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Protocol CV185057 A Safety and Efficacy Trial Evaluating the Use of Apixaban for the Extended Treatment of Deep Vein Thrombosis and Pulmonary Embolism

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Title: Protocol CV185057 A Safety and Efficacy Trial Evaluating the Use of Apixaban for the Extended Treatment of Deep Vein Thrombosis and Pulmonary Embolism


1
Protocol CV185057 A Safety and Efficacy Trial
Evaluating the Use of Apixaban for the Extended
Treatment of Deep Vein Thrombosis and Pulmonary
Embolism
  • Background
  • Design

The information in this presentation is for an
unapproved investigational product. Use of this
presentation is restricted to apixaban
investigator related activities.
2
Agenda
  • Background
  • Clinical need
  • CV185057 design
  • Discussion

3
Current Treatment Standard
  • Initial DVT/PE treatment
  • Heparin (LMWH) vitamin K antagonist (e.g.
    warfarin)
  • Typically 6 to 12 months for unprovoked events
    (e.g., cancer, idiopathic event,
    prothrombotic state)1.
  • Usually 3 months for provoked events (e.g.
    prolonged immobility)1 but may be longer--6
    mo--when there is persistent thrombosis risk2.

1Buller HR, et al. ACCP Guidelines2004. Chest
2004126Suppl 3401S-428S. 2Schulman S. New
Concepts. Thromb Haemost 2006 96 258-266.
4
Intrinsic
Current Standard Low
Molecular Weight Heparin
XII
XI
Extrinsic
IX
VII
VIII
X
V
Enoxaparin
II
I
Fibrin Clot
5
Current Standard Vitamin K Antagonist
XII
XI
Factor Half-lives
IX
24 hrs
6 hrs
VII
VIII
X
36 hrs
V
Warfarin
II
60 hrs
I
Fibrin Clot
6
Study Rationale
  • Risk for recurrent VTE persists after treatment
    ends
  • 3/year over 10 years1.
  • Uncertainty whether to extend treatment in this
    setting because bleeding risk with a vitamin K
    antagonist offsets potential benefit1.
  • Clinical need for an anticoagulant in this
    setting that is effective
    and has an acceptable safety risk.

1Schulman S. New Concepts. Thromb Haemost 2006
96 258-266.
7
The Clinical Need
current therapies are effective but have
limitations
  • Vitamin K Antagonists (VKAs)
    e.g., Warfarin
  • Slow onset and offset of action
  • Significant food and drug-drug interactions
  • High variability in response
  • Narrow therapeutic window
  • Blood monitoring (INR) and dose adjustments
    required
  • Low Molecular Weight Heparins (LMWHs) e.g.,
    Enoxaparin
  • Injectable
  • Difficult for chronic use

8
New Paradigm Factor Xa Inhibition
XII
XI
IX
VII
VIII
X
Apixaban
V
II
I
Fibrin Clot
9
Apixaban is being developed jointly by
Pfizer and Bristol Myers Squibb
10
Apixaban A FXa inhibitor
  • Apixaban is an orally administered, highly potent
    (Ki0.08 nM) reversible, direct inhibitor of FXa
  • The direct mechanism of action does not require
    the presence of antithrombin III
  • Apixaban has a small volume of distribution, good
    oral absorption, multiple (renal and non-renal)
    pathways of elimination

He K et al. Blood 2006 108(11) 910
Luettgen JM et al. Blood 2006
108(11) 4130
11
Apixaban A FXa inhibitor
  • Mean half-life 12 hours
  • No food effect
  • Effective in preclinical animal models of venous
    and arterial thrombosis
  • No organ specific toxicity in animal models of up
    to 12 months exposure duration

He K et al. Blood 2006 108(11) 910
Luettgen JM et al. Blood 2006
108(11) 4130
12
  • CV185057 A SAFETY AND EFFICACY TRIAL
    EVALUATING THE USE OF APIXABAN FOR THE EXTENDED
    TREATMENT OF DEEP VEIN THROMBOSIS AND PULMONARY
    EMBOLISM

13
CV185057 Research Hypothesis
  • Apixaban is superior to placebo for extended
    treatment of subjects who have
  • An objectively documented index event of
    symptomatic proximal DVT or symptomatic PE
  • Completed approximately 6 to 12 months of
    standard anticoagulant therapy for the treatment
    of the index event and
  • No objectively documented symptomatic recurrence
    of VTE after the index event.

14
CV185057 Study Details
  • Phase 3
  • Randomized
  • Double blinded
  • Placebo controlled
  • Three parallel treatment groups
  • Stratified by DVT or PE
  • Study Duration
  • 12 months of treatment
  • 30-day post-treatment follow-up.

15
CV185057 Primary Objective
  • To determine if at least one of the two apixaban
    doses is superior to placebo in the
    combined endpoint of
  • Symptomatic, recurrent VTE
    (nonfatal DVT or nonfatal PE) or
  • All-cause death

16
CV185057 Primary Outcomes
  • Primary Efficacy
  • Incidence of an adjudicated composite of
    recurrent symptomatic VTE (nonfatal DVT and/or
    nonfatal PE) or all-cause death.
  • Primary Safety
  • Incidence of adjudicated major bleeding during
    the treatment period.
  • All suspected thromboembolic events, deaths,
    episodes of bleeding will be adjudicated.

17
CV185057 Basis for Dose Selection
  • Phase 2 DVT prevention and treatment data
  • Decision based upon empiric experience

18
DVT Prevention A Proof of Concept Model
  • DVT prevention permitted assessment of a proposed
    anticoagulant as a Proof of Concept, since
    untreated, gt60 of patients undergoing knee
    replacement will develop venographically apparent
    DVT
  • Such a study also provided a safety assessment,
    as the surgical wound is a sensitive predictor of
    bleeding
  • The combination of high event rates for both VTE
    and total bleeding permitted an accurate dose
    ranging study
  • The short term exposure (lt 14 days) was
    appropriate early in phase 2, but limits the
    inferences that can be made to chronic exposure

The Seventh ACCP Conference on Antithrombotic and
Thrombolytic Therapy. Chest 2004 126 (3 Suppl)
19
CV185010 Phase 2 Prevention of VTE in Knee
Replacement Surgery
  • Randomized, parallel-arm, double-blind (apixaban
    and enoxaparin) and open-label (warfarin)
  • Treatments (150/arm total N1238)
  • Apixaban 2.5, 5, and 10 mg bid 5, 10, and 20 mg
    qd
  • Enoxaparin 30 mg sc q12h
  • Warfarin titrated to INR 1.8-3.0
  • Treatment duration 12/-2 days (first dose 12-24
    hrs post-op)
  • Efficacy endpoint symptomatic asymptomatic (by
    venogram) venous thromboembolism and all-cause
    death
  • Safety endpoints Bleeding (major and minor)

Lassen M et al. J Thromb Haemost 2007 5(12)
2368-2375.
20
CV185010 Results

Venous Thromboembolism/Death
Total Bleeding
Daily Dose 5 10 20
5 10 20
QD BID QD BID QD BID
Enox Warf
QD BID QD BID QD BID
Enox Warf
(mg)
Lassen M et al. J Thromb Haemost 2007 5(12)
2368-2375.
21
CV185010 Exposure - Response Modeling
Simulation
  • Total of subjects 855 (gt90 of
    apixaban-treated subjects had PK samples)
  • Total of PK observations 4694

Feng Y et al. International Society of Thrombosis
and Haemostasis July 2007 Geneva, Switzerland.
Poster P-M-663.
22
CV185010 Observed and Fitted Rates for Composite
of VTE or Death
  • BID dosing chose for pivotal DVT prevention
    studies
  • Potential for superior efficacy vs active
    comparator
  • BID event rate 4 lower than QD event rate
  • Bleeding rate potentially lower versus active
    comparator

Feng Y et al. International Society of Thrombosis
and Haemostasis July 2007 Geneva, Switzerland.
Poster P-M-663.
23
CV185010 Summary/Implications
  • All doses of apixaban had lower VTE/death rates
    than either comparator (enoxaparin, warfarin)
  • For any given apixaban daily dose, bid
    administration had fewer VTE events than qd
  • Bleeding rates showed a dose response trend, and
    were acceptable
  • The above results supported the Proof of
    Concept of apixaban as an effective
    anticoagulant with an acceptable safety profile
    in short term exposure

Lassen M et al. J Thromb Haemost 2007 5(12)
2368-2375.
24
BOTTICELLI (Study CV 185017) 3-month Phase 2
study in DVT treatment N 520 pts
Randomized parallel-arm dose-ranging study
with
independent, blinded efficacy safety outcome
assessments
CUS/PLS
CUS/PLS
12 weeks Apixaban 5mg bid
3 0 D a y s
Symptomatic proximal or extensive calf-vein
thrombosis without PE
12 weeks Apixaban 10mg bid
R
12 weeks Apixaban 20mg od
LMWH/Fondaparinux and VKA

Buller H et al. A Dose Finding Study of the Oral
Direct Factor Xa Inhibitor Apixaban in the
Treatment of Patients With Acute Symptomatic Deep
Vein Thrombosis. Late Breaking Clinical Trial
21st Congress of the International Society on
Thrombosis and Haemostasis (ISTH). 8 June 2007
  • Blinded Apixaban / OL Comparator
  • 12 weeks of treatment followed by a 30 day
    observational period

CUS compression ultrasound PLS perfusion lung
scan
25
BOTTICELLI (Study CV 185017) Results
Buller H et al. A Dose Finding Study of the Oral
Direct Factor Xa Inhibitor Apixaban in the
Treatment of Patients With Acute Symptomatic Deep
Vein Thrombosis. Late Breaking Clinical Trial
21st Congress of the International Society on
Thrombosis and Haemostasis (ISTH). 8 June 2007
26
BOTTICELLI (Study CV 185017) Incidence of
Symptomatic VTE
LMWH/VKA
Buller H et al. Late Breaking Clinical Trial
21st Congress of the International Society on
Thrombosis and Haemostasis (ISTH). 8 June 2007.
Lagerstedt CI et al. Lancet, 1985
515-518. Hull R et al. NEJM, 1979 301855-858
27
BOTTICELLI Study (CV185017) Conclusions/Implicatio
ns
  • Rates of symptomatic VTE events were comparable
    across all apixaban dosing regimens studied and
    to LMWH/VKA
  • Rates of adjudicated major or clinically relevant
    non-major bleeding were comparable across all
    apixaban dosing regimens studied and similar to
    LMWH/VKA
  • Chronic exposure to apixaban was not associated
    with any appreciable liver function test
    abnormality or other significant laboratory
    abnormality

Buller H et al. A Dose Finding Study of the Oral
Direct Factor Xa Inhibitor Apixaban in the
Treatment of Patients With Acute Symptomatic Deep
Vein Thrombosis. Late Breaking Clinical Trial
21st Congress of the International Society on
Thrombosis and Haemostasis (ISTH). 8 June 2007
28
Previous Extended VTE Treatment Studies
STUDY POPULATION COMPARISON DUR VTE MB DEATHS (DRUG/COMPARATOR) DEATHS (DRUG/COMPARATOR) DEATHS (DRUG/COMPARATOR) DEATHS (DRUG/COMPARATOR) DEATHS (DRUG/COMPARATOR) DEATHS (DRUG/COMPARATOR)
PE CV Bleed Ca Other
PREVENT DVT or PE rx 6.5 mos Warfarin 1.5-2.0 Placebo 2.4 yr (mean) 2.6 7.2 0.9 0.4 0.7 1.4 0 2 --- --- 0 1 --- --- 4 5
THRIVE III DVT or PE rx 6 mos Ximelagatran 36 BID Placebo 18 mo 2.8 12.6 1.1 1.3 1.1 1.4 0 3 1 1 0 0 2 3 3 0
VAN GOGH Extension DVT or PE rx 6 mos Idraparinux Placebo 6 mo 1 3.7 1.9 0 1.5 0.6 2 1 --- --- 3 0 2 2 2 1
ELATE DVT or PE rx 3 mo for unprovoked Warfarin INR 2.0-3.0 Warfarin INR 1.5-1.9 2.1 yr (mean) 0.7 1.9 0.9 1.1 0.9 1.9 2 1 --- --- --- --- 1 7 5 8
DB Double-Blind

DTI Direct Thrombin Inhibitor

DUR Duration

MB Major Bleeding

PE
Pulmonary embolism
rx
Previous treatment duration
VTE
Venous thromboembolism (symptomatic, nonfatal
DVT or nonfatal PE) --- Not
reported

Annual rate (except VAN GOGH
Extension 6 mo and Thrive III 18 mo
PREVENT. NEJM 2003 348 1425-1434.
THRIVE
III. NEJM 2003 3491713-1721.
VAN GOGH
Ext. Blood 2006 108172A. ELATE. NEJM
2003 349631-639.
29
Uniqueness of Apixaban Development Program
  • All phase 3 studies are double-blind, randomized
    trials for all indications
  • VTE prevention,
  • VTE treatment, and
  • Atrial fibrillation
  • These studies individually and overall should
    provide unbiased data of the highest scientific
    quality

30
CV185057 12-Month Double-Blind Placebo-Controlled
Extended Treatment Study
Placebo BID
n810
DVT/PE subjects who have completed 6-12 mos of
standard anti-coagulant rx
End of Treatment
30-Day Follow-up
Apixaban 2.5 mg BID
n810
R
Apixaban 5 mg BID
n810
Day 1 12 Mo
30 Days
  • N based on power 90 to detect superiority of
    apixaban to placebo (60 RRR)
    using two-sided
    alpha0.025 for comparing each apixaban arm to
    placebo.
  • Study ends after all subjects have completed 12
    months of treatment.

2,430 subjects planned
31
CV185057 Apixaban Dose Selection
  • Clinical uncertainty regarding which dose
    provides the best
    balance of efficacy and safety
  • Therefore, two doses selected
  • 5 mg bid same dose for initial DVT/PE treatment
    (CV185056)
  • 2.5 mg bid same dose for pivotal VTE prevention
    studies

32
Rationale for Placebo Control
  • Previous extended treatment studies have
    suggested a potential benefit.
  • However, none of the studies has included a
    placebo-controlled trial of an approved drug.
  • There is no approved alternative therapy
    available currently for such patients.
  • Therefore, placebo is an appropriate comparator
    for this study.

33
CV185057 Key Inclusion Criteria
  • Subjects must have an objectively documented
    index event of symptomatic proximal DVT or
    symptomatic PE.
  • Subjects must have
  • completed approximately 6 to 12 months of
    standard anticoagulant therapy for the treatment
    of the index event and
  • no objectively documented symptomatic recurrence
    of VTE after the index event.
  • In order to ensure entry of appropriate study
    subjects, the index DVT or PE will be adjudicated.

34
CV185057 Key Exclusion Criteria
  • Subjects will be excluded if they are intended
    for long-term treatment with a vitamin K
    antagonist, such as
  • Mechanical valve
  • Atrial fibrillation or atrial flutter with
    moderate to high risk of systemic
    thromboembolism
  • Multiple episodes of unprovoked DVT or PE
  • Documented anti-phospholipid antibodies,
    anti-thrombin III deficiency, protein C
    deficiency, protein S deficiency, homozygous
    factor V Leiden, or homozygous prothrombin.

35
CV185057 Key Exclusion Criteria
  • Subjects whose index DVT or index PE was due
    solely to a transient (reversible) risk factor
    (i.e. provoked event, e.g. secondary to surgery).
  • Subjects with cancer who will be treated
    indefinitely with anticoagulation therapy are
    ineligible for this study.

36
CV185057 Subject Safety
  • Regular assessments and clinical laboratory
    monitoring will be performed during the study.
  • Subjects will not be charged for these services.

37
CV185057 Committees Internationally recognized
experts
  • Steering Committee
  • Responsible for ensuring that the study design,
    execution and management are of the highest
    quality.
  • Independent Data Monitoring Committee
  • Responsible for ongoing review of the safety of
    all investigational treatments and to ensure the
    study has acquired adequate information to
    address the primary objectives
  • Independent Central Adjudication Committee
  • Will adjudicate the index events
  • Will adjudicate all suspected venous or arterial
    thromboembolic events, all deaths, and all
    episodes of suspected bleeding

38
Discussion
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