1. Eylea (Aflibercept)
Pitt Street Health Plan P & T Committee

2. Outline
• Disease State
• Pharmacology and Pharmacokinetics of
Aflibercept
• Evidence for Clincal Efficacy
• Cost Effectiveness
• Recommendations

3. Disease State

4. Wet Age-Related Macular Degeneration (AMD)
•Leading cause of vision loss in Americans over 50
•Symptoms: blurred/black spots in central vision
•Pathophysiology:
– Abnormal new blood vessels form during choroidal
neovascularization
– Vessels leak up through the layers of the eye
– Result in scar tissue building up under macula
•Vision loss negatively impacts patient’s quality of
life significantly

5. Central Retinal Vein Occlusion (CRVO)
• Second most prevalent cause of vision loss from
retinal vascular disease
• Symptoms: blurred vision, transient vision loss
• Pathophysiology:
– Central retinal vein becomes occluded by thrombus
– Leads to signs which include retinal edema, optic disc
hyperemia or edema, scattered and deep retinal
hemorrhages, and venous dilation
• Negatively impacts patient’s quality of life

6. Current Treatments
Wet AMD
Ranibizumab {formulary}
Bevacizumab {formulary}
Pegaptanib {non-formulary}
Aflibercept {non-formulary}
CRVO
Observation
Ranibizumab {formulary}
Bevacizumab {formulary}
Aflibercept {non-formulary}

7. Pharmacology and Pharmokinetics
of Aflibercept

8. Eylea® Pharmacology
• Binds to VEGF-A, VEGF-B, and PIGF creating inert
complexes.
– These receptors play a role in angiogenesis

9. Eylea® Pharmacokinetics
Route of Administration Intravitreal
Bioavailability Mean Cmax of free aflibercept in the plasma
was 0.02 mcg/mL (range: 0-0.054 mcg/mL),
attained in 1-3 days.
Time to Peak 1-3 days
Multiple Dosing 2 mg monthly for the first 3 months,
followed by 2 mg every 2 months
Clearance No drug metabolism studies have been
conducted. Expected to undergo elimination
through both target-mediated disposition
via binding to free endogenous VEGF and
metabolism via proteolysis.

10. Adverse Reactions (>5%): Wet AMD
Adverse Reaction Eylea
(N=1824)
Active control
(ranibizumab) (N=595)
Conjunctival hemorrhage 25% 28%
Eye pain 9% 9%
Cataract 7% 7%
Vitreous detachment 6% 6%
Vitreous floaters 6% 7%
Intraocular pressure
increased
5% 7%

11. Adverse Reactions (>5%): CRVO
Adverse Reaction Eylea
(N=218)
Control
(N=142)
Eye pain 13% 5%
Conjunctival hemorrhage 12% 11%
Intraocular pressure
increased
8% 6%
Corneal erosion 5% 4%
Vitreous floaters 5% 1%
Conjunctival hyperemia 5% 3%

12. Evidence for Clinical Efficacy

13. Clinical Efficacy of Eylea (aflibercept)
•Eylea (aflibercept) Phase III Clinical Trials
–VIEW 1 and VIEW 2---Study indication for wet
AMD
–Copernicus---Study indication for macular
edema due to CRVO
–Galileo---Study indication for macular edema
due to CRVO
Wet AMD=neovascular age-related macular degenerate
CRVO=central retinal vein occlusion

14. VIEW 1 and VIEW 2
• Phase III, Randomized, Double-Blind
• Head-to-head against ranibizumab
• 52 Week Total for each study
– Clinic visits every 4 weeks for 52 weeks
• Primary Endpoint
– Proportion of patients who maintained vision at
Week 52
– Maintenance of vision defined as loss of ≤ 15 letters
in the ETDRS letter score as compared to baseline
ETDRS= Early Treatment Diabetic Retinopathy Study

15. Primary Endpoint Results
Study Group VIEW 1 VIEW 2
Aflibercept 2mg every 4
weeks
95.1% 95.6%
Aflibercept 0.5mg every 4
weeks
95.9% 96.3%
Aflibercept 2mg every 8
weeks
95.1% 95.7%
Ranibizumab 0.5mg every 4
weeks
94.4% 94.4%
*All results are at Week 52

16. VIEW 1 and VIEW 2
• Strengths
– Power set and met
• Power was set at 190, and +260 enrolled in each study
group
– Randomized and Double-blind
• Limitations
– No clear reporting of withdraws from trial
– Exclusion criteria of: “No prior treatment with anti-VEGF.”
– Manufacturer funded study
• Delfini Evidence: Grade B
VEGF=vascular endothelial growth factor

17. Copernicus
• Phase III, Randomized, Double-Blind
• 52 Weeks
– Either Aflibercept or sham injection every 4 weeks
for 24 weeks, then XO PRN aflibercept injections
• Primary Endpoint
– Proportion of patients who gained vision at Week 24
and Week 52
– Gain in vision defined as gain of ≥ 15 letters in the
ETDRS letter score as compared to baseline
ETDRS= Early Treatment Diabetic Retinopathy Study

18. Primary Endpoint Results
Study Group for Copernicus Week 24 Week 52
Aflibercept 2mg every 4 weeks 56.1% ---
Sham Injections every 4 weeks 12.3% ---
Aflibercept 2mg every 4 weeks
to Aflibercept 2mg PRN
--- 55.3%
Sham Injections every 4 weeks
to Aflibercept 2mg PRN
--- 30.1%

19. Copernicus
• Strengths
– Power was set and met
• Power set at 169, and 189 patients enrolled in study
– Randomized and Double-blind
• Limitations
– Lack of head-to-head study design
– Manufacturer funded study
• Delfini Evidence: Grade B-U

20. Galileo
• Phase III, Randomized, Double-Blind
• 52 Weeks
– Either Aflibercept or sham injection every 4 weeks
• Primary Endpoint
– Proportion of patients who gained vision at Week 24
and Week 52
– Gain in vision defined as gain of ≥ 15 letters in the
ETDRS letter score as compared to baseline
ETDRS= Early Treatment Diabetic Retinopathy Study

21. Primary Endpoint Results
Study Groups for
Galileo
Week 24 Week 52
Aflibercept 2mg every 4
weeks
63.1% 60.2%
Sham injections every 4
weeks
22.1% 32.4%

22. Galileo
• Strengths
– Randomized and Double-blind
• Limitations
– Power was not set or met
– Lack of head-to-head study design
– Manufacturer funded study
• Delfini Evidence: Grade B-U

23. Cost Effectiveness of Aflibercept

24. ICER Rating Comparison
Wet AMD CRVO

25. Aflibercept cost analysis
Wet AMD
Budgetary
Impact
Total PMPM
Yr 1 17,277,634 1.44
Yr 2 25,679,859 2.06
Yr 3 36,615,577 3.03
Yr 4 47,454,923 3.95
Yr 5 55,759,640 4.64
CRVO
Budgetary
Impact
Total PMPM
Yr 1 169,589 0.01
Yr 2 245,689 0.02
Yr 3 - -
Yr 4 - -
Yr 5 - -

26. Budget Impact for Pitt Street
Yr 1 Yr 2 Yr 3 Yr 4 Yr 5
Wet AMD
Total 17,277,634 25,679,859 36,615,577 47,454,923 55,759,640
PMPM $0.42 $0.63 $0.90 $1.16 $1.37
CRVO
Total 169,589 245,689 - - -
PMPM $0.004 $0.006
Pitt Street Health
3.4 million covered lives
10.5% of covered lives >65 years old

27. Recommendations

28. Formulary Recommendation
• Keep Alibercept on the formulary as non-
preferred for indications of both wet AMD and
CRVO
• Criteria for use:
– Failed bevacizumab treatment
– Failed ranibizumab treatment
• Revaluate cost effectiveness as more data is
published.

29. Questions

30. References
1. Aflibercept . REDBOOK online. Ann Arbor, MI: Truven Health Analytics, 2013.
2. American Academy of Ophthalmology Retina Panel. Preferred Practice Pattern®
Guidelines. Vision Rehabilitation for Adults. San Francisco, CA:
American Academy of Ophthalmology; 2008. http://www.aao.org/ppp. Accessed on December 22, 2013.
3. "Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group. (2012). Ranibizumab and Bevacizumab for
Treatment of Neovascular Age-related Macular Degeneration: Two-Year Results. Ophthalmology, 1388-1398.
4. David Brown, J. H. (2013). Intravitreal Aflibercept Injection for Macular Edema Secondary to Central Retinal Vein Occlusion: 1-Year Results
From the Phase 3 COPERNICUS Study. American Journal of Ophthalmology, 429-437.
5. Frampton, J. E. (2012). Aflibercept for Intravitreal Injection: In Neovascular Age-Related Macular Degeneration. Drugs & Aging, 839-846.
6. Johnston, Stephen S., Wilson, Kathleen, Huang, Alice, Smith, David, Varker, Helen, et al. Retrospective Analysis of First-Line Anti-Vascular
Endothelial Growth Factor Treatment Patterns in Wet Age-Related Macular Degeneration. Advances in Therapy (2013) 30:1111–1127. DOI
10.1007/s12325-013-0078-4
7. "LUCENTIS® (ranibizumab Injection) for Neovascular (Wet) Age-Related Macular Degeneration (Wet AMD) Treatment." LUCENTIS®
(ranibizumab Injection). Genentech, 2012. Web. 30 Dec. 2013.
8. Michael Thomas, S. M. (2013). Comparative Effectiveness of aflibercept for the treatment of patients with neovascular age-related macular
degeneration. Clinical Opthalmology, 495-501.
9. National Eye Institute. Facts about AMD. 2010.
10. http://www.nei.nih.gov/health/maculardegen/armd_facts.asp. Accessed on: December 19, 2013.
11. "Physician Fee Schedule." Centers for Medicare & Medicaid Services. CMS, n.d. Web. 06 Jan. 2014.
12. Regeneron (2011). Eylea® (aflibercept) Injection: Highlights of prescribing information. Retrieved from:
http://www.regeneron.com/Eylea/eylea-fpi.pdf.
13. Rein DB, Zhang P, Wirth KE, et al. The economic burden of major adult visual disorders in the United States. Arch Ophthalmol. 2006;124:1754-
1760.
14. Stephen Johnston, K. W. (2013). Retrospective analysis of first-line anti-vascular endothelial growth factor treatment patterns in wet age-
relatedmacular degeneration. Advances in therapy, 1111-27.
15. VIEW 1 and VIEW 2 study groups. (2012). Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology,
2537-2548.