It’s still tough to get an antiobesity drug through the FDA

Topiramate

Phentermine

2010 was supposed to be the year in which one or more new obesity drugs would be approved by the FDA and reach the market. Three new drugs developed by small California companies–Vivus Pharmaceuticals’ Qnexa, Orexigen Therapeutics’ Contrave, and Arena Therapeutics’ lorcaserin, were up for review by the FDA. This follows a long hiatus, since the FDA has approved no anti-obesity drug since 1999.

On July 15, 2010, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted against FDA approval of Vivus’ Qnexa (phentermine/topiramate), with six votes in favor and 10 against. The FDA usually follows the advice of its advisory panels, but does not always do so.

The advisory committee agreed that the drug caused significant weight loss, with patients who took the highest doses of the drug having lost over 10 percent of their weight in a year. But many panelists questioned the lack of long-term data on efficacy, since the real issue with weight loss regimens (whether diet and exercise alone or with drug treatments) is the inability of patients to keep weight off once it has been lost.

But above all, panelists had concerns about Qnexa’s safety. Major concerns included the potential for fetal exposure during pregnancy and birth defects, depression, cognitive issues, and increases in heart rate. Most panelists who voted no were not strongly against approval, but they had lingering concerns, especially since the drug if approved would be given to large numbers of essentially healthy people over a long period of time–perhaps a lifetime.

Vivus said that it would work with the FDA to address the panelists concerns. For example, the company expects to have longer-term safety data on the drug in the next several months.

Qnexa is a low-dose, controlled release formulation of two FDA-approved drugs: phentermine and topiramate. Qnexa is designed to both suppress appetite (phentermine) and promote satiety (topiramate). Phentermine, an amphetamine, is prescribed as a weight-loss aid that is used short-term. It was the “phen” half of the notorious “Fen-Phen” combination. The “fen” part, fenfluramine (Pondimin) or dexfenfluramine (Redux), were serotonin modulators that caused cardiovascular side-effects. Topiramate is an anticonvulsant. As separate agents, phentermine and topiramate have minimal effects on weight loss. However, according to Vivus’ studies, the two drugs appear to have a synergistic effect, even at low doses, that results in significant weight loss. Vivus’ studies also indicate that the two drugs mitigate each other’s side effects; the low does and controlled release is also designed to reduce side effects.

Side effects of phentermine may include increase in blood pressure and heart palpitations, as well as gastrointestinal side effects. Side effects of topirmate may include cognitive issues, lack of coordination, aggressiveness, changes in ability to taste food and loss of appetite, cardiovascular side effects, and others. The risk of birth defects with ether of these drugs is unknown. However, there is preliminary evidence that topiramate might cause birth defects.

Lorcaserin is up for FDA Advisory Panel review in September 2010 and Contrave is tentatively scheduled for review in December 2010. Lorcaserin is a selective serotonin receptor agonist, which is specific for the 5-HT2C receptor. This contrasts with the nonselective serotonin reuptake inhibitor and serotonin-releasing agents, fenfluramine and dexfenfluramine. Lorcaserin is thus designed to be a more selective agent that works by a similar mechanism to dexfenfluramine or fenfluramine. Since the anorectic effects of fenfluramine/dexfenfluramine is due to their activity on 5-HT2C, but the adverse effects of these agents appears to be due to their activity on 5-HT2B, lorcaserin may be a safer agent that fenfluramine/dexfenfluramine. But like fenfluramine and dexfenfluramine, the efficacy of lorcaserin appears to be minimal.

Contrave, like Qnexa, is a combination of long-acting formulations of two FDA-approved drugs–bupropion and naltrexone. Orexigen designed Contrave to have a dual effect on pathways within the hypothalamus of the brain that control energy balance–increasing anorexia and inhibiting the reward effects of food. The company also believes that Contrave may block the body’s compensation for weight loss–i.e., decreased energy use and increased feeding. (For additional details, see our 2008 book-length obesity report, published by Cambridge Healthtech Institute.)

The Endocrinologic and Metabolic Drugs Advisory Committee’s recommendation against Qnexa casts a cloud on the upcoming reviews by the same committee of the other two drugs. However, the jury is still out on lorcaserin and Contrave. And approval of Qnexa may (or may not) be reconsidered as Vivus presents additional data.

However, antiobesity drugs that work via the CNS to control appetite by modulating the activity of common neurotransmitter pathways have a generally poor record. First was the fenfluramine/dexfenfluramine/Fen-Phen debacle, in which fenfluramine and dexfenfluramine (Interneuron/Wyeth) were found in the postmarking period to cause heart valve damage, leading to market withdrawal in 1997 and a host of lawsuits. Sanofi Aventis’ rimonabant never reached the U.S. market–in 2007 the FDA rejected the drug due to neurologic and psychological adverse effects. Rimonabant was also suspended from use in Europe in 2008. A related Merck drug, taranabant, was never submitted to the FDA, since it had similar adverse effects to rimonabant. And despite a growing understanding of pathways (involving neurotransmitters and neuropeptides) in the hypothalamus that control appetite, and despite a large number of promising leads that emerged from that research, not one drug derived from this research has yet emerged from early clinical trials.

In many cases, drugs that were designed to address these pathways had unacceptable adverse effects, since the neurotransmitter or neuropeptide receptors that they addressed are also involved in other CNS and/or peripheral tissue pathways that do not control body weight or energy balance. This is also the problem with appetite control drugs that have reached the IND or post-marketing stage. Such drugs as fenfluramine/dexfenfluramine and sibutramine target receptors for such common neurotransmitters as serotonin and noradrenaline, which are involved in many pathways within the CNS and peripheral tissues. Rimonabant is an antagonist of the CB1 cannabinoid receptor, which is widely expressed in the brain and in other tissues and modulates multiple pathways.

Sibutramine (Abbott’s Meridia/ Reductil) is an approved and marketed appetite-control drug that works via the CNS. It is a serotonin–norepinephrine reuptake inhibitor. Sibutramine causes increases in blood pressure and heart rate. Therefore, the drug is contraindicated in patients with uncontrolled blood pressure and certain other conditions.

There is also concern that sibutramine may cause more serious cardiovascular conditions. Early in 2010, the FDA issued a warning that the drug posed an increased risk of heart attack and stroke in patients with a history of cardiovascular disease. This resulted in an additional contraindication on the drug’s label. And a few patients taking sibutramine may experience psychological adverse effects. Because of concerns about sibutramine’s safety, the drug has recently been suspended from use in the U.K. and the E.U. Sibutramine is also under continued review by the FDA.

Sibutramine and the other approved antiobesity drug, orlistat (Roche’s Xenical–also marketed as a low-dose over the counter formulation, GlaxoSmithKline’s alli) have only marginal efficacy. And orlistat, which works not in the CNS, but in the gut to block fat absorption, has unpleasant gastrointestinal adverse effects. Therefore there is a need for safer, more efficacious antiobesity drugs.

Nevertheless, the history of failure of antiobesity drugs, especially appetite-control drugs that work via the CNS and modulate neurotransmitter receptors that are involved in multiple pathways, continues, with the decision of the FDA Advisory Committee on Qnexa being the latest episode.

Perhaps companies will have more success developing antiobesity drugs that primarily address metabolic pathways involved in both obesity and diabetes, rather than being directed at appetite-control pathways in the CNS that involve common neurotransmitters. We discussed this strategy in two earlier articles on this blog, dated October 25, 2009 and January 28, 2010. These articles focused on the incretin mimetics, especially liraglutide (Novo Nordisk’s Victoza). Incretin mimetics [which also include exenatide (Amylin/Lilly’s Byetta)] trigger an increase in insulin secretion by the pancreas, and also reduces gastric emptying. The latter effect slows nutrient release into the bloodstream and appears to increase satiety and thus reduce food intake.

Part of the mechanisms of action of the natural incretin glucagon-like peptide-1 (GLP-1) and of incretin mimetics involves activity in the CNS. However, GLP-1 receptors in the brain appear to be more specific in their activity than receptors for common neurotransmitters like serotonin and norepinephrine. The main adverse effect that has been seen with the incretin mimetics exenatide and liraglutide is a transient nausea. Thus incretin mimetics do not appear to cause the psychological and neurological side effects seen with such drugs as sibutramine, rimonabant, and phentermine, and presumably Qnexa.

Nevertheless, acute pancreatitis has been seen in some patients taking exenatide (which resulted in a warning on the label that patients with a history of pancreatitis should not take the drug, and that the drug should be discontinued if symptoms suggesting pancreatitis should develop). Rodents receiving either exenatide or liraglutide have developed thyroid C-cell focal hyperplasia and C-cell tumors. There is no evidence that humans develop thyroid tumors as the result of taking ether drug, however. Nevertheless, the label for liraglutide carries a “back box” warning highlighting the thyroid tumor results in rodents, and including a contraindicating the use of the drug in patents with a history of medullary thyroid carcinoma.

Companies usually develop dual diabetes/obesity drugs first for diabetes, since the regulatory pathway for that disease is easier than for obesity. This has been the case for both exenatide and liraglutide. However, Novo Nordisk announced on June 22, 2010, that following the FDA approval of liraglutide for treatment of type 2 diabetes, it was restarting Phase III clinical trials of the drug in obesity.

As we noted in our October 25, 2009 article, there are at least several companies with early stage dual diabetes/obesity drugs, which they are developing for diabetes. Early-stage obesity drug development has been mainly on hold, awaiting the regulatory approval of Qnexa, Contrave, and/or lorcaserin. Now the results of the regulatory reviews of these three drugs are starting to come in. If none of the three is approved, than early-stage obesity drug development may remain on hold indefinitely.

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