The Quest for an Antidote
Xarelto overrides the body’s system of checks and balances for blood clotting: too much clotting can lead to strokes or other thrombotic events, but too little clotting can lead to serious bleeding events. Tipping the scales too far in one direction can cause uncontrolled bleeding in the presence of any anticoagulant, even though all manufacturers of Factor Xa inhibitors claim that this type of anticoagulant is safer than warfarin.
Because no Factor Xa inhibitor has an antidote yet to stop uncontrolled bleeding, it is important to understand the therapies that are being developed to counteract this class of drug.
Bayer teamed with Janssen, a subsidiary of Johnson & Johnson, to make Xarelto.
Boehringer Ingelheim makes Pradaxa (dabigatran).
Pfizer and Bristol-Myers Squibb joined forces in making Eliquis (apixaban).
Daiichi Sankyo makes Lixiana (edoxaban).
How does one stop bleeding if it runs amok? Doctors must attempt to reverse it, with an antidote that counteracts the effects of the anticoagulant. Two drug manufacturers are attempting to develop an antidote for Factor Xa inhibition, namely Boehringer Ingelheim (the manufacturer of Pradaxa) and Portola Pharmaceuticals.
Because no Factor Xa inhibitor has an antidote [yet] to stop uncontrolled bleeding, it is important to understand the therapies that are being developed to counteract this class of drug. All four drugs are direct Factor Xa inhibitors.
While Boehringer Ingelheim is working on its own proprietary antidote, 5 a small company called Portola Pharmaceuticals has been developing a compound whose purpose is to block the actions of any direct thrombin (FXa) inhibitor.
Boehringer Ingelheim’s antidote is a monoclonal antibody called idarucizumab. Operating like a lock and key, the antibody selectively binds to Pradaxa, neutralizing the FXa inhibitor so it can’t hinder the clotting cascade. If the body can clot, it can arrest an uncontrolled bleeding event. Idarucizumab passed Phase 1 and 2 trials, and enrollment has started in a Phase 3 trial. 6
In contrast, Portola’s antidote is a Factor Xa decoy: it attracts the FXa inhibitor more strongly than the drug’s target protein in the cascade sequence. This makes the inhibitor bind more readily to the antidote, enabling the clotting cascade to proceed. Portola’s decoy (PRT4445, or andexanet alfa) is in Phase 3 trials. Johnson & Johnson and Pfizer have already signed an agreement with Portola to utilize its new antidote (providing it attains FDA approval). If PRT4445 gains FDA approval, J&J will license the decoy as Xarelto’s antidote. 7
Of note, Portola is also in late-stage trials for its own FXa inhibitor, purported to be safer for people with diminished renal function and less likely to cause drug interactions because it, unlike the other Factor Xa inhibitors, is not metabolized in the liver. 8
Specifically, some FDA committee members expressed concern about the exclusion of certain drugs (like warfarin) and procedures (such as cardioversion) from the trials, which potentially skewed the results of the data presented by Johnson & Johnson.
The FDA’s 2011 approval of Xarelto for reducing the risk of stroke in people with NVAF 9 was accompanied by a number of concerns, related both to side effects of the drug and the methods used during the ROCKET-AF trials.
Specifically, some FDA committee members expressed concern about the exclusion of certain drugs (like warfarin) and procedures (such as cardioversion) from the trials, which potentially skewed the results of the data presented by Johnson & Johnson. Other concerns were expressed with regard to the difference in dosing levels and frequency during the trial versus non-trial conditions. 10
Notably, an FDA advisory committee rejected Bayer’s latest application to approve Xarelto for preventing recurrent cardiovascular events after Acute Coronary Syndrome (ACS, a term describing any sudden interruption to the heart muscle’s blood supply). This was the second denial for an indication that used ATLAS ACS TIMI 51 trial data, and no additional trials had been conducted since the first rejection of this data. 11
Product liability attorneys are reviewing potential lawsuits, alleging a link between Xarelto and wrongful deaths from brain hemorrhage, hemorrhagic stroke, and other types of bleeding.
Continuing Push for Expanded Use, Despite Controversy
Despite public concerns regarding Pradaxa and Xarelto, neither Xarelto nor its competitors have curbed their push to expand the uses for their anticoagulants. Collectively, 435 clinical trials were registered for Xarelto and its top two competitors when this article was written. 12
Johnson & Johnson is conducting clinical trials to investigate additional uses for Xarelto in broader patient populations: 13
- Children (0 – 17 years of age)
- People with severely impaired renal function (CrCl 15 – 30 mL/min)
- People with nonvalvular afibrillation who undergo stent placement after acute coronary syndrome (ACS)
- Patients with peripheral artery disease
- Hemodialysis patients
- Patients with heart valve prostheses
- Patients with cancer and certain autoimmune diseases, where the condition itself or one of its treatments may predispose patients to developing blood clots
Pivotal Clinical Trials for Xarelto
How does Xarelto compare to other anticoagulants? Clinical trials must prove that a new drug is safe, works better than giving a placebo (a sham with no drug activity, equivalent to no intervention), and is not inferior to an existing drug. A chart summarizing key Xarelto clinical trials follows. Interestingly, all the current FDA-approved indications for Xarelto use doses of 10, 15 or 20 mg. Janssen’s push for expanded uses focuses on conditions that might benefit from lower doses (2.5 or 5 mg) but potentially longer-term usage. How the FDA may view that as it considers Xarelto’s applications for additional indications is yet unknown.
|FDA-approved indications (listed chronologically)
|EINSTEIN DVT 14 and PE 15
||Treat DVT and PE and reduce risk of recurrence
||Non-inferior to enoxaparin (a low-molecular-weight heparin, or LMWH) for treating DVT and PE; also, risk reduction for recurrence
DVT = NEJM 2010;363:2499-2510PE = NEJM 2012;366:1287-1297
|EINSTEIN Extension study 16
||Reduce the risk of VTE recurrence in people who need additional anticoagulant therapy after standard treatment
||A subanalysis of the other EINSTEIN studies comparing Xarelto to placebo. After 6 to 12 months of additional treatment with Xarelto, the study found that it “significantly” reduced the risk of recurrent VTE at the cost of a “moderate” increase in bleeding complications. Study limitations included lack of diversity of patient types represented.
Expert Rev Cardiovasc Ther. 2011(7):841-844
|ROCKET AF 17
||Reduce stroke risk in nonvalvular atrial fibrillation (NVAF)
||Demonstrated non-inferiority to warfarin but could not claim superiority in patients whose anticoagulation was well controlled with warfarin
FDA approved this indication, but not without reservations
NEJM 2011; 365:883-891
|RECORD 1, 2, and 3 18 19 20
||Prevent deep vein thrombosis (DVT) after hip or knee replacement surgery
||10 – 50% fewer occurrences of DVT when 10 mg Xarelto used before and after surgery, compared to treatment with enoxaparin
RECORD 1: NEJM 2008;358:2776-2786
RECORD 2: The Lancet, 2008;372(9632):, 31-39
RECORD 3: NEJM 2008; 358:2776-2786
|Studies that Evaluated Uses NOT Approved by the FDA
|EINSTEIN CYP 21
||Determine the effect of giving Xarelto to patients who are taking various drugs that strongly induce CYP3A4 (a liver enzyme that oxidizes toxins and drugs so the body can remove them)
||25 patients studied; only 14 finished the study
20-mg dosing appeared to be safe enough to be acceptable in patients that must take a CYP3A4 inducer at the same time
Results not published, except in a Bayer brief
2012 Bayer synopsis
2-TIMI 51 22
|To lower the risk of recurrent CV events after ACS [Indication REJECTED twice by FDA]
||Twice-daily dosing at low levels (2.5 and 5 mg) ↓ death from MI or stroke by 8.9 and 10.7%, respectively, so overall reduction in CV mortality; but ↑ risk of non-fatal bleeding with higher dose
Rates of TIMI bleeding not related to CABG were lower in the 2.5 mg arm
Statistical analyses were labeled as “descriptive”
||Phase 3b study of people with NVAF who will undergo electrical or pharmacological cardioversion
Compared Xarelto to warfarin/similar vit K antagonists (VKA)
|Did not have the statistical power to establish Xarelto as non-inferior to VKA, so statistical analyses were “exploratory”
Sept. 2, 2014 e-pub in advance of print: Eur Heart Journal
||To prevent major CV events in coronary or peripheral artery disease
||Twice-daily dosing at low levels (2.5 and 5 mg)
Comparator arm: aspirin
Study in progress through 2018: NCT NCT01776424
|KEY: ACS = acute coronary syndrome; AF = afibrillation; CABG = coronary artery bypass graft; coag = coagulation; CV = cardiovascular; DVT = deep vein thrombosis; LMWH = low molecular weight heparin; NEJM = New England Journal of Medicine; PE = pulmonary embolism; TIMI = thrombolysis in myocardial infarction; NVAF = nonvalvular afibrillation; VKA = vitamin K antagonist