Avandia’s Reckoning Day

After years of debate over the safety of GlaxoSmithKline’s diabetes drug Avandia, U.S. and European regulatory agencies have finally made a decision about the future of the drug. European authorities have recommended suspending marketing of the drug, while FDA is severely restricting access to the drug, but seems to be leaving the door open to further actions. GSK, meanwhile, issued a press release saying it would stop promoting Avandia worldwide. Today’s announcements mark yet another chapter in the Avandia saga, which began in May 2007, when Cleveland Clinic cardiologist Steve Nissen published an analysis of the combined data from 42 previous clinical trials of GSK’s diabetes drug. The results weren’t pretty: Nissen’s article in the New England Journal of Medicine claimed that patients taking Avandia were 43% more likely to have a heart attack than those who were not on the pill. The next three years brought a series of safety alerts, conflicting data analyses, advisory panels, and questions over whether GSK tried to cover up the cardiovascular safety risk associated with the drug. In July, a panel of FDA advisors had mixed views on Avandia: 12 of the 33 panelists voted to remove the drug from the market, while 10 said it could stay on the market with strong restrictions on prescribing the drug. FDA today sided with those 10 panelists and imposed strict limitations on who can take Avandia. The agency will also adjust the drug’s label to reflect the safety risk. Under a risk evaluation and mitigation strategy, or REMS, Avandia can only be prescribed to new patients if they have been unable to control their blood sugar with other diabetes drugs. People already taking Avandia can continue taking the drug, but will have to register in the REMS program and sign a document saying they are aware of the cardiovascular concerns associated with the drug. FDA did not provide a clear timeline on how long it would take to implement the REMS. “We believe this action will severely limit the number of people on this drug,” Janet Woodcock said this morning in a conference call with reporters. FDA believes the REMS requirement will cause diabetics to “think twice” before they continue on the drug or start taking it, she said. FDA said about 600,000 people are currently taking Avandia, a number that the agency believes will drop precipitously under these new requirements. Patients will surely be confused by the mixed messages being sent by the agencies: after all, if it’s not safe in Europe, why would it be safe here? FDA defended its action by pointing out that European regulatory authorities lack the ability to...

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Future Cloudy for GSK’s Avandia

A panel of FDA advisors decided yesterday that GlaxoSmithKline’s diabetes drug Avandia should either be withdrawn from the market or its use seriously restricted. The panel had been assembled after several years of ongoing questions over the safety of the drug, which has been linked to an increased risk of cardiovascular events. The final vote came down to this: 12 panel members said the drug should be removed from the market, while 10 said it could stay on the market, but with strong restrictions on who could both prescribe and take the drug. The remaining members voted to either keep the label the same or revise it somehow to better reflect the safety concerns. With that mixed bag in hand, its up to FDA to decide what to do. For those of you having trouble keeping track of the ins an outs of the Avandia story, here’s a little primer. GlaxoSmithKline’s Avandia problems—the public ones, at least—began in May 2007, when the safety of the drug was questioned by Cleveland Clinic cardiologist Steve Nissen, previously known for blowing the lid off the cardiovascular issues associated with Merck’s arthritis drug Vioxx. In an article in The New England Journal of Medicine, Nissen said an analysis of the combined data from 42 previous clinical trials of Avandia showed that patients taking the drug were 43% more likely to have a heart attack than those who weren’t. FDA issued a safety alert about the drug, which brought in $3 billion for GSK in 2006. In August 2007, an FDA advisory panel voted 22-1 to keep Avandia on the market. Still, Avandia franchise sales fell 22% to $2.4 billion in 2007. But GSK’s troubles with Avandia go beyond the financial pain of lost sales. As you might expect, the company is at the receiving end of a flood of lawsuits related to the drug. It could get worse. This week, the NY Times said it had reviewed internal documents suggesting GSK knew as early as 1999 that the drug posed a safety risk, but actively worked to conceal those findings from FDA. Yesterday, GSK said it would take a charge of $2.36 billion in the second quarter, in part to help pay to settle lawsuits related to Avandia and its antidepressant Paxil. Avandia works by lowering blood glucose levels by increasing cells’ responsiveness to insulin. This isn’t the first time drugs acting on Avandia’s target, the peroxisome proliferator-activated receptor (PPAR), have run into safety trouble. In 2005, Merck and Bristol-Myers Squibb withdrew a New Drug Application for their PPAR agonist Pargluva after FDA asked for a five-year cardiovascular safety study. And Warner-Lambert pulled...

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Takeda’s Diabetes Drug Candidate TAK-875 In Phase III Trials
Oct19

Takeda’s Diabetes Drug Candidate TAK-875 In Phase III Trials

Takeda Pharmaceutical today announced it has begun Phase III clinical trials of TAK-875, a first-in-class drug candidate for treating type 2 diabetes. The experimental therapy activates GPR40, a G-protein-coupled receptor that resides in pacreatic islet cells. The TAK-875 story is as much about the biology of the target as it is about the molecule itself. And it’s a story that owes much to the company’s willingness to delve into uncharted territory. In the early 2000s, scientists knew GPR40 existed, but didn’t know what GPR40’s purpose was in the body. Plenty of proteins fit this description– they’re called “orphan receptors” in the industry parlance. Much of Takeda’s drug discovery strategy is based on figuring out what orphan receptors do. In a 2003 paper in Nature (DOI: 10.1038/nature01478), Takeda laid out what it learned about GPR40. The receptor responds to a variety of long-chain fatty acids. In response to fatty acid binding, GPR40 activates and boosts insulin secretion from pancreatic beta cells. GPR40 became a viable drug target for Takeda for several reasons. First, one of the hallmarks of type 2 diabetes is a reduction in insulin secretion from pancreatic beta cells, something GPR40 activation could help counter. Second, G-protein-coupled receptors are established drug targets– and GPR40 happens to be in the class of GPCRs for which researchers know the most about structure— the Class A, or rhodopsin-like, GPCRs. (Note: other GPR-type receptors are diabetes targets as well– C&EN contributing editor Aaron Rowe has written about Arena Pharmaceuticals’ activators of GPR119 as diabetes drug candidates.) Takeda used structural knowledge to its advantage in the discovery of TAK-875 (ACS Med. Chem. Lett., DOI: 10.1021/ml1000855). Researchers were able to build a model of GPR40 based on its similarity to GPCRs of known structure, and dock potential drug candidates inside to see how well they could bind. This is far from the only drug discovery story that has to do with “de-orphanizing” orphan receptors. In fact, as far back as 1997, pharmaceutical company researchers were writing about orphan receptors as a neglected drug discovery opportunity (Trends Pharmacol. Sci., DOI: 10.1016/S0165-6147(97)90676-3). And of course, just because researchers have “de-orphanized” a receptor doesn’t mean all of the complex biology is pinned down. Case in point: the PPAR receptors (J. Med. Chem., DOI: 10.1021/jm990554g). Despite these receptors’ promise as targets for obesity and diabetes, drugs designed to target them have tanked in development or had unexpected problems after arrival on the market (read: Avandia). So as TAK-875 enters Phase III trials, the news might be about the drug candidate’s clinical performance, but you can be sure that Takeda’s researchers are still working hard to unravel as much...

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Takeda Keeps On Truckin’ With Obesity Drug Research
Dec28

Takeda Keeps On Truckin’ With Obesity Drug Research

This year’s additions to the pile of setbacks in the obesity drug arena are enough to make anybody wonder whether big pharma companies will continue to invest in the field (was it already two years ago that Pfizer exited obesity research entirely?!). But news today of a pact between Takeda and Sanford-Burnham Medical Research Institute suggests the Japanese drug maker is in it for the long haul. Takeda’s agreement with Florida Hospital and Sanford-Burnham Medical Research Institute creates a partnership to evaluate potential new obesity drug targets. Today’s deal is the latest in a string of obesity-related investments for Takeda. Haystack readers may recall that Takeda is Orexigen’s partner for the development of Contrave, the weight-loss drug that is awaiting a decision from FDA in the wake of a thumbs-up from the agency’s advisory panel. The company also has a stake in peptides from Amylin Pharmaceuticals as potential obesity treatments, and it is conducting clinical development in Japan for Alizyme’s lipase blocker cetilistat, a next-generation pill to Xenical (orlistat), the drug sold over-the-counter as alli. Takeda’s interest in obesity makes sense given its strong history with type 2 diabetes drugs, a class with close ties to the obesity area. A quick look at Takeda’s pipeline is a whirlwind tour of diabetes drug targets, like glucokinase activators and dipeptidyl peptidase-4 inhibitors. The company has also discovered a protein, TGR5, that could be a target for drugs that mimic gastric bypass surgery‘s ability to control diabetes. And they are behind Actos, the well-known diabetes medication which shares its mechanism of action with Avandia. Unlike Avandia, Actos remains on the market, although FDA is currently investigating its safety. Will Takeda’s strategy pay off? Time will tell- beginning with FDA’s official decision on Contrave by the end of...

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Haystack 2010 Year-In-Review

This Friday, we’re looking back at 2010’s big news in pharma and biotech, both the good and the bad. Check out our picks and be sure to weigh in on what you think we missed. 1. Provenge Approved In April, Dendreon’s Provenge became the first approved cancer immunotherapy. Dendreon CEO Mitch Gold called it “the dawn of an entirely new era in medicine.” And while prostate cancer patients are excited for a new treatment option, the approval is perhaps most exciting for its potential to reignite interest in cancer immunotherapy research. There’s a lot of room for improving the approach—Provenge is, after all, expensive and highly individualized. Now that immunotherapy have been proven to work, there’s hope that the lessons learned in both its discovery and clinical development will aid scientists in inventing even better cancer vaccines. 2. Obesity Field Slims The obesity drug race played out in dramatic fashion in 2010, with three biotech companies-Vivus, Arena, and Orexigen, each making their case for its weight-loss medication before FDA. As of this writing, Orexigen’s drug Contrave seems to be on the surest footing to approval, but longtime obesity-drug watchers know that caution seems to rule the day at FDA, so nothing is a sure bet. Orexigen’s Contrave and Vivus’s Qnexa are both combinations of already-approved drugs, whereas Arena’s Lorqess is a completely new molecule. When C&EN covered the obesity race in 2009, it seemed that Lorqess (then going by the non-brand-name lorcaserin) had the cleanest safety profile, but Qnexa was best at helping patients lose weight. But FDA’s panels didn’t always play out the way folks expected. There were safety surprises- notably the worries about tumors that cropped up in rats on high doses of Lorqess, and the extensive questioning about birth defect risks from one of the ingredients in Vivus’ Qnexa. The fact that FDA’s panel voted favorably for Orexigen’s Contrave, a drug that’s thought to have some cardiovascular risks, generated discussion because FDA pulled Abbott’s Meridia, a diet drug with cardiovascular risks, from the market in October. The dust still hasn’t fully settled. Arena and Vivus received Complete Response Letters from FDA for Lorqess and Qnexa. Vivus has submitted additional documentation and a followup FDA meeting on Qnexa is happening in January. Also to come in January is the agency’s formal decision on Contrave. And if you’re interested in learning about the next wave of obesity drugs coming up in clinical trials, read this story in Nature News. 3. Sanofi & Genzyme: The Neverending Story Speaking of drama, Sanofi’s pursuit of Genzyme has been in the headlines for months now, and promises to stretch well into 2011. The...

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