Reversal Agents for NOACs (Novel Oral Anticoagulants)

Transcription

1 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

2 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: Decision Resources. Atrial Fibrillation Report. December Miyasaka Y et al. Circulation 2006; 114: Lloyd-Jones DM et al. Circulation 2004; 110:

3 CM-3 One-sixth of All Strokes Attributable to AF 30 AF prevalence Strokes attributable to AF Percent 20 Framingham Study Age range, yrs Wolf PA, et al. Stroke. 1991;22:

4 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, % 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:

5 National Estimates of Medications Commonly Implicated in Emergency Hospitalizations for Adverse Drug Events In Older U.S. Adults, 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, ( ) 46.2 Insulins 13, ( ) 40.6 Oral antiplatelet agents 13, ( ) 41.5 Oral hypoglycemic agents 10, ( ) 51.8 Opioid analgesics 4, ( ) 32.4 Budnitz DS et al. NEJM, 2011

6 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:

7 Stroke or systemic embolic events Ruff et al. Lancet 2014; 383:

8 Major Bleeding Ruff et al. Lancet 2014; 383:

9 Major Bleeding in Phase III Trials (per 100 patient-years) Warfarin NOAC RE-LY , 2.9 ROCKET ARISTOTLE ENGAGE , 1.6

10 Fatal Bleeds Majeed et al. Circulation 2013; 128:

11 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

12 Can We Improve Treatment Rates? Fear of bleeding? Absence of reversal agents may impede the uptake of NOACs by both patients and physicians

13 Time to Reversal: Oral Versus IV Vitamin K Lubetsky A et al. Arch Intern Med 2003;163:

14 Normalizing INR with Prothrombin Complex Concentrates (PCCs) Sarode et al. Circulation 2013; 128:

15 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

16 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

17 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

18 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

19 Effect of andexanet alpha in reversing anticoagulant effect of factor Xa inhibitors Apixaban (Annexa-A) Rivaroxaban (Annexa R) Anti-FXa (%) End of bolus End of infusion Placebo (Part 1, n=9) 400 mg bolus (n=24) Placebo (Part 2, n=8) 400 mg bolus mg x 2-h infusion (n=23) Anti-FXa (ng/ml) End of bolus End of infusion Placebo (Cohorts 1 3, n=9) Time after bolus (h) Time after bolus (h) Siegal DM et al. N Engl J Med

20 ANNEXA-4 Results in Patients Connolly et al. NEJM, 2016; DOI: /NEJMoa

21 Endogenous thrombin potential (ETP) with andexanet alfa in volunteers 2500 End of bolus End of infusion Placebo (n=8) 400 mg bolus 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) Baseline 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

22 Andexanet: Opportunities & Challenges Opportunities Factor Xa antidote Apixaban Rivaroxaban Edoxaban LMWH Peak reversal effect 89-93% within minutes Hemostasis excellent or 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?

23 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

24 Relative Size and Affinity of Dabigatran, Idarucizumab and Thrombin Dabigatran ~500 daltons Thrombin ~36000 daltons Idarucizumab ~47800 daltons

25 Reversal of Dabigatran Anticoagulation by Idarucizumab in Healthy Volunteers dtt (s) 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 Time after end of infusion (h) (8-9 healthy volunteers per group) Glund et al, Lancet 2015:S (15)

26 RESULTS: Primary endpoint in Group A (Bleeding) Reversal of dabigatran-anticoagulation with idarucizumab 130 Diluted thrombin time dtt (s) Idarucizumab 2x 2.5 g Assay upper limit of normal 20 Baseline Between vials min 1h 2h 4h 12h 24h Time post idarucizumab

27 Dabigatran levels before and after treatment with idarucizumab Group A (n = 51) Active Bleeding Group B (n = 39) Urgent Surgery Unb, dabigatran (ng/ml) Idarucizumab 2x 2.5 g Unb, dabigatran (ng/ml) Idarucizumab 2x 2.5 g Baseline Between vials min Time post idarucizumab 1h 2h 4h 12h 24h 0 Baseline Between 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

28 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

29 Idarucizumab: Opportunities & Challenges Opportunities Available in > 35 countries Peak effect of 100% reversal within minutes, sustained for h Normal hemostasis in 93% of emergency surgery cohort Challenges Complete Phase III trial as condition of approval

30 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 ,3 Submitted to EMA/FDA and others Feb/Mar 2015 Approval FDA Oct EMA Nov 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 Submitted to FDA Dec Accepted for review by EMA Aug Complete response letter by FDA, Aug 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: NCT ; 7. Portola Pharmaceuticals press release, 18 Dec 2015; 8. Portola Pharmaceuticals press release 17 August 2016; 9. Portola Pharmaceuticals press release 19 August 2016

31 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

32 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

33 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

34 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