US-based biopharmaceutical firm Portola Pharmaceuticals has released initial results from a Phase II proof-of-concept trial of its investigational Factor Xa inhibitor antidote ‘andexanet alfa (PRT4445)’, in healthy volunteers administered the Factor Xa inhibitor Xarelto (rivaroxaban).
In the randomised, placebo-controlled, double-blind, cohort dose-escalation Phase II proof-of-concept trial, healthy volunteers were treated with an oral dose of Xarelto at 20mg qd for six days and then randomised them in a 6:3 ratio to andexanet alfa in different dosing cohorts.
The first two cohorts were given a single IV bolus of andexanet alfa at 210mg or 420mg respectively.
The company said that within two minutes after completion of the 210mg and 420mg bolus of andexanet alfa, anti-Factor Xa activity decreased dose-dependently by 20% and 53% respectively.
According to the results secured from the first two dosing groups in the trial, andexanet alfa showed that it is able to dose-dependently reverse the anticoagulant effects of Xarelto.
PRT4445 is being developed as universal antidote for patients who experience an uncontrolled bleeding episode or who need emergency surgery while being anticoagulated with a Factor Xa inhibitor.
The company intends to commence registration-enabling studies in 2014 as part of a potential Accelerated Approval pathway to address the major unmet need due to a lack of an approved antidote.
Portola executive vice-president of research and development John Curnutte said: "We are now increasingly confident that the positive proof-of-concept data shown with both Eliquis and Xarelto to date will help us determine an appropriate and effective dosing regimen for all oral Factor Xa inhibitors and enoxaparin for use in the conduct of our planned pivotal registration studies."
The company expects to present the data on additional cohorts evaluating higher doses of andexanet in healthy volunteers treated with Xarelto at the American Society of Hematology (ASH) to be held in New Orleans from 7-10 December 2013.
According to the interim safety data, andexanet alfa was well-tolerated, with no thrombotic events, or serious or severe adverse events reported.
Andexanet alfa acts as a Factor Xa decoy that binds and sequesters direct Factor Xa inhibitors in the blood, preventing them from inhibiting native Factor Xa.
According to Portola, andexanet alfa has the potential to be the first universal antidote to reverse the effects of Factor Xa inhibitors in patients who suffer an uncontrolled bleeding episode or require emergency surgery.
Portola has previously signed clinical collaboration agreements with the manufacturers of currently approved Factor Xa inhibitors, including Bristol-Myers Squibb and Pfizer (Eliquis [apixaban]), Bayer HealthCare and Janssen Pharmaceuticals (Xarelto [rivaroxaban]), and Daiichi Sankyo (Lixiana [edoxaban]), but retained all rights to the programme.
According to the company, millions of patients are treated with Factor Xa inhibitors for short-term use or chronic conditions in the G7 countries, and the anticoagulant market is expected to continue to grow with the adoption of novel oral anticoagulants.
Of them, based on their underlying medical condition, annually between 1% and 4% of these patients will experience major bleeding and an additional 1% may require emergency surgery.
Based on these data and projected use of Factor Xa inhibitors, Portola estimates there could be approximately 500,000 hospital visits each year by patients who would benefit from an antidote by the year 2020.