About two and a half years ago, we were introduced to andexanet alfa (Andexxa), a modified recombinant form of factor Xa designed as a reversal option for factor Xa inhibitors. The mechanism of action is simple: andexanet mimics native factor Xa, providing the various Xa inhibitors (rivaroxaban, apixaban, edoxiban, betrixiban, and enoxaparin) an alternative target. When sufficient Xa inhibitor is bound to andexanet, the native version is freed to return to its normal work in hemostasis.
The problem, however, is the reversal is not durable. The half-life of andexanet is approximately 1 hour, after which point the factor Xa inhibitor levels rise and hemostasis is again impaired. This necessitates a bolus and an infusion. A bolus and infusion that costs ~$3,000 per 100mg vial – and requires 900mg for a “low dose” protocol or 1,800mg for a “high dose” protocol. And, it all vanishes to dust when the infusion completes.
The first NEJM publication regarding andexanet featured just the first 67 patients from ANNEXA-4, an open-label, single-arm descriptive study of patients given andexanet for major bleeding. Now, presented at the International Stroke Conference 2019 in Honolulu, we have the results from the full 352 patient cohort – and they’re every bit as uninspiring as the preview.
Nearly all patients were receiving rivaroxaban (half-life 7 to 13 hours) or apixaban (half-life 12 hours), with a handful on enoxaparin. As in the preview, the bolus of andexanet effectively dropped circulating levels of the factor Xa inhibitor down to negligible amounts. Again, as seen before, after cessation of the bolus, factor Xa levels returned to a level consistent with their terminal half-lives. Case in point: “At 4, 8, and 12 hours after andexanet infusion, the median value for anti–factor Xa activity was reduced from baseline by 32%, 34%, and 38%, respectively, for apixaban and by 42%, 48%, and 62%, respectively, for rivaroxaban.” This is just normal metabolism, not andexanet magic.
Death occurred in 14% of patients within 30 days, and there were thrombotic events in 10%. Hemostasis at 12 hours, their primary outcome, was 82% “in 204 of 249 patients who could be evaluated”. Specifically, they excluded a third of their population because they were effectively enrolled in error, as they met bleeding criteria but not Factor Xa inhibitor level criteria. This is similar to the idarucizumab open-label demonstration, in which many patients who were not actually coagulopathic were treated with anticoagulation reversal. This represents tremendous waste and cost.
Finally, the nail in the coffin, this admission in the abstract and the text: “Overall, there was no significant relationship between hemostatic efficacy and a reduction in anti–factor Xa activity during andexanet treatment.” The primary outcome wasn’t even correlated with their intervention!
As you can tell from the tone of this post, I am profoundly unimpressed with the value demonstrated here. There’s no evidence this is clinically useful, nor a potentially preferred strategy to use of prothrombin concentrate complexes to replete missing factor. The company and the FDA effectively admit the same:
The most important limitation of this trial is that it did not include a randomized comparison with a control group. At the time of study initiation, it was determined that a randomized, controlled trial would have logistic and ethical challenges, given the perceived risks of placebo assignment in this highly vulnerable population. However, continued use of unapproved agents, despite a lack of rigorous clinical data, has changed the equipoise for a trial. Thus, under the guidance of the FDA and as a condition of accelerated approval in the United States, the sponsor is conducting a randomized trial (ClinicalTrials.gov number, NCT03661528) that is expected to begin later this year.
I’m sure more will be made to unpack even further unfavorable details as time passes – and, until further reliable evidence can be presented, I’d pass on andexanet, as well.
“Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors”
https://www.nejm.org/doi/full/10.1056/NEJMoa1814051
You’re making a lot of assumptions without a complete understanding of all the preclinical work done here.
FDA allowed a surrogate endpoint for accelerated approval based on significant preclinical evidence that short term reversal of Xa inhibition rapidly controls bleeding and correlated with bleeding control and survival. This is highly dose dependent and correlated with the most important outcomes.
Here’s some data:
https://ash.confex.com/ash/2018/webprogram/Paper114426.html
The most important thing is rapid induction of reversal. Once a clot forms, the data shows that bleeding stops and you no longer need (and you may not even want) full reversal of Xa inhibition. You want to avoid thrombosis as well.
The lack of a correlation with the hemostasis endpoint makes perfect sense and is irrelevant. 92% of patients had rapid reversal of Xa. Hence there was almost no variability and nearly all patients had enough reversal to form a clot. The variability has nothing to do with Xa reversal and everything to do with the characteristics of the bleed. Arterial bleeds versus venous bleeds. Large bleeds versus small bleeds. Some bleeds just cannot be stopped even with zero activity.
Now does Xa inhibition matter for outcomes. The evidence screams yea. Look at the pig study. In the trauma pig model, the pigs that had no reversal lost over 3L and has 100% mortality. Pigs receiving a subtherapeutic dose of Andexxa had some reduction of bleeding and mortality, but only a partial improvement. The therapeutic dose decrease bleeding to 1L and left 100% survival. This is the same drug that only provides short term reversal yet it demonstrated durable hemostasis that impacted survival.
It’s easy to criticize the company and FDA for allowing approval based on surrogate endpoints. However, the whole purpose of accelerated approval is to reduce the risk of drug development on investors to promote drug development and to bring therapies to patients more quickly. This is exactly what FDA did with Andexxa. Now it’s perfectly reasonable to ask whether the drug actually improves mortality. This question will be answered in the postmarketing trial. Drugs like this would be impractical to develop if not for these new programs and they would not exist.
There’s a massive leap between “small pig study conducted by pharma” and improving outcomes in practical, pragmatic usage. If this is what the accelerated approval is supposed to result in – widespread marketing of an expensive, untested medication – it’s not appropriately designed. It seems inauspicious to be arguing, effectively, the basis of this trial: “it ought to clot up the way we think it does when anti-Xa is bound, and therefore there’s not even equipoise to have a control arm“. Would you similarly argue that platelet transfusions for ICH on clopidogrel ought not be tested?
Surrogate outcomes are not reliably correlated with patient-oriented outcomes, and abuse of such leads ultimately to low-value care. The pendulum is swinging too far back towards protecting investors, and we’re not doing enough to protect our health system from the consequences.
I agree with you Ryan.
Look at the entire list of accelerated approval drugs and there endpoints. None is perfect. I’d say reversal of anticogulation has more evidence for being effective than many others out there. Compare that to An example in NASH for which a decrease in some metabolic markers should equate to a reduction in downstream M&M. Most of these break through drugs would be an impossible risk reward to develop without this model. People can be skeptical, but the savings does eventually get passed on to the consumer. The bigger problem here is that few ex-US countries are willing to pay their share in the cost of bringing drugs to market so US patients bear the majority of the burden. The company needs to recoup 15 years of R&D costs in the billioms just to break even, and that’s just how it is.
Just to add one thing:
If you think about the value proposition from a wider perspective…
FDA approved NOACs almost a decade ago even without reversal agents available because they still had less ICH and were potentially more effective. So clearly FDA felt some ownership over that decision and a responsibility to provide a reversal agent to close the loop. Still, the main reason for patients to be started on warfarin has been a lack of direct reversal (so clearly docs think it’s kmportsnt). And with Andexxa reversal available, essentially all patients will now slowly be transitioned over to Xa inhibitors or at least all new patients will get Xais. The reduction in adverse events with Xa inhibitors makes them highly cost effective even with their high direct drug cost. If you ignore Andexxa efficacy and potential for lives to be saved or at least improvement in QOL post-bleed, the agent is needed to complete the transition to Xa inhibitors which is a good thing for patients. You can think of Andexxa as a 10% increase in the average drug cost for Xais to make them just a bit safer. From a public health standpoint, this makes sense IMO. For individual hospitals, the decision will be based on a fear of liability and just simply not wanting to fall behind stand of care. Small hospitals fortunately will not bear his burden once ASP+6% pass through payment is installed for patients transferred from community hospitals to trauma centers.
I’m not necessarily going to engage on the economic arguments, as they’re somewhat distinct from the physiologic and clinical issues. I appreciate your position as a realist, at least, with regard to justifying the investment and risks in the context of the current macro structural defects in the drug development and approval process. Surrogates – sigh. When PFS replaces OS … we’re just getting lower-quality drugs with more ambiguity in their appropriate clinical use, leading to indication creep and waste.
Andexanet needs to do more that show pharmacokinetic and single-arm hemostatic data. It needs a control arm, and it needs a comparison to PCCs. This should have been done before approval, not the other way around. It’s not idarucizumab which truly has no alternative – and even that ought to have been more rigorously evaluated.
IMO, accelerated approval will save an uncountable number of lives at a reasonable cost to society. It is a game of probability and avoiding risk with a reasonable chance for benefit. The key is the measuring stick for AA: a reasonable likelihood to provide a net benefit for patients with an urgent unmet medical need, with a reasonably low risk for harm (either its proven to be safe or patient has no other alternatives anyway).
The old model (A):
A long-term clinical outcome study would take an extra 3-5 years (10-12 years total) at which time only about 300 patients would have received the potentially life-saving drug instead of the 75,000-100,000 that may have urgently needed it. If the risk to benefit for shareholders is too high, the drug may never move forward and the innovation never occurs. If the drug does move forward, the costs of 3-5 years could be $1B additional dollars and often shareholder dilution. The biotech company has spent 10 years, $3B, and diluted the shareholders so that there are 120M shares.
The new model (B):
The drug gets to the market and quite possibly begins improving outcomes for 75,000-100,000 patients. If mortality is reduced by even 10%, that’s 7,500-10,000 lives. If there is no mortality benefit, possibly there is at least a quality of life or functional benefit. Or there could be absolutely no benefit. In this case, CMS will pay for a majority of the $2B cost to treat these patients during this time (~$200k per life saved if 10% reduction in mortality). The biotech company has earned a profit of $500M over the first 3-5 years instead of a cash burn of $1B, so the net cost is $1.5B instead of $3B to market. They only have 60M share outstanding instead of 120M.
In model A, the drug company has to make up an additional $1.5B deficit and earnings would essentially need to double to provide the same earnings per share as in model B. As much as people don’t realize, a large part of drug pricing is based on the revenue that needs to be returned to shareholders to provide a certain multiple on the initial investment. Lower R&D costs will lead to lower drug costs. The cost of the drugs reflects not only the R&D for that drug, but all the companies failures that came before that. In the meantime, many of these drugs will end up being effective and actually saving lives with little risk for harm (most AA drugs either have no safety signal or the patients have few options anyway and face little chance for recovery without the drug). This is a game of probability and the AA program saves lives and actually saves $$.
Didn’t quite understand your comment about Praxbind not having an alternative. Kcentra has just about the same amount of evidence for possible reversal of effects of Pradaxa as Xais. If you take a shotgun approach and throw all the factors into the mix, you probably will have some hemostatic effect theoretically.
Might want to take a look at some comparison studies of Andexanet and 4-PCC/rFVIIa
The key is rapid, potent reversal… Short acting is also key to avoid arterial thrombosis which is a common secondary morbidity event (MI, CVA, etc). Even if 4-PCC can non-specifically reverse some of these effects, the data acts slower and is less effective reversal (50%-60% versus 90+%). The question becomes number needed to treat. How large a study is required to detect a difference in a meaningful clinical outcome.
https://charts.stocktwits.com/production/original_153296223.png
http://www.bloodjournal.org/content/120/21/3414
Re: Praxbind – I can at least conceive how reasonable people could argue it’s unethical to have a control “untreated” arm in RE-VERSE AD, since the alternative is non-treatment with any reversal agent. However, we’re left to make treatment decisions on the same basic assumptions – that idarucizumab is effective and safe, without really _knowing_ – as we are after this single-arm trial.
I do not disagree with you in the least that both physiologic surrogates and clinical outcomes appear to consistently favor andexanet, both in isolation and in comparison with other reversal agents. The leap from these artificial environments to pragmatic real-world use is vast. I believe you are conflating effectiveness with efficacy, as well as ignoring how frequently patients enrolled in ANNEXA-4 didn’t even have anti-Xa levels high enough to be included in the efficacy analysis. This is likely to be similar or higher in real-world use, as well.
Finally, with much respect regarding your well-considered economic arguments regarding accelerated approval, I find such thought experiments to be so speculative and based on various assumptions as to be akin to chasing chimeras.
Appreciate this back and forth between two folks who are trying to understand the complexities of placing new drugs on the market and just what impacts it can have. The sad fact remains that for approx $100 dollars per year for the treatment of afib or cheaper for short term vte diesease while we truly do have a reversal agent for warfarin(finally). Then the slow inexorable creep and push placing a new drug on the market for it’s purported benefits, followed by it’s (their reversal agents)reversal agent is concerning.
The county population i work with has little to no access to the medical system. Here’s how it works, our hospital system takes on the ‘new more expensive drug’, begins to train the youger physician with Xa inhibitors and direct thrombin inhibitors and voila, coumadin has become a worse drug(it’s inconvenient, there are dietary restrictions, they need to be tested on a regular basis) and it is easy to see folks pick a drug without even an understanding of the pros and cons, never mind the machinations of big pharma that allow direct to consumer advertising, on and on… So, pt is given a free 1 month sample and is then sacked with a discounted, heavy monthly bill of close to $500 per month. Then the arguments of savings to pts and society is put out there. Number one cause of bankruptcy in the USA remains medical bills.
Until we begin making it paramount that the drug industry must provide medicines which are not only better than, but safer than and affordable to our patients. When the only requirement is equipoise to get a more expensive drug on the market, it is concerning. Of course it is big business, but I do not believe that should take precedence over the individual as they are the ones who work for 30-40 years keeping our system moving along. This begins to dip towards healthcare as a right vs healthcare as a privilege. That is a different discussion.
I have worked in multiple county facilities and I have followed this healthcare system as we know it for the past 30 plus years…whoa, starting to recognize the concept of age! The Xas and DTIs are here along with their purported benefits and their reversal agents. What to do? We will continue to see ICH, bloody pericardial effusions,retroperitoneal bleeds, GI bleeds and of course nosebleeds caused by these agents. Some with resolution and a return to outpatient life and others with worse outcomes. At least coumadin remains an option for the time being, but I can imagine that one day warfarin/coumadin will be gone, replaced by these newer yet not better agents.
Andexxanet still not widely available for now. It was only on our formulary for a short time as our hospital was part of one of the reversal trials.
Are patients in your ER receiving andexxanet or not?
Not on hospital formulary (I am not part of that decision-making process).
The same data exists for efficacy of Kcentra for reversing the effects of pradaxa as Xais albeit there is less of it (which makes sense since Xais are more common).
The experts and guideline writers in the field clearly disagree with your sentiment. In a rare move, EU guideline writers recommended Andexanet for direct reversal as first like before the drug is even approved in the EU. Development of a direct reversal agent has been considered a major unmet medical need for a long time even with the existence of Kcentra. And it took the approval of Gen 2 Andexanet for the ACC and ACCP to make a major shift in their guidelines in that they now no longer recommend warfarin as a first like agent for afib.
Accelerated approval is coming and it’s a game changer. Of course it’s a philosophical change from the past and it requires a broad view to see the potential benefit. But it’s been a long time coming. Drug development is too risky, is too costly, and takes too long.
I might only half-jokingly say, if experts and guideline authors disagree with me, then I’m in a good place – considering the unfortunate penetration of conflict-of-interest.
Thank you again for adding to the discussion!
Good point. A tiny company with almost no cash reserves bribed there way into three major guidelines in multiple countries.
I’m not sure to which EU guideline you are referring, but if it’s this:
https://academic.oup.com/eurheartj/article/39/16/1330/4942493
… then, yes, I would say this is a pro-pharma document, replete with conflict-of-interest:
This article and derived educational materials (slide set, website, booklet, and NOAC card) were produced by and under the sole responsibility of the European Heart Rhythm Association, and supported by Bayer Pharma AG, Boehringer Ingelheim, Bristol-Myers Squibb, and Pfizer Alliance and Daiichi-Sankyo Europe GmbH in the form of an Unrestricted Educational Grant.
The EHRA writing committee collaborated with medical advisors from the different companies to assure data accuracy and completeness.
Conflict of interest: J. S. has received consultant and/or speaker fees from Amgen, Astra-Zeneca, Atricure, Bayer, Biosense Webster, Biotronik, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cook Medical, Daiichi Sankyo, Medtronic, Novartis, Pfizer, Sanofi-Aventis, Sorin, St. Jude Medical/Abbott, and Zoll. He reports ownership of CorXL. J.S. has received grant support through his institution from Bayer Healthcare, Biosense Webster, Biotronik, Boston Scientific, Daiichi Sankyo, Medtronic, and St. Jude Medical/Abbott. P. V. reports grants and personal fees from Bayer, Boehringer Ingelheim, BMS, Leo Pharma, Daiichi-Sankyo; and personal fees from Pfizer, Medtronic, and Portola. T.S. P. has received speaker fees from Pfizer and Bayer. P. A. reports personal fees from Boehringer Ingelheim, personal fees and non-financial support from Bayer and Portola, and grants, personal fees and non-financial support from Pfizer-BMS and Csl-Behring. M. A. reports personal fees from Bayer, Boehringer Ingelheim, Daiichi Sankyo, personal fees from Pfizer, Sanofi Aventis, Medtronic, Biosense Webster, Novartis, Abbott, and Biotronik. L.D. has no conflict of interest to disclose. K.G. H. reports personal fees from Bayer, Boehringer-Ingelheim, Pfizer, Bristol-Myers Squibb, Daiichi Sankyo, Medtronic, Edwards Lifesciences, Sanofi, EIP Pharma, non-financial support from Getemed AG, and grants from Bayer. J. O. reports fees to his institution from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daichii-Sankyo, Pfizer, and Sanofi. H. R. reports personal fees from BMS, MedUpdate, NephroUpdate, Pfizer, and Pluristem; and grants from the German Federal Ministry for Education and Research (BMBF), Bard, Bayer, and Biotronik. V. R. has received consultant and/or speaker fees from Bayer Healthcare, Boehringer-Ingelheim, Bristol-Myers Squibb, Leo Pharma, Pfizer, and Rovi. N. R. reports personal fees from BMS, Pfizer, Daiichi-Sankyo, Bayer and Boehringer Ingelheim. P. S. reports grants from Daiichi Sankyo and Astra Zeneca, and institutional fees from BMS, Pfizer, and Boehringer. R. C. reports personal fees from Daichii Sankyo, Pfizer, Bayer and Boehringer Ingelheim. A. J.C. has received institutional research grants and personal fees for advice and for speaking from Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Pfizer/BMS. H. H. reports personal fees (before June 2017) from Abbott, Pfizer/BMS, Daiichi-Sankyo, Boehringer-Ingelheim, Cardiome; he received no personal fees after June 2017; he received research grants from Bayer, Bracco Imaging Europe, Medtronic, and St. Jude Medical through the University of Hasselt or Antwerp.