Date: 2012-03-02
Type of information: Refusal of a Market Authorisation in the US
Product name: Xarelto®
Compound: rivaroxaban
Therapeutic area: Cardiovascular diseases
Action mechanism: anticoagulant agent/oral direct Factor Xa inhibitor
Company: Bayer Healthcare (Germany) Janssen Research & Development (J&J - USA)
Disease: secondary prevention after an acute coronary syndrome (ACS)
Latest news:
- • On January 16, 2014, Janssen Research & Development has announced that the FDA Cardiovascular and Renal Drugs Advisory Committee has voted against the approval of the use of Xarelto® (rivaroxaban) to reduce the risk of thrombotic cardiovascular events in patients with Acute Coronary Syndrome (ACS) in combination with standard antiplatelet therapy. Janssen is seeking approval of rivaroxaban at a proposed dose of 2.5 mg twice daily (BID) for a 90 day treatment duration. The advisory committee's recommendation was based on review of the 15,526-patient pivotal Phase 3 ATLAS ACS 2 TIMI 51 (Anti-Xa Therapy to Lower cardiovascular events in Addition to aspirin with/without thienopyridine therapy inSubjects with Acute Coronary Syndrome) clinical trial of rivaroxaban. In August 2013, Janssen issued a resubmission to the complete response from the FDA for rivaroxaban 2.5 mg twice daily (BID) to reduce the risk of secondary cardiovascular events in patients with ACS for a 90 day treatment duration. Recommendations from the advisory committee today will be considered by the FDA in its review of the supplemental New Drug Application (sNDA) for rivaroxaban in this indication, but the recommendation of the advisory committee panel is not binding. If approved by the FDA, rivaroxaban will be commercialized for this additional indication in the U.S. by Janssen Pharmaceuticals.
- Results from the ATLAS ACS 2 TIMI 51 study showed that rivaroxaban, given in combination with standard antiplatelet therapy, was superior to standard therapy alone in preventing secondary cardiovascular events in patients with ACS. In patients receiving rivaroxaban and standard therapy, rates of Thrombolysis In Myocardial Infarction (TIMI) major bleeding events not associated with coronary artery bypass graft (CABG) surgery were low overall, yet statistically significantly increased versus those treated with standard therapy plus a placebo. Importantly, these differences were not associated with an excess risk of fatal bleeding.
- • On May 24, 2013, Bayer HealthCare’s novel oral anticoagulant Xarelto® (rivaroxaban) has been approved by the European Commission for the prevention of atherothrombotic events (cardiovascular death, myocardial infarction or stroke) after an Acute Coronary Syndrome (ACS) in adult patients with elevated cardiac biomarkers at a dose of 2.5 mg twice-daily (BID) in combination with standard antiplatelet therapy. This approval makes rivaroxaban the only novel oral anticoagulant approved to protect patients with elevated cardiac biomarkers following an ACS event.
- The approval of rivaroxaban in this indication is based on pivotal Phase III ATLAS ACS 2-TIMI 51 study of more than 15,500 patients. The study demonstrated that the addition of rivaroxaban 2.5 mg BID to standard antiplatelet therapy — low-dose aspirin with or without a thienopyridine (clopidogrel or ticlopidine) — significantly reduced the composite primary efficacy endpoint of cardiovascular death, myocardial infarction or stroke in patients after a recent ACS compared to those who received standard antiplatelet therapy alone.
- Rates of TIMI (Thrombolysis In Myocardial Infarction) major bleeding events not associated with coronary artery bypass graft (CABG) surgery and of intracranial haemorrhage (ICH) were low overall, yet increased with the addition of rivaroxaban. But importantly, there was no increase observed with rivaroxaban in the risk of fatal intracranial haemorrhage (ICH) or fatal bleeding.
- Based on the ATLAS ACS 2-TIMI 51 study findings, the 2012 European Society of Cardiology (ESC) Guidelines recommend that treatment with rivaroxaban 2.5 mg BID be considered for patients with ST-Segment Elevation Myocardial Infarction (STEMI) who are at low bleeding risk and are on antiplatelet therapy with aspirin and clopidogrel.
- • On March 5, 2013, Bayer HealthCare has announced that the FDA issued a second complete response letter regarding the supplemental New Drug Application (sNDA) for the oral anticoagulant Xarelto® (rivaroxaban) 2.5 mg BID in combination with standard antiplatelet therapy for the reduction of cardiovascular events (cardiovascular death, myocardial infarction or stroke) in patients with Acute Coronary Syndrome (ACS). Bayer is evaluating the complete response letter from the FDA together with its cooperation partner Janssen Research & Development, LLC, and will respond to the Agency’s questions.
- Xarelto® is approved for six clinical uses in the U.S.:
• to reduce the risk of blood clots in the legs and lungs of adults who have just had knee replacement surgery
• to reduce the risk of blood clots in the legs and lungs of adults who have just had hip replacement surgery
• to reduce the risk of both hemorrhagic and thrombotic strokes as well as other blood clots in adults with atrial fibrillation not caused by a heart valve problem
• to treat adults with pulmonary embolism (PE)
• to treat adults with deep vein thrombosis (DVT)
• to reduce the risk of recurrence of DVT or PE following an initial six months of treatment for acute venous thromboembolism
The sNDA includes results from the pivotal, global Phase III ATLAS ACS 2-TIMI 51 study, which showed that rivaroxaban 2.5 mg dosed twice daily in addition to standard antiplatelet therapy (low-dose aspirin with or without a thienopyridine such as clopidogrel or ticlopidine) significantly reduced the composite primary efficacy endpoint of cardiovascular death, myocardial infarction or stroke in patients after a recent ACS compared to those receiving standard antiplatelet therapy alone.
- Rates of TIMI (Thrombolysis In Myocardial Infarction) major bleeding events not associated with coronary artery bypass graft (CABG) surgery were low overall, but rivaroxaban was associated with higher rates of these bleeds compared with standard therapy alone. Importantly, these differences were not associated with an increase in the risk of fatal bleeding or fatal intracranial haemorrhage (ICH).
• On September 7, 2012, Janssen Research & Development, LLC (Janssen) has announced that it has submitted the Complete Response to the FDA for the use of Xarelto® to reduce the risk of secondary cardiovascular events in patients with acute coronary syndrome (ACS). The response includes specific information requested by the FDA in their letter issued to Janssen on June 21, 2012.
Janssen also has resubmitted the supplemental New Drug Application (sNDA) for Xarelto® to reduce the risk of stent thrombosis in patients with ACS, which the company withdrew on July 9, 2012 based on its connection to the above mentioned sNDA for Xarelto®. Data from the ATLAS ACS 2 TIMI 51 trial support both sNDAs.
• On June 21, 2012, Bayer HealthCare announced that the FDA has issued a complete response letter regarding the supplemental New Drug Application (sNDA) for Xarelto® (rivaroxaban) 2.5 mg BID in combination with standard antiplatelet therapy for the reduction of secondary cardiovascular events (cardiovascular death, myocardial infarction or stroke) in patients with Acute Coronary Syndrome (ACS). Bayer and its partners Janssen Research & Development are now evaluating the complete response letter from the FDA together and will respond to the Agency’s questions.
• On May 23, 2012, Bayer HealthCare has announced that the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted against the approval of the oral anticoagulant Xarelto® (rivaroxaban) 2.5 mg BID in combination with standard antiplatelet therapy to reduce the risk of secondary cardiovascular events in patients with Acute Coronary Syndrome (ACS).
• On February 28, 2012, Bayer and Janssen Research & Development announced that the FDA has granted Priority Review designation to the supplemental New Drug Application (sNDA) filed on December 29, 2011 for the oral anticoagulant Xarelto® (rivaroxaban) in combination with standard antiplatelet therapy to reduce the risk of (thrombotic) cardiovascular events in patients with Acute Coronary Syndrome (ACS). * On December 29, 2011, Bayer announced that its cooperation partner, Janssen Research & Development has submitted a Supplemental New Drug Application (sNDA) to the FDA for the oral anticoagulant Xarelto® (rivaroxaban) in combination with standard antiplatelet therapy to reduce the risk of (thrombotic) cardiovascular events in patients with Acute Coronary Syndrome (ACS). The FDA has previously granted rivaroxaban fast track designation, given the seriousness of ACS and the potential clinical benefit of rivaroxaban.
- • On December 22, 2011, Bayer HealthCare has submitted an application for marketing authorization to the European Medicines Agency (EMA) for the oral anticoagulant Xarelto® (rivaroxaban) in combination with standard antiplatelet therapy for secondary prevention after an Acute Coronary Syndrome (ACS).
- The submission for secondary prevention after an ACS is supported by data from the pivotal, global Phase III ATLAS ACS 2-TIMI 51 study. Results from the study, presented at the 2011 American Heart Association Scientific Sessions and simultaneously published by the New England Journal of Medicine (10.1056/NEJMoa1112277), showed that the combination of oral rivaroxaban 2.5 mg BID with standard antiplatelet therapy significantly reduced the composite primary efficacy endpoint of cardiovascular death, myocardial infarction or stroke in patients after a recent ACS compared to those receiving standard antiplatelet therapy alone. In addition, rivaroxaban 2.5 mg BID in combination with standard therapy significantly reduced both the rate of cardiovascular death and the incidence of all-cause mortality by more than 30% over standard therapy alone.
- The study also showed that 2.5 mg BID of rivaroxaban in combination with standard antiplatelet therapy exhibited a higher rate of TIMI major bleeding events not associated with coronary artery bypass graft (CABG) surgery, but importantly did not increase the risk of fatal bleeding over standard therapy alone.
Patents:
Submission of marketing authorization application USA : 2011-12-29
Submission of marketing authorization application UE: 2011-12-22
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization:
UE authorization: 2013-05-24
Favourable opinion UE:
Favourable opinion USA:
Orphan status USA:
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE:
OTC status:
Other news:
Is general: Yes
