Drugs on the way to tackle obesity epidemic

Acomplia, a novel drug treatment for obesity, was launched with great fanfare in London yesterday, by its inventor Sanofi-Aventis, Europe’s third largest pharmaceutical company. The move could be a turning point in treating obesity, with many other compounds, targeting known and novel targets, working their way through the development pipelines in Europe and elsewhere.

Over one billion people world-wide are overweight or obese according to the World Health Organisation. But while many would dismiss this on the grounds that it is a lifestyle issue and they have only themselves to blame, the statistic points at a huge, and growing health problem

Being obese makes life very uncomfortable. It also causes impaired mobility, decreased heat tolerance, excessive sweating and skin folds that can become infected. Beyond this it is implicated in life-threatening diseases ranging from diabetes to kidney failure, heart failure and cardiovascular disorders.

Indeed, obesity-related costs account for nearly 8% of overall healthcare spending, putting a tremendous burden on the public exchequer. And with no end in sight to the globesity (global obesity) epidemic, there is an urgent need for a solution.

The ideal drug would achieve significant and sustainable weight loss and do so safely. But the only two currently available, Roche’s Xenical (Orlistat) and Abbot’s Reductil (Sibutramine), have side effects and are not particularly effective.

Acomplia (Riminobant) is seen as the most promising drug to emerge in recent years and market watchers say it could outsell every drug ever made.

While the perfect anti-obesity pill remains illusive, a small number of technology companies are developing novel surgical and non-surgical devices designed to cash in on the escalating epidemic.

On the trail of the perfect fat drug

The market for treating obesity may be huge, but to date it has been a graveyard for pharmaceutical companies, who have experienced a string of expensive failures. In the1960s aminorex was withdrawn because of possible association with pulmonary hypertension. In the late 1990s, American Home Products (now Wyeth) got into trouble when patients taking the phentermine plus fenfluramine combination (Phen-Fen) developed pulmonary hypertension.

The resulting lawsuits plagued Wyeth for years and ended up costing the company over $13bn. Another legacy of the Phen-Fen debacle was to make patients wary of appetite suppressants. “Fears about appetite suppressants and the potential side-effects of tachycardia and increased blood pressure have been very off-putting,” explains Shahred Taheri, a metabolism specialist at the Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology in Bristol, UK.

Xenical too, has its own problems. “While promising in clinical trials, in practice patients don’t like it as they get upset stomachs and diarrhoea,” says Taheri. Xenical works by inactivating lipase, the enzyme that breaks down fat in the gut. As a result 30 percent of ingested dietary fat is not absorbed. Total energy intake is reduced, but faecal incontinence is common.

But with the emergence of Acomplia, the obesity market could be set for a transformation. The drug is an inhibitor of the cannabinoid-1(CB1), receptors, which are involved in glucose and lipid metabolism. Weight loss with Acomplia is no better than that with current agents, but its positive effects on cardiovascular disease, diabetes and smoking cessation is expected to give it an advantage.

More than 2,500 people took part in the Phase III trials, with adverse events described as mild to moderate.

But Xenical also looked good in clinical trials. “We need to find out more about how Acomplia works outside clinical trials and whether there are side-effects that these trials were not powered enough for,” says Taheri.

“There is the potential for problems,” agrees Steve Bloom, of the Department of Metabolic Medicine at Imperial College London. “Mostly the CB1 receptor system has nothing to do with appetite, it is involved in reproduction, motor and brain development,’ he says.

More treatments are on the way

Several other companies are on the verge of capitalising on the medicalisation of obesity. Hot on Sanofi’s heels is UK biotech Alizyme plc of Cambridge, which is about to put its drug Cetilistat through Phase III clinical trials. Cetilistat works on the same basis as Xenical: inhibiting lipase to block fat metabolism. The trials to date show that weight loss is similar to that obtained with Xenica, but with a superior side effect profile.

Most of the other drugs in late stage clinical development are agonists of natural gut or pancreatic hormones (see table). “We think these hormones are the way forward,” says Bloom, a co- founder of Thiakis Ltd, a spin out from Imperial College. “They are the natural way by which the body switches off appetite after eating a meal. It does this every day with no obvious side-effects,” he says.

Amylin Pharmaceutical Inc’s., Pramlintin, (Symlin), based on the gut hormone amylin is approved for the treatment of diabetes. Its potential use in obesity was investigated when diabetic patients taking the drug started to lose weight. But a potential downside is that the drug has to be injected.

Drugs based on another gut hormone, the PPY-peptide have shown promise but also have to be injected. Amylin is also working on a PPY drug, as is the Danish biotech 7TM Pharma. Recently completed PhaseI/II trials showed that a single daily injection of 7TM Pharma’s lead compound TM30338, a synthetic analogue of PYY and pancreatic polypeptide, suppresses appetite in obese individuals for at least 9 hours.

In May this year 7TM expanded its obesity portfolio by purchasing French firm CareX. CareX’s portfolio includes both a CB1 receptor antagonist and SGLT (sodium-dependent glucose co-transporter) inhibitors. Based on technology in-licensed from Thiakis, Nastech Pharmaceuticals Inc., and Merck are also working on a PPY drug, which they intend to develop as a nasally-administered spray.

Meanwhile, Arena Pharmaceutical’s ADP356 targets a completely different mechanism, the 5-HT2C receptor. This is the same target as Phen-Fen but, Arena claims ADP is far more selective, and therefore safer. ADP356 is 100-fold more selective for the 2C receptor and has a low affinity for the B receptor, which was implicated in heart valve disease.

It’s an ill wind

Another drug at Phase II is at Tesofensine, from Neurosearch AS of Ballerup, Denmark. Last August the compound failed in Phase IIb studies in both Alzheimer’s and Parkinson’s disease. But analysis of 312 patients in both trials, who were also obese, found they lost an average of 4 kilogrammes during the 14 week treatment.

To make this more impressive, there were no dietary restrictions during the trials. Among other effects, Tesofensine blocks reuptake of the neurotransmitter dopamine, which is proven to be involved in satiety (the sense of feeling full while eating). Having seen a partnership deal with the German pharmaceutical company Boehringer fall through because of the Phase IIb failures in Alzheimer’s and Parkinson’s, Neurosearch decided to test the compound in treating obesity.

Other factors that are known to play a role in overeating are melanocrotins and their receptors (MCRs). Companies like Merck, Amgen and Neurogen (see table) are all working on melanocrotin antagonists to reduce “feeding behaviour” and increase metabolism. But they are all still at either the preclinical or phase I stage.

Food companies also look to cash in

Also getting in on the act is the consumer products giant Unilever. The company has in-licensed rights to use an appetite-suppressant compound developed by the UK company Phytopharm plc, and plans to use it as a food ingredient. The product, which previously completed Phase II trials as a pharmaceutical, is based on an extract of a cactus plant hoodia gordonii, which grows in the Kalahari Desert in South Africa. Phytopharm’s research into the drug was prompted because the San people who live in the Kalahari chew the cactus to suppress their appetites

While the search for anti-obesity drugs continues, uptake of bypass and gastric banding surgeries is increasing dramatically. “We estimate that this market was worth $84.1m in Europe in 2005,” says Kavitha Ravikumar, healthcare analyst at Frost & Sullivan. She says the growth rate is around 10-10.5%.

“But although these surgeries are 75% successful, when there are complications they are terrible” Which is why non-invasive devices like intragastric balloons and stomach pacers, which use nerve stimulation to reduce appetite, are expected to become more popular.

Company	Product	Mode of Action	Phase
Sanofi Aventis	Acomplia	CB1 antagonist	Launched (rimonabant)
Alizyme	Cetilistat	Lipase inhibitor	about to start Phase III
GlaxoSmithKline	181771	small molecule cholecystokinin (a gut hormone) agonist	Phase II
Amylin Pharmaceuticals	Symlin (pramlintin)	synthetic analogue of pancreatic hormone amylin	Phase II
Amylin Pharmaceuticals	AC162352 (PYY 3-36)	Appetite control using gut hormone	Phase I/II
Arena	APD 356	5HTC agonist	Phase IIb
Nastech/Merck	Peptide YY3-36	5HTC agonist	Phase II
Metabolic Pharmaceuticals	AOD9604	Fat metabolism (hGH fragment)	Phase II
7TNPharma	TM30339	Appetite control using gut hormone	about to start Phase II
Neurosearch	Tesofensine(NS2330)	triple monanimo uptake inhibition	about to start Phase II
Shionogi	S-2367	CNS antagonist	Phase I
Amgen	AMG 076	MCH-1 antagonist	Phase I
Bayer/Pfizer	BAY 74-4113	DGAT-1 inhibitors	Phase I
Pfizer	-	Appetite control using PPY3-36	due to start Phase I
Neurogen	-	MCH-1 antagonist	preclinical
Kadmus	oleoylethanolamide	cannabinoid modulation	preclinical
Alizyme	-	MCH-1 antagonist	preclinical