Peering Into Pipeline for Weight-Loss Drugs



KEYSTONE, COLO. – The landscape is littered with failed anti-obesity drugs. Yet interest in weight-loss medications remains sky-high among obese patients.

One of the lessons of the fen-phen (fenfluramine/phentermine) experience is that patients will eagerly line up for an agent that achieves 12%-14% weight loss. Unfortunately, orlistat (Xenical), the sole anti-obesity drug approved by the Food and Drug Administration for long-term use, is considerably less effective than that. But one agent well along in the developmental pipeline does rack up fen-phen–type weight loss numbers: the low-dose combination of controlled-release phentermine and topiramate known as Qnexa, Dr. Daniel H. Bessesen said at a conference on practical ways to achieve targets in diabetes care.

Dr. Daniel Bessesen

Qnexa was one of three anti-obesity drugs whose marketing approval applications were nixed by the FDA in 2010. But the drug is far from dead. The agency wants to see 2-year safety data before reconsidering Qnexa, and Vivus, the drug’s developer, has indicated it will complete such a study.

The phase III clinical trials data reported to date have been encouraging, however. So much so that low-dose generic topiramate is now seeing a fair amount of off-label prescribing for weight loss, according to Dr. Bessesen, professor of medicine at the University of Colorado at Denver, and chief of endocrinology at Denver Health Medical Center.

"I personally have not been prescribing this drug for weight loss, but I know that people I respect are," he said.

His own practice at this point, Dr. Bessesen added, is that when he sees obese patients with an FDA-approved indication for topiramate – migraine prophylaxis, seizure disorders – he suggests they talk to their neurologist about the drug.

Among the phase III trials of Qnexa presented to the FDA as part of the failed marketing application was CONQUER, involving 2,487 overweight or obese patients with multiple comorbid conditions who were randomized to an office-based diet-and-exercise program plus either placebo or Qnexa at various strengths. Patients assigned to once-daily full-strength Qnexa at 15 mg of phentermine and 92 mg of topiramate averaged a 13.2% weight loss at 56 weeks. A total of 48% of those assigned to full-strength Qnexa had at least a 10% weight loss. Cardiovascular and metabolic risk factors improved significantly as well (Lancet 2011;377:1341-52).

The most common side effects were dry mouth, paraesthesia, insomnia, and nausea. Neurocognitive effects resulted in discontinuation of Qnexa in 2.6% of patients.

"Can you take the fact that there’s clinical experience with topiramate used for other conditions as reassuring regarding side effects? I’ve been struggling with this recently. I don’t know what the right answer is, but here we have a large trial in obese patients with lower-dose topiramate that shows some information about safety and effectiveness," Dr. Bessesen said at the meeting, sponsored by the University of Colorado Denver and the Children’s Diabetes Foundation at Denver.

Similarly, in the phase III EQUIP trial, involving 1,267 morbidly obese patients randomized to 1 year of lifestyle intervention plus placebo or Qnexa, patients who completed 56 weeks of dual therapy averaged a 14.7% weight loss.

Neither CONQUER nor EQUIP showed a significant increase in depression or suicidal ideation, adverse events that were the downfall of the cannabinoid receptor CB1 antagonist, rimonabant.

Off-label prescribing for weight loss is quite common. Pramlintide, liraglutide, and exenatide, all of which are approved for improvement of glycemic control in patients with diabetes, have weight loss as a side effect.

"A lot of you are comfortable in prescribing those drugs for diabetes, and I wonder if some of you are prescribing them for weight loss, even though they’re not indicated for weight loss. I think if you’re doing that, you have to be honest with people that it’s not approved for that and we don’t know the long-term safety and efficacy with regard to weight loss, although there are studies coming along," he said.

The anti-obesity drug pipeline looked a lot fuller a year or so ago. Then the FDA rejected Qnexa, as well as the selective serotonin receptor agonist lorcaserin, and Contrave, a proprietary combination of naltrexone and bupropion in sustained-release formulation.

Another setback is that leptin has "really been a big disappointment as a therapy," achieving only 1%-2% weight loss in clinical studies, Dr. Bessesen noted. And the oral melanocortin-4 receptor agonists, a novel drug class that looked very promising in animal studies, has also proved to be a bust in humans.

"For all the science we have in transgenic mice about the central control of feeding, we really haven’t gotten any effective drugs out of that. Maybe it’s because the feeding in a mouse is different from the feeding in humans. Maybe humans don’t eat because we’re hungry, but because the food tastes good and there are social aspects to it," he said.

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