Posted by Jeff Berk; BOLT International
Item #1: Re: Joey Chestnut (and this is not my quote and I don’t know the source), “He’s ingested more bad meat than Boy George”. The man is simply untouchable. Five consecutive championships. But Joey, please, please, PLEASE don’t you be another Lance Armstrong doping scandal. You BETTER be clean. ‘Nuf said.
Item #2: The one and only Nancy Pelosi told us all to “Pass Health Reform So You Can Find Out What’s In It”. On page 1,697, about halfway down the page, you will find the section that authorized Donald Berwick to decide what you have to eat for breakfast. DB thinks you should eat whole grain paper mache. It’s “good for society”, after all. Well, as we are deep into our next election season (did the last one ever end?), I’m taking this opportunity to recommend that instead of you voting for Baby Doc Duvalier once again, you vote for ME to be your dictator. I’ll declare that all BOLT Pharma Blog readers have to eat smiley eggs for breakfast. Even if it’s not “better” for you, at least it will be more tasty than Don’s whole grain anything.
On July 20, 2011, FDA is set to rule on AstraZeneca’s US Brilinta registration (note that the drug goes by the name “Brilique” in the Eastern US suburbs; which are themselves known by some as “Europe”). The FDA tardocrats turned down ticagrelor this past December. Will they shoot the drug down again? The 8-ball says “signs point to no”, but who the heck knows what Obama will decide to do about ticagrelor. I mean we haven’t had a tween running a major government function like FDA since Amy Carter ran the Nuclear Regulatory Agency. Do any of my readers think FDA makes a move without clearing it first through Barry? Now, I obviously can’t influence him (I admit it. I can’t speak a single word of Obanics), so what I’ve decided to do instead, is influence you with some of the opinions from BOLT’s Anticoagulants Thought Leader Panel #10. Our world renowned Cardiology Thought Leaders tell how they will use ticagrelor. The comments also offer a hint to the fate of cangrelor, and the direction Novartis should take with elinogrel. Enjoy…
Brilinta (ticagrelor; AstraZeneca)
The first patients who will see ticagrelor outside of the clinical trial environment is early on in the top 1/3 of high risk patients with acute coronary syndrome.
“Waiting for ticagrelor is still far and away the most exciting development. Nothing is even close”.
“I am going to use it in the hospital setting pretty much across the board in ACS during the early period. I am going to use it a lot to get some experience with the dyspnea. I believe the mortality benefit is likely to be real. I am likely to use it, not in everybody, but I think in at least the highest risk individuals with ACS, the top third for sure I think. I do believe that data is pretty compelling”.
Ticagrelor, dosed orally produces its antiplatelet effect in a very rapid 30 min post dose. Today this doesn’t leave much room for cangrelor. In the future, Novartis will have to show that elinogrel IV, with an on-time of about 8 min, offers a clinical advantage to ticagrelor. The opening may have presented itself in data from the PLATO platelet substudy, where one patient out of 12 with an ST elevation MI who received ticagrelor (by the oral route) had delayed onset of action.
“You have ticagrelor you get incredibly high antiplatelet effects; 30 minutes after an oral load. It sounds neat, but under what circumstances getting therapeutic in 8 minutes better than 30 minutes. It’s very rarely I think. I just don’t think that will make a difference in clinical outcomes. You sort of see that with the Cangrelor thing where it just didn’t seem to matter that much with the parenteral agent in that space”.
“Because in PLATO platelet substudy we had one patient who had ticagrelor with an ST elevation MI who had delayed onset of action. That was 1 out of 12. It was a very small study, but it did demonstrate the fact that you can’t be 100 percent sure that the drugs are going to be absorbed in that acute setting in a way that you would like to see them absorbed. We are getting into an age where we want very consistent antiplatelet response so we know exactly where we are similar with anticoagulants. You want to know where you are with these agents so that you can apply them in the most reliable and safe way. And so being able to give an IV bolus of a high grade P2Y12 inhibitor and know that you have got an effect has got some attraction”.
Discontinuation of ticagrelor must be done 5-days prior to surgery. Otherwise there is the same incidence of bleeding events anytime within the first five days post discontinuation. This is the same as clopidogrel. True, ticagrelor has a much faster off-time, but since it is starting from a much higher level of platelet inhibition than clopidogrel the offset time actually turns out to be the same.
“I don’t know if you follow the ticagrelor issues with the upstream and the bleeding early. Ticagrelor is reversible but the truth is it is not that reversible. In other words, if for example you go to an ER and you get the drug, okay the patient needs to go to surgery, okay send the patient the same day, the next day or after two or three days. You have really got to wait the five days. It is just like clopidogrel. It is reversible, but since you start such a high level of platelet inhibition it takes three to five days to get down to baseline. Now the OFFSET study shows three days with the primary endpoint, but all their functional endpoints is five days. And the clinical data in the CABG population from PLATO actually showed us five days. So even if you have a reversible agent you are really not overcoming the problem that we have with clopidogrel. Actually you are not overcoming it at all. The truth is with ticagrelor, and everybody thought it was going to be slam-dunk, everybody is going to get it in the ER. They may promote it that way and people may believe it that way, but the truth is it is not that way and the data are pretty clear”.
“What I thought you said to me was that ticagrelor isn’t really that much better than clopidogrel in that regard. In terms of washing out, yes. Wash out. So what I am trying to get a sense is… From the clinical trial. And this is data which is available from the data that was presented to the FDA and it is in the public domain. So basically within the first five days you are looking at the same incidence of bleeding events if the patient goes to surgery”.
AstraZeneca is studying lower dose ticagrelor (60 mg bid vs. the usual 90 mg bid) for the prevention of atherothrombotic events in a massive Ph-III prevention trial in patients with stable vascular disease. This is the same population as was studied in the CHARISMA (clopidogrel) trial, and that Merck is studying in TRA 2˚P-TIMI 50.
“You bring up a great point. It is fascinating that all the companies are going into this CHARISMA space, not just vorapaxar but AstraZeneca is going there with ticagrelor. They have a giant CHARISMA CAPRI-like outpatient trial that they are doing. Those really raise questions because if a relatively weak antiplatelet agent doesn’t have a favorable efficacy safety benefit in these stable outpatients what makes you think that a more potent drug that causes more bleeding won’t? I think it comes down to whether or not ticagrelor is a unique mechanism of action and whether the mortality benefit would extend to outside of the ACS arena. It is not impossible, but it is funny that everybody sees that as the great untapped market. What is the dose going to be for ticagrelor? In other words, if you are worried about this increased risk of bleeding? I have not seen the final protocol for that study yet. That is a great question. I don’t know what the dose is that is going forward in that. It might be 60 b.i.d. but I don’t know actually”.
elinogrel (PRT-128; Portola / Novartis)
For elinogrel to overtake ticagrelor, one of four events is going to be required: 1) dyspnea turns out to be a major problem with ticagrelor. 2) Ph-IV ticagrelor studies fail to confirm the mortality benefit. 3) Elinogrel also shows a mortality benefit, or 4) Novartis can convince physicians that the time to onset of IV elinogrel is so much faster than that for ticagrelor (8 min vs 30 min), or the offset is so much smoother, that there is a clinically relevant difference.
“I think the real nasty question is since ticagrelor is working fairly quickly can you really show that these new drugs are an advantage? Of course, if you give it intravenously you know you will get the effect immediately, but with ticagrelor you might get it fairly quickly, that is probably within the first hour at least. So maybe one could say that well maybe it is important that there is a blockage during the PCI procedure, but this is the step. I think you are entirely correct in that we haven’t got a clue yet whether these intravenous compounds really will help us. In theory they are attractive because they work immediately and when you take at least cangrelor away the effect also disappears. I am not sure but the concept with elinogrel is that it might be an advantage to go with the same drug all the time because it would be easier somehow to control the inhibition of the receptor in an optimal way. That is their hope. I think the drug company is now testing this”.
“Elinogrel is moving along. Its relevance to me is it is going to have to hit an absolute home run or have really, really good side effect profile to be a competitor in that field. One of four things has to happen for there to be space for a drug like that. One is that when we actually start using the ticagrelor the dyspnea turns out to be a major deal. Two is that that their additional phase IV studies do not confirm the mortality benefit, and then people will start to question whether there is mortality benefit. Three, elinogrel hits a homerun just like ticagrelor did and namely demonstrates mortality reduction, but we have seen how often that happens. I think that is what it is going to take for there to be space for that drug. You don’t need an IV formation when you have a drug that is rapidly acting as ticagrelor. Other than perhaps better side effect profile, I think ticagrelor is going to be hard to beat. How much of a value is this dual dose form, the IV and oral, for the same agent? It is a value for drugs where the oral has slow onset or a lot of variability but when you have ticagrelor you get incredibly high antiplatelet effects; 30 minutes after an oral load. It sounds neat, but under what circumstances getting therapeutic in 8 minutes better than 30 minutes. It’s very rarely I think. I just don’t think that will make a difference in clinical outcomes. You sort of see that with the Cangrelor thing where it just didn’t seem to matter that much with the parenteral agent in that space.
Side effects seen with elinogrel include transient dyspnea ( same as ticagrelor) and elevated liver transaminases (NOT a problem for ticagrelor).
“They compared elinogrel to clopidogrel loading in patients undergoing PCI and found actually that the drug in the doses used were reasonably safe and that their side effects were mainly a bit like the one we have seen with ticagrelor like dyspnea that they said were transient. And there were also some problems with elevation of transaminases and liver enzymes. So that was a little worrying, but I think still the efficacy of the drug when you did platelet testing was better than clopidogrel and it seemed to be fairly safe and tolerated”.
“Clearly ticagrelor is going to have a very strong hold on the ACS market. That clearly gives it a competitive edge. There is also the issue about liver function tests abnormalities with elinogrel. That makes it less attractive compared to ticagrelor, which doesn’t have any signal there. So for the long-term administration I can only envision elinogrel undercutting ticagrelor in terms of price would give it a significant footing in the market, for ACS at least. It will be very difficult to do an ACS study with elinogrel because how would you do that once ticagrelor is there and used in the population that you would need to study in order to show a benefit. Does a noninferiority trial against ticagrelor get you anywhere if you were Novartis or Portola? It would be so hugely expensive and you would still be left with the issue about adverse effect profiles”.
Elinogrel has an interesting and novel benefit in that for the first time there is a compound that can smoothly transition from an IV format to an oral format without any interaction. The IV formulation potentially could be attractive for the ST elevation MI population particularly, but also for centers who are doing their angiogram first looking at the anatomy and then deciding to proceed. With cangrelor the physician has to wait for the infusion to stop before he can give a thienopyridine; because otherwise cangrelor’s ongoing blockade of the receptor prevents attachment of the loading dose of the follow-on oral thienopyridine (clopidogrel, prasugrel, etc). The follow-on simply gets eliminated, and there is, in fact, no loading dose present to protect the patient. With elinogrel you do not have that problem. You can give the IV and oral medication at the same time and there is a smooth transition. If this is clinically relevant, #3 above should be valid and there should be a survival advantage with elinogrel. If however there is no survival advantage, there is little chance of physicians staying with elinogrel when moving from the bolus to the oral.
“You have got the advantage of elinogrel being able to use it intravenously. The IV formulation potentially could be attractive for the ST elevation MI population particularly, but also for centers who are doing their angiogram first looking at the anatomy and then deciding to proceed. It would be attractive there. So the IV formulation of elinogrel I think would warrant further study at least to perhaps compare pharmacodynamically with ticagrelor in terms of onset of action in that setting. Because in PLATO platelet substudy we had one patient who had ticagrelor with an ST elevation MI who had delayed onset of action. That was 1 out of 12. It was a very small study, but it did demonstrate the fact that you can’t be 100 percent sure that the drugs are going to be absorbed in that acute setting in a way that you would like to see them absorbed. We are getting into an age where we want very consistent antiplatelet response so we know exactly where we are similar with anticoagulants. You want to know where you are with these agents so that you can apply them in the most reliable and safe way. And so being able to give an IV bolus of a high grade P2Y12 inhibitor and know that you have got an effect has got some attraction”.
“I think there is a possible option there for elinogrel just as there has been for cangrelor. But it may be there will be some competition between those two as your sort of up front intravenous agent. But whether using IV elinogrel will them sort of lead to more people using oral elinogrel as a follow on I am not sure given the robust clinical outcomes data with ticagrelor. The rational step would be to perhaps using IV elinogrel or cangrelor and then follow on with ticagrelor straight afterwards”.
“With cangrelor one of the problems could be that when you take the patient off cangrelor and you want to put an oral drug in like, for example, clopidogrel, which it was at that time there might be some sort of problem with blocking the receptor in an optimal way. These will drugs will somehow compete in a bad way on the receptor. So that is the advantage of having a drug that is the same both on intravenous and for oral. I mean that is the thought”.
“It is an interesting property and a novel property that for the first time we actually do have a compound where you can transition from an IV format to an oral format without any interaction. You have this smooth transition. Why is that important? Because everybody thought in the past that Cangrelor was the big deal, but unfortunately you can’t transition smoothly to an oral agent. You have to wait for the infusion of Cangrelor to stop before you can give a thienopyridine because otherwise this interaction with the receptor this actually can be dangerous. For example, if you transition from Cangrelor to clopidogrel or prasugrel and the patient that is getting the drug at the same time with Cangrelor the receptor is occupied and so with prasugrel and clopidogrel you metabolize the drug, but since the active metabolites is very unstable they have nowhere to attach. They can’t attach and bind to the receptor, so they just get eliminated. So you believe that the patient got a loading dose of the oral medication but then the patient is without any antiplatelet coverage. So with elinogrel you do not have that problem. You can give the IV and oral medication at the same time. There is no interaction and there is a smooth transition. So it is a unique property. It is a unique property”.
Ticagrelor offset takes about the same 5-days prior to surgery as does clopidogrel. With elinogrel, an IV bolus given one day is gone by the second day. Patients can have their surgery and then be transitioned to the oral elinogrel.
“Ticagrelor is reversible but the truth is it is not that reversible. In other words, if for example you go to an ER and you get the drug, okay the patient needs to go to surgery, okay send the patient the same day, the next day or after two or three days. You have really got to wait the five days. It is just like clopidogrel. It is reversible, but since you start such a high level of platelet inhibition it takes three to five days to get down to baseline. Now the OFFSET study shows three days with the primary endpoint, but all their functional endpoints is five days. And the clinical data in the CABG population from PLATO actually showed us five days. So even if you have a reversible agent you are really not overcoming the problem that we have with clopidogrel. Actually you are not overcoming it at all. With prasugrel it is actually even longer so what is the other new kid on the block? Elinogrel. And elinogrel you can give the medication, you can give the IV bolus, you can give the oral drug, you transition smoothly, no interaction and if you just want to give the IV bolus just to have some protection, for example, if a patient comes in the ER and gets an IV bolus, by the following day you are not going to have the effect. I think it is something very, very useful in their hands. On a personal note, for example you are asking me the question, if I were to be in the public forum I would respond in staying, wait I am not disclosing any confidential information. I don’t even know if Novartis and Portola are moving in that direction, but as a clinician and somebody who analyzes and critiques the data out there, well, this is something where it would be interesting to invest in, in terms of developing a clinical trial really to show what happens in the acute setting. That is my personal opinion because the truth is with ticagrelor, and everybody thought it was going to be slam-dunk, everybody is going to get it in the ER. They may promote it that way and people may believe it that way, but the truth is it is not that way and the data are pretty clear. What do you expect to see if the patient is on oral elinogrel? The thing is you are probably going to have perhaps a more rapid return to baseline. The thing is you have an opportunity of just giving a bolus of elinogrel. You don’t even have to give the oral. You are just going to give an IV”.
Novartis/Portola are gearing up for a secondary prevention trial, similar to the protocol AstraZeneca is running with Brilinta. The Ph-III trial will be an estimated 20,000 patient study in patients who have survived an acute MI.
“This is Portola that had the drug, but I think now Novartis will help them to sort of make this a big study because clearly that will be a major study to perform. It may be 20,000 patients after surviving an acute myocardial infarction”.
“The truth is they have lots of plans. Nothing is carved in stone of where they want to take the drug. I understand they have a secondary prevention trial designed. Okay, that is public information. I would not say that everything is just so carved in stone yet”.
cangrelor (The Medicines Company)
Cangrelor is going to be overtaken by elinogrel. Elinogrel will not present the same challenge transitioning from parenteral to oral antiplatelet therapy.
The competitor in a way, if you talk intravenous, is the drug called cangrelor which was used in two major trials that were published last year in NEJM after also a fairly promising phase II program. And then they actually took this drug, which is just an intravenous drug, you just give it as bolus and infusion and then you block the platelets completely. When you take them off the drug this disappears. So very smart in a way if you want to have a quick action and maybe in particularly if you are also doing surgery. But for some reasons these trials were negative. And there you were talking about cangrelor? Yeah, that is right, but you see I would say with cangrelor one of the problems could be that when you take the patient off cangrelor and you want to put an oral drug in like, for example, clopidogrel, which it was at that time there might be some sort of problem with blocking the receptor in an optimal way. These will drugs will somehow compete in a bad way on the receptor. So that is the advantage of having a drug that is the same both on intravenous and for oral. I mean that is the thought”.
(From last report): The last hope for cangrelor is the BRIDGE trial, which will look at the drug as a bridging strategy in the setting of patients who need to undergo surgery. This is the right setting to niche the drug based on its short acting properties, but it becomes an acknowledgment that the market opportunity for a very short acting iv only agent for ACS is rather small.
“So it seems like with cangrelor the last hope for the drug really is this BRIDGE trial. It is a good drug. It is the shortest acting P2Y12 inhibitor. It has to have some sort of role to play perioperatively. It is just finding that. If it was on the shelf then I think people would use it in an ad-hoc way because there are always going to be patients who are particularly concerned about going into an operation and where you want to have absolute control over their antiplatelet response. So nothing else is competing with cangrelor in that sense. So it should find a way through with appropriate development. Whether BRIDGE will be enough to get it registered, I don’t know”.
“What I am going to say to you is in the public domain. Cangrelor right now having had their phase III which turned out to be what it turned out to be. It is going to go back to what its original niche was thought to be which is as a bridge strategy. There is a trial which is ongoing which is called BRIDGE taking advantage of the benefits of this drug as a bridging strategy for patients who need to undergo surgery. Now you can say well where do we put that if we have ticagrelor and then potentially down the road elinogrel? That is difficult to say, but I do believe that this is a very good drug and it is worthy to proceed with clinical investigation. Unfortunately, the phase III trial was in my opinion not designed in the most optimal of ways, which then obviously led to the outcomes, although we don’t know the details. What element would you have changed in the design? As we learn these elements and now we can look back and say I wish we hadn’t done that. I think one of the issues with Cangrelor I think the way the trial was designed it was not following what current practice patterns are. So it created its niche in something which was not within standard of care. Let’s put it that way, and it was designed somewhere in disconnect with what was originally their phase II development. Now you know that this was originally an AstraZeneca drug that was sold to the Medicine’s Company. AstraZeneca originally had their line of research and ideas for clinical development, and this is not a secret, which was changed. I think that in my opinion had an important role. It is just my hypothesis. We don’t know the details of the data. We will learn a lot more. But I think that a different trial design could have been useful”.