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Introduction: Tiara Baturiano
Drug Development: Mae Blythe
Clinical Trials: Vanessa Eugenio
Analysis and Future Outlook: Jocelyne Pepinós

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Introduction - Why was Xarelto developed?

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Introduction - Why was Xarelto developed?

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The development of Xarelto was in response to the growing need for improved oral blood thinners.

Previously, the market for blood thinners was dominated by unstructured heparins and  low molecular weight heparins, which are administered through subcutaneous injections. This makes them cumbersome for outpatients.

Xarelto offers a solution by providing them with an anticoagulant that can be taken orally, eliminating the need to learn how to self-inject or arrange for a nurse to inject it for them1,2.

There was also a need for more target-specific anticoagulants that had less interactions with other drugs and food, along with more predictable effects. Vitamin K antagonists were the only oral anticoagulant available before Xarelto's approval for clinical use in 20081,3. It had unpredictable pharmacokinetics, required frequent dose adjustments, and had multiple drug-drug and food interactions¹⁻³.

Xarelto addresses these issues by having predictable pharmacokinetics, reduced dose adjustments, less drug-drug interactions, and requiring no dietary restrictions 1,3.

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Image from medgadget.com

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Image from mayoclinic.org

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Image from Mayo Foundation for Medical Education and Research (2016)

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Image from health.harvard.edu

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Image from sonashomehealth.com

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Xarelto is used to treat diseases related to blood clots, such as:

Deep vein thrombosis 1 (DVT): a condition in which a blood clot forms in a deep vein, most commonly in the legs. This can lead to a more serious condition called a pulmonary embolism.

Pulmonary embolism 1 (PE): this condition comes about when a blood clot formed elsewhere, usually in the form of of deep vein thrombosis, breaks off and travels through the bloodstream until it reaches the lungs, causing a blockage in a pulmonary artery. This condition can be deadly and requires immediate treatment.

Venous thromboembolism 1,2: the condition that refers to the occurrence of DVT and then PE.

Nonvalvular atrial fibrillation ¹: as the name suggests, this form of atrial fibrillation is not caused by problems with the heart valves, but rather by factors such as high blood pressure. It results in arrhythmia due to pooling of the blood in the heart.

Coronary artery disease ¹: a condition caused by impacted arteries due the build up of plaque at a damage site in the inner wall of a coronary artery. If the plaque ruptures, a blood clot will form in the already narrowed artery, impeding blood flow. Left untreated, this can lead to a heart attack.

Peripheral artery disease ¹: similar to coronary artery disease, except in this case,  blood flow is restricted in the peripheral arteries. Although this most commonly affects those in the legs, it can also occur in the arteries leading to the arms and the head.

Xarelto is also prescribed preventatively for patients that have an increased risk of developing blood clots, such as those recovering from major surgeries, especially knee and hip surgeries, and those experiencing limited mobility1,2.

Studies concerning the use of Xarelto in children are promising. The dosage of Xarelto given to children is adjusted to their body weight¹⁰.

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2017 Statistics of Xarelto price in different countries

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2017 Statistics of Xarelto price in different countries

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Image from Mikulic (2017)

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Xarelto, otherwise known by its generic name of rivaroxaban, is an oral anticoagulant drug developed by Bayer HealthCare, but is marketed in the United States by Janssen Pharmaceuticals, the pharmaceutical arm of Johnson & Johnson. It is the first oral anticoagulant that directly targets clotting factor Xa.

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Xarelto+Aspirin for PAD patients after revascularization

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Xarelto+Aspirin for PAD patients after revascularization

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Image from Park (2020)

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Image from Perkins (2016)

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The 3 hip surgery studies were performed in Europe, whereas the knee surgery study was done in North America.

The primary efficacy endpoint was observed in 23.8%, 40.4%, 10.6% and 14%, of patients assigned to rivaroxaban 10mg in the four studies.

The primary efficacy endpoint occurred in 16.8% , 44.3%,25.2% and 17%of patients in the com- parator group.

Meanwhile The primary safety outcome was observed in 2.5%, 0%, 0.7% and 2.2%, of patients assigned to rivaroxaban 10mg in the four studies. Compare to 0%, 1.9% and 1.5% of patients in enaxoparin⁹.

Table from: Schulman S. 2009⁹

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Once and Daily dose response

Patients in the European phase II hip-replacement studies were subjected to blood sampling to compare equal daily doses given once daily or twice daily.

The results showed that although as expected the peaks were higherand the troughs lower with once than twice daily administra-tion, the 90%intervals overlapped.

The area-under-the-plasma-concentration-time curve showed 18%to 30%highervalues with once daily administration⁹.

Figure from Haas. 2009

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Image from Gupta (2015)

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RECORD1
‘Xarelto’ reduced in a 70% relative risk  (RRR) in total VTE composite of any deep vein  thrombosis (DVT), nonfatal pulmonary embolism (PE) and all cause mortality in patients undergoing total hip replacement (THR) surgery compared with enoxaparin, with a comparable safety profile including low rates of major bleeding⁷.

RECORD 2

The trial demonstrated a 79% RRR in total VTE and a comparable safety profile low rates of major bleeding, in patients undergoing THR surgery compared to patients  dosed with short-duration therapy with enoxaparin

the incidence of major bleeding at 5 wks was 0.1% in both groups confirming the benefits of extended prophylaxis over short-term prophylaxis and the safety of its use9⁷.

RECORD3

‘Xarelto’ showed 49% RRR in total VTE in patients undergoing total knee replacement (TKR) surgery compared to enoxaparin, with a comparable safety profile including low rates of major bleeding7.

RECORD4,

There was  31.4% RRRin total VTE in patients undergoing TKR surgery and taking 1omg of Xarelto compared with enoxaparin, with a comparable safety profile including low rates of major bleeding7.

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Analysis and Future Outlook - Innovations and improvements

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Analysis and Future Outlook - Innovations and improvements

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Innovations of direct oral anticoagulants (DOACs)

DOACs will expand to paediatric settings. Different studies .¹⁸

Improvements of Xarelto to keep it in the market

Decrease the risk of severe side effects such as gastrointestinal bleeding.¹⁸

Look for alternatives to reverse its effects

Decrease its cost

The future of Xarelto and its expansion towards new conditions.

Currently, it is expecting approval for use in patients with Peripheral Artery Disease (PAD) after lower-extremity revascularization (restore blood flow to lower limbs) to be taken along with aspirin. It was found that the combination of Xarelto plus aspirin produces more significant improvement than aspirin by itself.¹⁹

Xarelto is in trials to analyze if it can reduce the risk of clotting events in high-risk Covid-19 patients. Johnson & Johnson was the sponsor of a 4,000-patients trial to assess the role of Xarelto in the prevention or treatment of thromboses events caused by Covid-19.²⁰

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Image from Syrtis Solutions

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Analysis and Future Outlook - Competition

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Analysis and Future Outlook - Competition

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The main competition over the anticoagulant market is between Pradaxa, Xarelto, and Eliquis.

The three of them are more convenient than Warfarin .¹⁶

What benefits Xarelto is that it is more prescribed than Pradaxa and Eliquis in the U.S. However, Warfarin is still highly used by patients.¹⁷

Even though Pradaxa produces more severe side effects, it was the first to obtain FDA approval for an antidote that can stop internal bleeding in emergencies while Xarelto and Eliquis are still in clinical trials for an antidote.¹⁶

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Pradaxa (thrombin inhibitor) vs. Eliquis & Xarelto (Xa inhibitors)

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Pradaxa (thrombin inhibitor) vs. Eliquis & Xarelto (Xa inhibitors)

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Analysis and Future Outlook - Price fluctuations of Xarelto in different countries

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Analysis and Future Outlook - Price fluctuations of Xarelto in different countries

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In 2017, Janssen's/Bayer's pharmaceutical exposed fluctuation in the price of Xarelto in different countries. The price of Xarelto was higher in the U.S than in other countries as is illustrated in the figure below. The statistics show that the cost of Xarelto was $3.83 U.S. dollars per pill in India while it was significantly higher in the U.S. with a cost of $15.38 U.S. dollars per pill.¹⁵

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Comparison between Xarelto and other current drugs

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Comparison between Xarelto and other current drugs

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There was no evidence of liver function attributable.

Increases in liver enzyme levels were not dose dependent for rivaroxaban, and any increases were transient.

In the ODIXa-DVT study, two patients had early alanine aminotransferase elevations and aspartate aminotransferase levels treatment was stopped⁷.

Lessons Learned from the clinical trials

1. Anticoagulant therapy reduces thrombotic events, but excessive bleeding can completely overshadow this benefit.

2. Anticoagulant therapy is not one-size-fits-all:

For secondary prevention of cardiovascular events, very-low-dose rivaroxaban (combined with aspirin) seems to be the correct dose⁸

but 20 mg is needed to prevent stroke secondary to atrial fibrillation (15 mg if creatine clearance is 30-49 mL/min).

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Image from Farhan (2019)

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“Works well for me, saves many trips to control Coumadin (Warfarin)  which I used before. I think it is safe, my doctors say it is. Is not cheap but Medicare covers it with $33 copay (per month)” - A 73-year-old man using Xarelto .¹³

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Analysis and Future Outlook - Alternative drugs

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Analysis and Future Outlook - Alternative drugs

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CURRENT ANTICOAGULANTS

Eliquis vs. Pradaxa vs. Xarelto

- Eliquis and Xarelto are both direct Xa inhibitors while Pradaxa is a direct thrombin inhibitor.
- The three of them are effective in preventing blood clots; however, some studies suggested Eliquis is slightly more effective and has the fewest side effects.
- All of them are taken orally and can be expensive. The expenses of these drugs can be covered with private health insurance or Medicare which significantly decreases their price.
- The main advantage of Xarelto over Eliquis and Pradaxa is that it is taken only once a day while the others are taken twice a day.¹⁴

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Comparison between past drugs and Xarelto

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Comparison between past drugs and Xarelto

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Analysis and Future Outlook - Alternative drugs

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Analysis and Future Outlook - Alternative drugs

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PAST ANTICOAGULANTS
Some older alternatives that have been used in the market for decades were:

Low molecular weight heparins (LMWHs): used to prevent and treat thrombosis. They inhibit thrombin (factor Ila) and mainly factor Xa. Their main disadvantages were the indirect target and the use of injections for drug administration.¹¹

Warfarin or vitamin K antagonist (VKA): mainly used for arterial and venous thrombosis. Different studies determined its efficacy and safety. Since its discovery in 1941, it was the unique oral anticoagulant option until new drugs were developed. However, the main drawbacks for patients using warfarin were the inconvenient frequent monitoring and dose regulation because of its unpredictable effects and mechanism of action, as well as, many drug and food interactions. Patients require a diet low in vitamin K concentrations.¹²

In contrast, Xarelto is more suitable than LMWHs and VKA because of its oral administration, the one-size-fits-all dosage and it does not require blood tests to control blood coagulation. However, it can be more expensive because there are still no generic versions until the first patent expires in December 2020.¹

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Dietary restrictions and drug-drug interactions in older anticoagulants

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Dietary restrictions and drug-drug interactions in older anticoagulants

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Image from Adanma (2016)

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Blood clotting tests required by   patients using Warfarin (old anticoagulant)

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Blood clotting tests required by   patients using Warfarin (old anticoagulant)

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Image from Pharmaceutical Journal (2014)

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Analysis and Future Outlook - Success and impact on the quality of life

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Analysis and Future Outlook - Success and impact on the quality of life

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Xarelto solved the need for improved oral blood thinners ¹

The main advantages of Xarelto over the past anticoagulants are:

- The ease of oral administration instead of injections. ¹
- It is target-specific and it was the first direct inhibitor of factor Xa with approval for clinical settings. ¹
- Does not need any dietary restrictions because there are few interactions between this drug and food which can decrease its efficacy. It can be taken with or without food. ¹
- Decreases drug-drug interactions which occur when two different drugs are taken simultaneously and may interact with each other.  ¹

- Does not require a dose adjustment and regular coagulation monitoring because its safety and efficacy have already been analyzed and its probability of drug/food interactions is low. ¹

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Treatment of VTE with Xarelto-Phase IIb studies
Patients with acute, symptomatic, proximal DVT without symptomatic PE received double-blind rivaroxaban or open-label standard therapy for 3 months.

ODIXa-DVT

Rivaroxaban 10, 20 or 30 mg bid, or 40 mg  doses for  standard therapy

Study investigate  primary efficacy endpoint: reduced thrombus burden on day 21 without recurrent VTE or VTE-related death.

Results: The primary efficacy endpoint was achieved in 43.8–59.2% of patients receiving rivaroxaban and in 45.9% of patients receiving standard therapy.

The incidence of the primary safety endpoint was 1.7–3.3% in the rivaroxaban groups

In conclusion the oral, direct FXa inhibitor demonstrated good efficacy and safety for the treatment of acute symptomatic DVT⁷.

EINSTEIN-DVT
Rivaroxaban 20, 30 or 40 mg od were assessed to standard therapy.
Study investigate the primary efficacy endpoint: the composite of symptomatic, recurrent VTE and deterioration of thrombotic burden

Assessed by ultrasound and perfusion lung scan, at 3 months.

Results: the primary efficacy endpoint occurred in 5.4–6.6% of patients receiving rivaroxaban vs. 9.9% in the standard therapy group.

The primary safety endpoint occurred in 2.9–7.5% of patients receiving rivaroxaban vs. 8.8% in the standard therapy group.

Major bleeding occurred in 0–1.5% of patients receiving rivaroxaban vs. 1.5% of patients receiving standard therapy.

In conclusion:  rivaroxaban 20–40 mg od had good efficacy and safety for the treatment of acute symptomatic DVT⁷.
Table from: Haas S.2009⁷

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Short video describing the process of coagulation and the important factors.

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Blood Clot Formation - Coagulation Factors & Platelets

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Xarelto inhibits Factor Xa, an upstream clotting factor, to reduce blot clot formation.

Figure from: bioninja.com. Edited with PowerPoint.

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Development of Xarelto began in 1998 and was approved for clinical use in 2008.

Image from: Perzborn E, Roehrig S, Straub A et al. 2010¹. Edited with PowerPoint.

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Image from: Perzborn E, Strassburger J, Wilmen A, et al. 2005⁶.

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1. Perzborn E, Roehrig S, Straub A, et al. The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor. Nat Rev Drug Discov. 2011; 10(1): 61–75

2. Stacy Z, PharmD, BCPS. Novel Oral Anticoagulants for Venous Thromboembolism Prophylaxis After Total Hip or Knee Replacement An Update on Rivaroxaban (Xarelto). Pharmacy and Therapeutics. 2013; 38(1): 45-50

3. Kubitza D, Perzborn E, Berkowitz SD. The discovery of rivaroxaban: translating preclinical assessments into clinical practice. Front Pharmacol. 2013; 4: 145

4. Samama MM. The mechanism of action of rivaroxaban - an oral, direct factor Xa inhibitor - compared with other anticoagulants. Thromb Res. 2011; 127(6): 497-504.

5. Gerotziafas GT, Elalamy I, Depasse F, et al. In vitro inhibition of thrombin generation, after tissue factor pathway activation, by the oral, direct factor Xa inhibitor rivaroxaban. J Thromb Haemost. 2007; 5: 886– 8.

6. Perzborn E, Strassburger J, Wilmen A, et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939—an oral, direct Factor Xa inhibitor. J Thromb Haemost. 2005; 3: 514–21.

7. Haas S. Rivaroxaban -- an oral, direct Factor Xa inhibitor: lessons from a broad clinical study programme. Eur J Haematol. 2009;82(5):339-349.

8. Linkins LA. Rivaroxaban Clinical Trials in 2018: Successes, Failures, and Lessons Learned. The Hematologist. 2019;16 (1)

9. Schulman S. Rivaroxaban in orthopedic surgery--a change of paradigm? Clin Appl Thromb Hemost. 2009 Dec;15(6):613-20.

10. Monagle P, Lensing AWA, Thelen K, et al. Bodyweight-adjusted rivaroxaban for children with venous thromboembolism (EINSTEIN-Jr): results from three multicentre, single-arm, phase 2 studies.  Lancet Haematol. 2019; 6(10): e500-e509.

11. Lim W. et al. Safety and Efficacy of Low Molecular Weight Heparins for Hemodialysis in Patients with End-Stage Renal Failure: A Meta-analysis of Randomized Trials. JASN. 2004; 15(12): 3192-3206.

12. Apostolakis S, Lip GYH. Novel oral anticoagulants: focus on the direct factor Xa inhibitor darexaban. Expert Opinion on Investigational Drugs. 2012; 21: 1057-1064.

13. Fang MC. New Oral Anticoagulants. Patient Safety Network. 2013.

14. Gonsalves WI, et al. The New Oral Anticoagulants in Clinical Practice. Mayo Clinic. 2013;  88(5): 495-511.

15. Mikulic M. Price disparities for top product Xarelto - U.S. and international 2017. Statista. 2019.

16. DrugNews. New Report Ranks Xarelto, Eliquis & Pradaxa By Safety Profile. 2015.

17. Helfand C. Eliquis smashes rivals Xarelto, Pradaxa at cutting bleed-related costs in real-world study. Fierce Pharma. 2017.

18. Czuprynska J, et al. Current challenges and future prospects in oral anticoagulant therapy. British Journal of Haematology. 2017. 178(6): 838-851.

19. Raritan NJ. Janssen Submits Application to U.S. FDA for New Indication to Expand Use of XARELTO® (rivaroxaban) in Patients with Peripheral Artery Disease. Webwire. 2020.

20. Brown A, Elmhirst E. Scanning the horizon for future Covid-19 treatments. Evaluate Vantage. 2020.

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In Vivo Studies

After successful in vitro studies, the anticoagulant effects of Xarelto were studied in vivo. The study⁶ described here used:

Rat arterial thrombosis model (Figure 1)

Rabbit arterial thrombosis model (Figure 2)

This study demonstrated that when Xarelto was given preventatively (orally) there was a significant reduction in clot formation relative to controls. Also, at higher dosages thrombin generation was shown to be almost completely inhibited⁶.

This was demonstrated both in vitro ⁵ by previous studies and here in vivo, with both animal models.

The results of this study showed that Xarelto reduces thrombin generation and therefore clot formation in a dose-dependent manner⁶.

Figure A shows the inhibition of blood clot formation.

Figure B shows factor Xa inhibition.

Figure C shows prolongation of the initiation phase before triggering thrombin generation which results in clots.

All of the figures show that use of rivaroxaban was successful in reducing clot formation in vivo and was therefore moved to clinical trials.

Also in studies with rabbit models, it was shown that oral rivaroxaban significantly reduced the growth of preexisting blood clots, demonstrating this drug has the potential to treat already established thrombi and emboli⁴.

Figures from: Perzborn E, Strassburger J, Wilmen A, et al. 2005⁶.

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In Vitro Studies

Kinetic analysis highlighted the uniqueness of rivaroxaban in that it was selective, reversible and did not require a cofactor to produce its anticoagulant effects⁴.

The anticoagulant effects of rivaroxaban on thrombin generation were studied after chemical activation of the extrinsic coagulation pathway⁵.

Rivaroxaban significantly prolonged the initiation phase of thrombin generation (Figure A), and significantly reduced the rate of the amplification phase (Figure B).

Platelet rich plasma (Figure A).

Whole blood (Figure B).

This demonstration of efficacy allowed for in vivo preclinical trials to occur.

Figures from: Gerotziafas GT et al. 2007⁵.

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Xarelto is an anticoagulant that directly inhibits factor Xa, through competitive binding to its active site1,3.

Factor Xa is a clotting factor which is part of the coagulation cascade. This cascade is the steps that need to occur to create blood clots when there is bleeding, whether internal or external bleeding.

Factor Xa catalyzes the production of thrombin which leads to the formation of blood clots. The activity of factor Xa initiates the final common pathway of the cascade. It is the convergence point for the intrinsic and extrinsic pathways of coagulation, as seen in the attached figure, making this an ideal target for an anticoagulant drug1,3.

There are two phases of coagulation; initiation and amplification.

Due to this amplification phase, it has been estimated that one molecule of factor Xa can catalyze the production of over 1000 molecules of thrombin also known as a thrombin burst³.

Once thrombin is produced it activates fibrinogen to fibrin, which is the step that completes the clotting process.

Ultimately, Factor Xa inhibition results in a reduction of thrombin generation, which thins the blood and prevents clot formation ³.

Figure from: January et al. J Am Coll Cardiol. 2014. Edited with PowerPoint.

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There are many problems with conventional anticoagulant therapies, such as constant monitoring and dose changes, administration by injection and acting on multiple clotting targets1,2.

Goal: Develop single target, oral anticoagulant.

Factor Xa, the activated form of factor X, was identified as a viable drug target as it plays a key role in the coagulation cascade and hemostasis. Natural Xa inhibitors such as Antistasin and tick anticoagulant peptide (TAP) were isolated from Mexican leeches and soft ticks, respectively to test viability of Xa as a drug target1,3. Due to promising results pharmaceutical companies launched programs to develop synthetic, oral Xa inhibitor.

Bayer Healthcare launched a  program to develop the first, oral Factor Xa inhibitor in 1998¹. After testing a variety of compounds, Rivaroxaban showed high binding affinity and good oral bioavailability, so was chosen as the drug candidate for further testing¹.