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...

Read More

Blood Thinner Marketing, Soap Opera-Style

Let’s say your blood thinner got a unanimous thumbs-up from an FDA panel. And now, in anticipation of the drug’s possible approval, you’d like to raise awareness about atrial fibrillation, one of the conditions your drug candidate will treat. Why not send out some well-respected cardiologists or researchers to spread the word to the people? Not sexy enough, you say? OK, then, how about a soap opera star? Yes, this internal monologue may sound implausible, but it pretty much describes the latest news on the blood thinner Pradaxa’s front. Boehringer-Ingelheim, the maker of Pradaxa, has announced it is sponsoring a press conference in Rockefeller Center this Thursday, and the featured speaker is none other than longtime “All My Children” star Susan Lucci. Her husband, Helmut Huber (love that name!) has atrial fibrillation, an abnormal heart rhythm that increases the risk of stroke, so the two of them will be on hand to tell their story while the company trots out a study about atrial fibrillation and stroke. Here’s how atrial fibrillation can lead to stroke. The heart muscles in the atria normally coordinate their contraction to pump blood efficiently. But if you have atrial fibrillation, those muscles flutter around in an uncoordinated fashion instead. That leads to less efficient pumping, and what can happen is that blood will pool around in the atria. If that blood clots, and the clots end up traveling to the brain, then bam- you get a stroke. So using a blood thinner, which prevents clots, might reduce that stroke risk. I wish I could be on hand to see this event for myself. But I guess I’ll have to do with seeing Lucci on YouTube instead. Below is a video of Lucci finally winning a Lead Actress Emmy Award. She was snubbed at the Emmys 18 times before finally winning in 1999. I suppose we’ll see whether Lucci’s track record at marketing blood thinners turns out to be better than her track record at awards ceremonies. And thanks to Cardiobrief for pointing me to this event. I agree with Cardiobrief’s assessment- if Pradaxa is approved it’s a guarantee that it will be more expensive than warfarin (coumadin), the drug that it would be replacing. So Boehringer needs to convince folks Pradaxa is worth plunking down the extra...

Read More
Boehringer’s Blood Thinner Dabigatran (Pradaxa) Unanimously Endorsed
Sep22

Boehringer’s Blood Thinner Dabigatran (Pradaxa) Unanimously Endorsed

After last week’s Meridia and Lorqess drama, I could’ve really used some good news from an FDA panel. And on Monday, I got it- in the form of a unanimous endorsement for a new blood thinner. The drug getting the love is dabigatran etexilate, which was developed by family-owned Boehringer Ingelheim and will be marketed as Pradaxa if approved. It’s one of a cadre of drugs trying to replace warfarin (also known as coumadin), a medication that has been on the market for over 50 years and is among the most difficult to manage. Warfarin prevents formation of blood clots and can reduce ongoing clots. Doctors prescribe it to prevent painful leg clots in patients getting hip or knee replacements, to prevent stroke in patients with an abnormal heart rhythm called atrial fibrillation, and more. We recently wrote about how warfarin is a dirt cheap and effective medication, but it interacts with a plethora of foods, herbal supplements, and other drugs. Pradaxa is already approved in several countries outside the U.S. for short-term use, preventing leg clots in patients getting hip or knee replacements. The drug blocks thrombin, a protease enzyme that sits near the end of the complex biochemical pathway known as the coagulation cascade. Just about all of the drugs being developed to replace warfarin, at least the ones toward the end of the pipeline, target either thrombin or Factor Xa, the protein immediately before thrombin in the pathway. FDA’s cardiovascular and renal drugs advisory committee voted 9-0 in favor of approving Pradaxa for preventing stroke in patients with atrial fibrillation. (Boehringer-Ingelheim press release) This will be a longer-term stint on Pradaxa than post-hip or knee surgery patients typically experience. So the most important part of the panel’s discussion, to me, was their assessment of the drug’s effects on the liver. That’s because in 2006, another thrombin blocker called ximelagatran, developed by AstraZeneca, was pulled from the market because of liver toxicity. When you dig into the briefing documents that FDA provided to the panel, you find this blurb on page 103: Based on these data, the risk of severe drug induced liver injury from dabigatran appears to be low. Because the perceived risk is low and frequent liver monitoring may not prevent serious cases from occurring (even if an association did exist), regular monitoring of liver tests is not recommended. So it seems that ximelagatran’s liver issues may not be a class-wide problem. Still to be determined is what doses of the drug might be approved- read this post by Pharmalot for an assessment of why doses matter. FDA is expected to make its call on...

Read More
Genetic Tests And Rimonabant: Coulda, Woulda, Shoulda
Aug18

Genetic Tests And Rimonabant: Coulda, Woulda, Shoulda

Here’s something I missed while finishing up that blood thinner cover story. Last week Reuters reported that genetic testing might have helped save rimonabant, the ill-fated obesity medication once touted as a future blockbuster. Rimonabant, which blocks the cannabinoid-1 receptor, the target of marijuana’s psychoactive ingredient, appeared to help people lose weight. But it also increased the risk of psychiatric side effects, as we wrote back in 2009. The drug never won US approval and was pulled from the market in Europe in 2008. Reuters’ story was based on this report from The Lancet. The report (and accompanying press release) decribe CRESCENDO, a large clinical trial of rimonabant which was halted midway through because regulatory authorities were concerned about suicides in people taking the drug. The story actually focused on a small part of the Lancet paper’s discussion section, where Topol describes the lessons drugmakers should take away from the CRESCENDO trial. Endocannabinoid blockade could have proven viable, if a genome-wide association study had been done to establish what sequence variants are linked with suicides, suicide attempts, or significant neuropsychiatric side-effects. And here’s what Topol told Reuters about genetic testing. “Finding the gene for severe adverse drug reactions is a lot easier than we ever thought it would be,” Topol said in a telephone interview. Topol thinks if they had thought to collect genetic information on the study’s more than 18,000 participants, they might have spared the drug. “We probably could have figured out genomically who was susceptible and that drug could be quite viable,” Topol said in a telephone interview. I guess a genome-wide association study might have been interesting. It’s a shame one doesn’t seem to have been conducted. Still, I’m not sure it would have been guaranteed to determine which patients were more susceptible to suicide. These types of studies have limitations, which this article from JAMA describes best: GWA studies are an important advance in discovering genetic variants influencing disease but also have important limitations, including their potential for false-positive and false-negative results and for biases related to selection of study participants and genotyping errors....

Read More
On Blood Thinners And Rat Poison
Aug16

On Blood Thinners And Rat Poison

C&EN’s cover story this week is about finding replacements for the blood thinner warfarin, something that hasn’t happened in the more than fifty years since the drug went on the market. Warfarin prevents blood clots from forming and reduces active clots as well. When it works, it’s great for preventing strokes. As a bonus, it’s a dirt cheap pill, costing on the order of a couple of cents a day. But the trouble is that warfarin doesn’t always work well. It is extremely unpredictable in the body. Foods and other drugs affect its activity, as do certain genetic traits. The last thing you want to do is to take too much or too little warfarin. Too much warfarin could lead to uncontrolled bleeding, something that can be deadly in a place like the brain. And of course too little warfarin won’t be effective at preventing clots. So patients on warfarin must constantly monitor how well their blood is clotting, so their doctor can get their dose just right. The fact that it’s easy to overdose on warfarin is a pain for doctors and patients. But it comes in pretty handy in warfarin’s other, perhaps less well-known application: rat poison. It seems that messing with rodents’ blood clotting pathways is a very efficient way to off them. My cursory research indicates that we’ve got many rodenticide options, and warfarin isn’t the most common one. I couldn’t find warfarin at three different D.C. hardware stores. But it’s still available online. YOUR KEYWORD FOR THIS BLOG IS: COMING As an aside: medical websites seem to use the name “coumadin”, but the rat poison boxes read “warfarin”. I’d love to know the history behind this name divergence. It could be another instance of name-changing to assuage patient fears. I can certainly understand how a patient would find it disconcerting to see a giant box of their blood thinner in the pest control aisle at Home Depot. Think of how a nuclear magnetic resonance spectrometer uses essentially the same technology as a magnetic resonance imaging instrument. But the name you see used in the health field drops the...

Read More

Strong Panel Backing For AstraZeneca Blood Thinner Brilinta

The blood-thinning drug club is one step closer to getting a new member. Today, an FDA advisory panel gave a thumbs-up recommendation to Brilinta (ticagrelor), an experimental blood thinner from AstraZeneca. The vote was 7-1 in favor of approval, an enthusiastic endorsement that increases the chances that FDA will decide to approve the drug. The FDA is supposed to make its call on Brilinta by Sept. 16. Brilinta is in the same drug class as Plavix (clopidogrel), a blood thinner that’s the second best-selling drug in the world, and a drug that is going off-patent next year. Also in this class of drugs: Effient (prasugrel). Brilinta’s got the same molecular target as Plavix and Effient- P2Y12, a G-protein-coupled receptor on platelets that responds to the nucleotide adenosine diphosphate. But unlike the other two drugs, Brilinta targets P2Y12 reversibly. That reversibility could come in very handy in the clinic, as is implied in the opening sentences of this paper describing the clinical trial PLATO, which compared Plavix and Brilinta. Variation in and irreversibility of platelet inhibition with clopidogrel has led to controversy about its optimum dose and timing of administration in patients with acute coronary syndromes. We compared ticagrelor, a more potent reversible P2Y12 inhibitor with clopidogrel in such patients. And it seems that the vote at the FDA panel is a vote of confidence for that mechanism. The most uncertain moments in the meeting had to do with unexpected clinical trial results in U.S. patients. Here’s how Ed Silverman at Pharmalot described it. The key clinical trial compared Brilinta to Plavix in 18,624 patients in 43 countries who were being treated for a blocked artery or heart attack. The results showed the med reduced heart attacks, strokes and cardiovascular death 16 percent compared with Plavix after a year’s treatment. And all of the patients were given aspirin. But about 9 percent – who were from the US – saw no benefit. The FDA explained the difference by suggesting the dosage of aspirin given US patients was higher, but there was no clear understanding, as the panel grappled with differing patient treatment methods beyond aspirin dosing. It’s still not clear what happened in that subset of patients. I’ll be watching this space to see whether more clinical trials pop up. And a blast-from-the-past bonus: check out C&EN’s own coverage of the medicinal chemistry story behind Brilinta, from back in 2003. (It was called AZD6140 back...

Read More