One Pill Makes You Small

As recently as three years ago, pharmaceutical companies dared to believe that obesity drugs would become the next mega-blockbusters. Not only would Sanofi-Aventis' rimonabant (branded Acomplia in the EU and Zimulti in the US) begin to turn the tide of a worldwide obesity epidemic, but the new drug—and the other CB1 cannabinoid receptor blockers sure to follow—would also enable these drug giants to survive the expiration of their most valuable patents in 2010 and beyond. The media portrayed the CB1 receptor antagonists as the next wonder drug, promising to quell overeating, arrest the abuse of nicotine and alcohol, and even increase rates of "good" cholesterol.

But by late last year, pharma's hopes for rimonabant had been dashed. As reports of depression and suicide risk accumulated, the drug was mired at FDA, then yanked from the EU market, and finally withdrawn from clinical trials worldwide. In fact, rimonabant was being mentioned in the same breath as Fen-Phen, the diet drug that nearly brought down American Home Products (now Wyeth) in 1997.

In November 2008, just one day after Sanofi abandoned its rimonabant obesity program, Pfizer stopped Phase III development on otenabant, its own CB1 receptor antagonist; AstraZeneca, Merck, and Solvay also pulled the plugs on their own versions. In all, 27 obesity drug candidates were shelved during rimonabant's downward spiral in 2007 and 2008, according to Jon Angell, author of Datamonitor's July 2009 report, "Obesity: The $11 Billion Market That Never Was." Angell estimates that pharma's investment in those aborted clinical trials equaled the entire value of the obesity drug market during that time—about $1.1 billion.

Six Obesity Pipeline picks

In the wake of rimonabant, drugmakers have taken a conservative approach to weight-loss therapies. Instead of radical new mechanisms, the late-stage obesity pipeline now features combinations of already approved drugs and focuses on incremental improvements on drugs that previously failed. None of the half-dozen products likely to seek FDA approval over the next few years promises anything like the $2 billion–plus annual global sales once projected for rimonabant. In fact, the Datamonitor report predicts that most will be lucky to peak at $200 million in worldwide revenue, though other analysts are considerably more optimistic about the drugs' odds for success in this hugely underserved population.

The Big Fat Obesity Market

With 125 million overweight or obese adults in the big seven drug markets, obesity drugs take aim at one of the largest groups of chronically ill patients ever identified. The National Institutes of Health and the World Health Organization define overweight individuals as those with a body mass index (BMI, or weight in kilograms divided by height in meters squared) of 25 to 29.9, and obesity as a BMI of 30 or greater. (These numbers are sometimes revised downward in Asian countries.) And the overweight adult population in the US, Japan, France, Germany, Italy, Spain, and UK is projected to jump to at least 143 million by 2018, according to the Datamonitor report.

Obesity-related costs to the US healthcare system have doubled in the last decade to as much as $147 billion, according to a recent study commissioned by the Centers for Disease Control and Prevention (CDC). Obesity is now responsible for 9.1 percent of annual medical expenditures, compared with 6.5 percent in 1998, the study showed. The 26-year longitudinal Framingham Heart Study showed that obesity was a "significant independent predictor" of cardiovascular disease, especially in women. Obesity is also a leading risk factor in type-2 diabetes, as well as sleep apnea and some forms of cancer, according to the CDC. An obese American racks up $1,429 more—or 42 percent more—in medical bills each year than a person of normal weight. Obese Medicare recipients' prescription drug costs exceed those of normal-weight individuals by roughly $600 per year, the study found.

In a thought experiment, Datamonitor calculated that if just one in four of those adult patients was treated for one year with a dollar-per-day product, the market would have totaled $8.6 billion in 2008, increasing to $10.5 billion in 2018. "It is impossible to ignore this space," says Adam Cuttler, managing director and senior biotech analyst at Canaccord Adams. "The market is just too large. Big companies are desperate for new compounds to launch, especially those that could achieve blockbuster status." But at present, combined revenues of the three top-selling obesity drugs—Orlistat, sibutramine, and sertraline—seem stuck at about $550 million per year.

Each of these drugs is saddled with tolerability issues. Roche's Xenical (orlistat), one of the few weight-loss drugs whose mechanism of action is not focused on the central nervous system (CNS), prevents the absorption of fat in the intestines. But it leads to uncomfortable gastrointestinal side effects such as oily stool, flatulence, and spotting on underwear. The drug got an initial bump in sales when GlaxoSmithKline began marketing it as over-the-counter Alli in the United States in 2007, and the firm has sold it OTC since January in the EU. "People may use it broadly for weight loss," says Peter Chang, MD, an analyst at Sagient Research Systems in San Diego. "But I don't know that the over-the-counter drug will help people who are obese become not obese."

Meridia (sibutramine), by Abbott, has helped patients lose weight, according to Chang, but it has also been linked to high blood pressure. Since many overweight or obese people already face cardiovascular risks, this side effect has been a red flag against widespread use. Pfizer's antidepressant Zoloft (sertraline) is often prescribed for short-term, off-label use, but obese people need help over the long haul, and no long term trials have been conducted.

Yet if consumers aren't exactly clamoring for the obesity drugs, there is clearly a demand for weight-loss products. Weight Watchers branded products and services alone net an estimated $4 billion per year, according to the company.

Science and the CNS Connection

Researchers have acquired a growing appreciation for the complexity of the human appetite, which is backed up by redundant CNS pathways to guarantee that the body "desires" the calories it needs to survive. "The animals that can be convinced to voluntarily eat so little that they actually lose weight just through modifying a single biochemical pathway are all dead," wrote researcher Derek Lowe in his blog, In The Pipeline. "Our ancestors were the other guys."

Any CNS-based drug that helps people lose a significant amount of weight is likely to reach into overlapping CNS pathways, which in turn could create hard-to-predict safety hazards. The CB1 receptor antagonists would seem to be a case in point. Most of the drug candidates in Phase II or III attack one or more "upstream" target in the central nervous system, such as reward centers like serotonin receptors.

"The goal is always to go as far upstream as possible to control appetite," says Donny Wong, an analyst at Decision Resources. "But when you go so far upstream, the parts of the brain that control appetite also control many other functions as well."

In fact, the CNS approach is littered with failures. A decade before rimonabant was taken off the market, American Home Products' (AHP) highly effective Fen-phen was linked to high rates of heart valve failure and pulmonary hypertension following its extremely rapid uptake among an estimated 2 million Americans, most of whom were women aged 45 and under. Fenfluramine—one half of the combination drug—was taken off the market in 1997. AHP had been riding high on a drug that helped patients drop as much as 15 percent of their body weight. All of a sudden, the company was forced to settle a mammoth class-action lawsuit for about $3.75 billion.

In the decade since the Fen-phen debacle, other mass-marketed blockbusters such as Vioxx and Avandia were implicated in large numbers of injuries or deaths, and FDA has come under intense scrutiny from Congress and the media for failing to adequately monitor the safety of the drugs it approved. Rimonabant, widely viewed as the main driver in the giant merger between Sanofi-Synthélabo and Aventis in 2004, arrived at FDA in the midst of this turmoil two years later.

Rimonabant, R.I.P.

Sanofi's drug had seemed simple enough: It was designed to flip a common experience of cannabis smokers on its head. When cannabinoids bind to the CB1 receptors in the brain, the user experiences a sudden burst in appetite—commonly called "the munchies." By blocking the receptors' ability to bind the body's internal cannabinoids, known as endocannabinoids, the drug would reduce hunger and help obese people resist the temptation to overeat. Sanofi's new medication did meet its weight-loss end points; according to Chang, rimonabant trial subjects lost an average of 4.5 percent and 4.7 percent (according to dosage) compared to placebo in different Phase III trials,

The drug was launched in 18 EU countries, beginning with the UK in June 2006, under EMEA's conditional approval. But reports of psychiatric side effects limited its use, excluding patients with major depression. According to Wolters Kluwer, in May 2008, as adverse-events reports piled up, the European agency updated the label to indicate that depression may occur as a side effect in patients with no symptoms other than obesity. And more trouble surfaced in the US. After FDA issued an approvable letter in February 2006, the agency's advisory board voted 14-0 against recommending approval just four months later, stating that Sanofi had failed to provide sufficient safety data to demonstrate that rimonabant's benefits outweighed its risks. "The potential market for this drug and the continued uncertainty about its risks, both known and unknown, lead to our concern about the use of this drug in the general population," FDA staff medical reviewer Amy Egan told The New York Times. Egan's analysis indicated that the drug doubled a patient's risk of problems like anxiety, depression, aggression, and psychosis, while other data showed a rise in suicidality, including three suicides during clinical studies, according to the Times.

Despite some marketing successes, particularly after South American launches, the damage to the drug's reputation was generally seen as irreversible. In October 2008, EMEA suspended Sanofi's authorization to market Zimulti. On November 5, 2008, the company suspended all clinical development of rimonabant worldwide.

FDA is all but certain to maintain its careful monitoring of safety signals for obesity drugs. Cuttler, for one, expects the agency to extend the tighter cardiovascular standards for diabetes drugs to obesity therapies as well. But the agency's new Risk Evaluation and Mitigation Strategy (REMS) framework promises to enable drugmakers to begin working with national health authorities to develop strategies to report and control risk as they seek NDAs.

For CNS drugs being tested in obesity trials, new methods of identifying suicidality and other psychiatric risks may provide not only more accurate safety data, but also a better shot at approval. "Whether or not these drugs cause a risk is the critical question we have to answer," says Kelly Posner, a child psychologist and research scientist at Columbia University, who helped develop the new data-collection tools. "But up until now, none of the studies were set up to answer that question."

According to Posner, who helped FDA classify the suicide signals that sunk rimonabant, the data were troubling. Based on retrospective adverse-event reporting, they were not only inconsistent and poorly defined but tended to inflate the incidence in the drug group, because patients on a drug typically have more side effects and therefore more opportunity to talk to doctors about suicidality. This unbalanced counting problem is called "ascertainment bias."

The new methods correct this problem by prospectively monitoring a trial's participants—asking every patient across drug and placebo the same pre-determined questions on every visit. "We have obesity studies where, when we relied on spontaneously generated adverse events, there were approximately 450 [suicidality] hits," Posner says. "When we relied on prospective monitoring, there were about 12." (See "Should Rimonabant Get a Second Chance?").

The Five Percent Solution

FDA requires that an obesity drug to meet either one of two efficacy requirements. The top-ranked criterion is that patients on treatment lose an average of five percent more body weight than patients on placebo. Failing that, an NDA can win approval if it achieves what is referred to as "categorical efficacy," requiring that at least 35 percent of subjects in the drug group lose more than five percent of their body weight; this percentage must then be at least twice the percentage of those who lose more than 5 percent in the placebo group. In other words, if the drug does not work for everyone, it at least works well enough for a sizeable population.

While a 5 percent loss of body weight may not make a cosmetic difference for most obese people, it can provide significant health benefits, particularly by improving blood pressure, cholesterol, and blood glucose levels. Yet what's sufficient for FDA approval may not win over large numbers of doctors. "We've done some work surveying physicians, and they really want a drug to be in the double-digit weight-loss range," Wong says. Still, some prescribers are likely to take the chance that a patient may respond very well to a specific drug. Others may prescribe a drug for the metabolic benefits of modest weight loss.

Inside the Phase III Pipeline

The three Phase III candidates in the pipeline offer fairly modest weight loss; some miss the top 5 percent mark, but all promise to meet at least the secondary criterion. This overall middling efficacy, combined with the massive size of the market demand, makes winning a "race to market" less important than in any other therapeutic areas.

"The different drugs are close enough in time, and there is such a large, undeveloped market that no drug will have a huge first-to-market advantage," says Chang. "Being first won't put much of a restriction on subsequent drugs. Although if the first one is tolerable, the patients who go on it may not want to switch."

Qnexa, by Vivus, is a combination of two widely prescribed drugs available as generics: phentermine, an amphetamine derivative that was the safer half of Fen-phen; and topiramate, an anti-convulsive medication approved for epilepsy and used off-label for binge eating. Taken together for 28 weeks in a Phase III study, the two drugs (15 mg phentermine and 92 mg topiramate) dropped patients' weight 7.5 percent compared to placebo. Cutting the dose in half resulted in a 6.8 percent weight loss, according to a Vivus press release from May 2009.

The drug is likely to face some skepticism among primary-care physicians, according to Wong, as few may be comfortable with prescribing an epilepsy treatment for weight loss. Vivus expects to file an NDA for Qnexa by the end of 2009. Approval could come as soon as July 2010, according to Sagient's data. InThought, a unit of Wolters Kluwer, forecasts revenues of $522 million for Qnexa in 2016, while Sagient sees worldwide sales of $750 million the same year.

Contrave, by Orexigen, is another novel combination of two widely prescribed generics: the antidepressant bupropion is a dopamine and norepinephrine re-uptake inhibitor; Naltrexone is an opioid receptor antagonist used to treat alcohol dependence. Each has demonstrated modest weight-loss effects. "They show some synergies," Wong says. "Weight loss is about five to ten percent—nothing fantastic."

Contrave reported Phase III data in July. While the drug failed to achieve the primary end point of 5 percent weight loss compared to placebo, it did meet the FDA's categorical efficacy requirement. The percentage of patients in the drug group who lost at least 5 percent of their body weight was three times that in the placebo group—55.6 percent to 17.5 percent at 28 weeks; longer trial arms showed similar results. More important for reimbursement, the drug documented statistically significant improvements in cardiovascular risk factors. Orexigen expects to file an NDA in the first half of 2010, according to a company press release.

"Contrave has the best chance of approval." Cuttler says, noting that regulators are already familiar with the safety profile of both drugs in the new therapy. In 2016, Sagient predicts revenues of $406 million, compared to InThought's rosier $673 million.

The most ambitiously conceived drug in Phase III is Lorcaserin, by Arena Pharmaceuticals. The San Diego–based biotech designed a drug that closely resembles fenfluramine—the half of Fen-phen that damaged heart valves and was banned by FDA—but it appears to boast greater selectivity and therefore a much cleaner toxicity profile. "Arena is trying to make a drug that is specific for the [serotonin 2C] receptors in the brain without damaging those [serotonin 2B receptors] in the heart," Wong says.

So far, Lorcaserin's clinical efficacy has not been inspiring, Wong says. It hovers around 5 percent average weight loss. But when the drug works for a patient, it works well. About 48 percent of patients on the drug lost more than 5 percent of their body weight compared to about 20 percent for placebo. This satisfies FDA's categorical efficacy criterion. Additional Phase III data is due this month. Arena's latest press releases do not give a date for the NDA filing, but some analysts see it coming as early as December. InThought sees $849 million in revenues for the drug in 2016, while Sagient forecasts just $346 million the same year.

One of the main selling points for these drugs is the pent-up demand in a market that has not seen a new weight-loss drug since Glaxo's splashy OTC launch of Alli two years ago. "Doctors will prescribe them because their patients want a drug therapy, and there are not a lot of other options," Cuttler says. He also expects doctors to try newly approved obesity drugs in combination with diabetes drugs in the hope that it causes enough weight loss to improve cardiovascular health.

Some analysts, notably Datamonitor's Angell, are less optimistic: "The obesity market peaked in 2007 at about $600 million instead of $8 billion," he says. "Do we really think that by offering an incremental change in what we already have, we will get any closer to an $8 billion market?"

The Midstage Crop

The most exciting drugs in development, Wong believes, are those in Phase II, even though preliminary revenue forecasts currently lag behind the projections for Phase III candidates. Wong identifies three compounds that are showing the double-digit weight-loss percentage that prescribers want.

Tesofensine, by Neurosearch, a Danish biotech, is a dopamine, serotonin, and norepinephrine re-uptake inhibitor originally in development for Alzheimer's and Parkinson's diseases. The drug boasts weight-loss efficacy data of 29 to 33 pounds. Patients in typical obesity studies average 220 pounds, according to Wong. Tesofensine's performance rivals the efficacy of Fen-phen, and outstrips the weight losses achieved by either rimonabant or sibutramine. The triple mechanism of action, however, may present serious side-effect issues in large-scale trials.

Empatic, by Orexigen, is a combination of bupropion (the antidepressant in Orexigen's Contrave) and zonisamide, an antiepileptic drug. The combination has demonstrated a weight-loss average of 13 to 14 percent in 48 weeks. Although Wong likes the efficacy of the drug, he thinks regulators and prescribers will be wary of the anti-epileptic agent, as with Qnexa.

Wong's pick of the litter is Amylin Pharmaceuticals' combination of pramlintide, a glycemic control drug for insulin-dependent diabetics, and metreleptin, recombinant human leptin. Leptin is a messenger molecule produced naturally by a fat cell that tells the brain how much energy is stored inside the cell. When the brain perceives leptin, it believes it has sufficient energy stores and shuts down the appetite. Amgen began to develop a leptin drug in the 1990s; although the drug worked well in mice, it was ineffective in obese humans. The problem, Wong explains, was leptin resistance: Obesity appears to desensitize the brain to leptin, even when it is circulating in high quantities. Enter pramlintide, which apparently restores the brain's response to leptin. "And if you administer this combination with extra leptin, you can actually decrease appetite," Wong says. In a 28-week Phase II dosing study, patients with a starting BMI less than 35 who were treated with the highest dose lost 11 percent of their baseline weight, compared to 1.8 percent for placebo. InThought sees a 2013 launch with revenues reaching $389 million by 2016. Sagient sees a 2014 launch with $102 million in revenues by 2016.

The Tough Take-Home

It's far from certain which, if any, of these six drugs FDA will ultimately approve. All face unique safety hurdles, and it is unclear how high agency standards will be in the coming years. Big Pharma companies are not rushing to partner with any of the small companies that have drugs in Phases II and III, though all will likely need to make deals to fund further large-scale clinical trials or to access sales and marketing forces at launch time.

This situation is no surprise, says Cuttler. In the years when rimonabant looked like the next great blockbuster, most big companies were working on competing obesity agents, and had little incentive to acquire new ones, especially combinations based on compounds that would go generic sooner than their own candidates. Now, with CB1 receptor blockers out of the clinic (a handful remain in preclinical development), the smaller companies with viable candidates are in the driver's seat. They may choose to wait until their Phase III data is out before signing a licensing agreement, if only to push for a better deal.

If these modestly effective drugs do reach the market, the challenge for drugmakers will be targeting them to the populations where they'll do the most good and the least damage, according to Datamonitor, whose analysts also project the lowest revenues for today's late-stage drug candidates.

In the absence of effective drug therapies—and ignoring bariatric surgery, which is recommended for only the most obese patients—behavioral changes around diet and exercise offer the best chance for countering obesity. But lifestyle improvements, Datamonitor's Angell notes, have generally shown poor results in adult populations. Wong's research shows that most patients fail to stick to diet and exercise routines for more than two or three months at a time.

Yet such lifestyle interventions may prevent young people from becoming obese in the first place. In government-run health systems like that of the UK, the vast majority of money is being put into preventing obesity, not treating it. Regulators in the EU are currently debating tougher food advertising and labeling restrictions, as well as pushing the food and retailing industries to reformulate recipes, cutting back on salt and fat. Advocates in the US are mobilizing around similar goals.

Even if behavioral changes were to take root widely, rates of obesity would likely be slow to change—shrinking only as older obese people die and are replaced by fewer younger ones. A similar process is reducing the number of tobacco smokers, at least in countries with anti-smoking campaigns. This gradual process means that the present obese population—and the giant potential market for new drugs—is almost certain to remain underserved for another generation.

Should RIMONABANT Get a Second Chance?

One top researcher who advised FDA thinks so—and now all obesity drug trials are using her method for measuring suicide risk

BY RON FEEMSTER

Kelly Posner is an FDA troubleshooter for neuropsychiatric data in clinical trials. A child psychologist and research scientist at Columbia University, she gets called when the regulatory agency sees signs of psychiatric risk—particularly suicidality—and needs to make sense out of jumbled trial data. To develop interpretable data from inconsistent reports of adverse events in pediatric anti-depressant studies, she and her colleagues built the Columbia Classification Algorithm of Suicide Assessment (C-CASA). Her team worked through the data sets, classifying each incident as suicidal ideation, suicidal behavior, a bona fide attempt, or a false positive. In the end, they counted half as many actual suicide attempts as the sponsors' own doctors.

FDA called again on the director of the Center for Suicide Risk Assessment when it saw potential risks of suicidal ideation with rimonabant. Posner's group considered a total of 1,201 "patient narratives" from seven rimonabant trials. Using C-CASA, they classified 91 cases as either "possibly" or "definitely" suicidal, but eliminated some because they occurred in study arms without placebo control. The final tally of suicidality cases was 74, with 20 on placebo, 8 on rimonabant 5 mg, and 46 on rimonabant 20 mg; the overall drug-to-placebo ratio was 1.8 to 1. Suicidality was nearly twice as likely in the drug group based on data collected through self-reported adverse events.

Such retrospective studies based on adverse-event reporting could be misleading, Posner contends, because patients in the drug group typically spend more time talking to doctors and have more opportunity to self-report suicidal events than placebo patients. These retrospective studies would be unnecessary if FDA requested prospective monitoring of placebo-controlled trials using standardized language and a universal scale, she argues.

She may have made her case. In June 2006, when Posner presented her findings to the rimonabant advisory committee, she suggested using the Columbia-Suicide Severity Rating Scale, a data-collection tool she used in a National Institute of Mental Health study. "Assessing suicide systematically with a scale is pretty much all upside," Posner says. "Why would you want to set yourself up for a false signal or a false risk or a misleading result by relying on adverse-event reporting?"

Starting in late 2007, FDA began requiring that drugmakers testing specific compounds in a wide range of diseases use the scale in their trials. The instrument has since been translated into 90 languages. "C-SSRS is requested for all obesity trials now," Posner said. "Companies need to understand that it's protective to their medications and their data. When they systematically monitor, they haven't see any risk [of suicide]."

By implementing a prospective and systematic measurement of suicidality, companies can help clarify the causal relationship, if any, between suicidal adverse events and medications. "Association doesn't mean causality," Posner says. "Decreasing false positives and debunking false notions of risk are as important as knowing what risks exist. That gives a fair chance to very important medications."

Posner acknowledges that CNS-based obesity drugs may have unexpected psychiatric side effects because they affect more than one pathway. But the public-health upside of intervening in obesity is so great that she recommends proceeding with drug trials and carefully monitoring outcomes. Even if an effective obesity medication were found to have a risk of suicidal ideation, Posner says, depression and suicidality are treatable conditions. "Everything is about balancing risks and benefits," she says.

Posner, who says that she has never taken a dime in compensation from a drug company or FDA, has worked closely with the agency to come up with simple, low-burden methods to assess neuropsychiatric risks and benefits. "If you had listened to the discussion about rimonabant, you might have heard about 50 neuropsychiatric terms thrown around," Posner says. "What do we actually need to assess? In obesity drugs, it's boiled down at this point to the C-SSRS and the PHQ-9." Patient Health Questionnaire 9 is a nine-question self-report scale for monitoring signs of depression. Most patients can fill it out in the waiting room and score it in 10 seconds. C-SSRS can also be taken as a self-reported telephone interview known as IVR (interactive voice response).

Things might have been different for rimonabant if the Sanofi studies had used Posner's prospective method of measuring suicidality. "The sponsor pulled the drug, not FDA," Posner says. "Rimonabant and the other endocannabinoids are an area with tremendous potential that, because of a lot of different factors, probably hasn't had its fair chance. I definitely think it is not a space that should be given up on."