Clinical Trials

Date: 2016-05-27

Type of information: Publication of results in a medical journal

phase: 3

Announcement: publication of results in The New English Journal of Medicine

Company: Portola Pharmaceuticals

Product: betrixaban

Action mechanism:

• anticoagulant agent/oral direct Factor Xa inhibitor . Betrixaban is an oral, once-daily Factor Xa inhibitor anticoagulant. It is an FDA-designated Fast Track therapy for extended-duration VTE prophylaxis in acute medically ill patients.

Disease: prevention of venous thromboembolism (VTE)

Therapeutic area: Cardiovascular diseases

Country: Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, Croatia, Czech Republic, Denmark, Estonia, Finland, France, Georgia, Germany, Hungary, Israel, Italy, Latvia, Lithuania, Montserrat, Peru, Poland, Romania, Russian Federation, Serbia, Singapore, Slovakia, South Africa, Spain, Ukraine, UK, USA

Trial details:

• APEX was designed to assess the relative risk (RR) in the composite endpoint of ultrasound-detected (asymptomatic) proximal deep venous thrombosis (DVT), symptomatic DVT, non-fatal pulmonary embolism (PE) or VTE-related death in high-risk acute medically ill patients treated with oral betrixaban for 35-47 days versus standard of care preventive anticoagulation with injectable enoxaparin dosed for 10±4 days. APEX enrolled 7,513 patients at more than 450 clinical sites worldwide. (NCT01583218)

Latest news:

• • On May 27, 2016, Portola Pharmaceuticals announced that the full results of its pivotal Phase 3 APEX (Acute Medically Ill VTE Prevention with Extended Duration Betrixaban) Study were presented at the 62nd Annual International Society on Thrombosis and Haemostasis (ISTH) Scientific and Standardization Committee (SSC) Meeting. Full results from the APEX trial were published simultaneously online in The New England Journal of Medicine. APEX, which enrolled 7,513 patients at more than 450 clinical sites worldwide, assessed the superiority of extended-duration betrixaban for 35 days compared to standard-duration enoxaparin for 10+4 days. The trial was designed in cooperation with the FDA and EMA to incorporate a novel patient enrichment and statistical analysis plan derived from the 2012 FDA guidance document on enrichment strategies for clinical trials. Portola plans to submit the APEX Study data as part of a New Drug Application (NDA) for betrixaban in the United States and as part of a Marketing Authorization Application (MAA) in the EU.
• • On March 24, 2016, Portola Pharmaceuticals announced topline data from the Phase 3 APEX (Acute Medically Ill VTE Prevention with Extended Duration Betrixaban) Study, which evaluated the superiority of extended-duration anticoagulation with oral betrixaban compared with standard of care anticoagulation with injectable enoxaparin for the prevention of venous thromboembolism (VTE), or blood clots, in acute medically ill patients. These are patients who are hospitalized for serious common medical conditions, such as heart failure, stroke, infection and pulmonary disease.
• The primary efficacy and safety analysis consisted of three pre-specified patient groups of increasing sample size: Cohort 1 - patients with elevated D-dimer levels (62 percent of the overall study population), Cohort 2 - patients with elevated D-dimer levels or age ?75 years (91 percent of the overall study population), and the overall study population. By protocol definition, primary efficacy analysis testing of Cohort 1 was done first and required a p value of 0.05 or less in order to test Cohort 2, which in turn required a p value of 0.05 or less in order to test the overall study population.
• Cohort 1 achieved a p value of 0.054, which did not meet the threshold. Cohort 2 and the overall study population achieved p values of 0.029 and 0.006, respectively.
• There was no statistical difference in major bleeding between the betrixaban and enoxaparin arms in any of these three patient groups. The number of fatal bleeds was balanced between the two arms, and the number of intracranial hemorrhages was numerically lower in the betrixaban arm. Positive net clinical benefit with betrixaban was observed.
• A summary of key topline efficacy and safety data follows:

	Primary Efficacy Analysis (VTE)			Primary Safety Analysis (Major Bleeding)
	RR*	p value		RR*	p value
Cohort 1: Elevated D-Dimer	0.806	0.054		0.88	0.722
Cohort 2: Elevated D-Dimer or Age >75	0.800	0.029		1.19	0.564
Overall Study Population	0.760	0.006		1.19	0.554

• *RR = relative risk calculated as the frequency of events with betrixaban divided by the frequency of events with enoxaparin

Is general: Yes