the money to continue human trials of PP and also to try and develop a longer-lasting form of the hormone. Initially, the group are aiming for an injectable form that can be administered weekly but haven't ruled out the possibility of utilising other delivery methods in the future. Eventually, the drug could be given through a nasal spray or even a weight-busting chewing gum.
Prof Bloom told DrugResearcher.com that one method of achieving this would be altering the amino acid structure of the peptide to increase its affinity although this runs the risk of introducing side effects. The team can use PP analogues in other mammals to act as a guide.
The team could also encapsulate the peptide to prevent the body breaking it down as quickly, technology that is already used in contraceptive injections.
At the moment, the only drugs approved to treat obesity are: Sanofi Aventis' recently-introduced Acomplia (rimonabant), an oral appetite suppressant that is taken once a day and works by blocking cannabinoid binding to the CB-1 receptors found on the surface of cells; Abbott Laboratories' centrally-acting Reductil/Meridia (sibutramine) and Roche's Xenical (orlistat), a lipase inhibitor that prevents absorption of dietary fat in the gastrointestinal tract.
Despite what are perceived as relatively modest effects on weight loss, Xenical and Meridia account for a market valued at a little over $1 billion, while Sanofi-Aventis has high hopes for Acomplia, which debuted last year, predicting that sales will be in the 'billions of dollars' range at peak.
As pancreatic peptide is naturally occurring, a drug based on it could be used in people of all ages and also in cases of mild to moderate obesity. Obese people have the option of bariatric surgery but, according to Prof Bloom, the procedure carries a 1 in 30 chance of dying and is also dangerous if the patient subsequently gets a disease that reduces appetite further. Treatment with PP is superior as it is also reversible, he said.
