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New Medicines

OndexxyaAnticoagulation reversal - antidote to oral factor Xa inhibitors - first-line

Information

Ondexxya
New molecular entity
Portola Pharmaceuticals
Portola Pharmaceuticals

Development and Regulatory status

Launched
Launched
Launched
July 2019
Yes
Aug 19Portola Pharmaceuticals is conducting a phased launch of andexanet alfa in Germany, Austria, the UK, the Netherlands and Sweden [26].
Jul 19Available in the UK for Hospital use only. Price 4 x 200mg powder for solution vials = £11,100 [27].
Apr 19The EC has granted conditional Marketing Authorization for andexanet alfa for adult patients treated with the Factor Xa inhibitor apixaban or rivaroxaban when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding [24].
Feb 19Recommended for EU approval by CHMP - the full indication is "For adult patients treated with a direct factor Xa (FXa) inhibitor (apixaban or rivaroxaban) when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding” [23].
Jan 19Final approval granted by the FDA in the US and launch announced. Although approval was granted in May 18, the company was only allowed to offer limited supplies while commercial production methods were tested. Large-scale production may now commence and the product is to be distributed to hospitals nationwide [21].
May 18US FDA approved Andexxa as an antidote for rivaroxaban and apixaban under the FDA’s Accelerated Approval pathway based on the change from baseline in anti-Factor Xa activity in healthy volunteers. As a part of that pathway, continued approval may be contingent on post-marketing data showing improvement in haemostasis in pts.[20]
May 18A formal decision regarding approval is expected by the EMA´s CHMP by the end of this year, with the European Commission (EC) expected to make a final decision in early 2019.[20]
Aug 17Re-filed in US [19].
Jul 17Following a request from the EU for further data in December 2016, in July 2017 the company requested further time to respond to this [18]
Aug 16The EMA has accepted Portola´s Marketing Authorisation Application (MAA), according to a company media release: the company is seeking conditional approval (approval subject to post-marketing conditions such as further data collection) based on two published PIII studies plus limited data from the on-going ANNEXA-4 study [16].
Aug 16FDA issues a complete response letter asking Portola for additional information, primarily related to manufacturing. It also asked for more data to support inclusion of edoxaban and enoxaparin in the label; these are specific Factor Xa inhibitors, with the others named in its planned indication being apixaban and rivaroxaban [15].
Dec 15The FDA application was completed in December 2015 with a review deadline of 17 August 2016. The submission is supported by l data from phase III ANNEXA-A, ANNEXA-R and the phase IV ANNEXA-4. The company expects to launch the product in the US in 2016 [14].
Sep 15Portola begins a rolling FDA submission of andexanet alfa, planning to hand in the final part of its application by end 2015 [13].
Apr 15Portola plans to submit data from the ANNEXA-A (apixaban) and ANNEXA-R (rivaroxaban) studies, and initial data from a Phase 4 study, as part of its Biologics License Application to the FDA under an Accelerated Approval pathway by the end of 2015 [10].
Mar 15Portola completes its PIII program and expects to file andexanet alfa for FDA approval by end 2015 [8].
Mar 15Andexanet alfa receives orphan drug designation in US for reversing the anticoagulant effect of direct or indirect Factor Xa inhibitors in patients experiencing a serious uncontrolled bleeding event or who require urgent or emergent surgery [7].
Jul 14CMC Biologics enters in to a commercial supply agreement with Portola Pharmaceuticals, for development of andexanet alfa for use in patients with a major bleed/who require emergency surgery [3].
Jan 14Portola Pharmaceuticals have indicated their intention to submit a Biologics License Application [BLA] at the end of 2015 for approval of andexanet alfa under an Accelerated Approval pathway [6].
Nov 13Portola is pursuing an accelerated approval pathway for andexanet alfa and plans to statrt registration-enabling studies in 2014 [1].
Nov 13FDA has granted breakthrough therapy designation to andexanet alfa

Category

Factor Xa inhibitor antidote. First-in-class recombinant, modified Factor Xa molecule that directly reverses the effects of Factor Xa inhibitors.
It has been estimated that around 1-4% of pts treated with Factor Xa inhibitors may experience major bleeding and 1% may require emergency surgery. Development of a specific antidote designed to reverse the anticoagulant activity of Factor Xa inhibitors may provide an important treatment option for pts who experience a major bleeding event or require emergency surgery [10].
Anticoagulation reversal - antidote to oral factor Xa inhibitors - first-line
Intravenous

Further information

Yes
May 2021

Trial or other data

May 19Data around spontaneous intracranial hemorrhage (ICH) from a subgroup of the PIIIb/IV ANNEXA-4 trial published. Among the 352 pts in the trial, 227 experienced an ICH and 128 were treated with 98 evaluable for hemostatic efficacy. Of this subset, 79% achieved excellent or good hemostasis during the 12-hr period after receiving andexanet alfa.[25]
Feb 19Results of ANNEXA-4 are published (n=352). The study found that in patients with acute major bleeding associated with the use of a factor Xa inhibitor, andexanet reduced anti–factor Xa activity by 93% from baseline, and that 82% of patients achieved haemostatic efficacy at 12 hours [22].
May 18The FDA´s post-marketing requirement calls for a clinical trial that randomises patients to receive either Andexxa or usual care. The study is expected to start in 2019 and report in 2023.[20]
Aug 16Portola announces interim results presented at the European Society of Cardiology’s annual meeting in which AndexXa rapidly and substantially reversed the effects of NOACs in patients for whom the drug had triggered major bleeding. And following infusion, 79% of patients saw bleeding stoppage classed as “excellent” or “good” over a 12-hour period. Patients receiving Xarelto experienced an 89% decrease in anti-Factor Xa activity following their AndexXa dose, while those on Eliquis saw activity sink by a median 93% [17].
Nov 15Results of ANNEXA-A and ANNEXA-R (NCT02207725 & NCT02220725) published in the New England Journal of Medicine. In 154 healthy older volunteers taking apixaban or rivaroxaban andexanet reversed anticoagulant activity within minutes after administration (92-94%) vs. placebo (18-21%), andfor duration of infusion, without evidence of clinical toxic effects [12].
Sep 15It has been estimated that around 1-4% of pts treated with Factor Xa inhibitors may experience major bleeding and 1% may require emergency surgery. Development of a specific antidote designed to reverse the anticoagulant activity of Factor Xa inhibitors may provide an important treatment option for pts who experience a major bleeding event or require emergency surgery [10].
Jun 15Portola Pharmaceuticals, Bristol-Myers Squibb Company and Pfizer jointly announced that andexanet alfa met all primary and secondary endpoints in a PIII study determining safety and efficacy. The PIII ANNEXA-A study showed andexanet alfa significantly reduced the level of free unbound apixaban in plasma and restored thrombin generation to normal [11].
Apr 15Portola announced topline results from the second part of the PIII ANNEXA-A study, in which 31 healthy volunteers were given apixaban 5 mg twice daily for four days and then randomized in a 3:1 ratio to andexanet alfa administered as a 400 mg IV bolus followed by a continuous infusion of 4 mg/min for 120 minutes (n=23) or to placebo (n=8). Andexanet alfa produced rapid reversal of the anticoagulant effect of apixaban, as measured by anti-Factor Xa activity, which was sustained for the duration of the infusion. In the study, andexanet alfa was well tolerated, with no serious adverse events, thrombotic events, or antibodies to Factor X or Xa reported [10].
Mar 15ANNEXA-R study reported at conference. Data show that, for the primary endpoint, andexanet alfa 800mg iv (n=27) reduced the anti-Factor Xa activity of rivaroxaban from baseline to nadir by >90% compared with those randomised to receive placebo (n=14), a statistically significant difference (p<0.0001) [9].
Jan 15Portola Pharmaceuticals announced the initiation of a single-arm Phase 4 study to support the approval of andexanet alfa by the US FDA under an accelerated approval pathway. The open-label, single-arm, Phase 4 study is evaluating andexanet alfa´s ability to decrease anti-Factor Xa activity and restore haemostasis in patients. It is being conducted over 50 sites in North America and Europe in patients receiving apixaban, rivaroxaban or enoxaparin (a low molecular weight heparin) who present with an acute major bleed, including life-threatening bleeding associated with very low blood counts, or bleeding that occurs in a critical area such as the brain or heart. The trial excludes bleeding due to major trauma and large blood vessel rupture. Patients will receive andexanet alfa as an IV bolus followed immediately by a continuous infusion. Safety endpoints include overall 45 day safety, including an evaluation of thrombotic activity and antibody development [6].
Jan 15Portola Pharmaceuticals announced topline results from the first part of the Phase 3 ANNEXA™-R (Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of FXa Inhibitors – Rivaroxaban) study. In this first part of the ANNEXA-R study, reported, 41 healthy volunteers were given XARELTO® 20 mg once daily for four days and randomized to andexanet alfa 800 mg IV bolus (n=27) or to placebo (n=14). The study achieved its primary endpoint with high statistical significance; andexanet alfa significantly and immediately reversed the anticoagulation activity of XARELTO®. Andexanet alfa was shown to be well tolerated. In the second part of the ANNEXA-R study, approximately 40 healthy volunteers will be given XARELTO® 20 mg once daily for four days and will be randomized to andexanet alfa administered 800 mg IV bolus followed by a continuous infusion of 8 mg/min for 120 minutes or to placebo. Data from this part of the study are expected in mid-2015. [5]
Oct 14Portola announce that its first of two PIII ANNEXA-A (Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of fXA Inhibitors – Apixaban) studies met its primary and secondary endpoints with high statistical significance. Andexanet alfa was well tolerated with no serious adverse events reported. Top-line efficacy data from the first demonstrated that an intravenous (IV) bolus of andexanet alfa immediately and significantly reversed the anticoagulation activity of apixaban [4].
Mar 14PIII study starts. The randomized, double-blind, placebo-controlled study will evaluate the efficacy of andexanet alfa in older healthy volunteers (ages 50-75 years) as demonstrated by biomarker endpoints, including anti-Factor Xa levels, plasma free fraction of the anticoagulant and thrombin generation. In the first part of the study, 32 subjects will be given apixaban 5mg twice daily and then randomized in a 3:1 ratio to andexanet alfa administered as a 400mg IV bolus or to placebo. In the second part, 32 subjects will be randomized in a 3:1 ratio to andexanet alfa administered as a 400mg IV bolus followed by a continuous infusion of 480mg at 4mg/min for 120 minutes or to placebo. Study participants will be followed for up to 43 days to assess safety. The first part of the study is expected to report in Q4 2014 and the second part in early 2015 [3]
Feb 14Portola Pharmaceuticals has entered into a second clinical collaboration agreement with Bayer and Janssen to evaluate andexanet alfa in PIII registration studies with rivaroxaban which are expected to start in H1 2014 [2].
Nov 13The Company has previously reported data from its ongoing PII proof-of-concept studies of andexanet alfa and the Factor Xa inhibitors apixaban and rivaroxaban. Additional studies are ongoing with enoxaparin, edoxaban and betrixaban. To date, PII results have demonstrated that andexanet alfa can immediately reverse the anticoagulant activity of Factor Xa following IV bolus; reversal can be prolonged when necessary by extended infusion. Once administration is stopped, andexanet alfa is rapidly cleared and anticoagulant therapy can be re-started. No serious adverse events or antibodies to Factor Xa or Factor X have been observed in ongoing studies. Portola has entered into clinical collaboration agreements with all of the manufacturers of direct Factor Xa inhibitors, while retaining all rights to the programme [1].

Evidence based evaluations

OndexxyaAnticoagulation reversal - antidote to edoxaban

Information

Ondexxya
Licence extension / variation
Portola Pharmaceuticals
Portola Pharmaceuticals

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials
Jun 20Extensions of the ANNEXA-4 study, are enrolling patients in Germany and Japan. The purpose of the extensions is to gain experience with patients receiving edoxaban and with Japanese patients [6].
Jun 20Portola anticipates Andexxa approval as a reversal agent to edoxaban in late 2022 [5].

Category

Factor Xa inhibitor antidote. First-in-class recombinant, modified Factor Xa molecule that directly reverses the effects of Factor Xa inhibitors.
It has been estimated that around 1-4% of pts treated with Factor Xa inhibitors may experience major bleeding and 1% may require emergency surgery. Development of a specific antidote designed to reverse the anticoagulant activity of Factor Xa inhibitors may provide an important treatment option for pts who experience a major bleeding event or require emergency surgery [10].
Anticoagulation reversal - antidote to edoxaban
Intravenous

Trial or other data

Nov 19Two PII studies are now complete. PII (NCT03310021) study was a single-center, randomised, double-blind, and placebo-controlled trial designed to: 1) demonstrate the degree to which administered andexanet doses can reverse Factor Ten A (FXa)-inhibitor induced anticoagulation; and 2) evaluate the safety and PK/PD of andexanet in healthy subjects taking direct FXa inhibitors at therapeutic doses. 108 subjects were recruited in the US. PII (NCT03551743) study aimed to evaluate the ability of PRT064445 to reverse the effects of several blood thinner drugs on laboratory tests. The study also is evaluating the blood levels of PRT064445 given at different doses. 28 subjects were enrolled [3].