ANTI-VEGF IN VASCULAR PATHOLOGIES · vascular disorders –Affects ~180,000 people each year in the...

G. Fasolino MD

ANTI-VEGF IN VASCULAR

PATHOLOGIES

G. Fasolino MD

Retinal Vein Occlusion

Overview • Retinal vein occlusion (RVO) is a blockage of

the veins that carry blood away from the retina1

• After diabetic retinopathy, RVO is the second

most common cause of visual loss from retinal

vascular disorders

– Affects ~180,000 people each year in the US2

– Prevalence in US population-based studies

ranges from 0.3 to 8.37 cases per 1000

persons3

– Prevalence increases with age3

2

1. Hayreh SS. Prevalent misconceptions about acute retinal vascular occlusive disorders. Prog Ret Eye Res. 2005;24:493–519.

2. Klein R, Moss SE, Meuer SM, Klein BE. The 15-year cumulative incidence of retinal vein occlusion: the Beaver Dam Eye Study. Arch

Ophthalmol. 2008;126(4):513-518.

3. Rogers S, McIntosh RL, Cheung N, et al. The prevalence of retinal vein occlusion: pooled data from population studies from the United

States, Europe, Asia, and Australia. Ophthalmology. 2010 Feb;117(2):313-9.e1.

RVO Pathogenesis

• Exact pathogenesis of RVO is unclear

• Believed to be a combination of

systemic changes known as

Virchow’s triad

– Hemodynamic changes

– Vessel wall degeneration

– Blood hypercoagulability

3 1. Wong TY, Scott IU. N Engl J Med. 2010;363(22):2135-2144.

Hypercoagulable

State

Stasis Injury

Thrombosis

CRVO: Risk Factors

• Increasing age > 65

years

• Systemic hypertension

• Carotid artery disease

• Diabetes mellitus

• Primary open angle

glaucoma

4

Wong TY, Marino Larsen EK, Klein R, et al. Cardiovascular risk factors for

retinal vein occlusion and arteriolar emboli: the atherosclerosis risk in communities

and cardiovascular health studies. Ophthalmol. 2005;112:540-547.

Klein R, Moss SE, Meuer SM, et al. The 15-year cumulative incidence of

retinal vein occlusion: the Beaver Dam study. Arch Ophthalmol.2008;126(4):513-518.

Rogers S, McIntosh RL, Cheung N, et al. The prevalence of retinal vein occlusion:

pooled data from population studies from the United States, Europe, Asia, and

Australia. Ophthalmology. 2010 Feb;117(2):313-9.e1.

MACULAR EDEMA

FOLLOWING CRVO

Disease Overview

5

CRVO: Pathology

Suggested pathogenesis

• Initial clot forms in the central retinal vein

• Blood flow into and out of retina is impaired

• Hypoxia (oxygen deprivation) in retinal tissue

• Hypoxia induced up-regulation of VEGF

• Overexpression of VEGF

• Macular edema and neovascularization

6 Mruthyunjaya P, Fekrat S. Central retinal vein occlusion. In: Ryan SJ, ed. Retina. 4th ed.

Philadelphia, PA: Elsevier; 2009

Central retinal artery Lamina cribrosa

Central retinal vein

Retinal hemorrhages

Occluded

central retinal vein

Macular Edema Pathophysiology

• Leukocytes migrate across

through the vascular wall and

into retinal tissues

• Inflammatory mediators IL-1,

TNF-α, and VEGF are

secreted and amplify the

inflammatory response

• Blood-retinal barrier breaks

down, causing increased

vascular permeability and

fluid leakage

• Fluid accumulates in the retinal

extracellular matrix

7

IL-1 = interleukin 1; TNF-α = tumor necrosis factor alpha;

VEGF = vascular endothelial growth factor

IL-1

TNF-α VEGF

1. Kent D, et al. Br J Ophthalmol. 2000;84(45):542-545.

CRVO: Key Diagnostic Tests

• Visual Acuity Testing

• Ophthalmic examination – Including testing pupils for an afferent pupillary defect

(indicating that retinal detection of light is abnormal, typically seen in ischemic CRVO)

• Optical coherence tomography (OCT)

• Fluorescein Angiography (FA) – A finding of retinal capillary nonperfusion or obliteration is

considered the diagnostic criterion for ischemic CRVO

• Fundus Photography

• OCTA

8

FLUORESCEIN

ANGIOGRAPHY

9

13

RVO: Milestones in Treatment

Laser

Photocoagulation

BVOS1

1997 2004 2007 2010

CVOS2 SCORE3 GENEVA6

Anti-VEGF

2012 1977

Steroids

BRAVO4

Treatment first used

Trial data first published

HORIZON7

CRUISE5

GALILEO9

COPERNICUS8

1984 2011 2013 2009

VIBRANT

Comparison of BRVO and CRVO

management with aflibercept

14

Date of preparation: January 2015

VIBRANT, COPERNICUS and GALILEO

15

VIBRANT1 COPERNICUS2,3,4 GALILEO5,6,7

Design Phase III, randomised, multicentre,

double-masked

Phase III, randomised, multicentre, double-masked

Duration 52 weeks 100 weeks 76 weeks

Intervention Aflibercept

•2q4 to Week 24 and 2q8 thereafter

•Laser rescue at Week 36

Aflibercept

2q4 to Week 24 and PRN thereafter

Comparator Laser

•One treatment at Week 0

•Laser rescue at Weeks 12, 16 and 20

•Aflibercept rescue from Week 24

Sham

•Monthly sham injection to

Week 24

Sham

•Monthly sham injection to

Week 52

Primary

endpoint

Proportion of subjects who gained

≥15 letters in BCVA from baseline to

Week 24

Proportion of subjects who gained ≥15 letters in BCVA from

baseline to Week 24

Crossover Aflibercept arm:

none

Laser arm:

none

Aflibercept

arm:

none

Sham arm:

Aflibercept

PRN from

Week 24

Aflibercept

arm:

none

Sham arm:

Aflibercept

PRN from

Week 52

Rescue

treatment

Laser at Week 36 Aflibercept 3x2q4

then 2q8 from

Week 24

Laser treatment if neovascularisation occurred

2q4, 2 mg every 4 weeks; 2q8, 2 mg every 8 weeks; BCVA, best corrected visual acuity; PRN, pro re nata (as needed).

1. Bayer. VIBRANT 52-week study data 2014. 2. Boyer D et al Ophthalomology 2012;119:1024-1032 3. Brown DM et al. Am J Ophthalmol 2013;

155: 429–437. 4. Heier JS et al. Ophthalmology 2014; 1-7 5. 5. Holz FG et al. Br J Ophthalmol 2013; 97: 278–284. 6. Korobelnik JF et al.

Ophthalmology 2014;121:202-208 7. Ogura Y et al. AJO 2014; in press

Study Design

Patients

randomized 3:2

Treatment to Week 24

(primary endpoint)

Randomized, multicenter, double-masked trial in treatment

naïve patients with macular edema secondary to CRVO with

CRT 250 m and ETDRS BCVA of 20/40 to 20/320

Primary endpoint:

Proportion of 3-line gainers

Key secondary endpoints:

Change in BCVA and CRT

Continued treatment

PRP available for all patients

Sham IVT-AFL

2q4

COPERNICUS:

All patients eligible to receive IVT-AFL 2mg on

a PRN basis from Week 24 onward

GALILEO:

IVT-AFL arm eligible to receive IVT-AFL 2mg on

a PRN basis from Week 24 onward; Sham arm

eligible from Week 52 onward

Week 76 Week 100

16

17

ET

DR

S le

tte

rs

Week

*P < 0.0001

vs. Sham

+13.0

IVT-AFL 2q4

PRN

+17.3*

-4.0

+13.7

IVT-AFL 2q4

PRN

+6.2

Sham

IVT-AFL PRN

COPERNICUS

GALILEO

*P < 0.0001

vs. Sham Patients crossed over to IVT-AFL; LOCF; full analysis set;

+18.0*

+3.3

Mean Change in Visual Acuity

+1.5

Sham

IVT-AFL PRN

18

Week

-390.0

2q4PRN

-343.3

ShamPRN

Patients crossed over to IAI

LOCF; full analysis set;

-389.4*

2q4PRN

-306.4

ShamPRN

Mean Change in Central Retinal Thickness

µm

COPERNICUS

GALILEO

19

Proportion of Patients Who Gained ≥ 15 EDTRS Letters

Compared to baseline; Sham n=73; 2q4 n=114; full analysis set;

patients discontinued before week 24 with < 5 injections judged as nonresponders, otherwise LOCF

Pro

po

rtio

n o

f P

ati

en

ts Week 24

Sham IVT-AFL

2q4

*P <0.01 vs. Sham

Week 52

Sham PRN

Sham PRN

IVT-AFL 2q4PRN

IVT-AFL 2q4 PRN

Proportion of Patients Who Gained ≥ 15 ETDRS Letters

Pro

po

rtio

n o

f P

ati

en

ts

Compared to baseline; Sham n=68; 2q4 n=103; full analysis set;

Patients discontinued before Week 24 judged as failures; Week 52 and 76: Last observation carried forward (LOCF)

*descriptive

Sham

IVT-AFL 2q4

20

Sham

PRN

IVT-AFL 2q4

PRN

Sham IVT-AFL 2q4

PRN

Treatment Summary

Total PRN Injections

COPERNICUS* (from Week 24 - 100)

Mean (SD) Min - Max* Median

Sham PRN

(n = 50) 7.1 (3.4) 0 - 15 7.0

IVT-AFL 2q4 PRN

(n = 102) 6.0 (3.4) 0 - 15 6.0

* Patients completing Week 100 21

Treatment Summary

22 *Patients completing Week 52; Sham IVT-AFL PRN (n=52), IVT-AFL 2q4 IVT-AFL PRN (n=91)

Sham PRN mean (SD)

IVT-AFL 2q4 PRN mean (SD)

Week 0 – 24 0 6

Week 24 – 52 0 2.5 (1.7)

Week 52 – 76* 1.7 (1.1) 1.3 (1.1)

Patients crossed over from Fixed IVT-AFL to IVT-AFL PRN or from Sham to IVT-AFL PRN

Total PRN Injections

Date of preparation: January 2015

Adverse events

VIBRANT1

to Week 52

COPERNICUS2

to Week 100

GALILEO3

to Week 76

Number of patients, (%) AFL

(n=91)

Laser/AFL

(n=92)

AFL

(n=114)

Sham

(n=74)

AFL

(n=104)

Sham

(n=68)

Study eye TEAE 45 (49.5) 44 (47.8) 87.7% 85.1% 78.8% 75.0%

Study eye serious TEAE 1 (1.1) 0 8.8% 16.2% 11 (10.6) 6 (8.8)

Non-ocular TEAE 61 (67.0) 63 (68.5) 77.2% 81.1% 68.3% 73.5%

Non-ocular serious TEAE 13 (14.3) 10 (10.9) 21.1% 25.7% 11.5% 14.7%

Death 0 1 (1.1) 0 2 (2.7) 0 0

APTC-adjudicated events 0 2 (2.2) 2 (1.8) 2 (2.7) 0 0

Non-fatal stroke 0 1 (1.1) 0 0 0 0

Non-fatal MI 0 1 (1.1) 1 (0.9) 0 0 0

Vascular death 0 0 1 (0.9) 2 (2.7) 0 0

*Death due to pneumonia 3 months after start of treatment.

24

BRVO CRVO

Most common ocular TEAEs: increased IOP, conjunctival haemorrhage,

decreased visual acuity and eye pain.

AFL, aflibercept; APTC, Antiplatelet Trialists’ Collaboration; BRVO, branch retinal vein occlusion; CRVO, central retinal vein occlusion;

IOP, intraocular pressure; MI, myocardial infarction; NR, not reported; PRN, pro re nata (as needed); TEAE, treatment-emergent adverse event.

1. Bayer. VIBRANT 52-week study data 2014. 2. Heier JS et al. Ophthalmology 2014; 1-7. 3. Korobelnik J-F et al. Ophthalmology 2014; 121: 202–

208.

AFLIBERCEPT IN BRVO: VIBRANT

VIBRANT is the first phase III BRVO trial to compare anti-VEGF therapy with an active control

VEGF, vascular endothelial growth factor. 1. Campochiaro PA, et al. Ophthalmology. 2015;122(3):538–544.

Compared the efficacy and safety of intravitreal aflibercept injection versus macular grid laser photocoagulation for the treatment of macular edema secondary to BRVO or HRVO

• BRVO: Presence of retinal hemorrhages or other biomicroscopic evidence of RVO and a dilated venous system in < 2 quadrants or less of the retina drained by the affected vein

• HRVO: RVO that involved two quadrants

First study to investigate anti-VEGF treatment in non-perfused retinas

• Strict definition: ≥ 10 disc areas of retinal capillary non-perfusion

Gains in BCVA were rapid and sustained through to 52 weeks in eyes treated with aflibercept1,2

Full analysis set. Missing data imputed using the LOCF method. *p<0.0001; **p=0.0035 versus laser. AFL, aflibercept; BCVA, best-corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study; LOCF, last observation carried forward; 2q4, 2 mg every 4 weeks; 2q8, 2 mg every 8 weeks. 1. Campochiaro PA, et al. Ophthalmology. 2015;122(3):538–544. 2. Haller JA. Presented at Retina Society, Philadelphia, USA, September 11–14, 2014.

Time (weeks)

Me

an c

han

ge f

rom

bas

elin

e

in B

CV

A (

ETD

RS

lett

ers

)

AFL 2q4 (0–24 weeks)

Laser (0–24 weeks)


Laser + rescue AFL (24–52 weeks)

Reductions in CRT were rapid and sustained over 52 weeks in eyes treated with aflibercept1,2

Full analysis set. Missing data imputed using the LOCF method. *p<0.0001; **p=0.02 versus laser. AFL, aflibercept; CRT = central retinal thickness; LOCF, last observation carried forward; 2q4, 2 mg every 4 weeks; 2q8, 2 mg every 8 weeks. 1. Campochiaro PA, et al. Ophthalmology. 2015;122(3):538–544. 2. Haller JA. Presented at Retina Society, Philadelphia, USA, September 11–14, 2014.

Time (weeks)

Me

an c

han

ge f

rom

b

ase

line

in C

RT

(μm

)


Laser (0–24 weeks)


Laser + rescue AFL (24–52 weeks)

Significantly more eyes gained ≥ 15 ETDRS letters with aflibercept versus laser therapy1,2

Full analysis set. Missing data imputed using the LOCF method. *p=0.0003 versus laser; **p<0.03 versus laser. AFL, aflibercept; BCVA, best-corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study; LOCF, last observation carried forward; 2q4, 2 mg every 4 weeks; 2q8, 2 mg every 8 weeks. 1. Campochiaro PA, et al. Ophthalmology. 2015;122(3):538–544. 2. Haller JA. Presented at Retina Society, Philadelphia, USA, September 11–14, 2014.

Laser AFL 2q4 AFL 2q8 Laser + rescue AFL

0–24 weeks 24–52 weeks

Pro

po

rtio

n o

f p

atie

nts

wh

o g

ain

ed

≥

15

lett

ers

fro

m b

ase

line

(%

)

Fewer patients given aflibercept versus laser photocoagulation required rescue treatment1–3

AFL, aflibercept. 1. Campochiaro PA, et al. Ophthalmology. 2015;122(3):538–544. 2. Haller JA. Presented at Retina Society, Philadelphia, USA, September 11–14, 2014.

Aflibercept arm Baseline to

week 24 Week 24 to

week 52 Baseline to

week 52

Mean number of AFL injections received in the AFL arm

5.7 9.0

Patients receiving rescue laser in the AFL arm, n (%) 9 (10.0)

Laser arm

Mean number of laser treatments received 1.7

Mean number of rescue AFL injections received 4.4

Patients receiving rescue AFL injections in the laser arm, n (%)

67 (74.4)

At 52 weeks, after rescue aflibercept treatment in the laser arm, the perfusion status was effectively identical between the two arms

Findings suggest an important effect of aflibercept on the underlying disease mechanism

Aflibercept increased the proportion of eyes with retinal capillary perfusion1–3

*p<0.05 aflibercept versus laser. AFL, aflibercept; LOCF, last observation carried forward; 2q4, 2 mg every 4 weeks; 2q8, 2 mg every 8 weeks; AFL, aflibercept. 1. Campochiaro PA, et al. Ophthalmology. 2015;122(3):538–544. 2. Haller JA. Presented at Retina Society, Philadelphia, USA, September 11–14, 2014. 3. Data on File. Regeneron Pharmaceuticals Inc. Clinical trial Report VGFTe-RVO-1027 (Week 52). 2014.

Pro

po

rtio

n o

f p

erf

use

d e

yes

(%)

Baseline Week 24

AFL 2q4

Laser

Ranibizumab

A wealth of randomized, controlled trials have been performed in CRVO with ranibizumab

CRUISE1

•Primary outcomes: • Efficacy • Safety profile

•versus sham

HORIZON2

•Extension of CRUISE

•Long-term efficacy and safety profile

RETAIN3

•Extension of CRUISE and HORIZON

COMRADE-C6

•Ranibizumab vs dexamethasone implant

2010 2011 2012 2013 2014 2015

CRYSTAL5 •Long term efficacy of ranibizumab in ischemic CRVO patients

SHORE4

•Monthly vs PRN dosing

Completed Ongoing

1. Campochiaro PA, et al. Ophthalmology 2011;118:2041-9 2. Heier JS, et al. Ophthalmology 2012;119:802–9

3. Campochiaro PA et al. Ophthalmology 2014;121:209-19 4. Campochiaro PA, et al. Ophthalmology 2014;121:2432–42

5. www.clinicaltrials.gov/ct2/show/NCT01535261 6. www.clinicaltrials.gov/show/NCT01396083

http://www.clinicaltrials.gov/ct2/show/NCT01535261

A wealth of randomized, controlled trials have been performed in BRVO with ranibizumab

BRAVO1

•Primary outcomes: • Efficacy • Safety profile

•vs sham

HORIZON2

•Extension of BRAVO

•Long-term efficacy and safety profile

RETAIN3

•Extension of BRAVO and HORIZON

COMRADE-B6

•Ranibizumab vs dexamethasone implant

2010 2011 2012 2013 2014 2015

BRIGHTER5 •Ranibizumab vs laser

SHORE4

•Monthly vs PRN dosing

1. Brown DM, et al. Ophthalmology 2011;118:1594–602 2. Heier JS, et al. Ophthalmology 2012;119:802–9

3. Campochiaro PA et al. Ophthalmology 2014;121:209–19 4. Campochiaro PA, et al. Ophthalmology 2014; doi: 10.1016/j.ophtha.2014.06.011. [Epub ahead of print]

5. www.clinicaltrials.gov/ct2/show/NCT01599650 6. www.clinicaltrials.gov/ct2/show/NCT01396057

Completed Ongoing

Me

an c

han

ge (±

SE)

in B

CV

A f

rom

b

ase

line

(ET

DR

S le

tte

rs)

*P<0.0001 versus sham (ANCOVA t-test), **P<0.001 versus sham/0.5 mg group (post hoc analysis, pair-wise ANOVA) Randomized patients/LOCF Sham patients received ranibizumab 0.5 mg PRN treatment from Month 6 to 11; vertical bars are ±1 SE of the mean

Modified from: 1. Brown DM et al. Ophthalmology 2010;117:1124–33 2. Campochiaro et al. Ophthalmology 2011;118:2041-49

14.9*

0.8

Time (month)

Primary endpoint

13.9**

7.3

CRUISE: Ranibizumab treatment led to rapid and significant VA gain in CRVO patients1,2

*p<0.0001 versus sham (pairwise ANOVA), **p<0.001 versus sham/ranibizumab 0.5 mg (post hoc analysis, pairwise ANOVA); Randomized set, LOCF (last observation carried forward); Sham patients received ranibizumab 0.5 mg PRN treatment from Month 6 to 11 Vertical bars are ±1 SE of the mean

Modified from: 1. Brown DM et al. Ophthalmology 2010;117:1124–33 2. Campochiaro et al. Ophthalmology 2011;118:2041-49

-345.2*

-347.4**

-157.7

-273.7

-400

-350

-300

-250

-200

-150

-100

-50

0

50

0 1 2 3 4 5 6 7 8 9 10 11 12

Mea

n ch

ange

(±S

E) in

CFT

from

bas

elin

e (µ

m)

Sham (n=132) Ranibizumab 0.5 mg (n=131) Sham/ranibizumab 0.5 mg (n=115)

Time (month)

CRUISE: rapid, sustained and significant CFT decrease with ranibizumab

Significant reduction in CFT with ranibizumab monthly versus sham (P<0.0001) at Month 6, sustained with PRN treatment over 12 months1,2

BRAVO: Ranibizumab treatment led to rapid and significant VA gain in BRVO patients1,2

*P<0.0001 versus sham (pair-wise ANOVA); **P<0.01 versus sham/ranibizumab 0.5 mg (post hoc analyses, pairwise ANOVA) Randomized patients/LOCF Sham patients received ranibizumab 0.5 mg PRN treatment from Month 6 to 11

Primary endpoint

Months

Me

an c

han

ge (±

SE)

in B

CV

A

fro

m b

ase

line

(ET

DR

S le

tte

rs)

D7

Modified from: 1. Campochiaro PA et al. Ophthalmology 2010;117:1102–12

2. Brown DM et al. Ophthalmology 2011;118:1594–602

BRAVO: rapid, sustained and significant CFT decrease with ranibizumab

*P<0.0001 versus sham (ANOVA t-test) **P<0.05 versus sham/0.3 mg group (post hoc analysis, pair-wise ANOVA) Randomized patients/LOCF Sham patients received ranibizumab 0.5 mg PRN treatment from Months 6 to 11 Vertical bars are ±1 SE of the mean

Months

Me

an c

han

ge (±

SE)

in C

FT

fro

m b

ase

line

(μ

m)

D7

Significant reduction in CFT with ranibizumab monthly versus sham (P<0.0001) at Month 6, sustained with PRN treatment over 12 months1,2

Modified from: 1. Campochiaro PA et al. Ophthalmology 2010;117:1102–12

2. Brown DM et al. Ophthalmology 2011;118:1594–602

HORIZON: study design

Open-label, multicenter, 2-year extension study in patients who completed the 12-month BRAVO and CRUISE studies1,2

4. Brown DM, et al. Ophthalmology 2011;118:1594–602 4. Brown DM, et al. Ophthalmology 2010;117:1124 6. Campochiaro PA, et al. Ophthalmology 2011;118:2041

*PRN retreatment criteria: mean CRT ≥ 250 µm on optical coherence tomography or ME judged by investigator to be affecting patient’s visual acuity †M6-M11: all patients could receive monthly intravitreal ranibizumab PRN, if mean CRT ≥ 250 µm on optical coherence tomography

Ranibizumab 0.5 mg PRN* with quarterly monitoring visits (or more frequently, at the discretion of the investigator) up to Month 24 or until 30 days after FDA approval of ranibizumab for treatment of RVO

HORIZON (cohort 2 [N = 608])

Ranibizumab 0.5 mg

Completed the 12-month trial (N=356)

Enrolled in the extension trial (n=304)

Sham/ ranibizumab

0.5 mg†

Ranibizumab 0.3 mg†


BRAVO3,4 (ME secondary to BRVO [N = 397])

Completed the 12-month trial (N=356)

Enrolled in the extension trial(n=304)

Sham/ ranibizumab

0.5 mg†



CRUISE5,6 (ME secondary to CRVO [N = 392])

1. http://www.clinicaltrials.gov/ct2/show/NCT01442064 2. Heier JS, et al. Ophthalmology 2012;119:802–93 3. Campochiaro PA, et al. Ophthalmology 2010;117:1102–12

RETAIN study design

• Patients with RVO were eligible for the RETAIN study if they completed the BRAVO or CRUISE trials and had subsequent follow-up in HORIZON

† M6-M11: RBZ 0.5 mg PRN

Monitoring visits every month for 12 months, then every 3 months or more frequently for an additional 12 months. Patients were eligible to receive ranibizumab 0.5 mg if intraretinal fluid was present with foveal involvement

Completed 12-month trial (N=356) Completed 12-month trial (N=349)

HORIZON (cohort 2 [N=608])

Enrolled in extension study (n=304) Enrolled in extension study (n=304)

Sham/ RBZ 0.5 mg† RBZ 0.3 mg RBZ 0.5 mg

Sham/ RBZ 0.5 mg†

RBZ 0.3 mg RBZ 0.5 mg

CRUISE ME secondary to CRVO (N=392)

BRAVO ME secondary to BRVO (N=397)

RETAIN (N=66)

Campochiaro et al. Ophthalmology 2010;117:1102; Brown et al. Ophthalmology 2010;117:1124; Brown et al. Ophthalmology 2011;118:1594; Campochiaro et al. Ophthalmology 2011;118:2041; Campochiaro PA et al. Ophthalmology 2014;121:209-19

CRUISE HORIZON (CRVO)

16.2* 9.4*

12.0* 7.6*

PRN Monthly

Sham patients switched to ranibizumab 0.5 mg PRN

HORIZON: VA gains from CRUISE were sustained over time

Observed data; *Includes patients with data available at that time point and CRUISE baseline

Modified from: Heier JS et al. Ophthalmology 2012;119:802-809

12 months CRUISE

baseline HORIZON baseline

Sham Ranibizumab 0.5 mg Sham/ranibizumab 0.5 mg

Time (month)

HORIZON: CFT decreases in CRUISE were maintained over time

Observed data; *Includes patients with data available at that time point and CRUISE baseline; Vertical bars are ±1 SEM

Modified from: Heier JS et al. Ophthalmology 2012;119:802-809

PRN Monthly

―481.4* ―484.6*


―412.2* ―418.7*

Time (month) 12 months CRUISE

baseline HORIZON baseline



HORIZON: VA gains from BRAVO sustained over time

Observed data; *Includes patients with data available at that time point and BRAVO baseline

+19.2* +13.2*

+17.5* +15.6*

Months


12 months BRAVO baseline

HORIZON baseline

Me

an c

han

ge (±

SE)

in B

CV

A

fro

m b

ase

line

(ET

DR

S le

tte

rs)

BRAVO HORIZON (BRVO)


Modified from: Heier JS, et al. Ophthalmology 2012;119:802–9e

PRN Monthly

HORIZON: CFT decreases in BRAVO were maintained over time

Observed data; *Includes patients with data available at that time point and BRAVO baseline

Modified from:

Heier JS, et al. Ophthalmology 2012;119:802–9e

Months 12 months BRAVO baseline

HORIZON baseline

Me

an c

han

ge (±

SE)

in C

FT

fro

m b

ase

line

(μ

m)


BRAVO HORIZON (BRVO)


PRN Monthly

HORIZON: proportion of ≥15 letter gainers in CRUISE were maintained over time


PRN Monthly

n=130 n=130 n=110 n=130 Pro

po

rtio

n o

f p

atie

nts

gai

nin

g

1

5 le

tte

rs (

%)

Sham/ranibizumab 0.5 mg Ranibizumab 0.5 mg Sham/ranibizumab 0.5 mg

*P<0.0001 for each ranibizumab group vs sham/ranibizumab 0.5 mg **P<0.05 for each ranibizumab group vs sham/ranibizumab 0.5 mg Includes patients with data available at that time point and CRUISE baseline

Extracted from:

1. Brown DM et al. Ophthalmology 2010;117:1124–33 2. Campochiaro et al. Ophthalmology 2011;118:2041-49

3. Heier JS, et al. Ophthalmology 2012;119:802-9

HORIZON: Proportion of ≥15 letter gainers in BRAVO were maintained over time

Pro

po

rtio

n o

f p

atie

nts

wit

h

≥15

ETD

RS

lett

ers

gai

n, %

n = 66 n = 73 n = 132 n = 131 n = 115 n = 131

BRAVO HORIZON (BRVO)†

*P <0.0001 for each ranibizumab group versus sham **P <0.05 for each ranibizumab group versus sham/ranibizumab 0.5 mg †Includes patients with data available at that time point and BRAVO baseline


PRN Monthly

Extracted from:

1. Campochiaro PA, et al. Ophthalmology 2010;117:1102–12 2. Brown DM, et al. Ophthalmology 2011;118:1594–602

3. Heier JS, et al. Ophthalmology 2012;119:802–9e

HORIZON: overall, the incidence of non ocular SAEs was low across all treatments groups

Preferred term, n (%) Sham/ranibizumab 0.5 mg

(n = 93)

Ranibizumab 0.5 mg

(n = 104)

Non ocular SAEs, total 10 (10.8) 18 (17.3)

Key non ocular SAEs

Cardiac failure congestive 1 (1.1) 3 (2.9)

Coronary artery disease 1 (1.1) 2 (1.9)

Fall 2 (2.2) 0

Gastrointestinal hemorrhage 0 2 (1.9)

Osteoarthritis 0 1 (1.0)

APTC-defined ATEs* 1 (1.1) 4 (3.8)

Deaths, total 0 3 (2.9)

Vascular death 0 1 (1.0)

Death of unknown cause 0 1 (1.0)

Nonfatal myocardial infarction 1 (1.1) 1 (1.0)

Nonfatal cerebrovascular accident 0 1 (1.0)

Heier JS, et al. Ophthalmology 2012;119:802–9e *Defined as vascular death, death of unknown cause, nonfatal myocardial infarction, or nonfatal cerebrovascular accident.

RETAIN: patients with CRVO treated with ranibizumab maintained their initial VA gains for 3.5 years

Campochiaro PA et al. Ophthalmology 2014;121(1): 209-19

53.1% of the 32 CRVO patients enrolled in the RETAIN study gained BCVA of 15 letters or more, and 43.8% of patients had a final BCVA of 20/40 or better.

32 patients with CRVO from the CRUISE study were enrolled in the RETAIN study. Of the patients enrolled, 27 of 32 with CRVO completed 2 years of follow-up.

Month

Me

an B

CV

A

(ETD

RS

lett

er

sco

re)

n = 32 32 32 32 32 31 29 29 28

CRUISE study primary endpoint

+13.9 +14.0

Ranibizumab 0.5 mg

+13.1

61.8% of the 34 BRVO patients enrolled in the RETAIN gained BCVA of 15 letters or more, and 79.4% had a final BCVA of 20/40 or better

RETAIN: Patients with BRVO treated with ranibizumab maintained their initial VA gains for 3.5 years

Extracted from: Campochiaro PA, et al. Ophthalmology 2014;121:209–19

Me

an B

CV

A (

ETD

RS

lett

er

sco

re) +18.6 +20.1

BRAVO primary end point

Months

n = 34 34 34 34 34 34 33 30 28

BRVO (n = 34)

Ranibizumab 0.5 mg

RETAIN: patients with CRVO treated with ranibizumab maintained their lower CFT for 3.5 years

Campochiaro PA et al. Ophthalmology 2014;121(1): 209-19 32 patients with CRVO from the CRUISE study were enrolled in the RETAIN study. Of the patients enrolled, 27 of 32 with CRVO completed 2 years of follow-up.

Me

an C

FT (

µm

)

n = 32 32 32 32 32 31 29 29 28

Months

Ranibizumab 0.5 mg

CRVO (n = 32)

220.6

Months

n = 34 34 34 34 34 34 33 30 28

Me

an C

FT (

μm

)

RETAIN: Patients with BRVO treated with ranibizumab maintained their lower CFT for 3.5 years

188.7

BRVO (n = 34)

Ranibizumab 0.5 mg

Campochiaro PA, et al. Ophthalmology 2014;121:209–19

Treatment exposure and monitoring frequency

Study Treatment Study duration

(months) Monitoring

Mean no. of ranibizumab 0.5 mg

injections

CRUISE1,2 Monthly 0-6* Monthly 5.4

CRUISE1,2 PRN 7-12† Monthly 3.3

HORIZON3 PRN 13-24‡ At least once in

3 months 3.9

RETAIN**4 PRN 25–36 Monthly 2.1

RETAIN**4 PRN 37–48 At least once in

3 months 2.0

After the initial monthly ranibizumab injections, the mean number of retreatment was reduced substantially with individualized ranibizumab treatment

1. Brown DM et al. Ophthalmology 2010;117:1124–33 2. Campochiaro et al. Ophthalmology 2011;118:2041-49

3. Heier JS, et al. Ophthalmology 2012;119:802-9

4. Campochiaro PA, et al. Ophthalmology 2014;121:209–19

*Patients in the sham group received a mean of 5.5 sham injections †Patients in the sham group received a mean of 3.7 ranibizumab injections ‡Data are summarized for patients who completed the month 12 study visit of HORIZON; patients in the sham group received a mean of 2.9 injections **Data for patients with BRVO (n = 34) from the HORIZON study, who were enrolled in the RETAIN study

Treatment exposure and monitoring frequency

Study Treatment Treatment duration (months)

Monitoring visits Mean no. of

Ranibizumab 0.5 mg injections

BRAVO*1 Monthly 0–6 Monthly 5.7

BRAVO#2 PRN 7–12 Monthly 2.7

HORIZON†3 PRN 13–24 At least once in 3

months 2.5

RETAIN**4 PRN 25–36 Monthly 2.4

RETAIN**4 PRN 37–48 At least once in 3

months 1.8

1. Campochiaro PA, et al. Ophthalmology 2010;117:1102–12 2. Brown DM, et al. Ophthalmology 2011;118:1594–602

3. Heier JS, et al. Ophthalmology 2012;119:802–9e 4. Campochiaro PA, et al. Ophthalmology 2014;121:209–19

*Patients in the sham group received a mean of 5.5 sham injections during Months 0–6 #Patients in the sham group received a mean of 3.6 ranibizumab injections during Months 7–12 †Patients in the sham group received a mean of 2.0 ranibizumab injections during Months 13–24 **Data for patients with BRVO (n = 34) from the HORIZON study, who were enrolled in the RETAIN study

After the initial monthly ranibizumab injections, the mean number of retreatment was reduced substantially with individualized ranibizumab treatment

SHORE study design: comparison of monthly vs PRN ranibizumab dosing in RVO patients

Eligible BRVO/CRVO Patients (N = 202) Age ≥ 18 y, BCVA 20/40 to 20/320, CST >300 μm

Months 0-6: Fixed Treatment 7 monthly ranibizumab injections

Monthly Regimen (n = 85)

PRN Regimen (n = 86)

Monthly Regimen (n = 80)

PRN Regimen (n = 82)

Non-Randomized Monthly Injections (n = 31)

Non-Randomized Monthly Injections (n = 13)††

Completed Final Study Visit (Month 15)

*During the alternate dose regimen period, patients were randomized into monthly or PRN arms when disease stability criteria were reached. #Premature discontinuations prior to month 7 (n = 12). †Discontinuations between months 7‒15 (n = 6). ††Completed study but did not meet stability criteria between months 7–14 (n = 13).

Alternate Dose Regimen* (Months 7-14) Monthly ranibizumab injections until meeting VA and OCT Stability Criteria

First month when stability criteria are met (n = 171)

Rolling Randomization (1:1)

Stability criteria not met prior to discontinuation#,†

or study completion††

Campochiaro PA et al. Ophthalmology 2014;121:2432-2442

+18.7

*n = number of patients in each group at baseline; number of patients with observed BCVA changes from baseline varies over time. Intent-to-treat observed data

Vertical bars are 1 SE of the mean

+21.0

+14.5

Protocol-driven fixed monthly dosing

Me

an c

han

ge in

BC

VA

fr

om

bas

elin

e (

ETD

RS

lett

ers

)

Primary efficacy analysis: no significant difference in the slopes of the BCVA change from baseline from Month 7 through Month 15 between treatment groups (P = 0.509)

Campochiaro PA, et al. Ophthalmology 2014;121:2432–42

Data for all patients enrolled in the SHORE study (BRVO + CRVO) Alternate dose regimen period: PRN group received a mean of

3.7 injections

SHORE: a durable response was achieved beyond 7 months with a low number of injections

Evaluation of ranibizumab for macular ischemia in retinal vein occlusion: evidence from the BRIGHTER and CRYSTAL studies Program Number: 5803 Jordi Mones: ARVO 2015 Annual Meeting

56 | | BRIGHTER & CHRYSTAL | Business Use Only Mones J, Invest Ophthalmol Vis Sci 2015; 56 (7): 5803. , ARVO 2015

BRIGHTER

Ranibizumab for macular ischemia in RVO


BRIGHTER

Mean BCVA over time based on baseline ischemia status

6M study results presented to ARVO 2015


BRIGHTER

Mean BCVA over time based on baseline ischemia status

12M study results presented to ARVO 2015


BRIGHTER

Conclusions from 6 month primary endpoint

The BRIGHTER and CRYSTAL studies demonstrated that the flexible administration of RBZ is an effective therapy for BRVO and CRVO patients regardless of baseline ischemic status.

Greater alignment on grading and reporting of retinal perfusion status in clinical studies should be considered.

Mones J, Invest Ophthalmol Vis Sci 2015; 56 (7): 5803. , ARVO 2015 60 | | BRIGHTER & CHRYSTAL | Business Use Only

Take home message • Anti-VEGF agents have a key role to play

in the treatment of RVO

• The early treatment gives the best chance

of visual recovery but…

• The studies show that later treatment, six

months after the onset, is effective

• Pro-active or Rea-active treatment

• Ischaemia is not a controindication

ANTI-VEGF IN VASCULAR PATHOLOGIES · vascular disorders –Affects ~180,000 people each year in the...

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Transcript of ANTI-VEGF IN VASCULAR PATHOLOGIES · vascular disorders –Affects ~180,000 people each year in the...