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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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June 24, 2008

Prasugrel: Come Back This Fall

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Posted by Derek

This week was supposed to reveal the FDA's decision on Dai-Ichii Sankyo and Eli Lilly's anticlotting drug prasugrel. That one's in the same chemical class as Plavix (clopidogrel), and works by the same mechanism. Since Plavix did about eight billion dollars of business last year, and the anticlotting area seems to be a limitlessly huge market in general, you can understand why another drug is entering the space.

Both clopidogrel and pasugrel are prodrugs - their structures, as they come out of the bottle, are inactive. But they're converted by cytochrome P450 enzymes in the liver to their active forms, which bind irreversibly to the P2Y12 purinergic receptor on platelets. The clopidogrel link above shows the active form - that thiophene ring gets broken open, and a reactive SH is exposed. The P2Y12 receptor mediates platelet aggregation, so shutting it down extends clotting time.

A few points: for one, you'll note that the structures of the two drugs are very similar indeed. Is pasugrel just a "me-too", then? Well, it certainly is trying to do the same thing by the same mechanism, but as I've said here many times, it's hard to sell a drug unless you can point to some difference. The advantage that prasugrel has is that its metabolic activation takes place through a broader number of liver enzymes, so more of the active metabolite is produced across a wider patient population. And it is indeed about ten times more potent in humans - which may, though, prove to be its downfall.

In the clinic, the large TRITON-TIMI trial ran the two drugs head to head in over 13,000 patients, which is certainly the expensive (and definitive) way to go. The end result was that the prasugrel-treated group had fewer cardiovascular problems of all kinds (good!), but more episodes of severe bleeding (bad!). Overall mortality was the same between the two groups, and that's where the arguing has started. There's a lot of room to break down the numbers more thoroughly to see if there's some real benefit to the drug (or alternatively, to show that it really isn't any more useful than Plavix).

Of course, this is the job of the FDA. And now it seems that they've chosen to punt, delaying their decision by three months. Since the companies don't seem to have been asked to submit any more data, this seems to be an internal wrangle at the agency. I'm not sure what they're going to accomplish by holding their heads and moaning for another quarter, unless the hope is that the numbers can be crunched in some direction which will offer enough of a fingerhold to justify a decision. This is a very, very close call.

If I had to predict - and hey, I write this blog, so I've got a license to do that sort of thing - I'd say that the agency will ultimately approve the drug, but with label restrictions. In the end, they'll turf the problem over to the cardiologists, but with enough warning language on it that no one should be surprised if patients bleed out on occasion. The best outcome would be for some sort of clinical sign to indicate which patients should avoid the drug. The FDA will probably head in that direction, since it appears that the majority of bleeding problems occurred in the oldest and/or lowest-body-weight groups in the trial.

Update: but is that the case? Looking at the NEJM paper, it appears that patients not in these groups did have better efficacy with prasugrel, which improves the numbers. But the hazard ratio for major bleeding was 1.42 in the risky patients (>75 years old, or body weight < 60 kilos, or history of stroke/TIA), but still 1.24 in the ones outside these groups. So it's not at all fair to say that most of the bleeding events were in the risky patients - frankly, it looks like everyone bled, but the healthier cohort just responded better to the drug at the same time. That complicates my guess in the above paragraph, and raises the worst-case chance that the FDA might want to wait until the current trial comes in. What a mess. . .

There's another 10,000 patient study underway which might clarify the situation, or might just emphasize what a tied-up tangle it all is. In the end, I think that the FDA will let the drug be sold until that one finishes up, with the option to revise its opinion when the data come in. The three-month delay will serve to show how seriously they're taking all the safety issues - a big political consideration these days - and to work up the most bulletproof labeling they can come up with.

Comments (12) + TrackBacks (0) | Category: Cardiovascular Disease


COMMENTS

1. Anderson on June 24, 2008 10:15 AM writes...

A very good article on what Pfizer did with all those
repatriated profits. Shows you what management thinks of the USA.

http://www.nytimes.com/2008/06/24/business/24tax.html?ref=business

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2. TW Andrews on June 24, 2008 11:35 AM writes...

I'm surprised that it's not sufficient to show that overall mortality is the same, but with different side-effects. If I were in a position to need an anti-clotting drug, I'd like to have the option of one which may be a bit too effective vs. one that may cause cardiac problems. It would at least let me take into account other factors affecting those two thing (i.e. For someone with a family history of heart disease, pasugrel sounds like the better option).

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3. Retread on June 25, 2008 9:00 AM writes...

"Since Plavix did about eight billion dollars of business last year". Hopefully the evidence for its use in preventing stroke is now far better than it was in the late 90s, which was mostly based on the CAPRIE study. (I retired from neurology in 11/00)

CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events) with some 19,185 patients at 400 centers in 16 countries. Eligible patients have established vascular disease (stroke in the past 6 months, heart attack in the past month, intermittent claudication -- e.g. a symptom of insufficient blood flow to the legs).

From a throwaway 11-12/96 -- There was an 8.7% decreased risk of ischemic stroke, myocardial infarction or death in those on clopidogrel than aspirin. The actual event rates (stroke, MI, death) were tiny -- 5.83% in the aspirin group and 5.32% in the clopidogrel group. You'd have to treat 200 people for a year to prevent one event ! The aspirin dose was low (325 mg/day) -- I used 1300 mg/day in practice -- so clopidogrel wasn't being compared to an effective dose of aspirin (for stroke prevention)

[ Stroke vol. 29 p. 1737 '98 (letter) ] When stroke patients alone in the CAPRIE study were evaluated (6400 patients 12000 patient years) were looked at again, there was no advantage at all in using clopidogrel.

[ Stroke vol. 30 pp. 1716 - 1721 '99 ] Over 75% of the therapeutic advantage of clopidogrel over aspirin in the CAPRIE study occured in the group with peripheral, arterial disease (there were 62 fewer events in the clopidogrel treated patients (out of a total difference of 82 events in the combined groups). There was less than an 8% reduction in events in the stroke group (.08 * .0583 = .005 ! ) in the stroke group.

Nonetheless, hordes of patients with stroke or a warning of stroke (called transient ischemic attack -- TIA) were put on Plavix (Clopidogrel) at huge cost (versus aspirin) and minimal benefit. A triumph of marketing. Also a triumph of just reading the summary -- an 8% reduction in event rate, and not thinking about what it meant. One can significantly reduce the chance of being eaten by a bear by not going to Yellowstone -- by more than 8% even, but the initial risk is small.

It's a pleasure to be back reading chemistry again where rational thought is dominant.

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4. B. Martin, MD on June 25, 2008 10:33 AM writes...

Prasugrel's angle--or really, the angle of Daiichi Sankyo/Lilly--is that the drug has a faster onset of action than clopidogrel. This comes in handy when you need to perform PCI as quickly as possible and don't have at least 6 hours to wait for clopidogrel's effect. Also, prasugrel's activity--as you imply--is shorter. This comes in handy if patients have to go on to CABG within 5 days after PCI. (Then surgery-associated bleeding risk is minimized.) So it may be that prasugrel will be preferentially given in the short term to pts with acute coronary syndrome, but that clopidogrel will still be given long-term to prevent recurrent coronary events and stent-related thrombosis.

So I'm surprised that the FDA is still mulling over approval. Maybe it's the indication for prasugrel that they're grappling with.

To Retread: The data as a whole (and there's a lot of it) convincingly indicate that lower-dose aspirin (even down to 50 mg/d) is just as effective as higher-dose aspirin for the prevention of stroke.

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5. Retread on June 25, 2008 12:46 PM writes...

B. Martin

As noted -- my comments only apply to up to 11/08 when I retired from Neurology. The situation at that time was far from settled despite numerous statements to the contrary. My reading of the literature up to then was in agreement with the following editorial.

[ Arch. Neurol. vol. 57 pp. 306 - 308 '00 ] Another editorial on how much aspirin is enough? Barnett -- argues again that we don't know. Most stroke trials recently have used piddling doses, and have studied people before the major age of stroke. They think a trial with higher doses is in order in men over 65 and women over 75 (with no known vascular disease). One should be on asymptomatic people and the other should be symptomatic, and the type of stroke suffered should also be written down.

So if "The data as a whole (and there's a lot of it) convincingly indicate that lower-dose aspirin (even down to 50 mg/d) is just as effective as higher-dose aspirin for the prevention of stroke." is in fact correct, I'd appreciate some references to studies published after 2000 showing this, because those published before that time certainly did not.

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6. jean on June 25, 2008 10:15 PM writes...

good article!Prasugrel could be a blockbuster if enough caution to the bleeding risk, but it really hard to catch Sanofi due to according low obedience.

Permalink to Comment

7. B. Martin, MD on June 26, 2008 10:18 AM writes...

To Retread:

I'd refer you to Singer DE et al. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126;483-512 (pp. 498-501). The recommendations for initial aspirin therapy to prevent ischemic stroke in pts with noncardioembolic stroke or TIA are based on the Swedish Aspirin Low-Dose Trial (1991), the Algra and van Gijn meta-analysis (1996), the Dutch TIA Trial (1991), the UK-TIA Trial (1991), ESPS-2 (1996), and the ACE Trial (1999).

The 8th ACCP conference report, which came out this month, recommends even lower aspirin doses--ie, 50-100 mg/d.

Barnett (although I haven't seen anything published by him on aspirin and stroke prevention since 2002) was a notable dissenter on the use of lower-dose aspirin.

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8. retread on June 26, 2008 3:38 PM writes...

B. Martin

Thanks for the reference to Chest '04. I'll get a copy (which will take a while). It does not sound as though it is based on new data however, and I find the old work you cited quite unconvincing. The followup in the ACE trial was all of 30 days and they were studying complications after surgery for carotid artery disease not day in day out prevention of stroke. The other studies are nearly 20 years old.

I've not trusted meta-analysis ever since 3 different meta-analyses concluded that estrogen replacement therapy decreases the risk of coronary heart disease by 35 - 50% -- these were all observational studies and not prospective and randomized. The results of the HERS study showed the opposite. For some references to otther meta-analyses which did not agree with subsequent decent clinical trials see [ New England J. Med. vol. 337 pp. 536 - 542 '97 ] -- I think this reference is correct, but it's based on notes I took at the time. It's likely that further examples have occurred subsequently.

Expert opinion is just that -- opinion. Expert opinion by the leading lights of American and British Neurology (Scheinberg, Walton, Rose etc. ) led to anticoagulation with coumadin for transient ischemic attack when I started training and practice in the 60s onward. Their studies wouldn't be publishable today and the results were disastrous.

Quoting experts is akin to quoting scripture (which has its place but not in matters scientific) and has a long history in medicine. It was really all we had when I started. It is data which is convincing. I'll see if I can get my hands on the 8th ACCP report. Where did it come out?

Thanks for you quick response

Permalink to Comment

9. B. Martin, MD on June 26, 2008 6:58 PM writes...

Well, whatever. It's not like this is the forum for continuing the longstanding debate on aspirin dose for stroke prevention. But it's unlikely that anymore data will be forthcoming to settle your mind.

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10. Dr Arvind on August 31, 2008 6:05 PM writes...

interesting to read above comments given more recent data on triton published. To note that clopidogrel was loaded in the cath lab, when it is well known that it takes about 6 hours to work, meaning prasugrel was against placebo in the first few hours.
Now in the non diabetic group, no significant net benefit ratio, due to bleeding. And also less benefit in the ua/nstemi group but with an increased bleeding rate. Looks like it will be niched in a high risk group of patients with stemi who are diabetic.

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11. tarek bassil on November 12, 2008 1:49 PM writes...

with clopidogrel's inhibition of activation by omeprazole according to the OCLA trial. pasugrel seems to be an alternative in such patients who are taking PPI.

Permalink to Comment

12. tarek bassil on January 13, 2009 5:17 PM writes...

hey you heard about the neurontin fiasco ?

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