Q&A: The making of prasugrel	February 2009

To learn more about the development process behind prasugrel,
Med Ad News spoke with Joseph Pieroni, president and CEO, Daiichi Sankyo Inc. and Francis Plat, M.D., VP of clinical development, cardiovascular medicine, Daiichi Sankyo Pharmaceutical Development.

Francis Plat: Our major activity now is in thrombosis and antiplatelet activities. In terms of antiplatelet drugs, we have a very large trial agent in the coronary intervention area (prasugrel). The teaming group has published in the New England Journal of Medicine the results of these trials showing good superiority versus the current treatment, which is clopidogrel (or Plavix), used in combination with aspirin. In parallel, we have to balance the risk and especially the [major] bleeding. We have identified populations who are at risk for which we can reduce this effect and adjust the dosage. We went to various authorities and found out we’re in good shape, and we are still in discussions with the major agencies. This is major step forward to treat the patients with PCI (percutaneous coronary intervention).

Joseph Pieroni: One thing that people are missing is that when you look at the evolution of antiplatelet therapy, it really starts with aspirin. If you look at the events reduced, when aspirin was compared to placebo, it showed a 20% reduction in outcomes such as stroke, death, and myocardial infarction. And then when you looked at Plavix over aspirin, you saw about a 20% improvement as well in outcomes. Now when you compare our product (prasugrel) to Plavix, you see that incremental 20%.

On the bleeding side, the bar is much smaller. The number of people that have serious bleeds is much smaller compared to the lives that you save. With Aspirin compared to placebo, there was a 30% increase in bleeding. When Plavix was compared to Aspirin, there was a 30% increase in bleeding. And when we compared ourselves to Plavix, there was 30% increase in bleeding. So it's a mechanism based phenomenon, but the outcomes of advantage versus the risk of bleeding, unfortunately, is completely different.

One of the other advantages is that Plavix is the standard of care, but it takes several hours for it to reach its effect. So your person comes in, needs a stent. Ours basically achieves peek levels within an hour.

Francis Plat: The process to get this active substance is much more direct with Effient (slated branded name for prasugrel) than it is with clopidogrel. That's the reason why we are more active.

Joseph Pieroni: This is an advancement area, which is really important. The importance of this field is in cardiovascular medicine; you're always trying to show a surrogate marker to predict what a future outcome will be. To lower cholesterol, it takes many, many years to show the original preventing the outcome. In this case, within the trial period, you are preventing outcomes in three months, six months, one year. You see the immediate effect, and you can show not only a clinical advantage, but the pharmacoeconomic advantage of preventing the unbelievable costs of hospitalizations.

Francis Plat: The comparison versus an active compound is always a challenge because it’s very difficult to show superiority. Here, we took the challenge and we won. We get superiority versus clopidogrel at the beginning of the treatment but [also] all along the study during one year, which is very important because when you start a treatment of that kind, you have to make sure that the benefit is still there when you continue to treat. So we have a period of superiority within the period of one year.

That gives us really a good reason to believe that the higher your activity on the platelets, the better your outcome. Of course, there is a price to be paid, but in this particular case, in all the populations that are going to be proposed for our treatment, the net clinical benefit is always in favor of Effient versus Plavix. That's the most important message that is going to be conveyed in the future. The net clinical benefit is always in our favor. We are not robbing Peter to pay Paul. We are having net clinical benefit.

Joseph Pieroni: Probably the most interesting aspect of cardiovascular medicine right now is thrombosis, the prevention of blood clots. So in this case, you enter the hospital with crushing chest pain. They either say you need a stent, so you go right into that category of the 60% of people who get stents, and virtually 100% go on Plavix. I think everybody realizes that it’s not an acute treatment, but people generally have to stay on Plavix for one year, because the aftermath of the stent is obviously harmful. So that’s the standard of care. We feel that we're bringing something to an important area of medicine.

Our surrogate marker is platelet activation. We have shown that our product is better than Plavix in making sure that platelets are not activated.

Francis Plat: Maybe you’ve heard a recent concern expressed by the authorities at the FDA regarding prasugrel. They said that with drug-eluting stents – which are the strands with a special compound in it to prevent the restenosis of the vessel – the problem is they seem to promote more clotting inside. We are now considering the effect of these drugs. What we are now trying to show is that maybe two years or three years of treatment is going to be the gold standard. We are going to contribute to a major trial that has been announced. It’s going to be a moving target. It’s probably going to be the most important medical topic of this day. We treated for one year. The future will be to test whether or not we need to treat longer, but for the time being the current standard is to treat one year. We have an extension of the trial.

Joseph Pieroni: So we talked about the 60% of patients that get a stent. What about the 40% that leave the hospital with crushing pain that don’t get a stent? We’re doing a second study, and we call these medically managed. They don't have a stent, they leave the hospital, but obviously they’re in serious territory. We’re doing, again, a head-to-head comparison against Plavix to see whether or not we can save heart attacks, stroke, and death in these people who are medically matched.