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Protocol CV 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.
07 May 2008
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Agenda
Background
Clinical need
CV design
Discussion
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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 Guidelines Chest 2004;126:Suppl 3:401S-428S. 2Schulman S. New Concepts. Thromb Haemost 2006; 96:
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Intrinsic
Current Standard Low Molecular Weight Heparin
XII XI
Extrinsic IX
VII
VIII X
Enoxaparin V II I
Fibrin Clot
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Current Standard Vitamin K Antagonist
XII XI
Factor Half-lives IX
24 hrs
6 hrs
VII
VIII X
36 hrs
Warfarin V II
60 hrs I
Fibrin Clot
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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:
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7. The Clinical Need
…current therapies are effective but have limitations…
Low Molecular Weight Heparins (LMWHs) [e.g., Enoxaparin]
Injectable
Difficult for chronic use
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
Second generation bisphosphonate
OD Fosamax has been available in the US since 1995 and in EU since 1996.
The OW Fosamax is also available in all countries except Japan and is the major driver of revenue.
The once weekly formulation of Fosamax was developed to alleviate one of the agent’s major side effects: upper GI events such as reflux.
07 May 2008
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New Paradigm:
Factor Xa Inhibition
XII XI IX
VII
VIII X
Apixaban V II I
Fibrin Clot
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9. Apixaban is being developed jointly by Pfizer and Bristol Myers Squibb
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10. Apixaban: A FXa inhibitor
Apixaban is an orally administered, highly potent (Ki=0.08 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): Luettgen JM et al. Blood 2006; 108(11): 4130
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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): Luettgen JM et al. Blood 2006; 108(11): 4130
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CV185057: A SAFETY AND EFFICACY TRIAL EVALUATING THE USE OF APIXABAN FOR THE EXTENDED TREATMENT OF DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM
07 May 2008
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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.
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CV 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.
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CV 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
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CV 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.
07 May 2008
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17. CV185057 Basis for Dose Selection
Phase 2 DVT prevention and treatment data
Decision based upon empiric experience
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18. DVT Prevention: A Proof of Concept Model
DVT prevention permitted assessment of a proposed anticoagulant as a “Proof of Concept”, since untreated, >60% 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 (< 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)
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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 N=1238):
Apixaban 2.5, 5, and 10 mg bid; 5, 10, and 20 mg qd
Enoxaparin 30 mg sc q12h
Warfarin titrated to INR
Treatment duration: 12+/-2 days (first dose 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):
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20. Venous Thromboembolism/Death
CV185010
Results %
Venous Thromboembolism/Death
Total Bleeding
Lowest dose of apix still maintained a 30% RRR compared to enox, the gold standard
Event rate with warfarin was similar in previous studies (EXULT-A 27%, EXULT-B 31%)
Not a “fair” trial vs warfarin
There does appear to be at least a trend of dose response in bleeding (89% of major bleeding at the wound site)
No other safety (e.g. LFT) issues raised
Daily Dose:
QD BID QD BID QD BID
Enox Warf
(mg)
QD BID QD BID QD BID
Enox Warf
Lassen M et al. J Thromb Haemost 2007; 5(12):
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21. CV185010: Exposure - Response Modeling & Simulation
Total # of subjects = 855 (>90% 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.
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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.
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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):
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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 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
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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
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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 Lagerstedt CI et al. Lancet, 1985; Hull R et al. NEJM, 1979; 301:
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27. BOTTICELLI Study (CV185017) Conclusions/Implications
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
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28. Previous Extended VTE Treatment Studies
STUDY
POPULATION
COMPARISON
DUR
%VTE*
%MB
DEATHS* (DRUG/COMPARATOR) % PE CV
Bleed Ca
Other
PREVENT
DVT or PE rx 6.5 mos
Warfarin
Placebo
2.4 yr (mean)
2.6
7.2
0.9
0.4
0.7
1.4 2
--- 1 4 5
THRIVE III
DVT or PE rx 6 mos
Ximelagatran 36 BID
18 mo
2.8
12.6
1.1
1.3 3
VAN GOGH Extension
DVT or PE rx 6 mos
Idraparinux
6 mo
3.7
1.9
1.5
0.6
ELATE
DVT or PE rx ≥3 mo for unprovoked
Warfarin INR
Warfarin INR
2.1 yr
(mean) 7 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: THRIVE III. NEJM 2003: 349: VAN GOGH Ext. Blood 2006; 108:172A ELATE. NEJM 2003; 349:
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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
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CV Month Double-Blind Placebo-Controlled Extended Treatment Study
Placebo BID
n~810
DVT/PE subjects who have completed 6-12 mos of standard anti-coagulant rx
End of Treatment
30-Day Follow-up
n~810
Apixaban 2.5 mg BID R
Apixaban 5 mg BID
n~810
Day Mo
30 Days
N based on power 90% to detect superiority of apixaban to placebo (~60% RRR) using two-sided alpha=0.025 for comparing each apixaban arm to placebo.
Study ends after all subjects have completed 12 months of treatment.
…2,430 subjects planned…
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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
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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.
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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.
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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.
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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.
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CV Subject Safety
Regular assessments and clinical laboratory monitoring will be performed during the study.
Subjects will not be charged for these services.
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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
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Discussion
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