Portola pharmaceutical’s betrixaban, an oral, once daily factor Xa inhibitor anticoagulant, has been receiving a lot of attention following the Phase III APEX trial result presentation at the American College of Cardiology conference in May last year. The shares of the small biotech rose markedly in late December 2016 despite a less-than-stellar trial result. The trigger for the rise being the U.S. FDA acceptance of betrixaban for priority review for extended-duration prophylaxis of venous thromboembolism (VTE) in acute medically ill patients. This priority review shortened the review period by four months, and betrixaban's PDUFA date has now been set as June 24, 2017.
What supported the priority review?
The NDA filing was supported by data from the APEX trial. The study enrolled 7,513 hospitalized medically ill patients and compared use of extended-duration betrixaban (35–42 days) with a standard regimen of enoxaparin (10±4 days) 1. The trial incorporated an FDA approved “enrichment strategy”, dividing the study into different cohorts which aided in the selection of an appropriate patient set to demonstrate better efficacy2. Theoretically speaking, the APEX trial demonstrated that betrixaban was able to mitigate the risk of VTE in acute medically ill patients. The failure of cohort 1 (patients with an elevated D-dimer levels) to achieve statistical significance did not translate into failure of the two remaining two larger cohorts. Both cohort 2 (patients with elevated D-dimer or age ≥75 years) and the overall study population were able to demonstrate that betrixaban was significantly better than enoxaparin at reducing VTE in medically ill patients post hospital discharge. Betrixaban treatment also reduced the risk of bleeding when compared with enoxaparin and resulted in a risk reduction of 24% in the overall study population1, 3.
Prior to the APEX study, two other oral direct factor Xa inhibitors, rivaroxaban and apixaban, have been evaluated for VTE prophylaxis in acute medically ill patients in the MAGELLAN and ADOPT trials, respectively. These trials were unsuccessful in showing a net clinical benefit with respect to VTE reduction and major bleeding events in acute medically ill patients. So what was different about APEX? Learning lessons from the failure of others, the APEX trial included a reduced dose of 40 mg for patients with renal insufficiency, or those receiving a concomitant strong P-glycoprotein inhibitor 3, 4. To improve betrixaban’s prospects of demonstrating a significant efficacy benefit over enoxaparin, the trial used a biomarker-based design to enroll patients at higher VTE risk. Another distinguishing feature between the trials was the patient mobility criteria, which was more stringent in the APEX trial compared to the MAGELLAN and ADOPT trials. Therefore, APEX enrolled more severely immobilized patients2.
Current treatment paradigm for medically ill patients and KOL viewpoint on betrixaban
Decision Resources Group (DRG) estimates 20 million acute medically ill patients are at risk of VTE across the G7 countries each year. Primary market research conducted by DRG shows that the thromboprophylaxis for medically ill patients is typically managed with standard injectable enoxaparin, unfractioned heparins, or other LMWHs until either full mobility is restored or the patient is discharged from hospital. Notably, none of these therapies address the need of extended thromboprophylaxis beyond the period of hospitalization, or in cases of patient immobilization. Physicians interviewed by DRG have also pointed out that almost 75 percent of all VTE events in medically ill patients occur after hospital discharge, with the peak incidences occurring within 20 days post hospitalization. These findings highlight physician concerns that the current prophylaxis regimen is not sufficient and the duration of prophylaxis to mitigate the risk of VTE events is too short.
We got a mixed-bag of reactions while interviewing physicians about betrixaban. Some of the physicians were of the view that betrixaban is particularly suited to fulfill a significant unmet need of treating VTE in medically ill patients. They mentioned the drug’s low renal clearance rate and minimal hepatic metabolism as important considerations during drug selection. Betrixaban’s reduced risk of major bleeding and drug-drug interactions were other notable features that appealed to physicians. While some physicians commented that overall, betrixaban is going to be useful because it shows efficacy in extended prophylaxis despite failure to reach significance in an APEX cohort; others stated that implementation of the drug for this sub population would be a challenge and would require enormous amounts of educational programs to change physician perspectives. While discussing the market potential of betrixaban, a number of physicians expect the cost of the drug to be the number one challenge for Portola. While the longer half-life of betrixaban was acknowledged as advantageous, physicians also commented that managing this drug in emergency situations would be difficult without availability of an approved antidote.
DRG’s take on the market potential of betrixaban
Keeping in view the notable unmet need in the current VTE settings for long term prophylaxis, betrixaban is being positioned as the first NOAC to address hospital-to-home prevention of VTE in acute medically ill patients. With the medically ill patients often being elderly, frail, and renally compromised, we believe that betrixaban with its long half-life, once-daily dosing, and low renal clearance, will offer some commercial advantages over the other alternative currently available therapies. In addition, betrixaban is expected to have enhanced commercial potential due to inclusion of both the in-hospital and post-discharge setting patients, maximizing the breadth of eligible patients. Finally, the development of an antidote (andexanet alfa) will further allay physicians’ concern of increased bleeding events due to longer half-life. Janssen and Bayer are conducting the Phase III MARINER trial evaluating the impact of rivaroxaban on VTE risk in acutely medically ill, post-hospital discharge patients. The rationale of the study is based on the findings from the MAGELLAN trial and the topline results are expected in the latter half of 2018. If rivaroxaban is able to demonstrate efficacy in this patient population this time around, betrixaban may still face stiff competition despite having first-to-market advantage among NOACs for medically ill patients. Other than that, betrixaban will also face competition from entrenched therapies currently used for medically ill patients, such as the LMWHs, especially in in-hospital patients at risk of VTE. If betrixaban is approved next week, it will be interesting to see how the market dynamics change for this high-risk patient population.
For a more in-depth analysis of dynamics and KOL insights on the venous thromboembolism market, please see our market assessment in Venous Thromboembolism | Landscape & Forecast |G7.
Disease Landscape & Forecast Module
DRG’s Disease Landscape & Forecast (DL&F) module is a comprehensive source of vital disease-specific business and market intelligence. It provides world-class epidemiology, keen insights into current treatment paradigms, in-depth pipeline assessments, and multivariable market forecasts—all supported by detailed primary and secondary research conducted by analysts with deep indication and therapy area expertise. Explore DL&F
Related DRG reports:
If you’re a client, access your insights here.
Learn how to gain access to DRG's suite of venous thromboembolism analytics, reports and experts:
- Portola Pharmaceuticals , press release, May 27, 2016
- Cohen AT, et al. The design and rationale for the Acute Medically Ill Venous Thromboembolism Prevention with Extended Duration Betrixaban (APEX) study. American Heart Journal. 2014; 167 (Issue 3; 335–341)
- Cohen AT, et al. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. The New England Journal of Medicine. 2016; 375:534-544
- Gibson C, et al. The safety and efficacy of full- versus reduced-dose betrixaban in the Acute Medically Ill VTE Prevention with Extended-Duration Betrixaban (APEX) trial. American Heart Journal. 2017; 185: 93–100