Financial Disclosures - Dannemiller...Retinal Vein Occlusion (RVO): Overview • RVO: Blockage of...

1

Cole Eye InstituteCole Eye Institute

Steroids For Retinal Vein OcclusionSteroids For Retinal Vein Occlusion

Rishi P. Singh, MDStaff Physician, Assistant Professor of Ophthalmology

Cleveland Clinic, Cleveland, Ohio


Financial Disclosures

• Advisor, consultant, or research support:

• Genentech, Ophthotech Corp, RegeneronPharmaceuticals, Inc., ThromboGenics, Inc., Valeant, Alcon

• Will be discussing off label use of triamcinolone acetonidefor macular edema secondary to RVO

• Advisor, consultant, or research support:

• Genentech, Ophthotech Corp, RegeneronPharmaceuticals, Inc., ThromboGenics, Inc., Valeant, Alcon

• Will be discussing off label use of triamcinolone acetonidefor macular edema secondary to RVO


Agenda

• Discuss the advancements in retinal vein occlusion therapy

• Highlight benefits and drawbacks of current treatments

• Focus on outcomes of recent clinical trials to guide management

• Discuss the advancements in retinal vein occlusion therapy

• Highlight benefits and drawbacks of current treatments

• Focus on outcomes of recent clinical trials to guide management


VA 20/100

CRT 485

s/p 3 bevacizumabinjection

VA 20/100

CRT 649

65 yr, hypertension, decrease in VA for 2 y

Audience Response:1. Switch Drugs to another anti-VEGF2. Switch Drugs to Intravitreal Triamcinolone3. Switch Drugs to Ozurdex

Audience Response:1. Start with Avastin2. Start with Lucentis3. Start with Eylea4. Start with steroid5. Observation - natural history is good

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Retinal Vein Occlusion (RVO): Overview

• RVO: Blockage of veins carrying blood away from the retina

• RVO: Second most common cause of vision loss due to retinal vascular disorders1,2

• Incidence: ~180,000 new cases annually3

• Prevalence: 0.3 to 8.4 cases per 1000 persons (US population-based studies)4

• RVO: Blockage of veins carrying blood away from the retina

• RVO: Second most common cause of vision loss due to retinal vascular disorders1,2

• Incidence: ~180,000 new cases annually3

• Prevalence: 0.3 to 8.4 cases per 1000 persons (US population-based studies)4

1.6 1.7

6.8

10.8

15.

17.3

0.2.4.6.8.

10.12.14.16.18.20.

30-39 40-49 50-59 60-69 70-79 ≥80

Prev

alen

ce p

er 1

,000

Age (yrs)

1. Orth DH, Patz A. Surv Ophthalmol 1978; 22:357-76. 2. Branch Vein Occlusion Group. Arch Ophthalmol 1986; 104:34-41. 3. Klein R et al. Arch Ophthalmol 2008;126:513-18 (projection to US population). 4. Rogers S et al. Ophthalmology 2010;117:313-19.e1.

Cole Eye InstituteCole Eye InstituteCole Eye InstituteCole Eye Institute4

(Branch) BRVO (Central) CRVO

Above fundus photograph and FA image courtesy of Retina Consultants of Houston.

collateral vessels

lamina cribrosa

region posterior to lamina cribrosa

Pathophysiology of BRVO and CRVO


Macular Edema

Pathogenesis of macular edema

Vasodilation Leukostasis

Diapedesis Vascular permeability

Inflammatory proteins

VEGF

Retinal Vein Occlusion

Retinal hypoxia-ischemia

Inflammatory MediatorsIL-1, TNF-alpha

Cole Eye InstituteCole Eye InstituteCole EyeCole Eye

Why macular edema?

Unique anatomy of the macula:

Extremely high cell count with increased metabolic activity

Potential reservoir for the accumulation of extravascular fluid due to the thickness and loose binding of inner connecting fibers in the outer plexiform layer

Central avascular zone creating a watershed arrangement between the choroidal and retinal circulation thus decreasing resorption of extracellular fluid.

Unique anatomy of the macula:

Extremely high cell count with increased metabolic activity

Potential reservoir for the accumulation of extravascular fluid due to the thickness and loose binding of inner connecting fibers in the outer plexiform layer

Central avascular zone creating a watershed arrangement between the choroidal and retinal circulation thus decreasing resorption of extracellular fluid.

3


Macular Edema is a common cause for vision loss in Retinal Vein Occlusion

• Pathogenesis

• Involves release of cytokines mediating the angiogenic & inflammatory processes

• Dysregulation of endothelial tight junction proteins

• Increased vascular permeability & further release of inflammatory mediators including IL-1, TNF-alpha, VEGF and others

Angiogenic, inflammatory

mediators

PermeabilityMigrationAdhesion


Macular Edema

Targets for Clinical Intervention

Vasodilation Leukostasis

Diapedesis Vascular permeability

Inflammatory proteins

VEGF

Retinal Vein Occlusion

Retinal hypoxia-ischemia

CorticosteroidsInflammatory Mediators

IL-1, TNF-alpha

LASERANTI-VEGF


Evolution of Treatment Targeting Macular Edema in CRVO

*Not approved specifically for use in treatment macular edema secondary to CRVO. †Intravenous formulation; experimental use1The Central Vein Occlusion Study Group. Ophthalmology 1995;102:1425-33. 2The Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study Research Group. Arch Ophthalmol 2009;127:1101-14. 3Haller JA et al. Ophthalmology 2010;117:1134-46.

4Haller JA et al. Ophthalmology 2011;118:2453-60. 5Brown DM et al. Ophthalmology 2010;117:1124-33. 6Campochiaro PA et al. Ophthalmology 2011;118:2041-49. 7Boyer D et al. Ophthalmology 2012;119:1024-32. 8Data on file. Regeneron Pharmaceuticals, Inc. 9Epstein DL et al. Ophthalmology 2012;119:1184-89. 10Singer MA et al. Retina 2012, 32:1289-94. 11Prager F et al. Br J Ophthalmol.

2009; 93:452-6.

Grid Photocoagulation(BVOS and CVOS)1

1995

Laser therapy Established:Laser as SOC for BRVOObservation as SOC for

CRVO


Drawbacks of BVOS and CVOS Trials

● No OCT determination of edema and response to treatment

● ETDRS visual acuity wasn’t used

● 90 days of waiting for natural history – was there a delayed response?

● No OCT determination of edema and response to treatment

● ETDRS visual acuity wasn’t used

● 90 days of waiting for natural history – was there a delayed response?

4


Triamcinolone* acetonide injection (SCORE)2

Dexamethasone intravitreal implant

(GENEVA)3,4

Corticosteroids

2010


1995

Laser therapy

*Not approved specifically for use in treatment macular edema secondary to CRVO. †Intravenous formulation; experimental use1The Central Vein Occlusion Study Group. Ophthalmology 1995;102:1425-33. 2The Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study Research Group. Arch Ophthalmol 2009;127:1101-14. 3Haller JA et al. Ophthalmology 2010;117:1134-46.

4Haller JA et al. Ophthalmology 2011;118:2453-60. 5Brown DM et al. Ophthalmology 2010;117:1124-33. 6Campochiaro PA et al. Ophthalmology 2011;118:2041-49. 7Boyer D et al. Ophthalmology 2012;119:1024-32. 8Data on file. Regeneron Pharmaceuticals, Inc. 9Epstein DL et al. Ophthalmology 2012;119:1184-89. 10Singer MA et al. Retina 2012, 32:1289-94. 11Prager F et al. Br J Ophthalmol.

2009; 93:452-6.




2010 2012

EYLEA® (aflibercept) Injection (COPERNICUS/

GALILEO)7,8

Lucentis (ranibizumab)(BRAVO and CRUISE)



(GENEVA)3,4

Corticosteroids

2010


1995

Laser therapy Anti-VEGF InjectionsAnti-VEGF Injections

*Not approved specifically for use in treatment macular edema secondary to CRVO. †Intravenous formulation; experimental use1The Central Vein Occlusion Study Group. Ophthalmology 1995;102:1425-33. 2The Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study Research Group. Arch Ophthalmol 2009;127:1101-14. 3Haller JA et al. Ophthalmology 2010;117:1134-46. 4Haller JA et al. Ophthalmology 2011;118:2453-60.

5Brown DM et al. Ophthalmology 2010;117:1124-33. 6Campochiaro PA et al. Ophthalmology 2011;118:2041-49. 7Boyer D et al. Ophthalmology 2012;119:1024-32. 8Data on file. Regeneron Pharmaceuticals, Inc. 9Epstein DL et al. Ophthalmology 2012;119:1184-89. 10Singer MA et al. Retina 2012, 32:1289-94. 11Prager F et

al. Br J Ophthalmol. 2009; 93:452-6.


CRUISE: Ranibizumab (RBZ) in the Management of Macular Edema Secondary to CRVO1,2

Me

an

ch

an

ge fr

om

ba

selin

e

BC

VA

(E

TD

RS

lett

ers

)

*Secondary endpoint. †P<0.01 vs sham. Earliest statistically significant group difference (P<0.01 vs sham) was at Day 7. Vertical bars are ±1 standard

error of the mean. The last-observation-carried-forward method was used to impute missing data. BCVA = best-corrected visual acuity; ETDRS = Early Treatment Diabetic Retinopathy Study.

MonthDay 0 to Month 6

Monthly TreatmentMonth 6 to 12

PRN Treatment

Sham/0.5 mg (n=130) LUCENTIS 0.5 mg (n=130)

-2

0

2

4

6

8

10

12

14

16

18

2 4 6 8 10 120 D7

+14.9†

+0.8

+13.9

+7.3

0

+12.2


Ranibizumab

Sham (n=130)

0.3 mg (n=132)

0.5 mg (n=130)

Months since diagnosis, mean (SD) 2.9 (2.9) 3.6 (3.2) 3.3 (3.7)

<3 months, n (%) 80 (61.5) 68 (51.5) 74 (56.9)

≥3 months, n (%) 50 (38.5) 64 (48.5) 56 (43.1)

BCVA (ETDRS letters), mean (SD) 49.2 (14.7) 47.4 (14.8) 48.1 (14.6)

BCVA (Snellen equivalent), median 20/100 20/100 20/100

Central foveal thickness* (μm), mean (SD)

687.0 (237.6) 679.9 (242.4) 688.7 (253.1)

Study Eye Characteristics

*No. of subjects assessed was 129, 131, and 130 in the sham, 0.3 mg, and 0.5 mg groups, respectively. SD=standard deviation, BCVA=best-corrected visual acuity, ETDRS=Early Treatment Diabetic Retinopathy Study.

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LUCENTIS Treatment

LUCENTIS TreatmentSham/0.5 mg

(n=130)

LUCENTIS0.5 mg (n=130)

Mean number of injections/ patient*

Treatment period† (Day 0 to Month 6) 5.4 5.5

Observation period (Month 6 to 12) 3.7 3.3

Patients receiving first PRN injection at Month 6, n (%) 100 (76.9) 64 (49.2)

*During the 6-month treatment period sham patients received sham injections (Day 0, Months 1–5). During the 6-month observation period sham patients received PRN LUCENTIS 0.5 mg if they met retreatment criteria (Months 6–11).

†Based on Month 6 database. 6 total possible injections.PRN = pro re nata.


HORIZON RVO: 1-Year Follow-Up of CRUISE Study1

+9.4+7.6

+16.2

+12.0

-5

0

5

10

15

20

0 3 6 9 12 15 18 21 24

Mean Change from CRUISE Baseline, ETDRS Letters

Sham/0.5 mg RBZ 0.5 mg RBZ

CRUISE HORIZON RVO

-4.2

-4.1

-7

-6

-5

-4

-3

-2

-1

0

12 15 18 21 24

Months

Mean Change from HORIZON Baseline, ETDRS Letters

Sham/0.5 mg RBZ 0.5 mg RBZ

1Heier JS et al.Ophthalmology 2012;119:802-9.

Months


Potential AEs of anti-VEGF treatment in patients

Ocular AEs

Vitreous hemorrhage

Vitreomacular traction

RPE tears

Retinal detachment

Elevated intraocular pressure

Intraocular inflammation

Endophthalmitis

Systemic AEs

Hypertension

Proteinuria

Impairment of wound healing

Arterial thromboembolic events

Myocardial infarctions

Stroke

Dyspnea


Conclusions from CRUISE and HORIZON studies:Limitations of anti-VEGF treatment

● Macular hypoxia is not alleviated with anti-VEGF

● Requires multiple injections over extended periods (average 8-9 injections over 12 months).

● If you inject less frequently you can lose vision.

● Not all people gain vision

● Some people lose vision

● Side effects are low but not zero

● Macular hypoxia is not alleviated with anti-VEGF

● Requires multiple injections over extended periods (average 8-9 injections over 12 months).

● If you inject less frequently you can lose vision.

● Not all people gain vision

● Some people lose vision

● Side effects are low but not zero

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More data to consider.....


Bhisitkul: Predictive value in RVO of early vs late or incomplete ranibizumab response defined by OCT

• Design: Post hoc analysis from the 2 prospective, randomized, controlled clinical trials of BRAVO and CRUISE

• Participants: 397 from BRAVO, 392 from CRUISE

• Methods: Time-domain OCT imaging data were analyzed

• Main Outcome Measure: Mean change from baseline BCVA letter score at month 6 and 12

• Design: Post hoc analysis from the 2 prospective, randomized, controlled clinical trials of BRAVO and CRUISE

• Participants: 397 from BRAVO, 392 from CRUISE

• Methods: Time-domain OCT imaging data were analyzed

• Main Outcome Measure: Mean change from baseline BCVA letter score at month 6 and 12


Study Design

• Patients in each study were classified according to their OCT characteristics at baseline into 3 groups• CFT ≤250 µm• Intraretinal cysts of fluids (CME)• Subretinal fluid (SRF)

• Patients were assessed for the effect of ranibizumab on these OCT parameters as well as on their visual acuity outcome at 6 and 12 months

• Patients in each study were classified according to their OCT characteristics at baseline into 3 groups• CFT ≤250 µm• Intraretinal cysts of fluids (CME)• Subretinal fluid (SRF)

• Patients were assessed for the effect of ranibizumab on these OCT parameters as well as on their visual acuity outcome at 6 and 12 months


Early vs Late or Incomplete Ranibizumab Responders in BRVO and CRVO Studies

Delayed OCT response means worse visual outcomes

BRAVO CRUISE

7


Effect of Ranibizumab on CME in BRVO and CRVO Studies

Many patient had CME despite therapy

If CME was present at Month 3, outcomes

were worse



2010 2012

EYLEA® (aflibercept) Injection (COPERNICUS/

GALILEO)7,8

Lucentis (ranibizumab)(BRAVO and CRUISE)



(GENEVA)3,4

Corticosteroids

2010


1995

Laser therapy Anti-VEGF InjectionsAnti-VEGF Injections

*Not approved specifically for use in treatment macular edema secondary to CRVO. †Intravenous formulation; experimental use1The Central Vein Occlusion Study Group. Ophthalmology 1995;102:1425-33. 2The Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study Research Group. Arch Ophthalmol 2009;127:1101-14. 3Haller JA et al. Ophthalmology 2010;117:1134-46. 4Haller JA et al. Ophthalmology 2011;118:2453-60.

5Brown DM et al. Ophthalmology 2010;117:1124-33. 6Campochiaro PA et al. Ophthalmology 2011;118:2041-49. 7Boyer D et al. Ophthalmology 2012;119:1024-32. 8Data on file. Regeneron Pharmaceuticals, Inc. 9Epstein DL et al. Ophthalmology 2012;119:1184-89. 10Singer MA et al. Retina 2012, 32:1289-94. 11Prager F et

al. Br J Ophthalmol. 2009; 93:452-6.


Primary Results: The Standard Care versus COrticosteroid

for REtinal Vein Occlusion Study(The SCORE Study)

SCORE Study Research Group

Sponsored by the National Eye Institute, National Institutes of Health, U.S. Department of Health and Human

Services(Funded by NEI 2003)


Retreat at 4 month intervals

SCORE Study group. Arch Ophthalmol. 2010;128:1140-1145.

SCORE Study Design

● Patients randomized to

● 1 mg steroid

● 4 mg steroid

● SOC treatment – BRVO grid laser, CRVO nothing

● Patients randomized to

● 1 mg steroid

● 4 mg steroid

● SOC treatment – BRVO grid laser, CRVO nothing

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SCORE BRVOChange in Visual Acuity

SCORE BRVOChange in Visual Acuity

M4 M8 M16 M20 M24 M28 M32 M36M12

BRVO Trial

After month 12 and through month 36, mean VA improvement was greatest in the SC group. Cole Eye InstituteCole Eye Institute

SCORE: BRVOMonth 12 Safety Outcomes

Outcome Grid Laser

1 mgSteroid

4 mgSteroid

IOP-lowering meds 2% 8% 41%

Cataract progression

13% 25% 35%



SCORE: BRVO Conclusions

● No difference in visual acuity outcomes at month 12 between standard care (grid laser) and triamcinolone groups

● Rate of adverse events (IOP elevation, cataract progression) were highest in 4-mg triamcinolone group

● Grid laser recommended over intravitreal triamcinolone for patients with macular edema due to BRVO

● No difference in visual acuity outcomes at month 12 between standard care (grid laser) and triamcinolone groups

● Rate of adverse events (IOP elevation, cataract progression) were highest in 4-mg triamcinolone group

● Grid laser recommended over intravitreal triamcinolone for patients with macular edema due to BRVO



SCORE: CRVO: Month 12 Visual Acuity Outcomes

VisionOutcome

Observation1 mg

Steroid4 mg

Steroid

≥15 letters 6.8% 26.5% 25.6%

Mean letter

change

-12.1 -1.2 -1.2


9


SCORE: CRVO: Month 12 Safety Outcomes

Outcome Observation1 mg

Steroid4 mg

Steroid

IOP-lowering meds 8% 20% 35%

Cataract progression

18% 26% 33%

SCORE Study group. Arch Ophthalmol. 2010;128:1140-1145. Cole Eye InstituteCole Eye Institute

SCORE: CRVO Conclusions

● Intravitreal triamcinolone is superior to observation for treating vision loss associated with macular edema

● 1-mg triamcinolone dose has fewer ocular adverse events than the 4-mg dose

● Treatment with 1 mg triamcinolone for up to 1 year should be considered in eyes with vision loss associated with macular edema in CRVO

● Intravitreal triamcinolone is superior to observation for treating vision loss associated with macular edema

● 1-mg triamcinolone dose has fewer ocular adverse events than the 4-mg dose

● Treatment with 1 mg triamcinolone for up to 1 year should be considered in eyes with vision loss associated with macular edema in CRVO



OZURDEX™ RVO DataDexamethasone intravitreal implant in patients with

vision loss due to macular edema associated with retinal vein occlusion

OZURDEX™ RVO DataDexamethasone intravitreal implant in patients with

vision loss due to macular edema associated with retinal vein occlusion

Two identical, 6-month, randomized, prospective, multicenter, masked, sham-controlled, parallel-group, phase 3 clinical

trials

Primary endpoint in the pooled analysis was time to ≥ 15 letter gain of the 2 identically designed studies


1267 Patients randomized1:1:1

DEX 350412 1st injection

Completed day 180396 patients

DEX 700421 1st injection

Sham Procedure423 sham injection



Discontinued prior to day 36014 patients






DEX 350/700329 OL injection

DEX 700/700341 OL injection

Sham/DEX 700327 OL injection

GENEVA Study: Trial Design and Patient Disposition 6-Month Study with 6-Month Open-Label Follow-up

6-Month Open-Label Extension997 patients rolled over to receive DEX 700 µg *

OL = open label* 199 patients did not receive an open-label injection

11 patients no injection

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0

10

20

30

40

50

60

70

80

90

100

Cu

mu

lativ

e R

esp

on

se R

ate

(%

)

GENEVA Trial: Best Corrected Visual Acuity: Time to the First Gain of ≥ 15 Letters – Kaplan-Meier Analysis

P < .001

Days from the First Dose

Sham (n = 426)

Dexamethasone-DDS 350 µg (n = 414)

Dexamethasone-DDS 700 µg (n = 427)DEX 700 vs Sham: <.001DEX 350 vs Sham: <.001

0 20 40 60 80 100 120 140 160 180


GENEVA Trial: Demographic and Baseline Characteristics

DEX Implant 0.7 mgn=427

DEX Implant 0.35 mgn=414

Sham n=426

Sex (female) 49.2% 46.9% 43.7%

Race (white) 75.2% 75.4% 74.6%

Mean age (years)(range)

64.7(33-90)

64.9(31-96)

63.9(31-91)

Mean VA (letters)(range)

54.3 (20/80)(34-68)

53.9 (20/80)(31-79)

54.8 (20/80)(28-80)

Mean OCT (µm)(range)

562(127-1320)

555(116-1369)

539(94-1218)

Diagnosis in study eye

CRVO 31.9% 37.2% 34.5%BRVO 68.1% 62.8% 65.5%

Duration of ME (days)< 90 16.4% 18.4% 15.3%90-179 51.3% 52.7% 51.6%> 180 32.3% 29.0% 33.1%

Haller J, et al. Ophthalmology. 2010;117:1134-1146.


GENEVA Trial: Patients With BCVA Improvement of≥15 Letters From Baseline

21.3

29.3

21.8 21.5

17.9

28.5

23.4

19.3

7.5

11.313.1

17.6

0

5

10

15

20

25

30

35

Day 30 Day 60 Day 90 Day 180

Pe

rce

nta

ge

of

Pa

tie

nts

Sham (n = 426)

Dexamethasone-DDS 350 µg (n = 414)Dexamethasone-DDS 700 µg (n = 427)

Study Day

P < .001

P < .001

P < .001

P values are for Dexamethasone-DDS 700 µg vs Sham(136 – 210 Days)


GENEVA Trial: Post-implant visit window varied considerably

Actual visits 136 to ≤180 days >180 to ≤200 days >200 days

Sham 203 (50.6%) 181 (45.1%) 17 (4.2%)

700 μg 188 (46.2%) 203 (49.9%) 16 (3.9%)

Per protocol specification

76–135 days

Day 90

46–75 days19–45 daysVisit window in days from implant

insertion

Day 60Day 30 Day 180

136–210 days

11


GENEVA Trial: Patients With BCVA Improvement of ≥15 Letters From Baseline (excluding visits beyond 180 days)

26.4

21.3

29.3

21.8

19.417.9

28.5

23.4

17.0

7.5

11.3

13.1

0

5

10

15

20

25

30

35

Day 30 Day 60 Day 90 Day 180

Pe

rcen

tag

e o

f P

ati

en

ts

Sham

Dexamethasone-DDS 350 µg Dexamethasone-DDS 700 µg

Study Day

P < .001

P < .001

P < .001

P values are for Dexamethasone-DDS 700 µg vs Sham

(n = 208)

(n = 216)

(n = 229)

(n = 427)

(n = 414)

(n = 426)

(n = 427)(n = 414)

(n = 426)

(n = 427)(n = 414)

(n = 426)

P < .017


GENEVA Trial: Mean Change in BCVA From Baseline Retreated Populations

Study Day

**

*

**

*

AllTreated

with DEX 700

P < .05 for DEX 700/700 vs Sham/700

0

2

4

6

8

10

12

14

Baseline Day 30 IT Day 60 IT Day 90 IT Day 120 IT Day 150 IT Day 180 IT Day 30 OL Day 60 OL Day 90 OL Day 120 OL Day 150 OL Day 180 OL

Mea

n B

CV

A Im

pro

vem

ent L

ette

rs

Dex 700/700 (n=341)Dex 350/700 (n=329)

Sham/700 (n=327)


GENEVA Trial: Mean BCVA improvement in BRVO & CRVO

-3

0

3

6

9

12

Baseline Day 30 Day 60 Day 90 Day 150 Day 180

0.7 mg (n=136)Sham (n=147)

CRVO

NS

P<0.001

P<0.001P<0.001

0

3

6

9

12

Baseline Day 30 Day 60 Day 90 Day 150 Day 180

0.7 mg (n=291)Sham (n=279)

BRVO P<0.001P<0.001

P<0.001P=0.008


% of Patients withIOP ≥ 35 m`mHg

% of Patients withIOP ≥ 25 mmHg

% of Patients with≥10 mmHg Change

from Baseline

GENEVA Trial: Changes in IOP Over 12 Months No increased IOP response following 2nd

Injection

12


GENEVA Trial: Selected Ocular Adverse Events at 12 Months

● Cataract extractions

● Study Eye

● DEX 700/700, n=4 (1.2%)

● DEX 350/700, n=5 (1.5%)

● Non-Study Eye

● DEX 700/700, n=1 (0.3%)

● DEX 350/700, n=2 (0.6%)

● Sham/DEX 700, n=2 (0.6%)

● Cataract extractions

● Study Eye

● DEX 700/700, n=4 (1.2%)

● DEX 350/700, n=5 (1.5%)

● Non-Study Eye

● DEX 700/700, n=1 (0.3%)

● DEX 350/700, n=2 (0.6%)

● Sham/DEX 700, n=2 (0.6%)

● IOP procedures

● Study Eye

● DEX 700/700, n=4 (1.2%)

● DEX 350/700, n=2 (0.6%)

● Sham/DEX 700, n=1 (0.3%)

● IOP procedures

● Study Eye

● DEX 700/700, n=4 (1.2%)

● DEX 350/700, n=2 (0.6%)

● Sham/DEX 700, n=1 (0.3%)


But what is real life experience with Ozurdex?


Retrospective Study of Two or MoreDexamethasone Intravitreal Implant 0.7 mg

Injections for Retinal Vein Occlusion

SHASTA Study

Antonio Capone, Jr., MD1; Michael Singer, MD2; David Dodwell, MD3; Richard Dryer, MD4; Kean Oh, MD5; John Walt, MBA6; Lanita C Scott, MD6; David A Hollander, MD,

MBA6

Antonio Capone, Jr., MD1; Michael Singer, MD2; David Dodwell, MD3; Richard Dryer, MD4; Kean Oh, MD5; John Walt, MBA6; Lanita C Scott, MD6; David A Hollander, MD,

MBA6

1Associated Retinal Consultants P.C., Novi, MI; 2Medical Center Ophthalmology Associates, San Antonio, TX; 3Illinios Retina Center, Springfield, IL; 4Retina Northwest P.C., Portland OR; 5Associated Retinal Consultants P.C., Traverse City, MI;

6Allergan, Inc. Irvine, CA


SHASTA Study: Purpose of Study

● To evaluate Dexamethasone Intravitreal Implant 0.7 mg (Ozurdex®) in the treatment of macular edema (ME) due to retinal vein occlusion (RVO) in patients receiving ≥2 Injections

● Safety

● Efficacy

● Reinjection interval

● To evaluate Dexamethasone Intravitreal Implant 0.7 mg (Ozurdex®) in the treatment of macular edema (ME) due to retinal vein occlusion (RVO) in patients receiving ≥2 Injections

● Safety

● Efficacy

● Reinjection interval

13


Study Design

● Retrospective, multicenter (26 sites) chart review

● Included were patients with ≥2 injections of Ozurdex®

● Additional RVO treatments were allowed

● Only 1 eye (most Ozurdex® injections) was included

● Data were collected from patient charts from the first Ozurdex® injection and included each subsequent visit through a minimumof 3 months and up to 6 months after the last Ozurdex® injection

● Retrospective, multicenter (26 sites) chart review

● Included were patients with ≥2 injections of Ozurdex®

● Additional RVO treatments were allowed

● Only 1 eye (most Ozurdex® injections) was included

● Data were collected from patient charts from the first Ozurdex® injection and included each subsequent visit through a minimumof 3 months and up to 6 months after the last Ozurdex® injection

Capone, Jr. et al. Retina. 2013Capone, Jr. et al. Retina. 2013Cole Eye InstituteCole Eye Institute

SHASTA Study: Patient Eligibility

● Inclusion Criteria

● At least 18 years of age

● Macular edema in the study eye due to BRVO or CRVO

● Patient had received ≥2 Ozurdex® in the study eye and had follow-up dataa minimum of 3 months after the latest injection

● Exclusion Criteria

● Received Ozurdex® as part of, or during, a clinical study

● Enrollment of the fellow eye in the study

● Inclusion Criteria

● At least 18 years of age

● Macular edema in the study eye due to BRVO or CRVO

● Patient had received ≥2 Ozurdex® in the study eye and had follow-up dataa minimum of 3 months after the latest injection

● Exclusion Criteria

● Received Ozurdex® as part of, or during, a clinical study

● Enrollment of the fellow eye in the study


SHASTA Study: Outcome Measures

● Primary Efficacy Endpoints

● Change in BCVA from baseline 4 to 20 weeks following last injection

● Secondary Efficacy Endpoints

● Change in BCVA from baseline following each injection

● Percent of patients with ≥2 lines increase in BCVA from baseline


● Change from baseline in central retinal thickness (CRT) by OCT

● Safety Measures

● Included adverse events, IOP, and ocular surgeries

● Primary Efficacy Endpoints

● Change in BCVA from baseline 4 to 20 weeks following last injection

● Secondary Efficacy Endpoints

● Change in BCVA from baseline following each injection



● Change from baseline in central retinal thickness (CRT) by OCT

● Safety Measures

● Included adverse events, IOP, and ocular surgeries


SHASTA Study: Demographics

Factor All PatientsN = 289

BRVO PatientsN = 157

CRVO PatientsN = 132

Age in YearsMean (SD) 71.9 (11.0) 72.2 (11.2) 71.6 (10.7)Range 39-94 39–94 39–91

Sex, n (%)Female 166 (57.4%) 92 (58.6%) 74 (56.1%)Male 123 (42.6%) 65 (41.4%) 58 (43.9%)

Diagnosis in Study EyeBRVO 157 (54.3%) – –CRVO 132 (45.7%) – –

RaceWhite 142 (49.1%) 67 (42.7%) 75 (56.8%)Black or African American 9 (3.1%) 6 (3.8%) 3 (2.3%)Asian 7 (2.4%) 6 (3.8%) 1 (0.8%)Pacific Islander 1 (0.3%) 0 (0.0%) 1 (0.8%)Not Recorded 130 (45.0%) 78 (49.7%) 52 (39.4%)

EthnicityHispanic or Latino 10 (3.5%) 8 (5.1%) 2 (1.5%)Not Hispanic or Latino 137 (47.4%) 65 (41.4%) 72 (54.5%)Not Recorded 142 (49.1%) 85 (53.5%) 58 (43.9%)

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SHASTA Study: Baseline Characteristics




Lens Status in Study Eye, n (%)Phakic 128 (44.3%) 69 (43.9%) 59 (44.7%)Pseudophakic 158 (54.7%) 86 (54.8%) 72 (54.5%)Not Recorded 3 (1.0%) 2 (1.3%) 1 (0.8%)

Ischemia in Study EyeYes 88 (30.4%) 55 (35.0%) 33 (25.0%)No 193 (66.8%) 97 (61.8%) 96 (72.7%)Unknown 6 (2.1%) 4 (2.5%) 2 (1.5%)Not Recorded 2 (0.7%) 1 (0.6%) 1 (0.8%)

History of IOP Response to SteroidYes 45 (15.6%) 22 (14.0%) 23 (17.4%)No 168 (58.1%) 92 (58.6%) 76 (57.6%)Not Recorded 76 (26.3%) 43 (27.4%) 33 (25.0%)

Glaucoma or Ocular Hypertension 91 (31.5%) 44 (28.0%) 47 (35.6%)

None or Not Recorded in Chart 198 (68.5%) 113 (72.0%) 85 (64.4%)Baseline IOP-Lowering MedicationYes 70 (24.2%) 35 (22.3%) 35 (26.5%)No 21 (7.3%) 9 (5.7%) 12 (9.1%)Not Recorded 198 (68.5%) 113 (72.0%) 85 (64.4%)


SHASTA Study: Baseline Characteristics




Duration of RVO at Time of First Ozurdex Implant Injection (Months)

Mean (SD) 18.4 (23.4) 20.1 (25.0) 16.4 (21.3)

Range 0–150.2 0–119.1 0–150.2

Mean (SD) Best-CorrectedVisual Acuity in the Study Eye (lines)

9.8 (4.6)(Snellen 20/100)

11.0 (4.3)(Snellen 20/80)

8.4 (4.7)(Snellen 20/160)

Mean (SD) Central Retinal Thickness, μm 438 (182) 413 (149) 469 (201)


Treatment Prior to 1st Ozurdex® No. of Patients %

Baseline Treatments/Procedures* 248 86%

Anti-VEGF Treatment (Intravitreal) 205 71%

Avastin 181 63%

Lucentis 40 14%

Macugen 3 1%

Triamcinolone (Intravitreal) 115 40%

Treatment Prior to 1st Ozurdex® No. of Patients %

Any Laser Treatment 112 39%

Focal Laser 85 29%

Panretinal Photocoagulation 45 16%

Pars Plana Vitrectomy 37 13%

No Baseline Treatment or Procedure for RVO 39 14%

* Patients may have received >1 type of additional treatment* Patients may have received >1 type of additional treatment

SHASTA Study: Treatments Pre Ozurdex


Number ofOzurdex®

TreatmentsN %

2 119 41%

3 80 28%

4 36 12%

5 32 11%

6 12 4%

7 5 2%

8 3 1%

9 2 1%

SHASTA Study: Number of Ozurdex® Treatments

All PatientsMean (SD) 3.2 (1.5)

Injections

BRVOMean 3.2 (1.4) Injections

CRVOMean 3.2 (1.5) Injections

15


* Based on the mean number of days between injections for each patient* Based on the mean number of days between injections for each patient

Mean Time Between Ozurdex® Injections*

Time(Months)

Number ofPatients %

1 0 0%

2 0 0%

3 25 9%

4 86 30%

5 73 25%

6 39 14%

>6 66 23%

Mean (SD) 169 (74) Days = 5.6 Months

Median 150 Days = 4.9 Months

Range 81-527 Days

91% had their next injection at 4 months and beyond


* P≤.037; Error bars represent SD* P≤.037; Error bars represent SD

SHASTA Study: Change in BCVA (Lines) from Baseline at 4−20 Weeks After Each Injection

N = 283 N = 276 N = 268 N = 143 N = 76 N = 39 N = 18Baseline

Mean peak change 4−20 weeks a er final Ozurdex® was an improvement of 1.0 (3.5 SD) line (5 ETDRS Letters)


7 injections: 83.3% (5/6 patients)8 injections: 100.0% (3/3 patients)9 injections: 100.0% (1/1 patient)


Percentage of Patients with ≥2 LinesImprovement After Each Injection

N = 283 N = 275 N = 148 N = 79 N = 39 N = 18




Percentage of Patients with ≥3 LinesImprovement After Each Injection

N = 283 N = 275 N = 148 N = 79 N = 39 N = 18

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2 Lines or More Improvement BRVO CRVO

Percent Overall 59.7% 66.7%

N 92 86

Range After Injections* 46.8–55.6% 26.3–55.6%

* Percent of patients after the first through sixth injections (range)* Percent of patients after the first through sixth injections (range)

SHASTA Study: Overall 2−3 Lines Improvement BRVO vs. CRVO

All Patients

Improvement Percent Overall N Range After Injections*

2 Lines or More 62.9% 178 38.5–55.6%

3 Lines or More 48.1% 136 30.4–50.0%


Change in CRT from Baseline After Each Injection

* P≤.002; Error bars represent SD* P≤.002; Error bars represent SD

SHASTA Study: Change in CRT from Baseline After Each Injection

BaselineN = 247 N = 247 N = 236 N = 133 N = 70 N = 33 N = 15


SHASTA Study: CRT ≤250 Microns

CRT All Patients BRVO CRVO

≤250 µm 65.3% 66.0% 64.4%

N 188/288 103/156 85/132

Measurements were by spectral and/or time‐domain OCT


Treatment Post 1st Ozurdex® No. of Patients %

Treatments/Procedures Other Than Ozurdex* 205 71%

Anti-VEGF Treatment (Intravitreal) 186 64%

Avastin 127 44%

Lucentis 94 33%

Macugen 0 0%

Triamcinolone (Intravitreal) 9 3%

* Patients may have received >1 type of additional treatment* Patients may have received >1 type of additional treatment

SHASTA Study: Treatments Post Ozurdex

Treatment Post 1st Ozurdex® No. of Patients %

No Study Treatments in Addition to Ozurdex* 84 29%

Any Laser Treatment 72 25%

Focal Laser 54 19%

Panretinal Photocoagulation 27 9%

Pars Plana Vitrectomy 3 1%

17


SHASTA Study: Time Between First Ozurdex® Injection and Next Anti-VEGF Injection

Time to Anti-VEGF InjectionTotal (N=186) %

Days Months

≤30 ~1 Month 11 5.9%

31–60 ~2 Months 12 6.5%

61–90 ~3 Months 12 6.5%

91–120 ~4 Months 45 24.2%

121–150 ~5 Months 23 12.4%

151–180 ~6 Months 9 4.8%

>180 ~6+ Months 74 39.8%

80% had an anti-VEGF 3 months and beyond40% lasted 6 months or more without an anti-VEGF injection


SHASTA Study: Ozurdex® Safety

● IOP increases and cataract progression were the only treatment-related adverse events with an incidence of 2% or higher

● IOP increases and cataract progression were the only treatment-related adverse events with an incidence of 2% or higher

There was 1 report of endophthalmitis during the study

There were no deaths and no serious adverse events relatedto treatment

Outcome N

Cataract Surgery During the Study 46

Lens Opacity at Baseline 39/46 (85%)

Grade 2 or 3 Lens Opacity at Baseline 28/46 (61%)


SHASTA Study: IOP Safety

Outcome N %

Glaucoma Surgery (Laser or Incisional) 9 3.1%

Glaucoma Laser Surgery 4 1.4%

Glaucoma Incisional Surgery 5 1.7%

IOP-lowering Medications Initiated Secondary to Ozurdex 109 38%

IOP at Any Point During Study

Change ≥10 mm Hg from Baseline 91 32.6%

Recorded ≥25 mm Hg at Any Visit 97 33.7%

Recorded ≥35 mm Hg at Any Visit 27 9.4%

IOP at Final Study Visit

Change ≥10 mm Hg from Baseline 12 4.3%

Recorded ≥25 mm Hg at Final Visit 14 4.9%

Recorded ≥35 mm Hg at Final Visit 5 1.8%


Summary of SHASTA Study

● 63% of patients had vision improve by 2 or more lines

● Average OCT improved approximately 200 µm with each injection

● 69% of patients required an Ozurdex® between 4-6 months

● 80% did not need an anti-VEGF within 3 months after the injection

● At baseline, 31.5% of patients had glaucoma/OHT, 15.6% had a history of IOP response to steroids, yet <5% of patients had clinically elevated IOP at their final visit

● 63% of patients had vision improve by 2 or more lines

● Average OCT improved approximately 200 µm with each injection

● 69% of patients required an Ozurdex® between 4-6 months

● 80% did not need an anti-VEGF within 3 months after the injection

● At baseline, 31.5% of patients had glaucoma/OHT, 15.6% had a history of IOP response to steroids, yet <5% of patients had clinically elevated IOP at their final visit

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SHASTA Study: Conclusions

• Clinical use of 2 or more dexamethasone implants, either alone or in combination with anti-VEGF treatments, is safe and effective in the treatment of macular edema following RVO if IOP increases are monitored and treated

• Decreases in macular edema and improvements in visual acuity were maintained with ongoing dexamethasone implant treatment

• No new safety concerns developed after the use of multiple implants

• There was no evidence of a cumulative effect of repeat dexamethasone implants on IOP

• Clinical use of 2 or more dexamethasone implants, either alone or in combination with anti-VEGF treatments, is safe and effective in the treatment of macular edema following RVO if IOP increases are monitored and treated

• Decreases in macular edema and improvements in visual acuity were maintained with ongoing dexamethasone implant treatment

• No new safety concerns developed after the use of multiple implants

• There was no evidence of a cumulative effect of repeat dexamethasone implants on IOP


RVO Considerations

● Which is more important:

● Efficacy?

● Cost?

● Convenience?

● Risks?

● Which is more important:

● Efficacy?

● Cost?

● Convenience?

● Risks?


RVO Conclusions

● Consider treatment with multimodalities:

● Gain benefits of each and reduces side effects of both

● Potentially helps improve outcomes

● Consider treatment with multimodalities:

● Gain benefits of each and reduces side effects of both

● Potentially helps improve outcomes


Evaluation of Therapies for CRVO

● Can a corticosteroid “rescue” eyes that are failing anti-VEGF therapy with aflibercept?

● Can anti-VEGF therapy with aflibercept “rescue” eyes that are failing treatment with bevacizumab?

● Can a corticosteroid “rescue” eyes that are failing anti-VEGF therapy with aflibercept?

● Can anti-VEGF therapy with aflibercept “rescue” eyes that are failing treatment with bevacizumab?

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Study of COmparative Treatments

in REtinal Vein Occlusion 2 (SCORE2)

Sponsored by the National Eye Institute, National Institutes of Health, U.S. Department of Health and Human Services

Grants: 1U10EY023533 -01, 1U10EY023529-01, 1U10EY023521-01


SCORE2: Current 2-Arm Design

R=1:1 RandomizationStatus assessment at Month 6 when

primary noninferiority outcome is assessed

Disposition after Month 6: Secondary outcomes measured at Month 12

Baseline

Aflibercept: Monthly injections through Month 5

Bevacizumab: Monthly injections through Month 5

Good response

Poor or marginal response

Good response

Poor or marginal response

R

R

R

Aflibercept monthly: Months 6-11

Aflibercept TAE**: Months 6-11

Dexamethasone implant @ M6, PRN @ M9, M10, M11

Bevacizumab monthly: Months 6-11

Bevacizumab TAE**: Months 6-11

Aflibercept monthly: M6, M7, M8 and TAE**

* Poor or marginal response: (1) Visual acuity letter score less than 58/less than 20/80) OR visual acuity letter score improvement of ≤5 from baseline (ie, Month 6 visual acuity letter score – Baseline visual acuity score <5 letter). [Note that at least some of the visual acuity deficit is attributed, by the investigator,

to macular edema secondary to CRVO] AND (2) OCT has 1 or more of the following: central subfield thickness of ≥300 µm on SD-OC-OCT (or ≥320 µm if measured on Heidelberg Spectralis Machine), presence of intraretinal cystoid spaces, subretinal fluid.

Good response: Otherwise

** TAE = Treatment and extend with 2-week extension increments


Back to our case


65 yr, hypertension, decrease in VA for 2 y

VA 20/100

CRT 485


VA 20/100

CRT 649

Audience Response:1. Switch Drugs to another anti-VEGF2. Switch Drugs to Intravitreal Triamcinolone3. Switch Drugs to Ozurdex

20


s/p 8 bevacizumabinjections VA 20/100

CRT 446

7 m post Ozurdex

VA 20/50 CRT 269

VA 20/100

CRT 485


VA 20/100

CRT 649


Thank You

Financial Disclosures - Dannemiller...Retinal Vein Occlusion (RVO): Overview • RVO: Blockage of...

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