Big pharma’s search for effective obesity treatments has proven harder than expected. Biotech is eager to step into the breach with new ideas.
Abstract
Success with weight-loss treatments has been mostly elusive for large pharmaceutical companies. Now the biotech industry is stepping forward, eager to contribute to an area that carries with it the potential for explosive growth.
A spritz a day keeps your fat at bay. For now, it’s not much more than a catchy phrase, but it may well stick if a fledgling biotech company succeeds with its obesity research. In this case, the medicine would be made available in the form of a nasal spray that is being developed by Nastech. It’s one of several such efforts by biotech companies, which are working furiously to develop a weight-loss treatment — a goal that has, by and large, eluded their big pharma rivals.
“With obesity, there are lots of potential targets in the brain and the body,” says Steven C. Quay, MD, PhD, Nastech’s chief executive and president, “but my prediction is that you’ll see biotech making more contributions than big pharma in this field.”
THE HESS COLLECTION/THE ISPOT.COM
BIG SPLASH, MODEST RESULT
It’s not that big pharma hasn’t tried. A decade ago, several of the largest prescription drug makers made a splash with a small handful of diet medications. Their products gained plenty of attention, as doctors and fly-by-night clinics began dispensing prescriptions to millions of Americans who were eager for anything that could shave a few pounds off their frames. But the effort largely failed.
“There’s going to be an increasing debate about whether treatments should be covered by health plans,” says Daniel Bradbury, COO at Amylin Pharmaceuticals, a biotech in San Diego that is developing an injectable compound to fight obesity. “Treatments will probably be covered, because morbid obesity reduces life expectancy.”
PHOTOGRAPH BY ROBERT BURROUGHS
Wyeth withdrew the notorious fen-phen combination because of evidence of serious heart and lung risks. David J. Graham, MD, MPH, of the Food and Drug Administration’s Office of Drug Safety, recently testified before a U.S. Senate committee and called sibutramine (Meridia), from Abbott Laboratories, one of the most troubling drugs on the market. Although these two drugs, which manipulate appetite signals sent to the brain, work differently from Roche’s orlistat (Xenical), a fat blocker, patients taking orlistat also reported side effects, namely gas and an oily discharge.
Beyond issues related to side effects, these pills had something else in common — an inability to generate a weight loss of more than 5 percent to 10 percent, a modest result by most standards. The products emerged just as scientists were discovering well-publicized insights into the causes of obesity, but these drugs were anything but magic.
Ten years later, there’s heightened awareness in the medical community about the dangers of obesity and understanding of the utility of any treatment that can make a difference. Yet obesity rates continue to rise. The result is that more people are suffering from diabetes and cardiovascular problems, which saps productivity and strains the healthcare system. One estimate has it that the problem accounts for $100 billion of the nation’s $1.8 trillion in healthcare spending each year. Put aside the puns — the problem is huge; about a third of U.S. adults are considered obese.
“There are a great many paths to obesity, including factors in our environment,” says Kelly D. Brownell, PhD, from Yale, where he is professor and chair of psychology and professor of epidemiology, as well as director of the Yale Center for Eating and Weight Disorders. “Some people eat for psychological reasons, others for cultural or biological reasons. I hope I’m wrong, but to expect a drug to work may be too much to wish for.”
But wish they might.
Biotech and big pharma, collectively, are pouring millions of dollars into obesity research. This area represents a tremendous money-making proposition for these companies, says Gbola Amusa, MD, CFA, a pharmaceutical-industry securities analyst at Sanford C. Bernstein & Co.
Look at it this way: if the atorvastatin (Lipitor) cholesterol pill could chalk up $12 billion in sales last year, according to IMS Health, a market research company, imagine how many times a useful diet drug would ring the cash register. All one needs to do is develop a treatment that yields substantial weight loss and minimizes side effects. “In the last 20 years, there’s always been a promising drug —but many didn’t work out,” says Amusa. “This speaks to the difficulty with obesity; the etiology is complex.”
Amusa points out that modifying the risk factors associated with obesity is key, as obese people without risk factors live long lives.
Before any biotech can grab the brass ring, though, one big pharma hopes to stake out a market-leading position. Sanofi-Aventis is in the final stages of testing rimonabant (Acomplia), designed to work by blocking a receptor in the brain that responds to marijuana. In other words, the drug would tell the brain not to respond to something pleasurable, such as food.
Whether this will amount to a breakthrough remains to be seen. A recent study of rimonabant found that patients lost twice as much weight as those on placebo. Moreover, nearly 60 percent of rimonabant patients lost more than 5 percent of their initial body weight, compared with only 23 percent of those given a placebo. Even so, a 5 percent weight loss isn’t very much.
“We haven’t broken the 10 percent barrier. We’re just not seeing that yet,” says David Cummings, MD, associate professor of medicine in the division of metabolism, endocrinology, and nutrition at the University of Washington. “So I think it’s likely that we’ll have to use more than one medical treatment to combat obesity.”
Typically, injectable proteins or peptides can cost several thousand dollars a year. So, it all depends on who pays.
— Jack Lief, Arena Pharmaceuticals
ENTER THE BIOTECH COMPANIES
It’s certainly possible that Sanofi-Aventis will soak up many millions of dollars that are just waiting to be spent by overweight people. But if the medicine has limited use, the need for still other treatments will beckon. And given the enormous health issues caused by obesity, managed care providers are expected to be more willing to pay for truly useful medicines.
“There’s going to be an increasing debate about whether treatments should be covered by health plans,” says Daniel Bradbury, COO at Amylin Pharmaceuticals, a biotech in San Diego that is developing an injectable compound to fight obesity. “I think treatments will probably be covered, because morbid obesity reduces life expectancy.”
These treatments aren’t going to be available anytime soon, however. Like Nastech’s spritz and Amylin’s injectable, the biotech companies still are researching their large molecules. The issue here is twofold —identifying the best pathways to attack the urge to overeat and, then, developing the most effective and efficient way to deliver such treatment into the body.
Many of these companies are chasing peptides and proteins. Amylin, for instance, is developing pramlintide (Symlin), a synthetic analog of human amylin, which is a naturally occurring hormone that is made in the beta cells of the pancreas. Last year, the company reported that obese patients in a phase 2 study achieved clinically and statistically significant weight loss when given the injectable. Nastech, meanwhile, calls its compound PYY, a hormone that is made in the small intestine and is sent to the brain to signal a feeling of fullness. The company believes that obese people make less of this hormone than, say, skinny people. In other words, obese people may be getting a weak signal about when it’s time to stop eating.
A study published last year in the New England Journal of Medicine found that after receiving an infusion of the hormone, obese people ate about 30 percent less food at a buffet luncheon than lean patients. Still, it’s not yet known whether the treatment would help a person keep weight off over a longer time period. Nonetheless, Nastech has partnered with Merck, which has taken over development and testing of the treatment. As part of the deal, Nastech can receive up to $341 million, based on approvals and sales targets, not to mention sales royalties. Although Merck is developing several obesity compounds, the deal signals big pharma’s willingness to rely on biotech for success in treating obesity.
“There are an increasing number of biologics like PYY out there,” says David Moller, MD, vice president of metabolic disorders at Merck Research Laboratories in Rahway, N.J. “The PYY concept is intriguing. There’s some evidence it works in humans. There’s also controversy over efficacy in rodents, but the real question is long-term human efficacy.”
Whether biotech ultimately will outperform big pharma in discovering new anti-obesity therapies is uncertain. “The floor is to look at the existing drugs and develop something that produces at least a 5 to 7 percent weight loss versus a placebo,” says Moller. “In general, the advantage of the biologics approach is that it can more rapidly identify an agent that can be used clinically. On the other hand, there are some limitations: injectables, which are less convenient and can, in some cases, cause allergic reactions, may also need to be taken two to three times a day — and the cost may be greater.
“As far as we know, nobody has got anything that works like gang-busters in humans. Obesity is an intrinsically difficult area. There really hasn’t been a lot of time devoted to the problem. It’s only since the mid ’90s that society and industry have fully appreciated the health consequences. Though the pace of scientific discovery grew in parallel with a recognition of the problem, we didn’t have many viable ideas until the last decade,” says Moller.
This explains why big pharma has largely spent the past few years on the sidelines, although Glaxo-SmithKline did try to develop a compound that recently failed. And Johnson & Johnson has agreed to invest up to $60 million in Adipo-Genix, a biotech based in Boston. Still, this isn’t much of a track record for an industry that touts its ability to discover breakthroughs.
“Big pharma would rather pay a lot of money for something where the risk has been rung out of it,” says Jack Lief, chief executive of Arena Pharmaceuticals in San Diego. “As a result, we’re talking to many companies. Getting a partner is very easy. But there aren’t a lot of targets out there that are compelling.” As Lief sees it, big pharma is right that proteins and peptides have some drawbacks — especially manufacturing issues, consumer convenience, and the ultimate cost to patients. As it happens, Arena is developing a small molecule that would activate a receptor in the brain called 5HT2C.
“There are,” says Lief, “many redundant mechanisms. The key is to come up with something safe and well accepted that also results in a significant weight loss. But, typically, injectable proteins or peptides can cost several thousand dollars a year. So it all depends on who ends up paying for it. I think health plans will look at costs and alternatives — a pill versus five times as much for a spray.”
Another biotech working on a small molecule is Palatin Technologies. The Cranbury, N.J., company is targeting melanocortin receptors, which control endocrine functions. In a recent rat study, the compound reduced food intake and body weight while improving metabolic parameters.
“The problem with most drugs so far ... [is that] they play with brain chemicals involved in things beyond body weight control,” says David Cummings, MD, of the University of Washington. “You can’t push the dose without inducing side effects.”
Similarly, Alizyme is banking on a small-molecule approach. The company, which is based in Cambridge, England, is working on a compound akin to Roche’s orlistat in that the pill has a comparable mechanism of action. Called ATL962, the compound works by blocking the digestion of fat, therefore reducing calorie intake.
So far, the results of a study involving 370 patients found that they experienced the usual weight loss of 5 percent to 10 percent, which occurred over three months. But they suffered fewer side effects, according to Richard Palmer, chief executive and director of research and development at Alizyme, in the United Kingdom.
“If you look at what’s been researched up to now, many of the drugs in late-stage testing were thought up years ago,” says Palmer. “The newer targets will appear thanks to the genome. But it’s still early. We’re really in what I call the stamp-collecting days. And, of course, early-stage testing is fraught with failure anyway. It’s a very challenging problem.”
Like other researchers, he agrees that it’s more than likely that a successful obesity treatment will have to target more than part of the body at once. While it would be convenient to say that a business strategy hinging on a combination cocktail makes room for more players, experts suggest that there really is no choice — given the complexity of the problem.
MULTIFACETED CHALLENGE
In part, the reason can be traced to lifestyle evolution. Many years ago, body weight was suited for life on the plains, in the forest, or wherever humans lived that required constant physical activity to satisfy basic needs. But with lifestyles that include high-caloric diets and that leave little time to burn the calories off, consumers are eating more than they actually need. And putting a stop to that is a Herculean task, according to University of Washington’s Cummings.
“This is a control system with six to eight different and important prongs,” he says. “The problem with most drugs, so far, is that they’re often discovered by chance or they play with brain chemicals involved in things beyond body weight control. So, you can’t push the dose without inducing side effects.”
That’s what happened to Regeneron Pharmaceuticals. The Tarry-town, N.Y.-based biotech was developing a compound called Axokine, which is a genetically engineered version of a protein that told the brain to stop eating. But the research was stopped in its tracks two years ago after patients developed antibodies — and that ended the compound’s effectiveness.
Between such failures and the excruciating amount of time needed to develop the latest round of compounds, some experts say that a more organic approach to weight loss is needed. The litany is familiar — a medical treatment, plenty of exercise, and a change in diet. Relying on medicine, even a biotech product that targets the brain still may not be enough, some say.
“I’m not saying that a biotech drug won’t be helpful, but we won’t find a magic answer. It will have to include the environment — making personal changes,” says Cathy Nonas, MS, RD, CDE, who directs the diabetes and obesity program at North General Hospital, in Harlem, N.Y., and is the author of “Managing Obesity: A Clinical Guide.”
“For now, I think it’s just going to be very hard to find a single biotech treatment that will work for a majority of people. And here’s a thought to keep in mind — even the buzz about this new spray suggests some challenges. What if the food tastes terribly of the spray? Will people stop eating, or stop using the spray?
“That’s why I say, the more tools we have, the better.”
Of course, there are other reasons that a cocktail is likely. Some people are obese — defined as a body-mass index above 30. Then there are those who are morbidly obese. And some treatments may work differently in men than women, or they may prove more effective in younger than older folks.
As a result, some researchers say that big pharma and biotech both will address obesity, especially as the amount of partnering continues to increase — a trend that reflects the need among big drug makers to beef up their pipelines in a number of key therapeutic areas.
And given the need of these big drug makers to come up with big winners as soon as possible, it’s more likely that patients will see small molecules leading the way. The genome may yield some ways to develop targets that work very well for certain subsets of people. But that day is not yet here, and big pharma wants whatever works as soon as possible.
“The key is to find molecules that regulate body weight and hit them hard,” says Cummings. “I consult for big pharma, and they have lots of targets — which is why I don’t see biotech as a separate piece to the puzzle. They work together. But I’d still put my money on small molecules, because they offer the most interaction with receptors that are druggable.”
“We have a systemic agent, not an oral agent,” says Roy Levitt, MD, CEO of Genaera, a biotechnology company based in Plymouth Meeting, Pa. This small molecule, trodusquemine, works independently of most of the reported appetite-controlling brain pathways and has activity in the brain and peripheral tissues.
Still, as Amylin’s Bradbury points out, small molecules cannot tackle all potential causes for obesity. Nonetheless, if one wants a pill, it has to be a small molecule. The pharmaceutical industry thus faces a quandary, and so, it must push ahead with biotech alliances. It’s a wedge that biotech executives hope to exploit.
Says Bradbury: “This is truly the challenge — and the opportunity — facing our industry.”