Reversal Agents for NOACs (Novel Oral Anticoagulants) Current status and future challenges Paul A Reilly, PhD Clinical Research, Boehringer Ingelheim, Inc CSRC Symposium Washington DC Oct 18, 2016
Atrial fibrillation AF is the most common arrhythmia in clinical practice 1 In 2007, 6.3 million people in the US, Japan, Germany, Italy, Spain, France and the UK were living with diagnosed AF 2 The number of AF patients is predicted to rise 3 It is estimated 1 in 4 individuals aged 40 years or older will develop AF 4 1. Go AS et al. JAMA 2001; 285:2370 2375. 2. Decision Resources. Atrial Fibrillation Report. December 2008. 3. Miyasaka Y et al. Circulation 2006; 114:119 125. 4. Lloyd-Jones DM et al. Circulation 2004; 110:1042 1046
CM-3 One-sixth of All Strokes Attributable to AF 30 AF prevalence Strokes attributable to AF Percent 20 Framingham Study 10 0 50 59 60 69 70 79 80-89 Age range, yrs Wolf PA, et al. Stroke. 1991;22:983-988.
Efficacy of Warfarin for Stroke Reduction Compared With Placebo or Control in 6 Studies CM-4 Study Year AFASAK I 1989; 1990 SPAF I 1991 BAATAF 1990 CAFA 1991 SPINAF 1992 EAFT 1993 Relative risk reduction (95% CI) All trials (n = 6) N = 2,900 100% 50% 0 50% 100% Favors warfarin Favors placebo or control Two Placebo controlled trials: CAFA and SPINAF Hart RG, et al. Ann Intern Med. 2007;146:857-867.
National Estimates of Medications Commonly Implicated in Emergency Hospitalizations for Adverse Drug Events In Older U.S. Adults, 2007-2009 Annual National Proportion of Medication Estimate of Emergency Dept. Hospitalizations Visits Resulting in (N=99,628) Hospitalization Most commonly implicated medications No. % (95% CI) % Warfarin 33,171 33.3 (28.0-38.5) 46.2 Insulins 13,854 13.9 (9.8-18.0) 40.6 Oral antiplatelet agents 13,263 13.3 (7.5-19.1) 41.5 Oral hypoglycemic agents 10,656 10.7 (8.1-13.3) 51.8 Opioid analgesics 4,778 4.8(3.5-6.1) 32.4 Budnitz DS et al. NEJM, 2011
Why Use NOACs? As an alternative to warfarin NOACs have a favourable benefit-risk profile compared to warfarin, based on outcomes data from >71,000 patients Ruff et al. Lancet 2014; 383: 955-962
Stroke or systemic embolic events Ruff et al. Lancet 2014; 383: 955-962
Major Bleeding Ruff et al. Lancet 2014; 383: 955-962
Major Bleeding in Phase III Trials (per 100 patient-years) Warfarin NOAC RE-LY 3.6 3.3, 2.9 ROCKET 3.45 3.6 ARISTOTLE 3.1 2.1 ENGAGE 3.4 2.8, 1.6
Fatal Bleeds Majeed et al. Circulation 2013; 128: 2325-2332
The Treatment Gap 3 to 4 million people in the US have AF Of those with additional risk factors for stroke, half are not treated with oral anticoagulants Of these, 5% per year experience a stroke Of these, 70% are preventable Over 50,000 preventable strokes each year in the US
Can We Improve Treatment Rates? Fear of bleeding? Absence of reversal agents may impede the uptake of NOACs by both patients and physicians
Time to Reversal: Oral Versus IV Vitamin K Lubetsky A et al. Arch Intern Med 2003;163:2469-2473
Normalizing INR with Prothrombin Complex Concentrates (PCCs) Sarode et al. Circulation 2013; 128: 1234-1243
Ciraparantag: Universal Inhibitor Small synthetic molecule that targets all direct and indirect anticoagulants Binds using both hydrogen bonding and charge-charge interactions No intrinsic procoagulant effects detected to date Heparin LMW Heparin IV administration as bolus of 300 mg Short half-life Clinical data only available in healthy volunteers for enoxaparin and edoxaban Ansell et al. N Engl J Med 2015; Ansell et al Thromb Res, 2016; Niessner et al, Eur Heart J 2015 15
Reversal of Edoxaban and Enoxaparin in Healthy Volunteers with Ciraparantag Reversal measured using whole blood assay Enoxaparin Edoxaban Ansell et al NEJM 2014; Ansell et al, Thromb Res 2016
Ciraparantag: Opportunities & Challenges Opportunities Small molecule Universal antidote Apixaban Rivaroxaban Edoxaban Heparins Dabigatran Challenges Whole blood clotting time (WBCT): companion diagnostic? By 12 h reversal effect is gone Highly charged cationic molecule drug-drug interactions? Dose-related minor AEs
Andexanet alfa: Factor Xa reversal agent Recombinant modified activated FXa, competitive binding with direct FXa inhibitors acts as a decoy Similar binding affinity as with endogenous FXa; binds FXa inhibitors and inactivates them Factor Xa Requires reconstitution prior to IV administration; bolus + infusion Increased thrombin generation during andexanet alfa in healthy volunteers Andexanet alfa Short half-life (30 60 min) Lu G et al. Nat Med 2013; Siegal DM et al. N Engl J Med 2015; 18
Effect of andexanet alpha in reversing anticoagulant effect of factor Xa inhibitors Apixaban (Annexa-A) Rivaroxaban (Annexa R) Anti-FXa (%) End of bolus 100 75 50 25 End of infusion Placebo (Part 1, n=9) 400 mg bolus (n=24) Placebo (Part 2, n=8) 400 mg bolus + 480 mg x 2-h infusion (n=23) Anti-FXa (ng/ml) End of bolus 400 300 200 100 End of infusion Placebo (Cohorts 1 3, n=9) 0 0 0.2 0.4 0.6 1 2 3 4 5 6 7 8 9 10 1112 Time after bolus (h) 0 0 0.2 0.4 0.6 1 2 3 4 5 6 7 8 9 10 Time after bolus (h) Siegal DM et al. N Engl J Med 2015 19
ANNEXA-4 Results in Patients Connolly et al. NEJM, 2016; DOI:10.1056/NEJMoa1607887
Endogenous thrombin potential (ETP) with andexanet alfa in volunteers 2500 End of bolus End of infusion Placebo (n=8) 400 mg bolus + 480 mg x 2-hr infusion (n=23) Increase of ETP with andexanet alfa bolus Significant increase in thrombin generation (p<0.001) ETP (nm.min) 2000 1500 1000 500 0 Baseline 0.0 0.2 0.4 0.6 2 4 6 8 10 12 14 16 18 20 22 Baseline range ETP returns to baseline range a few hours after bolus injection The mechanism is not clear related to tissue factor pathway inhibitor Time after bolus (h) Siegal DM et al. N Engl J Med 2015 21
Andexanet: Opportunities & Challenges Opportunities Factor Xa antidote Apixaban Rivaroxaban Edoxaban LMWH Peak reversal effect 89-93% within minutes Hemostasis excellent or good @12 h in 79% Challenges By 4 h reversal effect is 30-39% Different dose regimens for different agents Possible procoagulant effect? (thrombotic events in 18% within 30 days) CMC issues?
Idarucizumab: Specific reversal agent for dabigatran Humanized Fab fragment Binding affinity for dabigatran ~350 higher than dabigatran to thrombin Dabigatran IV administration, immediate onset of action Short half-life Idarucizumab No intrinsic procoagulant or anticoagulant activity expected Schiele et al. Blood 2013, Eikelboom et al, Circulation 2015
Relative Size and Affinity of Dabigatran, Idarucizumab and Thrombin Dabigatran ~500 daltons Thrombin ~36000 daltons Idarucizumab ~47800 daltons
Reversal of Dabigatran Anticoagulation by Idarucizumab in Healthy Volunteers dtt (s) 70 65 60 55 50 45 40 35 End of Idarucizumab injection (5 min infusion) + placebo + 1 g Fab + 2 g Fab + 4 g Fab Normal upper limit Mean baseline Dabigatran alone Dabigatran prolonged clotting times of dtt, ECT, aptt and TT Mean clotting times were reversed to baseline immediately after end of Fab infusion The effect was sustained for the 2000 and 4000 mg doses 30-2 0 2 4 6 8 1012 24 36 48 60 72 Time after end of infusion (h) (8-9 healthy volunteers per group) Glund et al, Lancet 2015:S0140-6736(15)60732-2 25
RESULTS: Primary endpoint in Group A (Bleeding) Reversal of dabigatran-anticoagulation with idarucizumab 130 Diluted thrombin time dtt (s) 120 110 100 90 80 70 60 50 Idarucizumab 2x 2.5 g 40 30 Assay upper limit of normal 20 Baseline Between vials 10 30 min 1h 2h 4h 12h 24h Time post idarucizumab
Dabigatran levels before and after treatment with idarucizumab 1500 1000 700 Group A (n = 51) Active Bleeding 1500 1000 700 Group B (n = 39) Urgent Surgery Unb, dabigatran (ng/ml) 600 500 400 300 200 Idarucizumab 2x 2.5 g Unb, dabigatran (ng/ml) 600 500 400 300 200 Idarucizumab 2x 2.5 g 100 100 0 Baseline Between 10-30 vials min Time post idarucizumab 1h 2h 4h 12h 24h 0 Baseline Between 10-30 vials min Time post idarucizumab 1h 2h 4h 12h 24h Dabigatran levels were below 20ng/ml in 89/90 patients already after infusion of first vial
Safety No cases of hypersensitivity were observed Five thrombotic events occurred (5 of 90=5.6%) 1 early event (DVT + PE) within 72 hours of idarucizumab administration 4 patients had events after 72 hours of idarucizumab administration (DVT, DVT+PE+LA thrombus, MI, ischemic stroke) None of these 5 patients was receiving any antithrombotic therapy when the events occurred 18 deaths occurred (9 in each Group) Related to presenting index event and comorbidities
Idarucizumab: Opportunities & Challenges Opportunities Available in > 35 countries Peak effect of 100% reversal within minutes, sustained for 12-24 h Normal hemostasis in 93% of emergency surgery cohort Challenges Complete Phase III trial as condition of approval
What specific reversal agents for NOACs are available or in development? Idarucizumab 1 Target: dabigatran Studies in healthy volunteers Study in patients requiring urgent surgery/with major bleeding; started May 2014 2,3 Submitted to EMA/FDA and others Feb/Mar 2015 Approval FDA Oct 2015 4 EMA Nov 2015 5 etc. Widespread availability (>5500 hospitals worldwide) following local approval Andexanet alfa 1 Target: FXa inhibitors Studies in healthy volunteers Study in patients with major bleeding only; started Jan 2015 6 Submitted to FDA Dec 2015 7 Accepted for review by EMA Aug 2016 9 Complete response letter by FDA, Aug 2016 8 Ciraparantag (PER977)1 Target: universal Phase I/II Phase II Ongoing Idarucizumab is not approved in all countries. Please check your local prescribing information for details. Andexanet alfa is an investigational compound and is not approved in any country. 1. Adapted from Greinacher A et al. Thromb Haemost 2015; 2. Pollack C et al. N Engl J Med 2015; 3. Pollack C et al. Thromb Haemost 2015; 4. US FDA 2015 press release, 16 October 2015; 5. European Commission Community Register of Medicinal Products for Human Use 2015; 6. ClinicalTrials.gov Identifier: NCT02329327; 7. Portola Pharmaceuticals press release, 18 Dec 2015; 8. Portola Pharmaceuticals press release 17 August 2016; 9. Portola Pharmaceuticals press release 19 August 2016
Regulatory Framework (clinical) Accelerated approval Phase I/II trials demonstrate reversibility in volunteers Placebo control group Dose response Pharmacodynamic endpoint (clotting test) Data in patients Uncontrolled trial Clinical efficacy cannot be established Completion of patient study for safety evaluation as post-marketing requirement
Clinical Outcomes in Reversal Trials Uncontrolled or life-threatening bleeding cessation of bleeding Emergency surgery Perioperative bleeding Thrombotic events (DVT, PE, MI, ischemic stroke) Mortality Hypersensitivity reactions
Is there a Therapeutic Benefit? Absent a controlled trial in the target patient population, powered to demonstrate reduction in mortality or other improvement in clinical outcomes (duration or extent of bleeding), pharmacologic endpoints are the primary basis for efficacy After >50 years, there is still no data to demonstrate the clinical benefit of reversal of VKAs with Vitamin K + plasma/pccs
A Possible Indirect Benefit If the availability of reversal agents increases the comfort level of the physician and/or the patient, it will increase the likelihood that untreated patients will be treated with a NOAC An increase in the number of patients with AF who are anticoagulated may represent the true therapeutic benefit of reversal agents