FDA’s Woodcock Talks Obesity Drug Safety

Janet Woodcock, head of FDA's drugs center, had a few things to say about obesity drugs at Monday's Reuters Health Summit in New York. Some of her comments weren't surprising. But some of them might offer a sliver of hope to companies hoping to succeed where Arena Pharmaceuticals, Orexigen Therapeutics, and Vivus have so far failed-- in bringing a new diet pill to market. From a Reuters story, which was brought to my attention via Twitter by David Pittman, a former C&EN contributor now working at FDA News (Thanks for the tip, David!): For diet drugs, Woodcock said companies might find success by showing benefits beyond weight loss such as a decrease in blood pressure or reversal of diabetes. "Those would be benefits you might accept more risk for," Woodcock said. The FDA recently rejected diet drugs with various safety issues from Arena Pharmaceuticals Inc (ARNA.O), Orexigen Therapeutics Inc (OREX.O) and Vivus Inc (VVUS.O). The agency also asked Abbott Laboratories Inc (ABT.N) to withdraw its diet medicine, Meridia, from the market due to heart risks and the company agreed. It's not surprising to hear Woodcock say that a potential weight loss pill's risks must be balanced by clear benefits. Having positive effects on things that can be consequences of obesity, such as blood pressure and blood sugar control, is one way of achieving that balance. Another way is to show FDA that your risks aren't all that risky. On that topic, I was intrigued to read Arena's announcementthat it isn't conducting the 12-month study FDA asked for to evaluate how its obesity drug candidate lorcaserin caused tumors in rats, and is conducting a three-month study instead. Now, what really caught my eye in Woodcock's statements was this gem: Woodcock said the FDA would not mandate additional benefits beyond weight loss diet drugs with relatively low risks. "There are some weight loss drugs out there that don't have much serious risk and cause modest weight loss and we think that's important for people," she said. Woodcock seems to be talking about drugs already on the market, but I'm not entirely sure. (Does anyone have a transcript of this talk?) This is the kind of sentence that makes me scratch my head and ask- just where does FDA's safety bar lie? We know that the experimental pills from Arena, Orexigen, and Vivus haven't cleared it. After that trio of rejections, stimulating discussions popped up on Matthew Herper's blog at Forbes and elsewhere about whether obesity drugs are dead. But maybe the key to a weight-loss drug, as opposed to a diabetes drug that happens to have the added benefit of weight...

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A Proton-Transporting Protein As An Obesity Drug Target

No matter how disappointing obesity drug research seems to be these days, I can't resist a good story about a hot biological target in the obesity area. And if obesity isn't a hot enough topic for you, add in the fact that the company chasing this target, Energesis Pharmaceuticals, happens to be co-founded by a veteran of Sirtris Pharmaceuticals, and the spotlights shining on this story start to look mighty bright. But I won't be talking about red wine compounds today. Instead, the focus is on brown fat. Today in Xconomy, Ryan McBride gives a great overview of Energesis, which is aiming to treat obesity, diabetes, and metabolic syndrome by harnessing brown fat's power. McBride's article has a good amount of detail on the company itself but I was intrigued by what seems to be an important molecular target for the company's strategy: uncoupling protein-1. So what is this protein? It "helps dissipate energy and contributes to weight loss," according to Energesis. Uncoupling protein-1 is specific to brown fat, and it's known to regulate body temperature by generating heat in animals. Scientists now think the protein might be involved in metabolism in human adults. Like many popular drug targets, it is a membrane-spanning protein. It can be found on the inner membrane of the cell's tiny energy-producing organelles called mitochondria, which are abundant in brown fat. When a fatty acid binds to uncoupling protein-1, the protein becomes a transporter for protons, moving them to the core, or matrix, of the mitochondria. This dissipates the electrochemical energy the body needs to generate ATP, the all-purpose molecular fuel of life. (This dissipation is also how heat is generated). But the body still needs ATP. So to generate that ATP, the body must burn more fuel from other sources, perhaps including fat reserves. That could be where the weight loss would come in. I speculate part of Energesis' strategy might entail artificially activating uncoupling protein-1, mimicking the natural uncoupling process to induce weight loss. (I wonder whether the activators need to resemble fatty acids to work!) Bonus obesity tidbit: Another of Energesis's co-founders was also a co-founder of Zafgen, yet another outfit with an obesity focus, which only recently unveiled the target of its experimental drugs. More reading: Background on how the body generates ATP for energy: Lehninger Principles of Biochemistry More on uncoupling protein-1: The Biology of Mitochondrial Uncoupling Proteins, Diabetes, DOI:...

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