Your Vioxx Lawyer - Vioxx, Celebrex & Bextra FDA Transcript

Your Vioxx lawyer provides you the complete transcript of the February 16^th, 2005 joint meeting of the FDA's Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee. We have formatted the complete transcript of the three day conference for easy of navigation to provide you with the best possible vioxx information. To contact a Vioxx Lawyer, click here for a FREE case evaluation.

Mechanism Based Adverse Cardiovascular Events and Specific Inhibitors of COX-2

DR. FITZGERALD: Thank you, Dr. Wood. You are, please, going to have to forgive me, I feel quite nauseated; I have a touch of the flu and I took a medicine to reduce my temperature, but I am not prepared to tell you what it is!

(Laughter)

I would like to thank Dr. Wood and the FDA and the committee for the opportunity to visit Gaithersburg at this time of the year.

(Laughter)

When I boarded the Metro last night at Union Station and began the apparently interminable trip to the sylvan embrace of Shady Grove I thought to myself it might be useful to try and summarize for you a message that will derive from my talk. The message is that, just as low dose aspirin affords cardioprotection and a small but absolute risk of serious GI bleeds, as you heard from Byron just now, through inhibition of COX-1, so specific inhibitors of cyclooxygenase-2 afford gastroprotection and a small but absolute risk of cardiovascular events. So, I have titled my talk mechanism-based adverse cardiovascular events and specific inhibitors of COX-2.

Well, as every lawyer and broker and journalist knows, this is the cyclooxygenase catalyzed pathway of arachidonic acid metabolism. Arachidonic acid is mobilized for release from cell membranes by activation of phospholipases and it is subject to metabolism by two enzymes which we call prostaglandin JH synthases 1 and 2 but which are known more commonly as cyclooxygenases 1 and 2. They give rise to a series of lipid products called prostaglandins which activate receptors and have very diverse biological effects.

One of the reasons we are here is that this, although depicted in a very simplistic way, is actually a quite complex system. To illustrate that, I will just mention two of these lipid products, prostaglandin E-2 and prostacyclin or prostaglandin I-2. When formed by cyclooxygenase-1, these two lipid products afford gastroprotection, and our thinking is that the common GI adverse events of typical non-steroidal anti-inflammatory drugs reflect the inhibition of COX-1-derived PGI-2 and PGE-2, thereby, exposing people to gastroduodenal liability.

But it turns out that when the very same lipids, prostacyclin and prostaglandin E-2, are formed by cyclooxygenase-2 as opposed to cyclooxygenase-1 they mediate pain and inflammation. Indeed, it is the suppression of the formation of these two prostaglandins by COX-2 inhibitors that retains the anti-inflammatory and analgesic efficacy of traditional non-steroidal anti-inflammatory drugs which inhibit the two enzymes together.

But it turns out that these two prostaglandins, prostaglandin I-2 and prostaglandin E-2, formed by cyclooxygenase-2 also afford cardioprotection which can manifest itself in various ways, and suppression of that capability is the cogent mechanism which explains the cardiovascular hazard which has emerged.

Well, I am sure this audience well knows that cyclooxygenase-2 inhibitors do not inhibit platelet aggregation, a way that we look at platelet activation in people that have been administered drugs. This just illustrates the absence of an effect at several doses of celecoxib in healthy volunteers compared to the inhibition of this signal by a mixed inhibitor at the time of peak drug action. Of course, that reflects the absence of cyclooxygenase-2. There should be a big shade here on this Western Blot if it was present but, unlike cyclooxygenase-1, which is there in abundance, cyclooxygenase-2 is not present in mature human platelets.

The wrinkle in all of this is that if you look at two structurally distinct members of the class of COX-2 inhibitors, the depression of the formation of that protective lipid, prostacyclin, as reflected by urinary excretion of its major metabolite which, believe it or not, is the gold standard of how you look at prostaglandin formation in people--this depression is comparable on specific inhibitors of COX-2 with the depression we see with structurally distinct mixed inhibitors like ibuprofen and indomethacin.

So, one might logically deduce from this that even under physiological conditions, never mind under conditions of pathology, a COX-2 might be induced by cytokines for example. It is a dominant source of prostacyclin. We hypothesized at the time that that reflected a mechanism which had been described in vitro by Topper and Jim Broney and which is illustrated here, which is when you subject endothelial cells to laminar shear force, which mimics the effect of the blood stream on the lining of blood vessels, you up-regulate the COX-2.

Well, that raised a question rather than answered a question even though it anteceded the approval of the first of these drugs. The first proof of principle that prostacyclin did actually modulate cardiovascular function in vivo stems from this study where we used mice lacking the prostacyclin receptor, known as the IP, or the thromboxane receptor, known as the TP, or both together. Thromboxane is the lipid which is formed by COX-1 in platelets and has harmful effects on the heart and cardiovascular system, and suppression of thromboxane reflects the cardioprotection of low dose aspirin.

In these studies we looked at the response to vascular injury in mice and we found that there was a signal of increased proliferation in response to vascular injury in the mice lacking the prostacyclin receptor which accorded with its in vitro properties.

Furthermore, when you injure the lining of a blood vessels in a mouse, just as if you do it in humans by performing an angioplasty, you get an attendant increase in platelet activation which is reflected by a time-dependent increase in excretion of a major thromboxane metabolite. We were interested to see that this signal was grossly augmented in the absence of the prostacyclin receptor, and that all of these reflections of the phenotype could be rescued by co-incidental deletion of the thromboxane receptor along with the prostacyclin receptor.

Now, these studies were criticized as to their relevance to the COX-2 inhibitor story mainly because people said, well, you have taken away the prostacyclin receptor but when we give the drugs, although we suppress prostacyclin, we do it to a substantial but incomplete degree, maybe 60-80 percent on average.

So, we performed these studies in another model of induced thrombogenesis in mice where we injured the vasculature in a free radical catalyzed fashion. In these studies we looked at the effect of a biochemically selective regimen of a COX-2 inhibitor, and we found that the response time to the thrombogenic stimulus was significantly accelerated. Furthermore, as opposed to looking at the absence of both copies of the prostacyclin receptor, we looked at the effect of deletion of just one copy and we found a significant and intermediate phenotype.

More recently we have devised a technique which permits us to remove cyclooxygenase-2 from particular cells. What I am showing here is the removal of only one copy of cyclooxygenase-2 from endothelial cells. As you can see, that also accelerates the response to a thrombogenic stimulus. So, these new studies are proof of concept of precisely the mechanism that we originally proposed.

Well, I think this is a point that we will come back to. We have some scientific evidence that there is a very non-linear relationship between inhibition of the capacity of platelets to make COX-1 derived thromboxane and inhibition of thromboxane-dependent function, that is, aggregation.

To get into the red zone for inhibition of platelet function you certainly have to be in excess of 95 percent inhibition of capacity, more like up in the 98 percent range. Where we have actually almost no experimental evidence is whether there is a discordance between that and the relationship between inhibition of prostacyclin and inhibition of its protective cardiovascular function. Perhaps the intermediate phenotype of the prostacyclin receptor deleted mice losing one copy of the gene may suggest that that is so.

So, we are back in the mouse model of induced thrombosis. The reason I am showing you this slide is that a theme that will recur and is relevant to the clinical consideration is whether inhibition of COX-1, along with inhibition of COX-2, modulates the implications of inhibiting COX-2.

So, in these studies we have looked at the rescue from thrombosis induced by intravenously administering arachidonic acid to mice at two different doses in mice that either lack completely COX-1 or in mice that lack 98 percent of the capacity to make COX-1 derived thromboxane by platelets. As you can see, these two genetically modified mice behaved very similarly in terms of the rescue from arachidonic acid induced thrombosis or, indeed, the time to complete occlusion induced by the thrombogenic stimulus I showed you in the earlier slide. This accords with that non-linearity of the relationship for COX-1 that I showed you. You would expect that to be suppressed in the 98 percent inhibited mice.

Now, that is all very well because it is in mice. So, you would way, well, how would we address this in terms of seeking a proof of concept in people? Well, if you delete the prostacyclin receptor mice don't fall over dead with thrombosis. They are more responsive to thrombogenic stimuli. So, if you wish to seek proof of concept in people, you would move to a population that had hemostatic activation and you would postulate that in such a population you would detect a signal faster and in a smaller study than might otherwise be the case.

Indeed, given the widespread recognition that patients undergoing coronary-artery bypass grafting exhibit hemostatic activation, and some suggestion also that they may be a model of aspirin resistance, it is perhaps unsurprising that we are able to detect a clear signal of cardiovascular hazard in two placebo-controlled trials in this condition.

Now, when I think of people at risk of thrombosis when one is considering where one goes with these drugs, I tend to think of middle-aged or elderly people who have suffered a myocardial infarction or stroke. But I think it is important to remember that risk of thrombosis can manifest itself in susceptibility to this cardiovascular hazard of these drugs in other populations.

This is a ventilation perfusion scan of a 23 year-old athlete who had been on the pill for 3 years, who went on a 6-hour car journey, having been put on valdecoxib for the antecedent 8 days and, at the end of the trip, developed left-sided chest pain; was misdiagnosed and continued on valdecoxib for another 10 days; had right-sided pleuritic chest pain that led to this VQ scan.

This is purely an anecdote but it brings to mind that individuals who have environmental predisposition to thrombosis, with a relatively small absolute risk such as being on the pill or prolonged stasis or genetic predispositions like Factor V Leiden, might be susceptible to a geometric interaction of relatively low risk from this class of drugs.

So, as far as thrombosis is concerned, where does this take us? Well, first of all, we have evidence that at least in vitro COX-2 can be induced in endothelial cells and produce prostacyclin. We have evidence that it constrains platelet activation and thrombogenesis in vivo. Suppression of prostacyclin does not cause spontaneous thrombosis but augments the response to thrombogenic stimuli in vivo. So, the hazard from coxibs would be expected to be particularly evident in those otherwise predisposed to thrombosis, and we have evidence that this hazard is modulated by inhibition of COX-1 in the appropriate zone.

Well, there has been a lot of talk, as we all know, about mechanisms and one of the things I have found really curious is the notion that hypertension is a distinct mechanism. People get hypertension on traditional non-steroidal anti-inflammatory drugs as well as COX-2 inhibitors for a reason. The reason is the same mechanism. Illustrated here from studies in mice by Matt Breyer and his colleagues is how inhibition of COX-2, shown in red, will augment the pressor response to an infused pressor like angiotensin-II. Again, as in the setting of thrombosis, COX-1 is not neutral. As you can see, if he uses a selective inhibitor of COX-1 he attenuates the response to angiotensin-II.

Now, these studies have been complemented by congruent data with gene-deleted mice. They raise the prospect that the incidence of hypertension would reflect not only the degree of inhibition of COX-2 but the selectivity with which it is attained. Indeed, in this week's Archives we have the first epidemiological evidence consistent with that concept.

Now, the products of COX-2 that buffer the response to pressor agents include prostacyclin and PGE-2. Here we are looking at the effect on blood pressure, of deletion of the prostacyclin receptor and, as you can see, blood pressure is elevated and the response to salt loading is increased. One sees exactly the same phenotype deleting one of the receptors for PGE-2.

So, as far as blood pressure is concerned, suppression of COX-2 derived PGI-2 and PGE-2 increases blood pressure and augments the response to hypertensive stimuli in mice. Deletion or inhibition of COX-1 depresses the response to vasoconstrictors in vivo so again we see COX-1 modulating the hazard from COX-2 inhibition. Hypertension on NSAIDs would be expected to relate to the inhibition of COX-2 and the selectivity with which it is attained.

Let's think of a more chronically unfolding cardiovascular hazard. These data arbitration taken from Narumiya. They are looking at the development of atherosclerosis in a genetically prone mouse, and you can see that deletion of the prostacyclin receptor accelerates atherogenesis in male ApoeE-deficient mice. In fact, the impact was most particularly marked at initiation and early development of atherosclerosis.

By contrast, deletion of the thromboxane receptor does the complete reverse, and other studies conducted by us and others have shown that inhibition of COX-1 selectively or antagonism of the thromboxane receptor will have the same effect as deleting the thromboxane receptor, as shown here.

So, as far as atherosclerosis is concerned, we see this buffering capacity between COX-1 and COX-2. Furthermore, we have shown recently that in a different genetically proned mouse model deletion of the prostacyclin receptor and inhibition of COX-2 dependent formation of prostacyclin is important in affording the atheroprotection conferred by estrogen in female mice.

So, here we see the atheroprotection in terms of reduction of lesion development with estrogen treatment in vasectomized mice being dramatically reduced by deletion of the prostacyclin receptor, which raises a whole new set of questions about the use of these drugs in premenopausal women.

So, as far as this other manifestation of a cardiovascular hazard is concerned, initiation and acceleration of early atherogenesis occurs in response to deletion of the prostacyclin receptor. I haven't gotten into mechanism but it fosters platelet and neutrophil activation and vascular interactions of these cells, and removes the constraint on attendant oxidant stress.

Now, we know that hypertension, which is also a consequence of inhibition of this pathway, itself accelerates atherogenesis. So, one could imagine that the direct and indirect effect could converge to transform cardiovascular risk. Finally, again COX-1 is playing a modulatory role.

There is a lot of speculation, which will no doubt be addressed in this meeting, as to whether in the APPROVe study we actually saw a delayed appearance of augmented cardiovascular risk. I think, for me, the answer is we are not so sure but, if we did, this mechanism would explain not only early events but also the delayed emergence of cardiovascular phenotype.

The other thing that is often trotted out is, well, but people on aspirin have had some of these events. Well, of course, people on aspirin also have myocardial infarctions. But I think it is worthwhile remembering as we consider that prostacyclin will buffer effects of thromboxane on blood pressure, atherogenesis, hemostasis and, indeed, cardiac damage, which I haven't gotten into today. It acts as a general constraint on any agonist that acts harmfully on these systems. So, one would expect aspirin, in a perfect world, to damp rather than abolish the signal.

So, I think, if you will pardon me just for a moment to muse, one could relate the ability to detect a signal, expressed here as maybe numbers needed to treat or trial duration, as a function of the underlying cardiovascular risk of the patients involved. The higher the risk, the more you would be able to detect it easily. The lower the risk, it may require that you either perform a very large study or go on for a very long time because we are all mindful of the fact that clinical trials, even randomized clinical trials, are very crude detector systems for uncommon risk.

Additionally, other elements will impact on this, including elements related to drug exposure and the degree of selectivity that is actually attained in vivo. So, I think in some of the efforts to dismiss this idea of a class-based effect some have lost sight of the fact that one would expect not only the underlying substrate to be relevant, but elements of drug exposure like dose, duration of dosing, duration of drug action and, indeed, concomitant therapy to be relevant to the ability to detect a risk. So, one is looking for a needle in the haystack and, to some extent, when one finds the needle it doesn't really matter how long it has been in the haystack.

So, let's consider the extreme phenotypes of cardiovascular benefit and hazard in this pathway. First of all, let's consider aspirin. Here we have a sustained mechanism of action that leads to complete and sustained inhibition of COX-1. Even low dose aspirin inhibits prostacyclin to a minor degree. But one would expect, and one sees, a cardiovascular benefit from aspirin, at least in the secondary prevention of stroke and myocardial infarction.

In the case of COX-2 inhibitors one sees a reversible inhibition of COX-2. One also sees variable degrees of inhibition of COX-1 but, because of that non-linearity that I mentioned to you in the relationship, effectively this makes these drugs selective for COX-2 because you have no inhibition of COX-1 dependent platelet function.

That brings me to the last topic that I would like to address, and that is what about the traditional NSAIDs? Well, here is one way of comparing aspirin to a prototypic NSAID, ibuprofen. You take healthy volunteers, you administer them low dose aspirin to stead-state efficacy, or ibuprofen 3 times a day to a steady-state effect, and you look at the offset of effect on enzyme inhibition and inhibition of function.

With aspirin you see sustained inhibition over the 24 hours after stopping the drug. As you would expect, with stopping ibuprofen you see offset of this reversible inhibitor on the enzyme. From whatever I have told you about that non-linearity in the relationship, you are not surprised to see a steeper offset of inhibition of function.

Well, of course, we have no randomized, placebo-controlled trials of traditional NSAIDs. We have various overviews of the epidemiological experience, with all the limitations of that approach and we can see that ibuprofen looks like it is not really altering cardiovascular hazard. There seems to be a sort of 10 percent or so reduction with naproxen, particularly 500 mg twice a day which was the most commonly used dosage in these studies.

Now, this would be like a dilute aspirin effect and, obviously, has relevance to the interpretation of studies like VIGOR and some of the experience with the etoricoxib that you will hear about as to whether naproxen is actually behaving like aspirin.

Well, I think actually the epidemiology is entirely consistent with the clinical pharmacology of naproxen. This elegant study was performed by Patrignani. Again we are looking at the offset action of aspirin and naproxen 500 mg per day administered to steady state. We are looking at inhibition of enzyme function, and we see with aspirin exactly what we would have expected, sustained inhibition. However, at the end of a typical dosing interval for naproxen we see heterogeneity of response. In fact, everybody is at 95 percent or lower, suggesting that within the dosing interval there is a variable degree of cardioprotection afforded through this mechanism, which would be consistent with the dilute aspirin effect from the epidemiology.

This is a plot of the IC-50 for inhibition of COX-2. This is inhibition of COX-1 in whole human blood. As we move in this direction we are getting more selective for COX-2. It brings us back to a point that arose in Byron's study, and that is that although there is a difference in potency, celecoxib and diclofenac look remarkably similar.

I would also remind you that naproxen, bearing in mind the Aleve study fiasco, is on the other side of the line, just like ibuprofen is, and exhibits preference for inhibition of COX-1.

Well, you have had a nice job giving you a full data set, demonstrating that actually in whole human blood diclofenac and celecoxib are superimposable. So, I would contend that through various lines of evidence diclofenac is probably a selective COX-2 inhibitor like Celebrex.

Consistent with that is a pharmacodynamic interaction where we showed that prior occupancy of the COX-1 site by a typical mixed inhibitor like ibuprofen would block access of aspirin to its target acetylation site. If we give aspirin and ibuprofen chronically we actually see a pattern that looks just like giving ibuprofen alone, an onset of action and a steep offset of function. However, if we substitute diclofenac for aspirin it looks like giving aspirin alone, which is consistent with the type of information you get with a selective COX-2 inhibitor like rofecoxib or celecoxib in this assay. So, I think we can start thinking of diclofenac as Celebrex with hepatic side effects. It has the same selectivity in whole blood in vitro. It has no pharmacodynamic interaction with aspirin. It has no clinical interaction with aspirin in the one epidemiological study which has addressed this interaction with the two drugs. Also, it is consistent with the superimposition of the GI and cardiovascular events in the retrospective look at CLASS in non-aspirin users.

So, I would suggest the two trials that you will hear about, EDGE and the ongoing MEDAL, are actually the first trials that are a comparison within the class.

Well, let's come back to this relationship. I would remind you that while we have very strong evidence for this being true, we have almost no evidence that this is true. The conjecture of this discordance underlies the argument for the fact that we have a problem with selective COX-2 inhibitors but, you know something, we have a problem with all of these drugs which clearly obscures the message. We have no evidence for that and you will hear people parsing in meta-analyses naproxen versus non-naproxen NSAIDs.

Well, I don't think that is a legitimate lumping of non-naproxen NSAIDs, which is really diclofenac plus ibuprofen in most instances. I think it is as legitimate to consider them all individually as it is to consider naproxen individually.

So, could there be a hazard from a non-naproxen NSAID like ibuprofen where there is coincident inhibition of COX-1 and COX-2 over typical multiple dosing interval? If there is a discordance in the relationship between inhibition of enzyme function and inhibition of enzyme product, then there might be a narrow part of the dosing interval where there could be a potential exposure to risk. But the likelihood of detecting this notional risk would be much less than the likelihood of detecting the clear evidence-based risk of selective inhibitors of COX-2.

So, there is some suggestion that naproxen achieves sustained platelet inhibition in some individuals. I like to think of it as a dilute aspirin. There is evidence that diclofenac is Celebrex. There is evidence that ibuprofen may undermine the benefit from aspirin, although that is not yet answered one way or the other with a controlled trial. And, I would say quite forcefully there is no rationale for lumping diclofenac and ibuprofen as non-naproxen NSAIDs in meta-analyses and the like.

I am not sure when a canard becomes a dead duck--

(Laughter)

--so I decided to dismiss some of the things that I think are worth dismissing and call them dead dragons. First of all, naproxen clearly is not the full explanation of VIGOR.

Here is another one that needs to be chopped down, hypertension is not a different mechanism.

There are a lot of off-target fantasies being touted around at the moment, strange chemical interactions that haven't actually been shown to occur in vivo yet but are postulated as the explanation for a drug-related rather than a class-based effect.

Oddly, we never heard any of this conjecture when we were considering how all the drugs in this class afforded relief from pain and inflammation.

Here is another nice notion that makes clinical pharmacologists squirm in their seat, it is just a matter of reducing the dose. Well, there is a lot of interindividual variability in response to COX-2 inhibitors and we all have our own dose-response curves. It has been an approach in the past when a hazard emerges to suggest that in a population sense one just cuts the dose--perhaps in a population sense but it certainly does not obviate the possibility of individual hazard.

Finally, if there ever was one, I think we have certainly moved beyond the need for a trial of a COX-2 inhibitor in patients with acute coronary syndrome. Indeed, I feel that the evidence that supports a trial in patients at high cardiovascular risk to detect protection is scientific quite weak, and in the face of an emergent hazard is ethically questionable.

Indeed, in the case of mice if one combines a thromboxane antagonist as a surrogate for the suppression of thromboxane by low dose aspirin with a COX-2 inhibitor, one doesn't see any benefit in terms of atheroprotection, but what one does see is the loss of the fibrous cap in the combination and necrosis of the atherosclerotic core, consistent with destabilization of the plaque.

Finally, and you will be glad to know it is finally, I would just like to mention a couple of things relating to where we might go from here. Well, I think clearly an easy thing to write down and perhaps a more tricky thing to do is to exclude patients at high intrinsic risk of thrombosis, and you have heard my views on that. Dose reduction alone is a simple message. It has a political and legal appeal but in pharmacological terms it is misleading.

I think we are likely to subject new drugs that might be approved from this class to significant hurdles before they are approved. It seems logical to me that existing drugs in this class should be subject to the same hurdles to retain approval, particularly for extended dosing. And, I think that frankly one should logically restrict the duration of dosing until the parameters of safety for extended dosing have been established.

I mentioned interindividual variability, and these are log scales but they illustrate looking at inhibition of COX-2 either in the typical ex vivo assay or by excretion of prostacyclin metabolite or inhibition of COX-1, that with this sort of display of the data to highlight it, there is considerable interindividual variability of response. This is no surprise. It is true of all drugs.

But perhaps we can exploit the biochemical variability, the physiological response variability and, indeed, perhaps some genetic markers such as these polymorphisms associated with metabolism of drug or these polymorphisms in cyclooxygenase-1 to try and identify those patients at emerging cardiovascular risk before they culminate in events. So, you might say that the future of these drugs or the challenge to the future of these drugs is that if their value--and I believe they have value as a class--is to be harvested, then to manage the risk we have to actually move to an example of personalized medicine.

One would want to obviously restrict these drugs in some way to people who really needed them, for GI reasons. We need to determine whether risk transformation actually occurs during chronic dosing and, if so, whether we can detect it. And, it is likely, because we have so few events in any one trial, we can only do this by a combined analysis across the class in relevant trials. Then, obviously, we would have to validate prospectively such an index of emergent risk in a prospective trial.

So, I really thank you for your patience and I would like to conclude. Selective inhibitors of COX-2 depress prostacyclin without a concomitant inhibition of thromboxane-A2. This can result in an augmented response to thrombotic and hypertensive stimuli and acceleration of atherogenesis in mice. Indeed, the terrible beauty of this unfolding drama is how faithfully the emerging clinical information has fitted the predictable science, and that should reassure us in terms of the likelihood that the science can predict a way to conserve the value of these drugs while managing the risk.

An increase in MI and/or stroke has been seen at last count, as of yesterday, in 5 placebo-controlled trials with 3 structurally distinct COX-2 inhibitors. Given the bulk of evidence, the mechanism-based evidence from mice and people, the pharmacopeidemiology and this, it seems to be that most rational people would accept a class-based mechanism as they did for efficacy.

Finally, hazard would be expected to relate at the individual level to the drug selectivity attained in vivo, dose and duration of exposure and to interindividual differences in drug response. Thank you.

DR. WOOD: Thank you. Just before you sit down, one thing you seemed to be saying is that we should exclude patients at high risk. The point estimate in the APPROVe trial for people with no symptomatic history of heart disease is 1.6 so that would be one way you would exclude people, I guess, but the point estimate remains 1.6. Does that bother you?

DR. FITZGERALD: No, as I alluded to, I think the nature of the information we have in the APPROVe trial so far remains to be played out. Clearly, there was an attempt to exclude people at high cardiovascular risk but we all know that people who are at risk slip through any exclusion criteria. So, one question is, is all that we are seeing people who, for one reason or another, are predisposed to thrombosis and they are the people that are having events? Or, are we seeing people who through atherogenesis transform their risk? Or, are we seeing some combination of the two? I don't think we know the answer to that.

DR. WOOD: We are running behind time so we will call a break right now and give everybody a moment or two to get out. Before we do that, Dr. Galson wants to say some things and then, whenever he is finished, we will take a break and we will reconvene at 10:15. So, those of you who don't want to hear what Dr. Galson has to say can get out now and the rest--

DR. GALSON: No, no, just a very brief announcement, and that is we have a space problem in this facility. There are more people than we have seats for. So, we have established a live video feed in our advisors and consultants conference room on the FDA campus at 5630 Fishers Lane, designed for FDA employees only. So, FDA employees who may be sitting in the public section, I strongly urge you to please move to that area to make more room for the public and, of course, you will need your FDA ID badge to get into that space. But it is ready now and if you could move at the break, it would be great. Thanks.

DR. WOOD: Okay, we start promptly at 10:15.

(Brief recess)

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