A Proton-Transporting Protein As An Obesity Drug Target
Nov03

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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FDA Rejects Vivus’s Obesity Drug Qnexa
Oct29

FDA Rejects Vivus’s Obesity Drug Qnexa

As was widely expected, the Food and Drug Administration has rejected Vivus's experimental weight-loss drug Qnexa, making it the second obesity drug in a week to be turned away by the agency. On Saturday, Arena Pharmaceuticals said it had received a complete response letter (CRL) for  its obesity drug Lorqess (lorcaserin), based largely on worries that the drug caused tumors in rats. The biggest concerns in Vivus' CRL were around birth defects and cardiovascular risk. Vivus had already submitted a plan to keep tabs on pregnancy and birth defects after the drug was approved, and the agency seems to want to continue evolving that monitoring strategy. FDA also wants data showing that the drug's propensity to raise heart rate does not lead to an increased risk of cardiovascular events. If eventually approved, FDA said Qnexa would be considered a controlled substance along the lines of Xanax and Valium. The good news  is that Vivus says it doesn't believe it needs to generate any new clinical data to fulfill FDA's requests. Further, the agency didn't ask any questions about the drug's ability to induce weight loss. In a conference call with investors this morning, Vivus CEO Leland Wilson said it would take the company about six weeks to prepare its response to the CRL, and depending on how FDA classifies the application, the drug could be reviewed two-to-six months after the submission. Shares of Vivus were up over 30% in pre-market trading. As a reminder, Qnexa is the only drug in the three-way obesity race to lack a partner. Arena has licensed Lorqess to Esai, and Takeda has bought into Orexigen's Contrave. Qnexa is a combination of two drugs that are already FDA-approved: it’s a combination of topiramate, an antiseizure medication that enhances feelings of fullness, and phentermine, the “Phen” part of Fen-Phen, which was not linked to heart valve defects. When FDA posted briefing documents in advance of the Qnexa panel meeting, we learned that the agency had no problem with Qnexa's ability to help patients lose weight. But the committee had safety concerns in five areas: effects on pregnant women, cardiovascular risks, psychiatric events, cognitive events, and metabolic acidosis. Last July, an FDA panel thought that Vivus needed more long-term safety data on Qnexa and voted not to recommend the drug for approval. (Seven panel members voted for approval but nine recommended against...

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Arena’s Weight-Loss Pill Lorqess (lorcaserin): Waiting For FDA
Oct21

Arena’s Weight-Loss Pill Lorqess (lorcaserin): Waiting For FDA

Tomorrow is the deadline for the Food and Drug Administration to make a decision about whether or not to approve Arena Pharmaceuticals' experimental obesity drug Lorqess (lorcaserin). In advance of the decision I've recapped some Lorqess news and information from the last several months. We will update you when FDA's decision comes in. Of the three potential new diet pills racing to reach the market, Lorqess (lorcaserin) is the only one where the active ingredient is a completely new molecule. Its competition, Vivus's Qnexa and Orexigen's Contrave, are both combinations of drug molecules that have already been FDA-approved for other conditions. Lorqess targets an appetite-suppressing serotonin receptor located in the brain. It's the same receptor that was targeted by fenfluramine, an ingredient in the infamous Fen-Phen obesity drug combo. Fenfluramine was associated with heart valve damage and a fatal lung disorder- it was pulled from the market in 1997. Lorcaserin is different from fenfluramine- it is more selective for the specific subtype of serotonin receptor found in the brain and avoids the one that’s found in the heart. Arena's idea behind Lorqess was that a more selective drug might have the weight-loss benefits with fewer side effects. Arena has had to pay special attention to safety throughout lorcaserin’s development and they haven’t run into heart valve trouble. In July, Arena landed a partner for marketing Lorqess- Japan's Eisai. But last month, when an FDA panel met to discuss Lorqess, the outcome was disappointing for Eisai and Arena. Background materials for the panel session raised questions about malignant tumors that occurred in rats given high doses of lorcaserin. And the panel itself recommended that FDA not approve Lorqess by a 9 to 5 vote. The panel decided not enough data was available to assuage concerns about safety, and was also concerned about how the drug would work in a wider population than was tested during clinical trials. In the aftermath of the panel recommendation, analysts suggested a number of pieces of data that Arena could provide to improve its overall package of information about Lorqess, and thus the drug's chances. But many of the suggestions, which included a detailed study of the mechanism behind the rat tumors, and a Phase II proof of concept trial of lorcaserin and phentermine in diabetics, take years, not months. Today's FDA decision is sure to set the tone for the next couple of months, since Lorqess is the first of the three big contenders to be judged. FDA could decide to ask for more data on Lorqess, or make a decision outright. Stay...

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Lilly Diabetes Setbacks Mount
Oct21

Lilly Diabetes Setbacks Mount

Lilly’s diabetes pipeline is taking its lumps this week, a situation that has all but quashed any notions of earnings growth in coming years. The first setback came on Tuesday, when FDA issued a complete response letter for Bydureon, a long-acting form of the diabetes treatment Byetta. Lilly and its partner Amylin won’t be able to submit a response to the CRL until late 2011, significantly pushing back the much-needed new revenue stream. Now, along with today’s third-quarter earnings report, Lilly said teplizumab, an anti-CD3 antibody, had failed Phase III trials in Type 1 diabetes. Although expectations for the treatment were modest, the latest disappointment doesn’t do much for confidence in the company’s pipeline. Further, the setbacks of Bydureon and teplizumab are not the only challenges to the company’s diabetes portfolio. Last month, in a move that was not entirely surprising, Lilly and Transition Therapeutics dropped development of TT-223, a gastrin analogue that failed to meet its goals in a small study testing the drug in combination with a Lilly GLP-1 analogue in Type 2 diabetes. Meanwhile, news this week that Pfizer was paying $200 million for Biocon’s biosimilar insulin program caused some to worry that Lilly’s generous slice of the insulin market was at risk. On a call with analysts this morning, Enrique Conterno, president of Lilly Diabetes, tried to quell investor concerns. Bangalore, India-based Biocon “basically sells when it comes to insulin about 1% of what Eli Lilly sells today,” he noted. Conterno acknowledged that Pfizer could put some heft into the Indian biotech’s commercial infrastructure, but suggested that innovation around delivery devices would differentiate players in diabetes. “Clearly this is something we will watch, but we feel very confident in our ability to be effective with our insulin portfolio,” he added. But Lilly’s pipeline woes are not limited to diabetes. In August, the company experienced a major blow when it ended development of semagacestat after the compound worsened cognition in people with Alzheimer’s disease. Semagacestat, a gamma secretase inhibitor, had been viewed as a leading contender to be the next big Alzheimer’s drug on the market. As it stands, Lilly’s profits through 2014 will be driven by what is in its pipeline and efforts to rein in costs. Last fall, the company said it would eliminate 5,500 jobs, and for those keeping track of industry-wide layoffs, today said it was only about halfway through that process and has no immediate plans to expand the cuts. The company is staring down a wave of patent expiries on key products, and with the recent pipeline setbacks, earnings growth is “moving into sharply negative territory from 2012-2015,” Bernstein Research...

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Abbott Takes Diet Drug Meridia (Sibutramine) Off The Market
Oct08

Abbott Takes Diet Drug Meridia (Sibutramine) Off The Market

A diet pill bit the dust today- the Food and Drug Administration has asked Abbott Laboratories to take its drug Meridia off the market in the U.S. Meridia, or sibutramine, was approved by FDA in 1997, but the company voluntarily pulled Meridia after FDA's request, and is also halting sales of the drug in Canada and Australia. FDA's request was based mostly on a large study from last fall called the SCOUT trial. The trial suggested that patients on Meridia had more cardiovascular events, such as heart attacks and strokes, compared to patients taking a placebo. “Meridia’s continued availability is not justified when you compare the very modest weight loss that people achieve on this drug to their risk of heart attack or stroke,” said John Jenkins, M.D., director of the Office of New Drugs in the FDA’s Center for Drug Evaluation and Research (CDER), in an FDA press release. “Physicians are advised to stop prescribing Meridia to their patients and patients should stop taking this medication. Patients should talk to their health care provider about alternative weight loss and weight loss maintenance programs,” Jenkins said. Meridia was already pulled from the market in the UK and other European nations earlier this year. You can click here to read more about how the drug works. And last month an FDA advisory panel was split as to whether to keep Meridia on the market here in the U.S. Of 16 panelists, 8 voted to withdraw the drug, 2 voted to keep it on the market with more strict warning label language, and 6 voted to keep it on the market with label revisions and restrictions on which doctors can prescribe the drug. The loss of Meridia isn't a big blow to Abbott's stock. Prescriptions for Meridia have already dropped over the years because of safety concerns, from a high of 1.3 million prescriptions in 1998 to 250,000 in 2009, according to FDA. But the next wave of obesity drug news, should it be similarly negative, could take a bigger toll on the companies involved, which are both smaller than Abbott. Mark your calendars for October 22 and October 28- these are the goal dates for FDA to finish reviewing applications for Arena Pharmaceuticals' drug candidate Lorqess and Vivus' Qnexa. FDA panels have recommended against approving both drugs. UPDATED 3:59 PM- to reflect withdrawal of Meridia from Canada and Australia as well as...

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Is Pfizer After Biocon’s Insulin Portfolio?
Oct07

Is Pfizer After Biocon’s Insulin Portfolio?

The Economic Times is reporting that Pfizer is interested in buying the U.S. and European rights to Bangalore-based Biocon’s insulin franchise in a deal that would include a $200 million upfront payment. Rumors that Pfizer would buy Biocon's oral insulin product emerged in August, but the specifics on a possible pricetag have caused shares of the Indian company to rise over 8%. Biocon’s diabetes pill is in Phase III trials in India and Phase I studies in the U.S. The potential for an oral insulin product is vast, but so is the risk—getting the right balance in insulin administration is a tricky business. (Click here for my colleague Ann Thayer’s take on efforts to make inhaled or oral insulin products.) One has to wonder how much money Pfizer would be willing to pay for another alternative insulin after the colossal failure of the inhaled insulin Exubera. Low demand for the treatment prompted Pfizer to pull it from the market a year after its approval, costing the company some $5 billion after licensing fees, R&D costs, and write-offs. To be fair, an insulin pill has been the holy grail for diabetes researchers for some time. It would be less onerous than daily injections and more discrete than the unwieldy to downright ridiculous inhaled insulin instruments. Some background on Biocon’s technology: Biocon’s oral insulin program came from its 2006 acquisition of Nobex, a N.C.-based biotech that developed a way to make a pill form of biologics, which normally need to be given as an injection or IV infusion. Nobex used what it called “PegAlkylation” technology, which links a polyethylene glycol chain (those same PEGs used to improve the delivery of interferons and other large molecules) and an alkyl to a biologic like a protein or peptide. The design creates a molecule with a water-soluble and fat-soluble end that can travel through the myriad environments inside our bodies. Nobex claimed its oral insulin drug effectively reproduces the “first-phase spike,” or the large hit of insulin the pancreas puts out after a meal, a challenge for injectable and inhaled forms of insulin. Pfizer wouldn’t be the first big pharma to invest in an insulin pill. GlaxoSmithKline licensed an earlier version of Nobex’s oral insulin drug, but gave back the rights in late 2003. Nobex abandoned worked on that molecule in favor of a newer and better one, which Biocon licensed in 2004, prior to its acquisition of Nobex. Oral insulin aside, its worth noting that today’s ET story says the $200 million is for Biocon’s insulin portfolio, whereas earlier stories focused on Pfizer’s interest in the oral insulin program. European regulatory authorities recently gave the...

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