Strong Panel Backing For AstraZeneca Blood Thinner Brilinta
Jul28

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...

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China, Heparin, And Heterogeneity
Jul22

China, Heparin, And Heterogeneity

Back in 2007 and 2008, tainted heparin from China was responsible for the deaths of over 80 people in the U.S. If you had some sort of warm and fuzzy reassurance that authorities were looking into the matter, a new congressional probe should quash that feeling pretty quickly. Today the Wall Street Journal reported that the probe, by two congressmen from Texas, has found that China never looked into the heparin scandal at all. This is despite repeated warnings from FDA, as C&EN wrote last year. The probe comes ahead of FDA Commissioner Margaret Hamburg's first trip to China in her new official capacity. The congressmen, Reps. Joe Barton and Michael Burgess, urged the commissioner to bring the issue up during her trip. According to the WSJ, a spokeswoman for China's State Food and Drug Administration said the results of the probe were "not true." It's a shame this scandal had to happen at all- all because heparin, a drug so many people rely on, is easier to harvest from a pig intestine than it is to make in the lab. As a refresher, heparin is a blood thinner, and chemically speaking, it's a variably sulfated glycosaminoglycan polysaccharide composed of alternating D-glucosamine and uronic acid residues. Now, the blood thinner term is sort of a misnomer- heparin doesn't actually thin the blood. What it really does is inhibit coagulation- prevent blood clots from forming or reduce clots actively present. Heparin does this by binding to a protein called antithrombin III, ultimately affecting the proteases thrombin and Factor Xa, which both play important roles in blood clot formation. You can read some of C&EN's heparin coverage here and here. We've known that heparin affects blood clotting since 1916, but the stuff's been extraordinarily tough to replace. Today there exist many different heparin-type products. Garden-variety unfractionated heparin is used in certain surgeries and in kidney-dialysis patients. Fractionated heparins like the low-molecular-weight heparin Lovenox are used to prevent and treat dangerous blood clots in the leg veins of patients on bedrest or who are having a hip or knee replacement. And there are synthetic pentasaccharides like fondaparinux, essentially made from the business end of heparin, which affect only Factor Xa. All of these products have the same inconvenience- they all must be given via injection. And outside the fondaparinux-type drugs, it's not easy to manufacture them from scratch in a lab because the structures are so unwieldy and heterogenous. There are a slew of drugs in the pipeline that target Factor Xa or thrombin directly, that are straightforward molecular entities, and that drugmakers would love to see replace heparins and their coagulation...

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Safety Data On Vivus’s Qnexa Doesn’t Cut It For FDA Panel-UPDATED
Jul15

Safety Data On Vivus’s Qnexa Doesn’t Cut It For FDA Panel-UPDATED

You have to feel for the FDA's Endocrinologic and Metabolic Drugs Advisory Committee this week. They'd just finished the Avandia slog, but there was no rest for the weary. No, instead, they got to sink their teeth into the first of the potential new obesity drugs, Vivus' Qnexa. In a vote that signals safety is king in the obesity drug realm, Qnexa got a thumbs down from the panel this afternoon. The panel was split, with 7 members recommending that FDA should approve the drug and 9 recommending against approval. The panel's take home message was that a lack of safety data led to their decision. Several journalists live-blogged the panel session. Here are the two play-by-plays I followed: Lisa LaMotta, Minyanville Adam Feuerstein, TheStreet This decision comes after what seemed like an optimistic week for Vivus. On Tuesday, when FDA released its briefing documents about Qnexa, media reports on the data suggested that even though the agency's review focused on safety, it didn't look like safety would be a dealbreaker. In a note to investors, Leerink Swann analyst Steve Yoo wrote, "Overall, we believe the language in the FDA briefing documents to be fairly benign, but the FDA is requesting a pregancy category X label that would include contraindication in pregnant women and a warning/ precaution for females of childbearing potential." At today's panel, as expected, nobody really dwelled on Qnexa's efficacy. But Vivus faced a lot of questions about safety, especially about the effects of Qnexa during a pregnancy. During clinical trials, 13 women on Qnexa gave birth, and none of the babies had birth defects. Because Qnexa is likely to be an appealing option for women of reproductive age if it's approved, panelists were concerned that more data are needed to make sure Qnexa is safe during pregnancy. That's because one of the components of Qnexa is topiramate, an epilepsy drug that is known to carry a risk of birth defects. What complicates things is that the dose of topiramate in Qnexa is lower than the dose used for treating epilepsy. It's also lower than the doses used in studies that suggested topiramate carries a risk of birth defects. The panel also discussed the other four safety concerns mentioned in the briefing documents: cardiovascular risks psychiatric events cognitive events metabolic acidosis But at the end of the day, panelists who voted 'no' felt like more long-term safety data was in order. From Feuerstein's liveblog: one of the "no" votes says obesity is a chronic disease, so tell me what happens to patients as they stay on the medication for years. The deadline for FDA to make...

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Future Cloudy for GSK’s Avandia
Jul15

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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Vivus’ Qnexa for Obesity: Connecting Activities With Adverse Effects?
Jul13

Vivus’ Qnexa for Obesity: Connecting Activities With Adverse Effects?

Today FDA posted briefing documents about Vivus' experimental weight-loss drug Qnexa. Recall that an FDA advisory committee is scheduled to meet this Thursday, July 15th, to discuss any concerns about the drug and give it either a thumbs-up or thumbs-down recommendation to the agency. Biotech journalist Lisa LaMotta of Minyanville had a great post earlier today on this subject, and she explains why these briefing documents are important. Historically, briefing documents can be a great indicator of how the eventual meeting will pan out. These documents usually show how the FDA is thinking and what questions will ultimately be raised when it comes time for an approval decision. (Although the FDA doesn’t have to follow the advice of the panel, they often do.) FDA's documents suggest that they've got no beef with Qnexa's efficacy- the stuff helps patients lose weight quite well. But the committee has safety concerns in five areas: effects on pregnant women cardiovascular risks psychiatric events cognitive events metabolic acidosis Today I tried to find a molecular link for some of these adverse effects and didn't find anything that was clear to me. Part of the problem is that scientists still aren't sure how topiramate, the monosaccharide molecule in the Qnexa combo, works. Now I'm not saying that's a bad thing. After all, we didn't know how aspirin worked for almost 100 years after it was on the market. But the chemist in me always loves to know more. Here's some of what I found. From a document at FDA's website: Topiramate appears to block voltage-dependent sodium channels Topiramate enhances the neurotransmitter GABA's activity at certain receptors Topiramate antagonizes a specific kind of glutamate receptor Topiramate blocks the enzyme carbonic anhydrase So there you have it. That's a lot of different activities for one little sugar molecule. It seems like it would be easier to connect some of these targets with a psychiatric adverse effect than it would be to say, effects on a fetus. But I'm just grasping at straws there....

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