On June 27, the FDA approved the first new weight-loss drug in 13 years, Arena’s lorcaserin (Belviq). The track record for anti-obesity drugs has not been very good—each has been withdrawn from the market, after approval, due to safety concerns. Why was this drug approved? How long will this one last before being yanked for adverse events?

Let’s look at the background and track record of lorcaserin’s predecessors.

Perspective on the need for weight loss drugs

Why the brouhaha over Arena’s new drug?

According to the Centers for Disease Control and Prevention, more than one-third of adults in the United States are obese, defined as having a Body-Mass Index (BMI) of ­> 35 (30-correction). In the U.S. alone, 78 million U.S. adults are obese; another 34% of adults are overweight > 30 (BMI 25 to 29.9-correction). So 70% of U.S. adults have a problem with weight. Worldwide, CDC estimates 500 million are currently affected. Overweight and obesity constitute the second leading cause of preventable death, after smoking, resulting in an estimated 300,000 deaths per year. The number of obese is expected to rise to 42% by 2030, with an additional 11% prevalence of severe obesity (BMI >40, or ~80+ lbs overweight).

In 2000, consumers spent approximately $35 billion on weight-reduction products and services; it is undoubtedly more now. There is enormously aggressive—and misleading—advertising for these products. The Federal Trade Commission noted that about half of these ads were false.

Annual health-care costs for patients with BMIs of 20 to 24.9 were 20% lower than costs for “overweight” patients with BMIs from 30 to 34.9 and almost 33% lower than for “obese” patients who had BMIs of 35 or more. There has been a steady increase in obesity over the past several decades, though this appears to be tapering off a bit. Finkelstein et al. estimate that costs of obesity may be as high as $147 billion per year, or roughly 9% of U.S. annual medical expenditures. “If obesity were to remain at 2010 levels, the combined savings in medical expenditures over the next 2 decades would be $549.5 billion.”

With such a huge health problem comes a correspondingly large business opportunity. According to Ernest Trent, cited in Bloomberg News, sales for Arena’s new drug may hit $2 billion by 2020.

Even modest weight loss, of 5-10%, is enormously difficult to achieve with diet, exercise, and behavior modification. Yet even that is enough to demonstrate significant health benefits—a reduction in diabetes or cardiovascular disease. Unfortunately, as many of us know all too well, such weight loss is often like a flash in the pan, enticing but all too transient.

One of the problems, to date, is that drugs that have been researched only show this modest benefit of 5% weight loss better than placebo. And the drug efficacy tends to plateau over time. Finally, weight is regained when the drugs are stopped. All of this leads to a lot of consumer and industry pressure to develop and approve new drugs. What often seems to be ignored is the contribution that the food industry makes to the problem through heavily advertised unhealthy offerings.

How obesity drugs work. What are their targets?

There are a number of different approaches pharmaceutical companies are taking to researching and developing drugs for obesity. The bottom line is that you need to “reduce energy intake” or “increase energy expenditure,” a professional way of saying eat or absorb less, or burn more calories through deliberate exercise or revved-up metabolism (thermogenesis). The paths companies are taking to this end are different.

Lois et al. provide a good overview of the physiology, if you are not faint of heart. Briefly, signals from the GI tract control our appetite by working closely with our brains to signal the need for food intake. There are chemical messengers from the upper GI tract (e.g., Cholecystokinin (CCK), secretin and GIP (glucose-dependent insulinotropic peptide or gastric inhibitory polypeptide), lower intestine (Glucagon-like peptide-1), from adipose tissue (leptin) and from the pancreas (insulin). These all communicate with the hypothalamus in our brains, and thus tell us whether to seek food (orexic) or fast (anorexic). For example, ghrelin enters the brain and increases our appetite (is orexigenic), while insulin and leptin do the opposite, having an anorexigenic signal.

Let’s look at where some of the anti-obesity drugs under development act.

Sympathomimetic drugs are related to stimulants. This acts as an appetite suppressant, and causes a feeling of early satiety, or fullness. Side effects include tachycardia (rapid heart beat) and elevated blood pressure. Many also have significant interactions with antidepressants and alcohol.

One member of this class, sibutramine (Meridia), worked by blocking both norepinephrine and serotonin reuptake. Sibutramine has since been withdrawn from the market due to cardiovascular safety concerns—hypertension and myocardial infarction.

Phentermine and diethylpropion, which stimulate the release of norepinephrine, are still marketed, but are indicated only for short term (<12 week) use, because they are classified as Schedule IV drugs, as having the potential for abuse.

The selective serotonin reuptake inhibitors (SSRIs) fluoxetine and bupropion (Wellbutrin), used for depression, have mild weight loss effects as well.

Pancreatic lipase inhibitors or gut absorption

Another weight loss mechanism is by impairing fat absorption and digestion, as is the case with Orlistat (Xenical, Alli), currently the only marketed FDA approved drug for obesity. Modest weight loss has occurred in a number of studies. There have been a number of reports of “fecal incontinence” as well as malabsorption of vitamins. Kidney stones and rare liver injuries have also been reported.

Neurotransmitter receptors

Rimonabant (Acomplia), which worked by blockading the endocannabinoid system, was sold in Europe briefly by Sanofi-Aventis. It was withdrawn because of reports of severe depression and suicide, thought to be a result of drug antagonism at the cannabinoid CB1 receptor in the brain.

Lorcaserin is a novel 5-hydroxytryptamine 2C (5HT2C) receptor agonist developed for obesity treatment. The 5HT2C receptor is concentrated in the central nervous system (CNS) where it regulates feeding behavior. Lorcaserin targets activation of the serotonin 5HT2C receptor.

There are other brain receptors under study as targets for drugs including the gut peptides glucagon-like peptide receptor 1 (GLP-1), Y receptors, ghrelin and melanocortin receptors.

Gut hormone mimetics

Exenatide (Byetta), a drug for diabetes, is an analogue of the intestinal hormone GLP-1, which produces satiety (a sense of fullness) by delaying gastric emptying. Similarly, Pramlintide (Symlin), is an analog of the pancreatic hormone amylin, which also causes delayed gastric emptying. Liraglutide (Victoza, Novo Nordisk), another glucagon-like-peptide-1 (GLP-1) receptor agonist, was approved in 2010 to improve glucose control, although it only reduced “glycated hemoglobin concentration of 0.8 to 1.4 percentage points as compared with placebo.” This seems small benefit to me, given the potential increase in pancreatitis and tumors (the latter in animal studies). Both drugs have weight loss benefits, though their indication is for diabetes.

Cholecystokinin (CCK) is produced in the duodenum (where the stomach enters the small intestine) and jejunum (upper portion of the small intestine) and signals satiety via the vagus nerve. It also delays gastric emptying. So far, no drugs have successfully exploited this mechanism of just stimulating satiety.

Other potential targets include:

Angiogenesis Antagonists (inhibit new blood vessel formation)

Neuropeptide mimetics

Neuropeptide Y (NPY) inhibitors

Adipokine mimetics. Adipokines are proteins secreted by adipose (fat) cells.

Leptin is a peptide (amino acids, protein precursor) in adipose tissue that stimulates the hypothalamus and promotes satiety. Obese patients tend to have high levels of leptin and are “leptin-resistant.”

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Combinations of drugs with different mechanisms of action are sometimes used. For example, Vivus’ QNEXA is a fixed-dose combination of phentermine hydrochloride and an old anti-seizure medication, topiramate.

History of anti-obesity drugs and why they failed

1997 Fen-Phen, a combination of fenfluramine and dexfenfluramine, sold as Redux, was pulled from the market because of causing heart valve abnormalities.

2004 Another, phenylpropanolamine, was withdrawn because of increased strokes. Ephedrine was also banned by the FDA as its amphetamine like action caused high blood pressure and cardiovascular deaths. In 2005, a suit by Nutraceutical claiming that the FDA had wrongly regulated ephedra as a drug, rather than as a food supplement, caused the ban to be lifted. “The judge said the law requires the FDA to prove that a dietary supplement is harmful, rather than requiring the manufacturer to prove it is safe, as is required with drugs.” Then in 2007, a federal appeals court upheld the FDA’s original ban, citing the high number of adverse events attributed to the drug.

2007 Rimonabant (Acomplia) was withdrawn because of reports of severe depression and suicidal ideation, even in patients without a prior history of depression.

2010 Sibutramine (Meridia) was removed from the market due to cardiovascular safety concerns—hypertension, myocardial infarction and strokes.

2010 Qnexa failed to win FDA approval, due to safety concerns: suicidality, cognitive dysfunction, metabolic acidosis, cardiovascular safety, and the potential teratogenic (20-fold increase in cleft palates) effect of PHEN/TPM. It is up for reconsideration next month.

2011 FDA requested a clinical trial specifically to look at the cardiovascular safety of the combination drug bupropion and naltrexone (Contrave, by Orexigen).

FDA guidance

In 2007, the FDA issued a Guidance for Industry: Developing Products for Weight Management. Their recommendations included:

The duration of the phase 2 trials should be sufficient to capture the maximal or near-maximal weight loss effects of the active doses;

Patients should have BMIs greater than or equal to 30 kg/m2 or greater than or equal to 27 kg/m2 if accompanied by comorbidities (other significant illnesses, as diabetes or heart disease);

Primary efficacy endpoint should be a comparison of the change in body weight between the active-product and placebo-treated groups and the proportion of patients in each treatment group who lose greater than or equal to 5 percent of baseline weight.

These criteria were all met in the Lorcaserin trials.

Lorcaserin

So let’s look back at Lorcaserin, a drug that the FDA rejected in 2010.

What changed their minds now? In Arena’s original submission, which included more than 7000 patients in their Phase 3 trials, the mean placebo-subtracted weight loss at Week 52 from baseline with lorcaserin 10 mg BID (twice daily) was 3.3%. Follow up studies, the BLOOM-DM trial, have shown a modest improvement in glucose control.

Reviewing all data, the FDA found:

Based on echocardiograms, a relative risk of 1.16 for valvular heart disease (VHD), defined as mitral regurgitation greater than mild or aortic regurgitation greater than trace;

a small imbalance in serious adverse events of depression, discontinuations due to adverse events of depression, and suicidality scores (and this was in studies that specifically excluded patients with a prior history of treatment for depression within 1-2 years);

cognitive impairment was seen more frequently in the lorcaserin-treated patients

Arena will have to conduct six follow-up safety studies, including whether Lorcaserin increases the risk of heart attack or stroke. (Post-marketing commitment studies have a poor track-record for enforcement, though there are now relatively small financial penalties for noncompliance.) Attention will also be given to valvular disease, as the Phase 3 trials excluded patients with significant underlying valve disease. The FDA advisory committee noted, “There’s probably not sufficient data at this time to rule out a clinically meaningful increase in the risk for valvular heart disease.” Given that heart attacks and valvular disease was what killed previous anti-obesity drugs (to say nothing of patients), it is surprising that the committee voted for approval. I suspect this will follow the pattern of other drugs—when any drug is released on the market, it is used by a broader population, including those with higher risk for adverse outcomes (e.g., people with underlying heart disease or more serious depression). Since the groups won’t be cherry-picked to produce the best outcome, it is quite possible that problems will soon become evident, and lorcaserin will ultimately be withdrawn. That will likely be a painful process, as the same group that approved the drug is also responsible for taking regulatory action against it post-marketing.

Conclusions:

The U.S. Preventive Services Task Force concluded that because of safety problems and a lack of data showing that people can keep weight off after discontinuing diet medications, the task force could not recommend that anyone use diet drugs. While modest weight loss has been seen, inadequate evidence was found about the effectiveness of these interventions on long-term health outcomes (for example, mortality, cardiovascular disease, and hospitalizations).

Given the very modest weight reduction seen with Lorcaserin (Belviq) and other anti-obesity drugs, that the weight loss is transient, and that there is inadequately demonstrated benefit, the FDA’s approval of this drug seems to be another example of the FDA bowing to industry. As Public Citizen’s Sidney Wolfe noted, “Marketing this drug to a population besieged by obesity and desperate for relief is irresponsible and a mistake that will benefit only the company that makes it.”

While this was said about the FDA’s approval of lap bands for weight loss, it seems as applicable today: “Today’s FDA report gives the impression that FDA backed down on several safeguards as a result of unfavorable comments,” Dr. Diana Zuckerman of the National Research Center for Women and Families said in a statement. “FDA decisions should not be based on a popularity contest, especially since lobbyists rig the results.” * (see related FDA at a Crossroads)

It is also quite striking that there are double standards with drug and device approval. Although the FDA has approved Locarserin, there has been no great rush to approve over-the-counter (OTC) Naloxone, a drug that treats overdoses and has an excellent safety record—known since at least 1996. There are roughly 15,000 opioid related deaths in the U.S. annually; 100 people die from drug overdoses every day in the United States alone. Naloxone has demonstrated far greater safety and efficacy than have drugs for weight loss. For some time, there have been efforts to have Naloxone be sold over-the-counter. What are we waiting for? But there is no politics at the FDA, right?

*Update: Dr. Zuckerman succinctly shared her thoughts with me regarding approval of the new weight drug: " All of us concerned about public health are very concerned about obesity, but we won't solve the problems with drugs with very modest benefits, serious risks, and no evidence of long-term effectiveness. FDA should be making decisions based on scientific evidence, not pressure to 'approve something as soon as possible.' "

Correction: An adult who has a BMI between 25 and 29.9 is considered overweight.

An adult who has a BMI of 30 or higher is considered obese.

Credits:

Fat adult image: Willie Lunchmeat, Flickr

Sumo wrestlers image: Edward Dalmulder, Flickr

Fast food, BKQuadStacker: Mychal Stanley, Wikimedia

First aid kit courtesy capl@washjeff.edu

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