One Pill Makes You Small - Pharmaceutical Executive


One Pill Makes You Small

Pharmaceutical Executive

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.


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