Transcript PIER - Dr. Kumar Saurabh

Phase IIIb Randomized, Double-Masked,
Sham-Controlled Trial of Ranibizumab
for Neovascular Age-related Macular
Degeneration
PIER Study Year 1
Regillo CD, Brown DM, Abraham P, Yue H, Ianchulev T, Schneider S, Shams N.
Am J Ophthalmol 2008: 145: 239-248.
Introduction
Ranibizumab
 Recombinant, humanized, monoclonal antibody antigen binding
fragment (Fab)
 Neutralizes all known active forms of vascular endothelial growth
factor-A (VEGF-A)
 First drug shown to improve average vision in choroidal neovascular
membrane (CNV) due to age related macular degeneration (AMD)#
#Source: ANCHOR Trial
Aims and Objectives

To determine whether a less frequent dosing of ranibizumab
would also prevent vision loss in AMD related subfoveal CNV.
Inclusion Criteria
 Best corrected visual acuity between 20/40 to 20/320.
 Total CNV area (occult + classic) >50% of total lesion area.
 Total lesion area <12 disc area (DA) in size.
 Minimally classic or occult CNV with:
Loss of >1 Snellen’s line during last 6 months.
More than 10% increase in size on FA during last 6 months.
Subretinal haemorrhage in last 1 month.
Exclusion Criteria
 Prior PDT, TTT, EBRT, subfoveal laser.
 Permanent structural damage to central fovea.
 Foveal subretinal haemorrhage >1 DA or >50% lesion area.
 Prior anti-VEGF treatment.
Materials and methods
Ranibizumab group: Monthly for 3 doses; quarterly thereafter
 Sixty subjects :- 0.3 mg
 Sixty one subjects :- 0.5 mg
Sham treatment group:
 Sixty three subjects :- sham injections
Primary endpoint:
 Mean change in visual acuity score.
Key secondary endpoints:
 Proportion of subjects gaining/loosing 15 letters or more.
 Mean change in area of CNV and area of leakage.
Results
Sham treated group
 Loss of 16.3 letters
Ranibizumab 0.3 mg
 Loss of 1.6 letters
Ranibizumab 0.5 mg
 Loss of 0.2 letters
Results
Sham treated group
 Loss of <15 letters in
49.2%
Ranibizumab 0.3 mg
 Loss of <15 letters in
83.3%
Ranibizumab 0.5 mg
 Loss of <15 letters in
90.2%
Results
Sham treated group
 Gain of >15 letters in
9.5%
Ranibizumab 0.3 mg
 Gain of >15 letters in
11.7%
Ranibizumab 0.5 mg
 Gain of >15 letters in
13.1%
Results
Sham treated group
 Increase in leakage
area
Ranibizumab 0.3 mg
 Decrease in leakage
area
Ranibizumab 0.5 mg
 Decrease in leakage
area
Discussion
 Both ranibizumab groups maintained baseline visual acuity at the end
of 12 months.
 Gain in visual acuity score was maximum in first 3 months.
 Decline in visual acuity score to baseline with quarterly dosing.
 Significantly greater number of ranibizumab group subjects lost less
than 15 letters.
 No significant benefit in number of subjects gaining 15 letters or more.
PIER vs. ANCHOR & MARINA
Minimally Classic/Occult Trial Of The AntiVEGF Antibody Ranibizumab In Treatment Of
Neovascular AMD
-: MARINA :
Larger sample size with monthly injections and 2 years follow
up results.

At 24 months, 90% subjects treated with ranibizumab had stable
vision compared to 53% in sham-treated group. (p<0.001)

Improvement of at least 15 letters or more in 34% subjects
receiving 0.5mg ranibizumab. (p<0.001)
Anti-VEGF Antibody For The Treatment Of
Predominantly Classic Choroidal
Neovascularization In AMD
-: ANCHOR :
Larger sample size with monthly injections.

With 0.5mg ranibizumab 96% subjects had stable vision
compared to 64% in verteporfin PDT group. (p<0.001)

Improvement of at least 15 letters or more in 40% subjects
receiving 0.5mg ranibizumab compared to 6% in verteporfin
PDT group. (p<0.001)
The 3-month results from PIER mirrored MARINA and
ANCHOR; however, visual acuity gains declined once quarterly
dosing began.
Quarterly injections of ranibizumab
might be less effective than monthly dosing.#
#Source: Genentech Press Release. Preliminary Results from a Phase IIIb Study Showed Patients with Wet AMD Treated with
Lucentis Quarterly Experienced a 16-Letter Benefit over the Control Group at One Year.
PIER study suggests that decline in visual acuity was due to increase
in vascular leakage and mean retinal thickness.
OCT data were lacking at 4, 6, 7, 9 and 10 months precluding any
assessment of temporal association between quarterly dosing and
increase in mean retinal thickness.
Prospective OCT Imaging of Patients with
Neovascular AMD Treated with
Intraocular Lucentis
-: PrONTO : OCT based, uncontrolled, variable dosing, single centre study.
 Monthly injections for three months.
 Further monthly injections during first year:
Increase in central retinal thickness of more than 100 micron
Loss of five or more letters.
 Injections during second year:
 Qualitative increase in amount of fluid on OCT.
Prospective OCT Imaging of Patients with
Neovascular AMD Treated with
Intraocular Lucentis
-: PrONTO :
Mean visual acuity improved by 11.1 letters

Forty three percent subjects gained 15 letters or more.

Average of 9.9 injections were given in 24 months.

OCT guided variable dosing regimen lead to comparable
results but with fewer injections.#
# Source: Am J Ophthalmol. 2009; 148: 43-58.e1.
Conclusion

PIER regimen of intravitreal ranibizumab for CNV due to
AMD provides less benefit in visual acuity than continued
monthly dosing.

Monthly or variable dosing may be needed in some patients
to achieve maximum benefit of ranibizumab.
Ongoing Trials
Comparison of Age-Related Macular Degeneration
Treatment Trials (CATT)
Vascular Endothelial Growth Factor (VEGF) Trap-Eye: Investigation
of Efficacy and Safety in Wet Age-Related Macular Degeneration
(AMD) (VIEW 2)