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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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November 14, 2011

Anticoagulants, One After Another

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Posted by Derek

Back earlier this year, when some bad results had come out about Merck's thrombin receptor antagonist, I wrote ". . .another result like this one, and vorapaxar could be completely sunk". Well, perhaps it is. Merck has unveiled the results of a large Phase III trial in 13,000 at-risk patients, and the drug failed completely to beat a placebo control. Moreover, there were higher bleeding risks in the treatment group, and theh follow-up phase of the trial was terminated early for safety reasons. There are a lot of potential markets for an anticoagulant, and a lot of trials that can potentially be run, but this compound is in a great deal of trouble at the very least.

Meanwhile, at the same AHA meeting, Pfizer and BMS had the unpleasant job of announcing that their anticoagulant hope, apixaban, did not beat heparin (in the form of enoxaparin, Lovenox) for protection against cardiovascular events. About 5,000 patient participated in that study.

You can see from this sort of news how much fun it is to work in the anticoagulant field. Great big expensive trials await you, and the standard of care is surprisingly hard to beat. That's not to say that the standard is so wonderful - physicians would be glad to ditch things like warfarin and heparin. But they're still out there, and with Plavix going generic, the cost/benefit bar isn't going down any, either.

One big drug that actually did provide some good news was the Bayer Factor Xa inhibitor rivaroxaban (Xarelto). That one did manage to beat placebo in post-heart-attack patients (a mere 15,500 of them), albeit with, again, an increased risk of bleeding. Overall, though, it was a grim weekend for a lot of big clinical programs.

Comments (17) + TrackBacks (0) | Category: Cardiovascular Disease


COMMENTS

1. Anonymous on November 14, 2011 9:04 AM writes...

"Overall, though, it was a grim weekend for a lot of big clinical programs."

And, by extension, a grim weekend for a lot of big pharma workers. So much for the overly heralded 9.0% unemployment rate. Let the layoffs begin.

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2. Moiety on November 14, 2011 9:07 AM writes...

Typo in the article. Sentance below

Moreover, there were higher bleeding risks in the treatment group, and theh

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3. Nick K on November 14, 2011 9:14 AM writes...

There seem to be a lot more bad weeks than good weeks in recent years.

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4. RB Woodweird on November 14, 2011 9:39 AM writes...

Somebody explain to me how an anticoagulant which did not increase bleeding would work.

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5. milkshake on November 14, 2011 10:14 AM writes...

I worked on VIIa inhibitors for Celera/Axys. They had very potent amidine compounds that were unfortunately injectable-only, and hard to transform into (reasonably potent) oral series. We were moving to clinical candidate selection, eventually the management balked at the prospect of trials with injectable agent for deep vein thrombosis against heparin and tried to re-purpose these compounds for cancer. Soon after the research site was closed, projects sold off and as far as I know nothing came out of this 7+ year project.

Inhibitors that do not increase risk of bleeding complications: selective VIIa inhibitors would affect only one arm of the coagulation cascade so you can have some advantage there.
The real winner would be coumarin-like oral agent that does not have narrow therapeutic window, idiosyncratic PK and multiple drug interactions, which is the reason why patients on coumarins have to have very frequent blood tests to titrate their dose. (Anti-platelet drugs like Plavix are not that effective, have serious bleeding risks and do not have an antidote)

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6. @Moiety on November 14, 2011 10:52 AM writes...

Typo in the comment. Sentence below

Typo in the article. Sentance below

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7. Anonymous on November 14, 2011 11:51 AM writes...

I'm just a lab monkey, so have little knowledge of this kind of thing, but is it unusual to see a potential drug fail to show greater than placebo usefulness at this stage? Is it stupid to ask why this lack of potency wasn't picked up before it went into a large (is this a large trial?) number of people?
Apologies if these questions are a bit naive.

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8. MLBpitcher_and_MedicinalChemist on November 14, 2011 11:52 AM writes...

"And, by extension, a grim weekend for a lot of big pharma workers. So much for the overly heralded 9.0% unemployment rate. Let the layoffs begin."

I am willing to bet the chemists have a lower rate of unemployment than the general population. BTW, why should I give a **** about the prospects of the chemists in the job market, when the general population is also suffering under a neoliberal economic regime? It seems like most people here hold the reactionary belief that they deserve better financial security simply because they are smarter than the non-STEM general population.

At least, Derek Lowe, the owner of this blog, would get another $15 million next year for doing a mediocre job throwing a ball; his previous employer traded him and would be paying 2/3s of this 2012 salary. (No offense Derek, your 2011 season accomplished more than what most your commenters accomplished during their lives; I bet most of them haven't developed a drug to market. And you at least have a World Series ring)

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9. pete on November 14, 2011 12:01 PM writes...

@8
- talking about clots..

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10. MLBpitcher_and_MedicinalChemist on November 14, 2011 12:19 PM writes...

Sorry, my comment was directed @1, and I always take the opportunity to show how impressed I am with a medicinal chemist pitching at the MLB level.

Ok, I wonder how prasugrel is doing ,especially when it will soon compete with generic plavix.


"Its worldwide prasugrel (Effient) sales were $36.3 million in the third quarter of 2010, up from $22.9 million in the second quarter of 2010, according to the Indianapolis-based company. U.S. prasugrel sales were $28.1 million, and sales outside the U.S. were $8.2 million."

http://www(dot)cardiovascularbusiness(dot)com/index.php?option=com_articles&view=article&id=24784:lilly-sees-q3-uptick-bolstered-by-strong-effient-sales

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11. johnnyboy on November 14, 2011 3:47 PM writes...

@7: your question is not naive, it's actually a very hot topic of concern at the moment. New drug candidates are commonly having a harder and harder time beating placebos significantly in clinical trials, and no one really knows why. It seems that rather than drugs being less effective, the placebo effect actually keeps getting stronger and stronger - perhaps as a result of patients in trials being monitored very closely, which might have in itself a therapeutic effect. But to answer your question more directly, a drug would likely not have made it to phase 3 if it hadn't shown at least a hint of better than placebo results in the preceding P2 trials.

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12. Paul on November 14, 2011 5:43 PM writes...

Speaking of coagulation... is anyone working on drugs for livedoid vasculopathy?

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13. MLBpitcher_and_MedicinalChemist on November 14, 2011 7:04 PM writes...

New drug candidates are commonly having a harder and harder time beating placebos significantly in clinical trials.

"New drug candidates are commonly having a harder and harder time beating placebos significantly in clinical trials, and no one really knows why."

I thought the problem was showing superiority over existing drug are already or would soon be generic, and showing a pronounced effect to justify consumers to pay a premium for it over the well-established generic counterpart.

Placebos? That would be necessary if the drug was exploring a new mechanism of action, but the anticoagulant were competing against establish clinic medicines, namely warfarin and heparin.

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14. AML on November 15, 2011 4:33 AM writes...

Placebo here means current standard of care (SOC), which happens to be Aspirin+Plavix. The expectation from a new anticoagulant is that when added to current SOC, efficacy will improve without significantly increasing side effect (bleeding risk) in comparison to SOC ...and this all will agree is indeed a tough job for an anticoagulant. Moreover, as Derek has mentioned, efficacy/ safety bar set by current SOC in ACS in itself is high.

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15. anon 1 on November 15, 2011 8:24 AM writes...

14, AML:

I have not had access to the primary source of this information, but placebo should be used for vehicle only, not including any presumed or known active ingredient. Inclusion of recognized active ingredient should be referred to as "active control" or "placebo with active control" to make the comparison clear and obvious.

Sometimes, people do get sloppy in use of terms or nomenclature, and it is possible that this is what has happened here. Use of clear, correct reference terms is very important for good, clear commmunication to the greater community, the scientific understandint and progres, and avoiding of any potential confusion (as has happened here).

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16. Dr Jimbo on November 15, 2011 11:05 AM writes...

Let's not be too harsh on the drug here. Varopaxar did reduce the primary endpoint compared to control (standard of care), but not by enough to hit the magic P of less than 0.05 - P was 0.072 for the primary endpoint, which included stroke, so the most serious non-fatal bleeding (cranial bleeding) is accounted for there.
And standard of care here would include aspirin AND plavix (or equivalent) for >80% of the subjects in the trial. So most of those randomised to vorapaxar will be on three different antiplatelets. What would be interesting would be to see if vorapaxar + aspirin OR plavix (i.e. two antiplatelets, one of them vorapaxar) would be better than the current standard of care of aspirin + plavix. But I don't think that's a trial that can be run in the real world.
The other problem is economics, with plavix going generic, aspirin + plavix is a very effective, relatively cheap standard of care that's very hard to beat, especially if the trials, like this one, have to add the new therapy to standard of care, which will almost always carry a bleeding risk.

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17. AML on November 16, 2011 3:36 AM writes...

15, anon 1:

I am in complete agreement; unfortunately, I have noticed financial analysts using wrong terminologies in reporting on several occasions and that results in the sort of confusion noticed here.

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