betrixaban (Portola / Merck)


Posted by Jeff Berk, BOLT International


This is an echinopsis hybrid.  They’re easy to crossbreed and sometimes they even have pretty color to them.  I hear that the Ohio valley had poopy weather today.  Nya Nya na na na.  We had another sunny day.  I’m laughing now.  You’ll be laughing at me when I’m stuck here in Arizona in July and it’s hot enough to fry an egg on my pool filter.  And we can’t cool the water down below 100F (that’s 37.8C for my South Asian guests).  This is a plea to any of you company peeps out there, doing Alzheimer’s research.  I’M AVAILABLE TO COVER ICAD IN PARIS IN JULY.  And given the option of doing that, or fried eggs, I’ll work for martinis.


So for the next few posts I want to drum up some interest in some of BOLT’s upcoming Thought Leader panels.  We’ll be running a slew of them in May.  My favorite is going to be lung cancer (non-small cell and small cell), just because it’s been a while since we last ran it and there’s going to be a lot to talk about.  We’ll definitely talk about BATTLE and its ramifications for drug development.  We’ll be running another Multiple Sclerosis panel, another IBD panel and another Anticoagulants panel.  I’m thinking that will be both antithrombotics and antiplatelets.  If you’re visiting from the pay side, and want to field questions, let me know.  We are also publishing this week our 51st Osteoporosis panel.


Okay, so now that the advertizing is out of the way, let’s talk about what comes a little bit later in the Factor Xa (FXa) space.  I flipped a coin on betrixaban and edoxaban.  Betrixaban won.  So here are some insights from the most recent two of BOLT’s Cardiology Thought Leader panels, with a focus on how the drug will do in SPAF (stroke prevention in atrial fibrillation):



  • 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”.


  • Betrixaban is being co-developed with an antidote which would be given intravenously to immediately reverse its action.  Portola appears to have the rights to the antidote; which should reverse the action of betrixaban as well as other FXas.  Having such an antidote to instantly stop acute bleeding is going to be a strong positive for use of a FXa vs. a direct thrombin inhibitor.


“Betrixaban is being co-developed with an antidote which would be given intravenously that has an immediate action.  So that is an advantage.  Having an antidote so basically you are going to reverse the anticoagulant effect? Immediately.  Immediately.  So is that going to be applicable only to the say use of the drug for ACS patients or is having that antidote available going to be relevant to the patient who has taken this daily for many years as a SPAF? The antidote as I understand it would apply to all FXa inhibitors including, of course, betrixaban.  So it is a kind of a generic antidote.  Who is developed by? It is being developed by Portola.  I don’t think Merck has purchased the rights to the antidote.  That has a different owner, which is Portola the biotech company”.



“Obviously, any acute bleed in an acutely ill patient is something that you would want to stop immediately.  So it would definitely have a role there, and the same with the hip and knee patients.  In SPAF it would be of value for serious GI bleeding.  But generally if you have serious GI bleeding you go after the source of the bleed; endoscopically you take care of it.  That is the way you treat these patients”.


“That is a very interesting question.  I think that would have to be proved.  Obviously, any acute bleed in an acutely ill patient is something that you would want to stop immediately.  So it would definitely have a role there, and the same with the hip and knee patients.  In SPAF it would be of value for serious GI bleeding.  But generally if you have serious GI bleeding you go after the source of the bleed; endoscopically you take care of it.  That is the way you treat these patients.  Intracranial bleeds now with dabigatran will become so uncommon that these newer agents would somehow have to match that.  So with intracranial bleeds stopping the bleeding, of course, is important, but again it is a surgical procedure.  I think time will tell.  It is a tantalizing question that you are asking.  Obviously if you have an intracranial bleed and you have an antidote you are not going to do any harm using the antidote.  It will be preferable.  We always think that warfarin has an antidote but when you give vitamin K antagonists that take 24 to 36 hours for them to work.  We always think that warfarin has an antidote and it works instantaneously.  That is not true because when you give vitamin K it takes 24 to 36 hours.  Fresh frozen plasma is the antidote, but you have to thaw the plasma; you have to identify the patient; you have to get enough of it in the patient, and it takes four or five hours to do that.  Whereas, this antidote will be given intravenously and it works almost instantaneously”.


Categories: Antithrombotics, Cardiovascular
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