ANTI-­‐VEGF  AND  NON  STEROIDAL  THERAPY  IN  AMD    

G.Fasolino  MD

Causes and Prevalence of Visual Impairment Among Adults in the United States Arch Ophthalmol.2004; 122:477-485

8,70%

6,40%

5,40%

25%

54,40%

Cataract

Glaucoma

Diabetic Retinopathy

Other

Leading Causes of Blindness in U.S.Adults (patients age 40 years or older)

AMD

Clinical Spectrum of ARMD

Normal population

Neovascular ARMD

Drusen RPE atrophy

Pigmentary changes

Inflamma=on  and  ARMD  •  Important  role  in  the  pathogenesis  •  Macrophage,  microglia,complement  system,  cytokines  and  

chemokines  •  An=-­‐VEGF  therapy  may  not  be  enough  to  control  the  disease  

Wang  Y,  et  al.  Eye  2011  Yoshinaga  N,  et  al.  Lab  Invest  2011  Augus<n  AJ,  et  al.  Expert  Opin  Ther  Targets    2009  

AMD e risposta immunitaria

Hageman. Prog Ret Eye Res 2001

Zealley, Gerontology 2012

7

Ranibizumab AFLIBERCEPT

VEGF VEGF

Bevacizumab VEGF VEGF VEGF VEGF

VEGF VEGF

VEGF

VEGF

ANTI VEGF MOLECULES

TREATMENT REGIMENS

Fixed treatment scheme (PROACTIVE)

Pro Re Nata treatment scheme (REACTIVE)

TREATMENT REGIMENS

Fixed treatment scheme (PROACTIVE)

STAB

ILIZAT

ION  

4  weeks   4  weeks   4  weeks  

Monitor  and  inject   Monitor  and  inject   Monitor  and  inject  

Fixed  intervals  between  injec<ons  (4  week  interval  for  ranibizumab)  

Pro Re Nata treatment scheme (REACTIVE)

STAB

ILIZAT

ION  

4  weeks   4  weeks   4  weeks  

MONITORING  INJECT?  

MONITORING  INJECT?  

MONITORING  INJECT?  

Inject  monthly  un<l  stabiliza<on  

Monthly  monitoring  and  decision  to  inject  or  not  

Treat and Extend therapeutic scheme (REACTIVE)

STAB

ILIZAT

ION  

Extended  interval  

Extended  interval   Extended  interval  

The  interval  between  monitoring  visit  /  injec<on  can  be  extended  or  reduced  according  to  visual  and  anatomic  outcomes  

Inject  monthly  un<l  stabiliza<on  

MONITORING  INJECT  

MONITORING  INJECT  

MONITORING  INJECT  

Real life

•  Significant   differences   among   countries   in   VA   outcomes;   best   VA  gains  and  sustained  improvements   in  UK,  where  they  perform  the  highest  number  of  visit/injec=ons  

 

aEffectiveness set (all patients who had ≥1 VA assessment for treated eye at baseline and ≥1 post-baseline assessment of VA for the treated eye); bLOCF. All data presented as mean. Only countries meeting or exceeding enrolment (n=444) were included.

Results

AURA:  Visual  acuity  outcomes  differed  substan<ally  between  

countries    •  Real-­‐life  use  of  an=-­‐VEGF  therapy  was  associated  with  poorer  than  expected  visual  

outcomes  

-­‐4  

-­‐2  

0  

2  

4  

6  

8  

0   30   60   90   120   150   180   210   240   270   300   330   360   390   420   450   480   510   540   570   600   630   660   690   720  Mea

n VA

diff

eren

ce

to b

asel

ine

by c

ount

ry (L

OC

F)

Days

+6.0  

Germany (n=420) France (n=398) United Kingdom (n=410) Italy (n=365) The Netherlands (n=350) Total* (n=2,227) (Europe, n=1,943)

Year 1

+3.8  

+1.1  +0.8  0.0  

+2.4  

Number of injections

over 2 years

9

8.7

5.6

6.3

5.2

*Effectiveness set (all patients who had ≥1 VA assessment for treated eye at baseline and ≥1 post-baseline assessment of VA for the treated eye). Only countries meeting or exceeding enrolment target (n=444) were included. LOCF, last observation carried forward; VA, visual acuity; VEGF, vascular endothelial growth factor. Holz FG et al. Br J Ophthalmol 2015; 99 (2): 220–226. Hykin P et al. Clin Opthalmol 2016; 10: 87–96.

Total 7.2

WICH ROLE FOR NSAID

Cycloxigenase: The Importance of COX-2 Inhibition

"  The activation of cyclooxygenase isoenzymes (COX-1 and COX-2) is involved in the production of the inflammatory mediators1.2 T "  The isoforms have similar molecular structures but different effects and sites of action

"  COX-1 is constantly expressed in most tissues "  Involved in many physiological functions: coagulation (thrombosgans), gastric secretion, etc. "  COX-2 is expressed in response to inflammation, injury and pain "  Action on damaged tissues (prostaglandin production)

•  Thus, the inhibition of COX-2 is essential in controlling post-operative inflammation

1 Donnenfeld ED, Donnenfeld A. Int Ophthalmol Clin 2006; 46:21-40; 2 Polansky JR, Weinreb RN. In: Pharmacology of the Eye. 1984:460–538;

Only the bromfenac concentration was continuously higher than the IC50 at its trough level in the retinochoroidal tissues

Topical bromfenac may have a better therapeutic benefit than diclofenac and nepafenac for retinochoroidal inflammatory diseases.

Bromfenac: A potent COX-2 inhibitor

"   Bromfenac has consistently shown highly potent COX-2 inhibition vs other NSAIDs1-4*

"   NSAIDs potency is measured as the concentration of drug required to inhibit COX enzyme activity by 50% (IC50)1

IC50 (mM) Relative Potency (vs. Bromfenac)

Bromfenac 0.0075 1.0

Amfenac 0.0204 0.37

Ketorolac 0.0279 0.27

Diclofenac 0.0307 0.25

Adapted from Kida et al. 2007.1 The implications of these data for clinical practice are unknown. Other data have been reported.2-4*

1Kida T et al. ASCRS Poster presentation, April 27-May 2, 2007, San Diego, CA. 2Gallemore RP. Rev Ophthalmol 2006; 13:81-89. 3Waterbury LD et al. Curr Med Res Opin 2006; 22:1133-1140. 4Walters T et al. J Cataract Refract Surg. 2007; 33:1539-1545.

* Study designs and technologies used in in vitro studies differ, making

interpretation of clinical outcomes difficult.

Kida et al., PLoS One. 2014 May 5;9(5):e96481.

Comparison of tissue concentrations of Diclofenac Bromfenac and Nepafenac in the corioretina after topical administration of 30 microliters of drug in the rabbit eye.

Yoshinaga  N,  et  al.  Laboratory  Inves<ga<on    2011  

Bromfenac  &  CNV  •  Rat  CNV  model  

•  Transloca=on  of  Nrf2  into  the  nucleus  

•  Expression  of  HO-­‐1  in  the  CNV    •  Inhibi=on  H2O2    induced  apoptosis  in  cultured  RPE  cells.  

•  Decreased  number  of  infiltra=ng  macrophages  at  the  CNV  

•  The  sizes  of  CNV  lesions  were  significantly  smaller  in  bromfenac  treated  rats  than  control  group  

PROSPECTVE RANDOMIZED CONTROLLED TRIAL OF COMBINATION RANIBIZUMAB (LUCENTIS) AND BROMFENAC (XIBROM) FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION Flaxel C, et al; Retina. 2012 Mar;32(3):417-23.

R 2:1

1 drop x2 bromfenac 0.09% bid + ranibizumab 0.5 mg

1x month* (n=20)

Ranibizumab 0.5 mg 1xmonth*

(n=10)

Age >50 years presence of new NV AMD (n=30 eyes)

Follow-up 12 months "   Purpose: "   To evaluate whether bromfenac eyedrops and ranibizumab intravitreal

injections would provide added efficacy over ranibizumab alone "   Endpoints:

"   Ocular adverse events at 12 months "   Mean change in CMT; study eyes achieving 50 µm or more reduction "   Mean change in study eye visual acuity (Score ETDRS)

                                         Decrease  CMT    

•  Compliance with the eyedrops appeared very high, and there were no safety concerns

-­‐70,9

-­‐79,8 -­‐81,6

-­‐43,1

-­‐38,4-­‐42,5

-­‐90

-­‐80

-­‐70

-­‐60

-­‐50

-­‐40

-­‐30

-­‐20

-­‐10

04  mesi 6  mesi   12  mesi

Varia

zione  media

Bromfenac + Ranibizumab Ranibizumab

p = 0.03

Flaxel C et al. Retina. 2012 Mar;32(3):417-23.

Topical Bromfenac As An Adjunctive Treatment With Intravitreal Ranibizumab for Exudative Age-Related Macular Degeneration. Gomi F, et al; Retina. 2012 Oct;32(9):1804-1810

Gomi F et al. Retina. 2012 Oct;32(9):1804-1810

R

1 drop /bromfenac 0.09% bid + ranibizumab 0.5 mg

1 + prn* (n=16)

1 drop/placebo bid + ranibizumab 0.5 mg

1 + prn* (n=22)

Age>50 years naive subfoveal CNV or PCV

(n=38eyes)

Follow-up 6 months "  Purpose: "   To evaluate the number of intravitreal injections in the Bromfenac group compared

with placebo group.

"   Endpoints: "   Difference in the injections frequencies between two groups during the follow up "   Mean change in CMT "   Mean change in visual acuity ( score ETDRS)

2:3

Topical Bromfenac decreased the frequency of Ranibizumab injection (average 2,2±1,3) compared with placebo(average 3,2±1,5)

0

5

10

15

20

25

30

35

40

%

1 iniez. 2 iniez. 3 iniez. 4 iniez. 5 iniez. 6 iniez.

Bromfenac Placebo

Gomi F et al. Retina. 2012 Oct;32(9):1804-1810

The final VA did not differ significantly and there were also no significant differences in the mean changes in VA over 6 months between the groups

0

0,1

0,2

0,3

0,4

0,5

logMAR

Bromfenac Placebo

n.s. p=0.9056 Gomi F et al. Retina. 2012 Oct;32(9):1804-1810

The decrease in the CRT between baseline and month 6 tended to be greater in the bromfenac group than in the sham group

-­‐122

-­‐94

-­‐140

-­‐120

-­‐100

-­‐80

-­‐60

-­‐40

-­‐20

06  mesi  

Varia

zione  media

•  Did not observe any averse

events related to the topical bromfenac

•  Bromfenac BID might decrease the frequency of ranibizumab injection over 6 months of treatment and to provide an additive effect in the reduction of retinal thickening

Bromfenac + Ranibizumab Ranibizumab

p = 0.03

Gomi F et al. Retina. 2012 Oct;32(9):1804-1810

CLINICAL  CASE  

Gomi  F,  et  al.  Re<na  2012  

Combination of Aflibercept and Bromfenac Therapy in Age-Related Macular Degeneration:

A Pilot Study Aflibercept and Bromfenac in AMD

R 1:1

1 bromfenac 0.09% bid + aflibercept 2 mg

3 + prn* (n=27)

Aflibercept 2 mg 3 + prn* (n=27)

Age >50 years ExudativeAMD

(n=54eyes)

Follow-up 6months "   Purpose: "   To evaluate whether bromfenac eyedrops and aflibercept intravitreal injections

would provide added efficacy over aflibercept alone Endpoints:

"   Mean variation VA "   Mean variation CMT "   Height and length of subretinal fluid

Wyględowska-Promieńska D, et al; Med Sci Monit, 2015; 21: 3906-3912.

Visual acuity (BCVA, log MAR) improved over the time in the study group and the differences between the groups were statistically significant.

Wyględowska-Promieńska D, et al; Med Sci Monit, 2015; 21: 3906-3912.

*visita 2 vs visita 1, p<0,02

*

**visita 3 vs visita 1, p<0,001

* *

Decrease of CRT in both groups. Positive correlation between CRT and VA in the study group

Wyględowska-Promieńska D, et al; Med Sci Monit, 2015; 21: 3906-3912.

Significant reduction of height of subretinal fluid in Bromfenac+Aflibercept group compared with Aflibercept alone. Positive correlations were found for VA and height of subretinal

Wyględowska-Promieńska D, et al; Med Sci Monit, 2015; 21: 3906-3912.

*visita 3 vs visita 1, p<0,001

*

Take  Home  Message  •  ARMD  is  an  inflammatory  disease  •  Beneficial  effects  of  NSAID  and  combina=on  therapy  with  ANTI-­‐VEGF  

•  The  topical  applica=on  of  Bromfenac  can  riduce  the  CRT  controlling  the  inflamma=on.  

•  Influence  of  Bromfenac  on  the  treatment  strategy  

THANK YOU