Reversal Agents for NOACs(Novel Oral Anticoagulants)

CSRC Symposium Washington DCOct 18, 2016

Current status and future challenges

Paul A Reilly, PhDClinical Research, Boehringer Ingelheim, Inc

Atrial fibrillation

• AF is the most common arrhythmia in clinical practice1

– In 2007, 6.3 million people in the US, Japan, Germany, Italy, Spain, France and the UK were living with diagnosed AF2

• The number of AF patients is predicted to rise3

– It is estimated 1 in 4 individuals aged 40 years or older will develop AF4

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

0

10

20

30

Perc

ent

AF prevalenceStrokes attributable to AF

Age range, yrs

One-sixth of All Strokes Attributable to AF

Framingham Study

50 – 59 60 – 69 70 – 79 80 - 89

Wolf PA, et al. Stroke. 1991;22:983-988.

CM-4

Study YearAFASAK I 1989; 1990

SPAF I 1991BAATAF 1990

CAFA 1991SPINAF 1992

EAFT 1993

All trials (n = 6)N = 2,900

Favors warfarin Favors placeboor control

100% 50% 0 −50% −100%

Hart RG, et al. Ann Intern Med. 2007;146:857-867.

Efficacy of Warfarin for Stroke ReductionCompared With Placebo or Control in 6 Studies

Relative risk reduction (95% CI)

Two Placebo controlled trials: CAFA and SPINAF

National Estimates of Medications Commonly Implicatedin Emergency Hospitalizations for Adverse Drug Events

In Older U.S. Adults, 2007-2009Annual National Proportion of

Medication Estimate of Emergency Dept.Hospitalizations Visits Resulting in

(N=99,628) Hospitalization

No. % (95% CI) %Most commonly implicated medications

Warfarin 33,171 33.3 (28.0-38.5) 46.2Insulins 13,854 13.9 (9.8-18.0) 40.6Oral antiplatelet agents 13,263 13.3 (7.5-19.1) 41.5Oral hypoglycemic agents 10,656 10.7 (8.1-13.3) 51.8Opioid 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 NOACRE-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

Ansell et al. N Engl J Med 2015; Ansell et al Thromb Res, 2016; Niessner et al, Eur Heart J 2015

Ciraparantag: Universal Inhibitor

15

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

Short half-life

IV administration as bolus of 300 mgHeparinLMW Heparin

Clinical data only available in healthy volunteers for enoxaparin and edoxaban

Ansell et al NEJM 2014; Ansell et al, Thromb Res 2016

Reversal of Edoxaban and Enoxaparin in Healthy Volunteers with Ciraparantag

Reversal measured using whole blood assay

Enoxaparin Edoxaban

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

Lu G et al. Nat Med 2013; Siegal DM et al. N Engl J Med 2015;

Andexanet alfa: Factor Xa reversal agent

18

Factor Xa

Andexanet alfa

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

Requires reconstitution prior to IV administration; bolus + infusion

Short half-life (30–60 min)

Increased thrombin generation during andexanet alfa in healthy volunteers

Siegal DM et al. N Engl J Med 2015

Effect of andexanet alpha in reversing anticoagulant effect of factor Xa inhibitors

19

Apixaban (Annexa-A) Rivaroxaban (Annexa R)

End of bolus End of infusion

100

75

50

25

00 0.2 0.4 0.6 1 2 3 4 5 6 7 8 9 10 1211

Time after bolus (h)

Ant

i-FXa

(%)

Placebo (Part 1, n=9)

400 mg bolus + 480 mg x 2-h infusion (n=23)

Placebo (Part 2, n=8)400 mg bolus (n=24)

400

0 0.2 0.4Time after bolus (h)

Anti-

FXa

(ng/

mL)

1 2 3 4 5 6 7 8 9 10

300

200

100

0

End of bolus End of infusion

0.6

Placebo (Cohorts 1–3, n=9)

ANNEXA-4 Results in Patients

Connolly et al. NEJM, 2016; DOI:10.1056/NEJMoa1607887

Siegal DM et al. N Engl J Med 2015

Endogenous thrombin potential (ETP) with andexanet alfa in volunteers

21

2500

2000

1500

1000

500

0Baseline 0.0 0.2 0.4 0.6 2 4 6 8 10 12 14 16 2218 20

Time after bolus (h)

ETP

(nM

.min

)

Baseline range

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 returns to baseline range a few hours after bolus injection

• The mechanism is not clear –related to tissue factor pathway inhibitor

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?

Schiele et al. Blood 2013, Eikelboom et al, Circulation 2015

Idarucizumab: Specific reversal agent for dabigatran

Dabigatran

Idarucizumab

Humanized Fab fragment

Binding affinity for dabigatran ~350×higher than dabigatran to thrombin

No intrinsic procoagulant or anticoagulant activity expected

IV administration,immediate onset of action

Short half-life

Relative Size and Affinity of Dabigatran, Idarucizumab and Thrombin

Thrombin~36000 daltons Idarucizumab

~47800 daltons

Dabigatran~500 daltons

Glund et al, Lancet 2015:S0140-6736(15)60732-2

Reversal of Dabigatran Anticoagulationby Idarucizumab in Healthy Volunteers

25

Dabigatran alone

121086420-2 24 36 48 60 72

Time after end of infusion (h)

70

65

60

55

50

45

40

35

30

dTT

(s)

+ placebo+ 1 g Fab+ 2 g Fab+ 4 g FabNormal upper limit Mean baseline

End of Idarucizumab injection (5 min infusion)

(8-9 healthy volunteers per group)

• 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

Assay upper limit of normal

Diluted thrombin time

Idarucizumab 2x 2.5 g

dTT

(s)

130

110

70

60

50

40

30

20

120

100

90

80

1h 2h 4h 12h 24hBaseline Betweenvials

10–30min

Time post idarucizumab

RESULTS: Primary endpoint in Group A (Bleeding)Reversal of dabigatran-anticoagulation with idarucizumab

Group A (n = 51)Active Bleeding

Group B (n = 39)Urgent Surgery

Unb

, dab

igat

ran

(ng/

mL)

1500

700

300

200

100

0

1000

600

500

400

1h 2h 4h 12h 24hBaseline Betweenvials

10-30min

Time post idarucizumab

Unb

, dab

igat

ran

(ng/

mL)

01h 2h 4h 12h 24hBaseline Between

vials10-30min

Time post idarucizumab

1500

700

300

200

100

1000

600

500

400

Dabigatran levels were below 20ng/ml in 89/90 patients already after infusion of first vial

Idarucizumab 2x 2.5 g

Idarucizumab 2x 2.5 g

Dabigatran levels before and after treatment with idarucizumab

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

Safety

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 availableor in development?

Phase IIOngoing

Phase I/II

Ciraparantag(PER977)1Target: universal

Widespread availabil ity (>5500 hospitals worldwide)following local approval

ApprovalFDAOct 20154

EMANov 20155

etc.

Submitted to EMA/FDAand othersFeb/Mar 2015

Study in patients requiring urgent surgery/with major bleeding; started May 20142,3

Studies in healthy volunteers

Idarucizumab1

Target: dabigatran

Complete response letterby FDA, Aug 20168

Accepted for review by EMAAug 20169

Submitted to FDADec 20157

Study in patientswith major bleeding only; started Jan 20156

Studies in healthy volunteers

Andexanet alfa1

Target:FXa inhibitors

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 bleedingcessation 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