After years of anti-obesity disappointments, Orexigen's Contrave, Vivus's Qnexa and Arena's lorcaserin stand on the verge of being filed with the US FDA. Professor Michael Cowley, inventor of Contrave and former chief scientific officer of Orexigen, speaks with Scrip's Asher Mullard about his views on the obesity field.

Obesity is different things to different people. For many obese people it is a burden, for doctors it’s a health risk and an unserved medical area. For companies it is a huge commercial opportunity. A Canaccord Adams analyst recently speculated, for instance, that a drug that captures 1% of the market share could achieve $1 billion in sales.

For Professor Michael Cowley, a physiologist at the University of Monash in Australia, obesity has fuelled a fruitful research career. For over 10 years he has studied the molecular underpinnings of the condition and, in the process, invented a new anti-obesity combination therapy – Orexigen's Contrave (bupropion plus naltrexone).

Having spent years as the chief scientific officer at California-based Orexigen – the company championing Contrave – he stepped down last year to return to his physiology lab at Monash University in Australia. There, he remains focussed on obesity, potential treatment options and the future of the field.

obesity as addiction?

While obesity is considered by some to be a moral failing, Professor Cowley argues that it is in fact a disease with biochemical, physiological and neurological underpinnings. For instance, he says, accumulating evidence suggests that obese individuals suffer from food addiction. Obese people who are shown their favourite food demonstrate the same pattern of neuronal activation as drug addicts who are shown their favourite drug. "This suggests to me that there really is a neurological basis," he says. "It's not just I like food so I'm going to eat it – there is a biological difference".

Consequently, he argues, if we are prepared to accept drug addiction as a disease for which individuals can seek medical intervention, then obese individuals should recourse to therapeutics as well.

Moreover, doctors and health policy experts have been urging citizens to exercise and watch their diets for decades, but obesity rates have largely continued to increase. Therapeutics, he says, could therefore represent a way to reverse the trend.

This is not to say that drugs alone can provide the solution. "My hope is that by providing a little bit of drug therapy we can get patients to go for a walk as well," he says. "If you can use behavioural therapy to drive weight down and then maintain that loss with a drug, you'll probably see a greater magnitude of weight loss than that with just stay at home, sit on the couch and take a tablet," he adds.

He adds a further caution. While some argue that anti-obesity therapies will reduce the risks of obesity-associated co-morbidities – such as diabetes, hypertension and cancer – the data remain inconclusive. "I think that's the $64 dollar question," says Professor Cowley. Late stage clinical data suggest that fat fighting treatments can decrease cardiovascular risk factors, he explains, but it will be years before we can conclude that decreased risk factors translate into decreased disease.

"No one's actually proven that pharmacologically-induced weight loss extends life. It's assumed that it will, but that trial hasn't been done."

the conception of Contrave

While anti-obesity drugs are already available, they are neither particularly effective nor as profitable as one might expect them to be given the size of the market. Roche's Xenical (orlistat) – the world's top selling obesity drug according to IMS Health – induces weight loss of only around five pounds and had global sales of $427 million over a recent 12 month period.

In trying to develop a new option, Professor Cowley went back to basics to come up with a rationally designed anti-obesity therapy.

Activated pro-opiomelanocortin (POMC) neurons, he knew, activate the melanocortin system, which regulates energy expenditure and appetite. They also, however, produce opioids that inhibit their own activity, thereby establishing a negative-feedback loop. What if, he wondered, you combine agents that simultaneously activate POMC neurons and inhibit the negative self-regulation?

Enter Contrave, a combination of the dopamine reuptake inhibitor bupropion – which increases dopamine levels and thereby activates POMC neurons – and the opioid-antagonist naltrexone.

Notably, bupropion has been approved for the treatment of depression and for nicotine addiction, whereas naltrexone is available for narcotic and alcohol addiction. Both components are already available as generics, meaning that they each have established safety profiles.

Doctors could conceivably make up their own home-grown formulation of the product – a problem that has previously affected some combinations, such as the heart failure product Bidil (isosorbide dinitrate plus hydralazine hydrochloride). But the price for Contrave will be "roughly equivalent to what you'd pay, as a co-pay, for the two tablets individually" says Professor Cowley.

Given that obese individuals might also be food addicts, the fact that both components are also approved as anti-addiction drugs could also prove beneficial, he notes.

the competition

After years of disappointments in the field, the past few months have seen a flurry of activity; in addition to Contrave, Vivus's Qnexa (topiramate and phentermine) and Arena's lorcaserin have led the charge, with regulatory filings expected imminently.

Qnexa – which combines the generically available appetite suppressant phentermine with the anti-epileptic and anti-migraine product topiramate – is favoured by many as the front runner. In recently completed Phase III trials, it induced weight loss of 18-37 pounds (7-14% of body weight) on a per protocol basis (scripnews.com, September 11th, 2009).

By contrast, Contrave induced weight loss of on average of 17lbs (8% of body weight) in completers in Phase III trials (scripnews.com, July 22nd, 2009). And Arena's lorcaserin – which, like Contrave, activates POMC neurons – induced weight loss of 17-18lbs (7-8% of body weight) on a per protocol basis (scripnews.com, September 22nd, 2009).

To achieve US FDA approval, 35% of treated patients must lose at least 5% of their body weight, and that group must include at least twice as many patients as the number who achieved similar weight loss on placebo. Alternatively, the therapy must induce at least a 5% placebo-corrected weight loss.

In Phase III trials, Qnexa has met both guidelines, Contrave met the first in two obesity trials but the second only once, and lorcaserin has yielded even more mixed results, with some analysts arguing that it may have missed both thresholds in one trial.

All three options will also have to meet stringent safety requirements, particularly as they may be used on a chronic basis and across a broad population base. Indeed, safety issues have been a major hurdle in the past. Sanofi-Aventis's Acomplia (rimonabant), for instance, was approved in 2006 in the EU but was subsequently withdrawn after being linked to psychiatric side-effects such as depression, never achieving US approval.

If deemed safe and effective enough by the agency, however, Professor Cowley says that there will be "plenty of space" for the approved products.

For one thing, he says, obese patients don't seem to tolerate side effects very well. Indeed, in the clinical trials of the leading as-yet unapproved obesity drugs, drop-out rates ranged from 30-50%, although these were not necessarily due to adverse events. While high drop out rates are by no means good news for anybody, they suggest that obese patients may need a selection of effective options so that they can find a therapy that works for them.

"I think it's important that patients have a series of different and perhaps complementary choices," he says.

top tips

Behind the leading three candidates lie a number of other potentially promising therapies. Two other drugs – Novo Nordisk's Victoza (liraglutide) and Alizyme's cetilistat – are in Phase III trials, 25 are in Phase II trials (see table below) and 20 are in Phase I, shows the Pharmaprojects database.

For Professor Cowley, the most promising of these is Amylin's hormone combination metreleptin plus pramlintide, which is in Phase II development. "You get leptin-induced weight loss even though leptin causes nothing and pramlintide causes nothing," he says. "It's the therapy that excites me the most."

He also has some more general suggestions for the future of anti-obesity research. “For me the exciting frontiers are trying to understand the neurological basis of these diseases and develop therapies that target that.” And a growing body of evidence is implicating epigenetics and histone deacetylases with obesity, he says, suggesting another avenue for research.

Back in his laboratory at Monash University, he has set his sights on better understanding what links obesity with diabetes and with heart disease, and on examining drug-induced weight gain, all of which he hopes could result in further therapeutics.

“It's a huge thrill to see something you've invented go through Phase III trials,” he says. “To do it again would be a huge kick.”

Drugs in Phase II trials as anti-obesity therapies