Posted by Jeff Berk, BOLT International; Merck announced today that they have returned to Portola all rights to betrixaban. BOLT spoke with our SPAF (prevention of stroke in patients with atrial fibrillation) Thought Leaders last month and asked them to identify any marketable advantages that were starting to emerge from the Ph-II EXPLORE-Xa trial. They came up with two. But the reality is that Pradaxa (dabigatran; Boehringer-Ingelheim) has a survival claim based on RE-LY, and Eliquis (apixaban; Pfizer / Bristol-Myers Squibb) is likely to as well (we’re optimistic that ARISTOTLE will be positive). Xarelto (rivaroxaban; Bayer-Schering / Johnson & Johnson) didn’t completely convince everybody with ROCKET-AF, but the drug also has its SPAF supporters. Net, the piece of the pie that will be available for betrixaban is most easily described as the 10% who are intolerant of dabigatran. This market is going to be perfectly fine for Portola, but is hardly worth Merck’s time.
Here’s what BOLT’s Cardiology Thought Leader panel had to say last month about betrixaban:
- The marketing tag line for betrixaban will be: “Consistent effect”, playing up the pharmacodynamic advantage of the drug. The detail materials will show competitors’ drug levels going up and down: Coumadin on one line and rivaroxaban on the other line. Then there is this straight line with betrixaban. The caption will say “Wouldn’t you want your patients to be there?”
“I don’t think the renal advantage alone will be. I think they are going to have to play up their pharmacodynamic data again. I can imagine a situation where their marketing materials have the word consistent or consistency plastered all over it; consistent effect, consistent efficacy. I think that is not going to be underestimated. Is it really going to be any better than the first three drugs?
“That is a good question. There are two ways to look at that. One is to say what does the science show? Is it better? Which we may not have an answer to. But the ultimate answer to that question from an industry perspective is can it be marketed to be better? We are all familiar with how marketing can influence prescribing patterns. You can imagine all kinds of detail materials that show all these different drug levels and going up and down and Coumadin on one line and rivaroxaban on the other line. And then there is this straight line with betrixaban and you say wouldn’t you want your patients to be there?”.
- On paper, betrixaban has one of the best safety profiles in the FXa class. It is minimally excreted through the kidney so it will be more useful in patients with renal impairment, and appears to have few drug interactions. It’s pharmacodynamic range is much more stable than rivaroxaban’s; which tends to have rising trough levels with more chronic usage. Furthermore there is a very positive psychological effect to be derived from Portola’s co-development of a FXa antidote.
“There are reasons to think at least scientifically that betrixaban may have an advantage because some of the issues related to drug clearance, but also because if you look at their pharmacodynamic effect they tend to be much more stable than rivaroxaban which tends to be up and down a little bit. What is interesting about the rivaroxaban, which really the early rivaroxaban data, is that there was some suggestion that the bleeding risk may be related to the elevated trough levels, which surprised me. That is not the way we generally think about it. We say, oh it has had such a robust peak effect, that is where you are going to bleed. It turns out that may not necessarily be the case and it may be related actually to the trough levels that as you take the drug chronically and that trough level sort of gradually rises that is where you see some of the bleeding risk; whereas betrixaban doesn’t have that sort of up and down. It appears at least pharmacodynamically to have a very stable effect. Now the big issue, of course, is that has got to be born out in clinical trials, whether that stability provides some kind of an advantage clinically – well they are going to test it against warfarin. No one is going to treat betrixaban against rivaroxaban. But they may have some ammunition there if that betrixaban data turns out to be similar to what we are seeing with rivaroxaban versus warfarin”.
“I think betrixaban on paper has the best profile of all the drugs. That is an interesting statement. Remember, I say on paper. And certainly what is in the public domain. What do you like about the profile? I like the profile that it is only minimally cleared by the kidney. So you don’t have to watch kidney function as closely as you have to do in older patients who are on the other drugs. Secondly, its metabolism is straightforward and that the chances – now I don’t know this for sure – of drug-drug interactions would be less and in that respect it is nearer to dabigatran. It is going to be co-developed with an antidote, which is not an easy thing to do if you really think about it. But there is a psychological advantage of that. It also being last would be able to capitalize on some of the errors that have been made in the trial designs of the other drugs and they will be able to collect data that the other studies have not collected. So it is gaining from experience. I think their challenge is to get the dose right. They have to get the dose right. It is like all these drugs in that if they get the dose right, unless things show up, and sometimes things do show up, they have a really good profile: high protein binding; the bioavailability is high. That is on paper. I think the trials have to prove that”.
“Betrixaban has a very interesting profile. First of all, it is not cleared by the kidneys so it could be used in patients with impaired renal disease, although in the phase II trial patients who were likely heading to dialysis were excluded”.
“It is a once a day drug. It does not have p450 metabolism so the drug-drug interactions are likely to be minimal. It is reabsorbed by P-glycoprotein back into the gut. Drugs that interfere with that process may affect it. It has a terrific profile. There is no question about it. Again, it is just a matter of getting the dose right”.
“So betrixaban seems to have, at least from what I have seen, a very steady level of anti-Xa inhibition. It is almost flat, whereas rivaroxaban goes up and down. Now I don’t know what those differences are going to mean in terms of clinical efficacy or safety, but it makes you wonder. If your level is going up and down and you miss a dose does that mean that you risk of thrombotic events goes up? Similarly with betrixaban, if the level if so steady then do you all of a sudden run into a bleeding risk where you have a procedure. So these are potential differences. My guess is that they are going to probably be small. I think at this point if the class of drugs is going to work, it is probably going to work across all agents with maybe some subtle differences. I doubt that we are going to run into – well I shouldn’t say that – but it may be end up being like the IIb/IIIa inhibitors where they all sort of showed efficacy over placebo. It wasn’t until someone did the TARGET trial that Merck was on the losing end when they compared tirofiban directly against abciximab. I wouldn’t doubt that we would see multiple agents within the same class approved”.
- By the time betrixaban is in Ph-III trials the “drug to beat” should be Pradaxa. Betrixaban will be studied against warfarin because that will be easier for Merck to demonstrate a relative clinical advantage. It’s still ethical to run that study since warfarin is standard of care.
“I think what that speaks to is this dichotomy between what is clinically most relevant versus what will get the drug approved. I think that is the challenge. It is sort of like what is the competitor when you do an ACS trial of oral antiplatelet therapy? Well, most people say you have got to compete against clopidogrel. Why? Because we know what the limitations of clopidogrel are, it is an easy drug to beat, you have a positive phase III trial, it is a recommended therapy in the guidelines and that is how you get your drug approved. Now practically speaking people will say, well if you show me a trial where it beats clopidogrel I am going to say well I am not using clopidogrel, I am using prasugrel. That is a very clinically valid point. The issue I think from the industry point of view my guess is they want to get the drug out there. And they want to do it in a way that is lowest risk for them. While Coumadin is not as much of a straw man as aspirin is, it does I think provide a little bit of a weaker competitor so you can have that all important p-value less than 0.05 in a phase III trial that the FDA seems to like so much for approval. I think that is the issue is what is going to get the drug approved versus what is going to get the drug used. Getting the drug used is a little bit of a lower bar. Physicians are like sheep, we respond to marketing much more than we respond to science. So once a drug gets approved they can market the crap out of it and get it used. That is my guess anyway”.