Apixaban

Discovery

Apixaban, also known under the brand name Eliquis, is a synthetic anticoagulant that is used to prevent deep vein thrombosis, pulmonary embolisms, as well as strokes and blood clots in patients who have atrial fibrillation.¹ Apixaban works by targeting the activated factor X (FXa) in the coagulation cascade. This factor is responsible for the activation of thrombin which in turn is responsible for activating platelets and conducting fibrin to clot. Apixaban targets the activation site of FXa and binds with it, blocking prothrombin from binding to the site and becoming thrombin.² By inhibiting this factor, the activation of thrombin is prevented which essentially halts the coagulation cascade and prevents blood from clotting.  However, adverse reactions such as nosebleeds, bloody urine, bloody stool, bleeding gums, and coughing up blood can occur. Bruising and bleeding occur more easily while taking apixaban, so cuts and injuries may be more serious. Other adverse reaction include headache, rash, and having trouble breathing.¹

            In comparison to its predecessor warfarin, apixaban is incredibly selective as it only targets the activated factor X in the coagulation cascade unlike warfarin which targets factors VII, IX, and X.³ Apixaban also does not have any dietary interactions unlike warfarin which requires patients to monitor their diet due to potential adverse reactions.^3,4 Another advantage to apixaban is that it has a reduced chance of major bleeding as opposed to warfarin which has a significantly larger chance to cause major bleeding in its patients.⁵ The effects of apixaban will also appear much faster than the effects of warfarin; apixaban works after only couple of hours while warfarin takes a couple of days.^4,6

Apixaban was discovered through development of activated factor X inhibitors. These inhibitors were being developed to find a better anticoagulant in place of warfarin. In the 1990s, scientists recognized the potential benefits of a FXa inhibitor and conducted a high-throughput screen to find molecules with potential to inhibit FXa.² Several derivatives were discovered through this screen and were continuously optimized; the first FXa inhibitor they discovered with pharmaceutical potential through this optimization was razaxaban.^2,3 Razaxaban managed to reach phase II clinical trials and proved its efficacy as an anticoagulant.^2,3 However, razaxaban was continually optimized and was eventually replaced by what is now known as apixaban as apixaban had a better pharmacokinetic profile than razaxaban.³ The aspect that was most compelling about the development of apixaban was the modification of its lactam group because modifying the lactam group caused large variations in its pharmacokinetic and pharmacodynamic profile. This variation is the reason why the modification of this lactam group appears to be the most compelling aspect to focus on for further refinement and modification of apixaban.

Development

            Apixaban was developed by a joint venture between Pfizer and Bristol-Meyers Squibb after Bristol-Meyers Squibb (BMS) initially discovered the drug. The companies made an agreement that Pfizer would finance most of the research being conducted by BMS and once the drug was on the market, the companies would split the marketing costs and profits.⁷  Apixaban, under the brand name Eliquis®, was approved by the FDA to reduce the risk of stroke and embolisms in patients with atrial fibrillation at the end of 2012 after the pivotal phase III clinical trials ARISTOTLE and AVERROES found significant evidence towards the efficacy of apixaban. ARISTOTLE compared apixaban’s efficacy versus warfarin’s efficacy in patients with atrial fibrillation while AVERROES compared apixaban’s efficacy versus aspirin’s efficacy in patients with atrial fibrilation.⁸ However, the ARISTOTLE trial was and remains controversial due to reported misconduct during the trial such as dispensing errors and potentially falsified results; it almost cost Pfizer and BMS the approval of Eliquis® but the FDA ruled that the misconduct present did not “substantially alter” the results.⁹ Eliquis® was later approved in 2014 for the treatment of deep vein thrombosis and pulmonary embolism.¹⁰

Commercialization

            Upon entering the market, Pfizer and BMS held the patent for Eliquis® and were granted market exclusivity by the FDA. Since then, the market exclusivity has expired, having ended in February 2017, but the companies still hold the patent which is set to expire in 2023. Pfizer and BMS have been using their patent to mount continuous lawsuits against generic manufacturers to slow the generic drug from coming to the market. This has resulted in Pfizer and BMS currently being and remaining the sole retailers of apixaban for a while.¹¹ Being the sole producer and seller of apixaban has paid off for the companies as Eliquis® raked in 4.9 billion USD worldwide (2.9 billion USD in the U.S. alone) for BMS in 2017 representing a growth of approximately 46% since 2016.¹² Meanwhile Pfizer saw an Eliquis® revenue of 2.5 billion USD worldwide (1.4 billion USD from the U.S.) also with a growth of approximately 47%.¹³ Eliquis® has been wildly profitable for both companies making up large bulks of their respective revenues. The revenue is also predicted to continue to experience growth until 2021 further increasing the profitability of the drug.¹⁴

            Despite the sheer revenue of Eliquis®, the drug still faces competition in the marketplace. Its main competitors are warfarin (a generic drug) and rivaroxaban (known under the brand name Xarelto®). However, Eliquis® is experiencing a market growth much larger than either of its competitors. Eliquis® surpassed Xarelto®’s market share lead in the novel oral anticoagulant category in 2017 while having a monstrous revenue growth of approximately 46%. In 2018, Eliquis® is set to overtake warfarin’s market share which is the leader of the overall oral anticoagulant market.¹⁵ Eliquis® has shown a relatively dominant performance in the marketplace and has been a powerhouse of a drug over the past few years in the drug marketplace.

References

1.     Apixaban: MedlinePlus Drug Information. MedlinePlus. https://medlineplus.gov/druginfo/meds/a613032.html. Accessed September 23, 2018.

2.     Wong P. C., Pinto D. J.P., Zhang D. Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor. Journal of Thrombosis and Thrombolysis. 2011;31(4):478-492. DOI: 10.1007/s11239-011-0551-3

3.     Pinto D. J.P., Orwat M. J., Koch S., et al. Discovery of 1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro- 1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Apixaban, BMS-562247), a Highly Potent, Selective, Efficacious, and Orally Bioavailable Inhibitor of Blood Coagulation Factor Xa. Journal of Medicinal Chemistry. 2007;50(22):5339-5356. DOI: 10.1021/jm070245n

4.     Frost C., Wang J., Nepal S., et al. Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects. British Journal of Clinical Pharmacology. 2013;75(2):476-487. DOI: 10.1111/j.1365-2125.2012.04369.x

5.     Granger C. B., Alexander J. H., McMurray J. J.V., et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation. New England Journal of Medicine. 2011;366:981-992. DOI: 10.1056/NEJMoa1107039

6.     Warfarin Sodium Monograph for Professionals. Drugs.com. https://www.drugs.com/monograph/warfarin-sodium.html. Accessed September 23, 2018.

7.     MacDonald J. Bristol-Myers Squibb and Pfizer Announce Worldwide Collaboration to Develop and Commercialize Anticoagulant and Metabolic Compounds. BMS Newsroom. https://news.bms.com/press-release/bristol-myers-squibb-and-pfizer-announce-worldwide-collaboration-develop-and-commercia. Published April 26, 2007. Accessed November 5, 2018.

8.     U.S. FDA Approves ELIQUIS® (apixaban) to Reduce the Risk of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial Fibrillation. BMS Newsroom. https://news.bms.com/press-release/rd-news/us-fda-approves-eliquis-apixaban-reduce-risk-stroke-and-systemic-embolism-pati. Published January 2, 2013. Accessed November 5, 2018.

9.     Husten L. Roller Coaster Path To Approval For Eliquis Uncovered By FDA Documents. Forbes. https://www.forbes.com/sites/larryhusten/2013/06/21/roller-coaster-path-to-approval-for-eliquis-uncovered-by-fda-documents/#681e015545d1. Published June 21, 2013. Accessed November 5, 2018.

10.  U.S. FDA Approves Eliquis (apixaban) for the Treatment of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE), and for the Reduction in the Risk of Recurrent DVT and PE Following Initial Therapy. Pfizer News. https://www.pfizer.com/news/press-release/press-release-detail/u_s_fda_approves_eliquis_apixaban_for_the_treatment_of_deep_vein_thrombosis_dvt_and_pulmonary_embolism_pe_and_for_the_reduction_in_the_risk_of_recurrent_dvt_and_pe_following_initial_therapy. Published August 21, 2014. Accessed November 5, 2018.

11.  Marsh T. Eliquis Generic Alternative Coming in 2018? The GoodRx Prescription Savings Blog. https://www.goodrx.com/blog/eliquis-generic-alternative-coming-in-2018/. Published November 17, 2017. Accessed November 5, 2018.

12.  Bristol-Myers Squibb Reports Fourth Quarter and Full Year Financial Results. BMS Newsroom. https://news.bms.com/press-release/corporatefinancial-news/bristol-myers-squibb-reports-fourth-quarter-and-full-year-fina. Published February 5, 2018. Accessed November 5, 2018.

13.  PFIZER REPORTS FOURTH-QUARTER AND FULL-YEAR 2017 RESULTS. Pfizer Investors. https://investors.pfizer.com/investor-news/press-release-details/2018/PFIZER-REPORTS-FOURTH-QUARTER-AND-FULL-YEAR-2017-RESULTS/default.aspx. Published January 30, 2018. Accessed November 5, 2018.

14.  Team T. How Important Is Eliquis For Bristol-Myers Squibb? Forbes. https://www.forbes.com/sites/greatspeculations/2017/10/05/how-important-is-eliquis-for-bristol-myers-squibb/#3da9fffa124b. Published October 5, 2017. Accessed November 5, 2018.

15.  Helfand C. BMS, Pfizer's fast-growing Eliquis is about to steamroll market-leader warfarin: executive. FiercePharma. https://www.fiercepharma.com/marketing/bms-pfizer-s-eliquis-will-unseat-market-leader-warfarin-coming-weeks-exec. Published July 30, 2018. Accessed November 5, 2018.