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Category → Cardiovascular

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.


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 “nuclear”.

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. Continue reading →

China, Heparin, And Heterogeneity

The antithrombin-III binding domain of heparin illustrates the chemical variety of the drug.

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. Continue reading →

RNAi Roundup #3

It’s time for another RNAi Roundup, this one featuring a few new faces and some oldies but goodies:

–Regulus Therapeutics, the microRNA company backed by Isis Pharmaceuticals and Alnylam, has signed a major partnership with Sanofi-Aventis. The French pharma firm will pay $25 million upfront, make a $10 million equity investment down the road, and provide three years of research support to gain access to Regulus’ fibrosis research program. The companies will collaborate on up to four microRNA targets, including Regulus’ most advanced efforts around microRNA-21. Regulus could score more than $750 million throughout the lifetime of the pact. The deal marks Sanofi’s second move in the RNAi space this year. In March, Sanofi signed up to use San Diego-based Traversa’s siRNA delivery technology.

–Santaris Pharma of Denmark and miRagen will jointly develop microRNA-targeted therapeutics for the treatment of cardiovascular disease. Boulder, Colo.-based miRagen will use Santaris’ locked nucleic acid drug platform to develop single-stranded LNA-based drug candidates. Santaris gets a minority stake in miRagen in exchange for use of its technology, and could see milestones and other payments as part of the pact.

–Cequent Pharmaceuticals has been granted patent protection in Europe for its TransKingdom RNAi technology, which uses non-pathogenic bacteria, such as modified E. coli, to deliver siRNA against certain genes. In April, Cequent was bought by Bothell, Wash.-based MDRNA in an all-stock deal worth $46 million. The purchase gives MDRNA two distinct siRNA delivery platforms.

–Mirna Therapeutics has won a $10.3 million “commercialization” award through the Cancer Prevention and Research Institute of Texas, a state-run investment program meant to spur innovation in cancer research. The money will be used to advance Austin, Tex.-based Mirna’s microRNA mimic discovery platform.

–Arrowhead Research, the parent corporation of Calando Pharmaceuticals, has raised $8.65 million in a direct stock offering. The money will be used to support Calando and Arrowhead’s other subsidiary, Unidym, a carbon nanotube technology firm. Calando recently showed in a Phase I study that its targeted nanoparticle technology could be used to deliver siRNA into cells.

–Alnylam came out with more data on the use of novel delivery lipids that carry siRNA into cell lines to improve the yield of biopharmaceutical manufacturing. Many biologics are produced by Chinese hamster ovary cells, but scientists have historically had few ways to control the output of those tiny drug factories. Alnylam’s goal is to turn off the activity of proteins that contribute to cell death, hopefully upping the yields of an otherwise expensive manufacturing process.

BMS and Pfizer’s blood thinner beats aspirin- now, what can it really do?

Yesterday, Bristol Myers Squibb and Pfizer agreed to stop AVERROES, a late-stage clinical trial of an experimental blood thinner, early. It’s relatively rare for a trial to be stopped for positive reasons, but that is what happened here. An independent analysis concluded that the blood thinner, called apixaban, was more effective than aspirin at reducing strokes and blood clots anywhere outside of the brain in patients with atrial fibrillation, a common abnormal heart rhythm. Stroke is a major complication for patients that have this heart problem, and drug companies would like to find a more manageable way to reduce patients’ chances of having one.

Apixaban is one of a slew of potential new blood thinners in the pipeline that is an oral inhibitor of Factor Xa, a protease enzyme that sits at a key point in the body’s complicated blood coagulation cascade. Matthew Herper at Forbes recently broke down how another drug in this same class, Merck’s betrixaban, works.

One thing to keep in mind is that none of the 5600 patients in this study were taking warfarin, a decades-old blood thinner that’s still one of the gold standards for preventing stroke. For patients with atrial fibrillation, warfarin, a vitamin K antagonist that interferes with the coagulation cascade, is generally considered to be a more effective option than aspirin, which prevents blood platelet activation.

The patients in the AVERROES trial, BMS’s press release explains, were either unable to take or chose not to take warfarin. I can understand the perspective of the folks choosing not to go that route. Warfarin works, it’s cheap, and it’s also an oral medication, but it’s far from perfect. People who take it must be very carefully monitored by a physician, because other drugs and even foods in the diet can alter its effects in the body. And with blood thinners, you’re always walking a tightrope- too high a dose can lead to excessive bleeding. Also, some genetic differences can affect how well warfarin will work. Patients who have that genetic makeup might want to have another option that they can take in the form of a pill.

But apixaban is still an investigational agent- FDA has yet to approve it. The news in this trial was good news, but given the relative effectiveness of aspirin I’m not sure how surprising it really was to those following this field closely. To get a complete picture of what apixaban can do, it will be good to see what comes of the ongoing ARISTOTLE trial. That trial, like AVERROES, is a Phase III, randomized, double blind clinical trial in patients with atrial fibrillation. But instead of pitting apixaban against aspirin, it pits apixaban against warfarin. Stay tuned.

Generic Lipitor Is All In The Crystal Forms

Lipitor’s got generic competition… at least in Canada. Reuters Health is reporting that three companies-Apotex, Teva, and Watson Pharmaceutical- have been authorized to distribute their generic cholesterol-battling wares in the U.S.’s neighbor to the north, where brand-name Lipitor last year enjoyed annual sales just over $1 billion. Pfizer says it plans to launch its own generic.

It’s a story that will get many pharma-watchers thinking about November 2011. That’s when Lipitor, the #1 drug in the world in terms of sales, loses its marketing exclusivity in the U.S., making it possible for still more generics to get a piece of that pie.

What’s interesting from a chemical standpoint is how Apotex told Reuters it was able to find a loophole in Pfizer’s patents. The company says it developed its own crystal form of Lipitor, which they’re selling under the name of Apo-Atorvastatin. The active ingredient in Lipitor is a molecule by the name of atorvastatin calcium. Here is a patent filed in 2001 from Teva for Atorvastatin hemi-calcium form VII. It has a decent discussion of the different crystal forms of atorvastatin known at the time and the pros and cons of their different properties.

The crystal form strategy is nothing new, as C&EN’s Ann Thayer wrote back in 2007.

Drug developers also want to identify and characterize as many [crystalline] forms of their proprietary compounds as possible. Beyond offering choices for optimal physical properties, each form may be patentable.

Drug companies usually file patents on all the different forms during development. Thus, when initial patents on the compound itself expire, they can conceivably extend a product’s life by moving to another form. In turn, generic drugmakers will target unprotected forms to avoid patent infringement. Nevertheless, high-profile lawsuits around GlaxoSmithKline’s Zantac and Paxil and Bristol-Myers Squibb’s cefadroxil have hinged on solid-form issues.

Read the entire article to learn more about the importance of different crystalline forms in drug development. Still want more? Here’s a particularly acrimonious tale about different forms of aspirin.

Merck Unveils Overhauled Pipeline

I’m in Whitehouse Station, N.J., today to get a birds-eye view of Merck’s overhauled pipeline following last year’s merger with Schering-Plough. The company is unveiling its pipeline as part of an overall business briefing for investors. Here are a few highlights after the R&D segment of today’s meeting:

–The company has jettisoned what had been expected to be its first biosimilars product, MK-2578, a pegylated form of erythropoietin that would have gone up against Amgen’s Aranesp. The product has been developed using technology acquired for $400 million in 2006 from GlycoFi, which figured out how to coax yeast into make homogeneous glycoforms. Peter Kim, president of Merck Research Laboratories, said that regulatory authorities indicated that given the safety concerns over erythopoeitin stimulating agents, the company would have to conduct a cardiovascular assessment for MK-2578. The delay—and one can assume the cost—caused the company to ditch the project. Merck BioVentures, its biologics business, still has two biosimilars in the clinic, and plans to have five in Phase III trials by 2012.

–Merck devoted a lot of time to its cardiovascular business, which seems to be almost an even distribution of legacy Schering-Plough and Merck products. Vorapaxar (Schering-Plough), in Phase III; betrixaban (Merck), expected to enter Phase III trials next year; Brinavess (Merck), a novel multi-ion channel blocker under regulatory review in Europe; Acadesine (Schering-Plough), an adenosine-regulating molecule in Phase III trials; Tredaptive (Merck), extended-release niacin combined with laropiprant, a compound that prevents flushing, expected to be submitted for regulatory approval in 2012; and anacetrapib (Merck), a reversible inhibitor of CETP in Phase III studies.

–Kim came out swinging in a discussion of boceprevir, a protease inhibitor for Hepatitis C compound that he called “potentially the most impactful near-term product” for Merck. Without ever mentioning boceprevir’s biggest potential competitor, Vertex Pharmaceutical’s telaprevir, by name, Kim went through a point-by-point discussion of areas where boceprevir might have an advantage over telaprevir. Neither Vertex nor Merck have unveiled Phase III data on their drugs, but as discussed in last week’s magazine, analysts have given telaprevir an edge over boceprevir on several fronts: its side effect profile appears milder (telaprevir causes a rash, boceprevir exacerbates anemia already caused by ribavirin, one of the two drugs given as the current standard of care) and, importantly, it appears to decrease treatment time to 24 weeks from 48 weeks. Kim described a “post-hoc” analysis of Phase II data for boceprevir that suggests it could also be effective after just 24 weeks. A Phase III study for boceprevir plus standard of care includes a “response-guided therapy” arm, which means that patients who have undetectable levels of the virus at four weeks after boceprevir treatment will stop standard of care therapy after 24 weeks. Merck expects to submit for regulatory approval for boceprevir later this year.

–Kim also walked through the differences between Odanacatib, the cathepsin K inhibitor in Phase III trials for osteoporosis, and Fosomax, its osteoporosis drug that has already lost patent protection. On the tolerability front, he pointed out that Odanacatib appears to have milder gastrointestinal side effects than Fosamax. The new drug appears to be just as effective at decreasing bone resorption as Fosamax, but offers improvements on the bone formation front.