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
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
7
Ranibizumab AFLIBERCEPT
VEGF VEGF
Bevacizumab VEGF VEGF VEGF VEGF
VEGF VEGF
VEGF
VEGF
ANTI VEGF MOLECULES
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
• 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
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
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