Type of information: Negative opinion for the granting of a Market Authorisation in the EU
Product name: Bevyxxa®(US)/Dexxience® (UE)
Therapeutic area: Cardiovascular diseases
- anticoagulant agent/oral direct Factor Xa inhibitor . Betrixaban is an oral, once-daily Factor Xa inhibitor anticoagulant. It blocks this protein which is involved in the production of thrombin. Thrombin is needed for blood to clot. By blocking factor Xa, the medicine reduces the levels of thrombin in the blood and this reduces
the risk of blood clots forming in blood vessels.
Company: Portola Pharmaceuticals (USA - CA)
Disease: prevention of venous thromboembolism (VTE)
- • On July 26, 2018, after considering the grounds for Portola's reexamination request, the CHMP confirmed the refusal of the marketing authorisation. The committee considered that the main study did not satisfactorily show Dexxience®’s effectiveness when
used for preventing blood clots in patients admitted to hospital for recent medical illness. Also, patients
treated with Dexxience® had more episodes of bleeding than those treated with the comparator medicine. This was considered an important concern given that the medicine was expected to be used in patients with serious underlying conditions for whom any episode of bleeding could have serious consequences, and Dexxience®’s long persistence in the body could complicate management of bleeding.
Therefore, at that point in time, the CHMP was of the opinion that the benefits of Dexxience® did not outweigh its risks and recommended that it be refused marketing authorisation. The CHMP refusal was confirmed after re-examination.
- • On March 23, 2018, Portola Pharmaceuticals announced that the company intends to appeal the opinion and seek a re-examination by the CHMP.
- • On March 22, 2018, the Committee for Medicinal Products for Human Use (CHMP) adopted a negative opinion, recommending the refusal of the marketing authorisation for Dexxience®, intended for the prevention of venous thromboembolism. The drug was expected to be used to be used in adults admitted to hospital for the treatment of a recent medical illness. These patients may be at high risk of blood clots because of reduced mobility during their hospital treatment as well as other underlying conditions that increase the risk. Portola Pharmaceuticals presented the results of one main study involving over 7,500 adults who had been admitted to hospital for a recent medical illness. The patients were at high risk of venous thromboembolism because of their age, presence of a protein indicating a blood clot, previous blood clots, cancer and lack of mobility during hospital treatment. Treatment with Dexxience® was compared with enoxaparin, another medicine for preventing blood clots. The main measure of effectiveness was the occurrence of deep vein thrombosis or of pulmonary embolism or death from a blood clot. The CHMP considered that the main study did not satisfactorily show that Dexxience®’s benefits outweighed its risk when used for preventing blood clots in patients admitted to hospital for recent medical illness. Moreover, the results of the study were not considered reliable because some results oftests for blood clots were not available. Patients treated with Dexxience® had more episodes of bleeding than those treated with the comparator medicine. This was considered an important concern given that the medicine was expected to be used in patients with serious underlying conditions. Therefore, the CHMP concluded that the benefits of Dexxience did not outweigh its risks and recommended that it be refused marketing authorisation.
- • On June 23, 2017, the FDA approved Bevyxxa® (betrixaban) for the prophylaxis of venous thromboembolism in adult patients hospitalized for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE.
- Approval was based on data from APEX (NCT01583218), a randomized, double-blind, multinational clinical trial comparing extended duration betrixaban (35 to 42 days) to short duration of enoxaparin (6 to 14 days) in the prevention of VTE in an acutely medically ill hospitalized population with risk factors for VTE. The trial randomized 7,513 patients to either betrixaban or enoxaparin treatment. Patients on the betrixaban arm took an initial dose of 160 mg orally on day 1, then took 80 mg once daily for 35 to 42 days and received a placebo injection once daily for 6 to 14 days. Patients on the enoxaparin arm received 40 mg subcutaneously once daily for 6 to 14 days and took a placebo pill orally once daily for 35 to 42 days.
- Efficacy was measured in 7,441 patients by a composite outcome score comprised of either the occurrence of asymptomatic or symptomatic proximal deep vein thrombosis, non-fatal pulmonary embolism, or VTE-related death. Fewer events were observed in patients receiving betrixaban (4.4%) compared with those taking enoxaparin (6%) (relative risk 0.75, 95% CI: 0.61, 0.91).
- The most common adverse reactions ?5%) with betrixaban were related to bleeding. Overall, 54% of patients receiving betrixaban experienced at least one adverse reaction compared with 52% taking enoxaparin. The frequency of patients reporting serious adverse reactions was similar between betrixaban (18%) and enoxaparin (17%). The most frequent reason for treatment discontinuation was bleeding, with an incidence rate for all bleeding episodes of 2.4% and 1.2% for betrixaban and enoxaparin, respectively. The incidence rate for major bleeding episodes was 0.67% and 0.57% for betrixaban and enoxaparin, respectively.
- The recommended dose of betrixaban is an initial single dose of 160 mg starting on day 1, followed by 80 mg once daily taken for 35 to 42 days at the same time each day with food.
Submission of marketing authorization application USA :
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2017-06-23
Favourable opinion UE: 2018-03-22
Favourable opinion USA:
Orphan status USA:
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE: