Drugs Log

Bayer HealthCare AG announced today the submission of a Marketing Authorization Application to the European Agency for the Evaluation of Medicinal Products (EMEA) for approval to market rivaroxaban (Xarelto®) for the prevention of venous thromboembolism (VTE) after major orthopedic surgery of the lower limbs. Rivaroxaban is an investigational, oral, once-daily direct Factor Xa inhibitor. Data from one of the pivotal studies (RECORD3) was presented prior to the EMEA submission and revealed that rivaroxaban significantly reduces the risk of VTE in patients undergoing total knee replacement surgery compared with enoxaparin, the current standard of care therapy. Rivaroxaban is being jointly developed by Bayer HealthCare and Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

“The submission of the data for VTE prevention to the EMEA is an important milestone in the development of this new treatment for the prevention of life-threatening blood clots,” said Dr. Kemal Malik, Head of Global Development and member of the Bayer HealthCare Executive Committee. “As an effective and convenient, once-daily oral treatment with a reassuring safety profile, we feel confident that rivaroxaban has the potential to set a new standard of care in the preventative treatment of thrombosis in patients undergoing major orthopedic surgery.”

VTE is a type of thromboembolic disease that is caused by the obstruction of a blood vessel by a blood clot. In the EU it is estimated that there are 543,000 deaths due to VTE each year. People undergoing major surgery, in particular total knee or hip replacement, are prone to developing VTE due to a combination of factors such as prolonged bed rest, damage to blood vessels and an increased tendency of the blood to clot. It is estimated that up to 50% of patients undergoing lower limb surgery develop VTE if they do not receive preventative care.

The Marketing Authorization Application is based on data from three Phase III studies of rivaroxaban involving nearly 10,000 patients in total, and an extensive Phase I and Phase II program. One of the Phase III studies was in patients undergoing total knee replacement surgery, the results of which were presented at the International Society on Thrombosis and Hemostasis (ISTH) in July 2007 (RECORD3). The results of the other two studies in patients undergoing hip replacement surgery (RECORD1 and RECORD2) will be presented at the upcoming 49th Annual Meeting of the American Society of Hematology (ASH) meeting, 8–11 December 2007.

About RECORD3
The results of this study in 2,531 patients undergoing knee replacement surgery revealed that once-daily oral rivaroxaban 10 mg was superior in preventing VTE to once-daily subcutaneous enoxaparin 40 mg, the current standard of care therapy. Specifically, patients in this RECORD3 study (REgulation of Coagulation in major Orthopedic surgery reducing the Risk of DVT and PE) who were treated with rivaroxaban demonstrated a 49% relative risk reduction (p<0.001) in the composite primary endpoint of deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE) and all-cause mortality compared to those treated with enoxaparin. Patients treated with rivaroxaban also had a 62% reduced risk (p=0.01) of developing major VTE (the composite of proximal DVT, non-fatal PE and VTE-related death), the main secondary endpoint of the trial. Importantly, there was a similar low rate of major bleeding for patients being treated with rivaroxaban and enoxaparin (0.6% and 0.5%, respectively).

About Rivaroxaban (Xarelto®)
To date, rivaroxaban is the most studied oral direct Factor Xa inhibitor in development. More than 20,000 patients have been evaluated in the completed Phase II programs and enrolled thus far in the Phase III programs. More than 40,000 patients are expected to be evaluated in total.

Upon regulatory approval, rivaroxaban will be commercialized in Europe by Bayer Schering Pharma. A filing for rivaroxaban for a similar indication in the United States is planned in 2008, where if approved, it will be will commercialized by Scios Inc. and Ortho-McNeil, Inc., both of which are Johnson & Johnson companies.

The trade name of rivaroxaban is expected to be Xarelto®, pending health authority approval.

CLINICAL PHARMACOLOGY: Rivaroxaban directly inhibits factor Xa therefore prolonging clotting times and reducing the formation of thrombin, an essential component to the development of thrombus formation. The L-shaped structure of rivaroxaban allows it to be highly selective for factor Xa.1, 3 This high selectivity allows the drug to inhibit free factor Xa, prothrombinase activity, and clot-associated factor Xa, giving it the ability to not only prevent clots from forming, but to also possibly break down clots already present. This drug does not have significant direct effects on thrombin or antithrombin activity.1, 3, 8 The mechanism of action of rivaroxaban is beneficial in the prevention and treatment of thromboembolic diseases.

PHARMACOKINETICS:

Absorption:

Peak plasma concentrations are reached 2 to 4 hours after oral administration, and the bioavailability of rivaroxaban ranges from 60-80%. The presence of food increased maximum concentration, time to maximum concentration, and AUC. Prothrombin time was also affected depending on if a patient was in a fed or fasting state. Maximum PT was increased by 53% (10mg) and 83% (20mg) if patients were fed compared to 44% (10mg) and 53% (20mg) in the fasting state. Maximum inhibition of factor Xa occurred within 1 to 4 hours after administration and ranged from 20-61% for the 5-80mg doses.

Distribution:

After multiple doses of rivaroxaban, dose-proportional increases in AUC were observed. It was also noted that once the drug reached steady state, there were no significant accumulations of the drug.1 It appears that body weight influences the volume of distribution, but this change has not been found to be significant.

A study by Kubitza et al. looked at the effects of extreme body weights (>= 120 kg and <= 50 kg) and gender on the PK and PD of rivaroxaban 10mg. Results showed no effects on Cmax in subjects >= 120 kg and up to a 24% increase in Cmax in subjects <= 50 kg. This increase in Cmax caused a slight increase in prothrombin time, but the investigators concluded that this was not clinically significant. No significant differences were seen between males and females as well. These results suggest that dose adjustments are not needed in patients with extreme body weights or between the different genders.

Metabolism:

It is unknown whether rivaroxaban is metabolized hepatically or renally. Other direct factor Xa inhibitors are metabolized by the liver, so there is a high probability that rivaroxaban is also metabolized through this route.

Elimination:

Rivaroxaban goes through both renal (66%) and biliary (28%) excretion, and 36% is excreted as unchanged drug in the urine. In young, healthy subjects, rivaroxaban has a half-life of around 9 hrs, but this number increases in elderly subjects (12 hrs) and patients with renal impairment. It has not been determined if dose-adjustments are needed in the elderly or renal impairment because of this increased half-life. In Phase III trials, patients with renal impairment received reduced doses of rivaroxaban. Most trials have excluded patients with creatinine clearances below 30 ml/min, but it has not been officially determined if this level of renal impairment required dosage adjustments.

PK parameters correlated closely with the inhibition of factor Xa activity and PT prolongation.

Because of its predictable pharmacokinetics, this drug does not require the routine monitoring like warfarin does.

DRUG INTERACTIONS: No significant drug interactions have been found with rivaroxaban, including with aspirin, NSAIDs, antacids, H2 antagonists and digoxin.

The interaction between rivaroxaban and aspirin was studied in a phase I trial to determine if aspirin influenced the effectiveness and safety of rivaroxaban. This combination was well tolerated in the healthy, male subjects studied. Aspirin did not affect the inhibition of factor Xa activity or prolongation of PT/aPTT by rivaroxaban. In addition, rivaroxaban did not interfere with the inhibitory effects of aspirin on platelet aggregation.

A phase II study in 2007 looked at the effects of the combination of naproxen and rivaroxaban on safety, tolerability, PK and PD. Patients were given naproxen alone, rivaroxaban alone, or a combination of the two drugs. This study showed no mechanistic interaction between rivaroxaban and naproxen, and the addition of naproxen did not effect the prothrombin time, pTT or platelet aggregation. There was a significant increase in bleeding seen with the combination group, however, this increase was less than that seen with naproxen alone. Further phase III studies are being conducted to confirm the safety of this combination.

DOSING: There have been several studies that have looked at various dosing ranges of rivaroxaban, from 2.5mg to 40mg, given either twice-daily or once-daily. Most strengths of rivaroxaban have proven to be effective, and no dose-efficacy response has been established. However, twice daily dosing has resulted in significantly more bleeding than once-daily dosing suggesting that dose frequency might influence bleeding risk independently of dose intensity.

Rivaroxaban 20mg once-daily is the strength that is being used in Phase III trials looking at treatment of VTE and prevention of stroke in A. fib. During the RECORD3 study, a phase III trial, it was determined that 10mg of rivaroxaban given once daily was the most effective and safest dose at preventing VTE after orthopedic surgery. This strength is currently being evaluated further in this population.

CONCLUSION: There is a need for a new anticoagulant that is just as effective as warfarin, but without the rigorous monitoring schedule. Once-daily dosing of rivaroxaban has been shown to produce 24 hours of inhibition of factor Xa and thrombin generation, allowing for convenient dosing. Rivaroxaban offers once-daily dosing, and there may be the potential for no monitoring with this drug. Unlike warfarin that has several different strengths and may need to be taken differently each day, rivaroxaban will be much easier to manage and may increase patient compliance as well.

Related drugs

Ximelagatran, a direct thrombin inhibitor, was not marketed further due to its potential side-effects; the related compound dabigatran is undergoing studies. Together with rivaroxaban, the related factor Xa-inhibitor apixaban (Bristol-Myers-Squibb) andLY517717 (Lilly) are under development as non-monitored antithrombotic drugs.