Emerging Anticoagulants for VTE Prevention and Treatment: Is change upon us

1
Emerging Anticoagulants for VTE Prevention and
Treatment Is change upon us?

• Amanda C. Walker, PharmD
• Clinical Pharmacist
• University of Utah
• University Thrombosis Service

2
Objectives

• Describe the pharmacology and mechanism of action
  for new and emerging anti-thrombotic agents
• Discuss and review current randomized controlled
  trials for new and emerging anti-thrombotic
  agents for VTE prevention and treatment
• Evaluate the adverse drug reactions and side
  effects associated with these new agents

3
Current Limitations
Lassen MR. Vasc Health Risk Manag.
20084(6)1373-86.
4
New and Emerging Anticoagulants

• Anti Xa direct
• Rivaroxaban (oral)
• Apixaban (oral)
• Betrixiban (oral)
• Edoxaban (oral)
• Otamixaban (parenteral)
• LY 517717 (oral)
• DU 176B (oral)
• DX 9065a (parenteral)
• PRT054021 (oral)
• Anti Xa indirect
• Idraparinux biotinylated (parenteral)

• Anti IIa
• Dabigatran (oral)
• Odiparcil (oral)
• Flovagatran (parenteral)
• Pegmusirudin (parenteral)
• Peg Hirudin
• Desiruidin

5
Site of Action for New Anti-thrombotic Agents
Extrinsic
XII
Intrinsic
XI
Tissue Factor
IX
VII
VIII
Direct Xa Inhibitors -xaban
X
V
II
Fibrinogen
Fibrin Clot
6
Factor Xa vs. Factor IIa

• Factor Xa
• One Xa forms many IIa
• Limited role in diversity of action outside of
  coagulation cascade
• Clinical effectiveness
• Fondaparinux

• Factor IIa
• Supports feedback amplification through Factor V,
  Factor VIII, and Factor IX
• Has many cellular effects
• inflammation
• Clinical effectiveness
• Argatroban
• Hirudins

7
Direct Factor Xa Inhibitors
XII
Intrinsic
Extrinsic
XI
TF
IX
VII
VIII
Direct Xa Inhibitors -xaban
X
V
II
Fibrinogen
Fibrin Clot
8
Apixaban

• Oral tablet
• Bioavailability 50
• Peak Plasma Levels 3 hrs
• Half-life 12 hours
• Metabolized in liver via CYP3A4 and CYP
  independent mechanisms

• Eliminated via multiple pathways
• No laboratory monitoring required
• Manufactured by Bristol-Myers Squibb/Pfizer
• Plan to submit for U.S. approval in 2009-2010

9
Apixaban Efficacy Outcomes in TKR (Phase II)
Incidence of VTE and all-cause death ()
Duration 10 -14 days
5 QDay
10 QDay
20 QDay
Enox 30mg BID (n152)
Warf (n153)
2.5 BID
5 BID
10 BID
Apixaban (mg) (n 933)
Lassen MR, et al. J Thromb Haemost. 200752368
2375.
10
Apixaban Safety Outcomes in TKR (Phase II)
Incidence of bleeding events ()
5 QDay
10 QDay
20 QDay
Enox 30mg BID (n152)
2.5 BID
5 BID
10 BID
Warf (n153)
Apixaban (mg) (n 933)
11
Apixaban Phase III Trials
12
ADVANCE 1 Results of Efficacy vs. Enoxaparin
30 mg BID
RR 1.02 (95 CI 0.78 to 1.32) P0.06 for
non-inferiorityAbsolute Difference 0.1 (95
CI -2.22 to 2.44) Plt0.001 for non-inferiority
8.99N 1157
8.85N 1130
Lassen MR, et al. NEJM 2009361594 604.
13
ADVANCE 2 Primary Efficacy Results
RR 0.62 95 CI 0.51 0.74plt0.0001
24.5n 997
15.1n 975
Composite of adjudicated asymptomatic DVT by
venography objectively confirmed symptomatic
DVT or PE or death from any cause. One-sided
p-value for superiority.
14
Summary of ADVANCE 2 Study

• Apixaban 2.5mg BID vs. Enoxaparin 40mg QD
• Superior for
• Primary endpoint of ANY DVT/PE/All-Cause Death
• Secondary endpoint for Major VTE
• Lower observed bleeding rates
• Major
• Clinically relevant non-major
• Similar overall safety profile

15
Rivaroxaban

• Brand name Xarelto, Bayer
• Oral tablet
• High oral bioavailability (gt80)
• Onset of action 2-4 hours
• Half-life 9-12 hours
• No observed effects on agonist-induced platelet
  aggregation

• Primarily renal elimination
• No laboratory monitoring required
• No dosage adjustment for gender, age, extreme
  body weight
• Approved by Europe and Canadian agencies, and
  under FDA review currently

16
Rivaroxaban in VTE PreventionRECORD 3 - TKA
2531 patients


No Difference
17
Rivaroxaban in VTE PreventionRECORD 4 - TKA

Rivarox RRR 31 ARR 3.2

Not Significant
Turpie, et al. Lancet 20093731673 80.
18
Rivaroxaban Ongoing Phase III Clinical Trials
DVT Einstein-DVT Rivarox 15mg BID x 3 wks then
20mg Qday vs
Enox/VKA
PE Einstein-PE Rivarox 15mg BID x 3 wks then 20mg
Qday vs Enox/VKA
DVT/PE Einstein-Extension Rivarox 20mg Qday
vs Placebo
AF Rivarox 20 mg Qday vs
Warfarin
Medically Ill Rivarox 10mg Qday x 35 days
vs Enox
40mg Qday x 10 days
19
Indirect Factor Xa Inhibitors
XII
Intrinsic
Extrinsic
XI
TF
IX
VII
VIII
X
V
II
Fibrinogen
Fibrin Clot
20
Idraparinux

• Once weekly SC injection
• 100 SC bioavailability
• Half-life 96-130 hours
• Renal elimination
• No monitoring required
• Manufactured by
• Sanofi-Aventis
• Plan to file for U.S. approval in 2009

21
Van Gogh Trials
Idraparinux 2.5 mg SC qweek vs standard therapy
(heparin/LMWH VKA)
DVT Study
PE Study
VTE Extended Study
Idraparinux vs placebo
2904 patients
2215 patients
1215 patients
? 3- and 6-month recurrence ? bleeding at
3 mo ? bleeding at 6 mo ? mortality
? 3- and 6-month recurrence ? bleeding at 3
and 6 mo ? mortality
? recurrent events ? bleeding ? mortality
22
Amadeus Trial
4576 patients

• Non-valvular atrial fibrillation
• Idraparinux 2.5 mg SC qweek vs VKA
• Trial stopped early due to excess clinically
  relevant bleeding with idraparinux

23
Idraparinux Biotinylated
Idraparinux sodium
Idraparinux Biotinylated
Avidin
Biotin arm with spacer

• No pharmacological effect
• IV injection
• Short half-life (10-16 min)

24
Phase III Clinical Trials with Idraparinux
Biotinylated
Idraparinux biotinylated 3 mg weekly
vs warfarin in 6-month PE
treatment (3200 patients)
Idraparinux biotinylated 3 mg weekly
vs idraparinux
2.5 mg weekly in 6-month
DVT tx (700 patients)
BOREALIS-AF
Idraparinux biotinylated 3 mg weekly vs
warfarin

in AF (9600 patients)
25
Direct Thrombin Inhibitors
XII
Intrinsic
Extrinsic
XI
TF
IX
VII
VIII
X
V
II
Fibrinogen
Fibrin Clot
26
COMPANY NEWS F.D.A. PANEL VOTES AGAINST BACKING
DRUG BY ASTRAZENECA
COMPANY NEWS F.D.A. REJECTS ASTRAZENECA'S
ANTI-CLOTTING DRUG
Published September 11, 2004
Published October 9, 2004
AstraZeneca failed to win backing from a federal
government panel for its Exanta blood thinner, a
possible first alternative to the drug Coumadin
in more than 50 years.
AstraZeneca said yesterday that federal
regulators did not approve its anti-clotting
drug, Exanta.
27
Dabigatran

• No dietary/food interactions
• Brand name Rendix or Pradaxa,
  Boehringer-Ingelheim
• Approved in Europe March 2008 plans are to
  obtain U.S. FDA approval by 2010

• Oral capsule
• Rapid onset of action
• Half-life 12-17 hours
• Renal elimination
• No routine monitoring required
• P-gp substrateuse with caution when administered
  concomitantly with P-gp inhibitors

28
Dabigatran in TKRRE-MODEL (Phase II)
Total VTE Death
Adverse Events
n1541 patients treated 6-10 days, followed for 3
months post-surgery
Dabigatran
29
Dabigatran in THRRE-NOVATE (Phase II)
Total VTE Mortality
Adverse Events
n2651 patients treated 28-35 days, followed for
3 months post-surgery
Eriksson BI et al. Lancet 2007370949-56.
30
Dabigatran RE-VOLUTION Trial Program (Phase III)
31
Summary
Time to Market for New Anti-Thrombotic Agents
Apixaban
Dabigatran
Otomaxiban
Idraparinuxbiotinylated
Rivaroxaban
2010
2011
2012
2013
32
Adapted from Gross, PL. Arterioscler Thromb Vasc
Biol. 2008 28380-386.
33
Potential Limitations of New Anticoagulants

• Antidotes
• None of the newer agents has a specific antidote
• Monitoring
• Adverse Drug Events
• Compliance
• Cost
• Clinical Trials vs. Actual Clinical Practice
• Patient populations not even studied (i.e. Cancer)

34
Conclusion

• Several oral and parenteral Anti Xa and Anti IIa
  drugs are under development at this time
• Rivaroxaban and Dabigatran are approved in the
  European Union and Canada for the prophylaxis of
  DVT and awaiting FDA review/approval
• Safety issues are of prime importance in the
  development of these drugs and will be strongly
  scrutinized upon review

35
What about RE-LY?

• Dabigatran versus Warfarin in Patients with
  Atrial Fibrillation
• Non-inferiority trial
• Over 18,000 patients
• Followup 2 years

Dabigatran 110 mg and 150mg vs. Adjusted dose
warfarin