Download Session 132 AMD and anti-VEGF therapy 1

ARVO 2017 Annual Meeting Abstracts
132 AMD and anti-VEGF therapy 1
Sunday, May 07, 2017 1:30 PM–3:15 PM
Exhibit/Poster Hall Poster Session
Program #/Board # Range: 406–440/A0272–A0306
Organizing Section: Retina
Program Number: 406 Poster Board Number: A0272
Presentation Time: 1:30 PM–3:15 PM
Pharmacokinetics of Free Aflibercept in Patients with
Neovascular Age Related Macular Degeneration
Diana V. Do, Quan D. Nguyen. Ophthalmology, Byers Eye Institute,
Stanford University School of Medicine, Palo Alto, CA.
Purpose: To investigate the pharmacokinetics (PK) of intravitreal
aflibercept injection (IAI) in eyes with neovascular age related
macular degeneration (NV AMD).
Methods: Five eyes from 5 patients with new onset NV AMD were
enrolled in this study. Subjects were followed for a 28-day period
and had 6 study visits (baseline, days 1, 3, 7, 14, and 28). All study
eyes were treatment naïve and received a single dose of 2mg IAI at
baseline. Anterior chamber paracentesis to collect aqueous humor
(AH) was performed at all study visits[SR1]. In addition, plasma
blood samples were also obtained. Free aflibercept concentrations in
AH and plasma were measured using enzyme-linked immunosorbent
assays (ELISA). Pharmacokinetics of free aflibercept in both AH and
plasma was also evaluated. Best-corrected visual acuity (BCVA) and
central retinal thickness (CRT) were also obtained at every visit.
Results: Following a single dose of 2mg IAI, the mean Cmax
(peak concentrations) of free aflibercept in AH was 111 mg/L
(range: 35 – 222 mg/L), and half-life of ~9 days was determined. The
mean AUCinf (area under the concentration-time curve extrapolated to
infinity) in AH was 846 mg*day/L. The mean Cmax of free aflibercept
in plasma was 0.03 mg/L based on measurements from
3 patients (2 out of 5 patients had no detectable concentrations).
Drug was undetectable one week post dosing in plasma in all
patients. Additional PK parameters in plasma were not calculated
because of the low concentrations of free aflibercept in the plasma.
Conclusions: A half-life of ~9 days for aflibercept was determined
based on AH samples from 5 eyes of patients with NV AMD. Free
aflibercept had ~1000-fold greater exposure in eyes as compared to
plasma concentrations. The plasma exposures of free aflibercept were
not substantial with low systemic concentrations following a single
dose which are consistent with previous studies.
Commercial Relationships: Diana V. Do; Quan D. Nguyen,
Genentech (C), Regeneron (F)
Program Number: 407 Poster Board Number: A0273
Presentation Time: 1:30 PM–3:15 PM
Posterior vitreous status did not impact ranibizumab treatment
outcomes in HARBOR study patients with neovascular AMD
Michelle V. Carle1, Lauren Hill2, Tatiana Ecoiffier2, Shamika Gune2.
1
EyeQ Vision Care, Fresno, CA; 2Genentech, South San Francisco,
CA.
Purpose: The status of the posterior vitreous (PV) may play a role in
inflammatory processes and oxygenation status of the retina. Whether
the PV is attached or detached may impact the effect of anti-VEGF
treatment of retinal diseases and the HARBOR study dataset may
inform us of any correlation between PV status and ranibizumab
treatment outcomes in the setting of Neovascular AMD. We evaluated
the impact of posterior vitreous (PV) status on 24-month ranibizumab
(RBZ)-treatment outcomes in HARBOR study patients with
neovascular AMD using a retrospective data analysis of existing OCT
scans.
Methods: A retrospective analysis of OCT scan data obtained on
patients during treatment in the HARBOR study was performed to
determine PV status based on macular cube scans from all scheduled
visits. There was no variable that directly assessed posterior vitreous
detachment (PVD); the posterior hyaloid attachment/detachment was
used to determine PVD. Status was categorized as: PV detached/not
detectable (PVD) or attached (no PVD). If a patient had PVD once,
they were considered to have PVD at all remaining visits. If a patient
did not have PVD at baseline, they could switch to PVD. PVD status
between three groups (PVD at baseline and persistent throughout,
PVD developed during treatment, and never developed PVD) were
compared using BCVA changes from baseline as well as changes in
central subfield thickness during the 24 month course of treatment
with ranibizumab.
Results: There were no clinically meaningful differences between
eyes with (840) or eyes without (249) PVD at baseline for mean
(95% CI) changes from baseline to Month 24 in BCVA
(letters; 8.3 [7.2, 9.4] vs 10.5 [8.4, 12.5], respectively) or central
subfield thickness (CST, µm; -152 [-161, -143] vs -149 [-167, -131],
respectively). For eyes without PVD at baseline, there were no
clinically meaningful differences between eyes that did
(193)/did not (56) develop PVD during the study for mean changes
from baseline to Month 24 in BCVA (10.6 [8.2, 13.0] vs
10.0 [5.8, 14.3], respectively) or CST (-156 [-177, -134]
vs -126 [-161, -90], respectively).
Conclusions: There was no relationship between PV status and
BCVA or CST outcomes at Month 24 in the HARBOR study.
Commercial Relationships: Michelle V. Carle, None; Lauren Hill,
Genentech (E); Tatiana Ecoiffier, Genentech (E); Shamika Gune,
Genentech (E)
Program Number: 408 Poster Board Number: A0274
Presentation Time: 1:30 PM–3:15 PM
Anatomical outcomes of ranibizumab 0.5 mg combined with
verteporfin photodynamic therapy vs ranibizumab monotherapy
in patients with polypoidal choroidal vasculopathy: 12-month
results from the EVEREST II study
Timothy Y. Lai1, Chrystel Feller2, Philippe Margaron2, Colin S. Tan3, 4.
1
Ophthalmology & Visual Sciences, Chinese University of Hong
Kong, Kowloon, Hong Kong; 2Novartis Pharma AG, Basel,
Switzerland; 3National Healthcare Group Eye Institute, Tan Tock
Seng Hospital, Singapore, Singapore; 4Fundus Image Reading Centre,
National Healthcare Group Eye Institute, Singapore, Singapore.
Purpose: To report 12-month (M) anatomical outcomes of the
EVEREST II study (NCT01846273), which compared ranibizumab
0.5 mg (RBZ) + verteporfin photodynamic therapy (vPDT) vs RBZ
monotherapy in Asian patients with symptomatic macular polypoidal
choroidal vasculopathy (PCV).
Methods: This 24M, phase IV, double-masked, multicenter study
included 322 PCV eyes with active polyps that were randomized
1:1 to receive RBZ + vPDT (n=168) or RBZ monotherapy
(n=154). Study eye eligibility was confirmed by indocyanine green
angiography (ICGA) and color fundus photography using specified
diagnostic criteria. Central subfield thickness (CSFT), presence of
intra- or subretinal fluid (SRF), and central choroidal thickness (CCT)
were assessed on spectral domain optical coherence tomography
(SD-OCT) by the central reading center at baseline, M3, M6,
and M12. Disease activity was defined as either best-corrected
visual acuity (BCVA) loss or OCT abnormality reported by the
investigators.
Results: Baseline OCT characteristics were well balanced between
treatment arms. The RBZ + vPDT arm showed greater mean CSFT
reduction at M12 than the RBZ arm (−163.8 μm vs −114.6 μm,
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ARVO 2017 Annual Meeting Abstracts
p<0.001; Fig. 1A). At M12, 83.2% and 60.3% patients in the RBZ
+ vPDT and RBZ arms, respectively, had CSFT <300 μm. Mean
CCT change from baseline to M12 was higher in the RBZ + vPDT
arm than the RBZ arm (−55.2 μm vs −30.1 μm; Fig. 1B). A smaller
proportion of patients in the RBZ + vPDT arm had disease activity
from M3 to M11 vs the RBZ arm (M3, 26.4% vs 60.7%; M11, 20.5%
vs 50.0%). At M3 and M12, 62.0% and 56.8% patients in the RBZ +
vPDT arm and 37.1% and 28.7% in the RBZ arm had fluid-free
retina, respectively (Fig. 2A). The proportion of patients with SRF
present at baseline, but absent at M3 and M12, was higher with
RBZ + vPDT than RBZ monotherapy (M3, 73.0% vs 44.1%; M12,
69.8% vs 39.7%; Fig. 2B).
Conclusions: These findings are consistent with the primary
outcomes of EVEREST II which confirmed that both RBZ and RBZ
in combination with vPDT are effective treatment options for patients
with PCV. RBZ in combination with vPDT resulted in additional
BCVA improvement and higher polyp regression as well as had more
marked anatomical benefits over RBZ monotherapy.
Figure 1
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ARVO 2017 Annual Meeting Abstracts
Purpose: Decreasing the frequency of intravitreal injections
of standard anti-VEGF therapies by means of extended release
formulations would not only result in reduced burden to patients
but may also result in improved clinical outcomes in the treatment
of posterior angiogenesis. We demonstrate the ability to formulate
extended release intravitreal implants by encapsulating solid state
micronized protein in biodegradable hydrogel matrices. Protein
release can be tuned to desired release rate and recent formulation
optimization shows increased protein stability in vitro
Methods: In vitro release rate and monomer content of released
aflibercept were monitored in 1X PBS pH 7.4 at 37 degreesoC
using total protein assays, VEGF ELISA, and size exclusion
chromatography. Formulations were screened for protein stability
using accelerated degradation conditions (40oC/75% Relative
Humidity). African Green monkeys received either a bolus injection
of Eylea® (n=4 eyes) or ENV1305 extended release aflibercept
implants (n=8 eye) by bilateral intravitreal injection, and were
followed for up to 3 months. Vitreous humor was assayed for
aflibercept using an ELISA assay.
Results: Addition of excipients to the protein formulations reduced
aggregation of aflibercept under accelerated degradation conditions
resulting in increased stability of protein released from hydrogel
formulations in vitro. In vitro release studies demonstrate complete
release of protein over several months at therapeutically relevant
levels and physicochemical characterization indicates that the
released protein is comparable to initial starting material with
respect to VEGF binding (ELISA) and monomer content (SEC).
ENV1305 extended release implants demonstrated sustained vitreous
concentrations out to 3 months in African Green Monkeys at relevant
levels compared to Eylea.
Conclusions: We demonstrate the ability to formulate biodegradable
intravitreal implants with tunable, reproducible release kinetics of
anti-VEGF biologics. Optimization based on accelerated degradation
led to formulations that release stable protein over the duration
of the implant. Our in vitro data establishes proof of concept for
multi-month extended release of active anti-VEGF biologics, and
supporting data collected in primates demonstrates the potential for
therapeutically-relevant aflibercept release in vivo for up to 3 months.
Commercial Relationships: Gary Owens, envisia therapeutics
(E); Melissa Sandahl, envisia therapeutics (E); Janet Tully,
envisia therapeutics (E); Jennifer Haley, envisia therapeutics (E);
Kwadwo Caesar, envisia therapeutics (E); Stuart Williams, envisia
therapeutics (E); Rozemarijn S. Verhoeven, envisia therapeutics (E);
Andres Garcia, envisia therapeutics (E); Tomas Navratil, envisia
therapeutics (E); Benjamin R. Yerxa, envisia therapeutics (E)
Figure 2
Commercial Relationships: Timothy Y. Lai, Genentech (C),
Novartis (C), Bayer (C), Allergan (C); Chrystel Feller, Novartis
(E); Philippe Margaron, Novartis (E); Colin S. Tan, Heidelberg
Engineering (R), Novartis (R), Bayer (R)
Clinical Trial: NCT01846273
Program Number: 409 Poster Board Number: A0275
Presentation Time: 1:30 PM–3:15 PM
Extended release aflibercept with sustained vitreous
concentration in non-human primates from biodegradable
hydrogel implants
Gary Owens, Melissa Sandahl, Janet Tully, Jennifer Haley,
Kwadwo Caesar, Stuart Williams, Rozemarijn S. Verhoeven,
Andres Garcia, Tomas Navratil, Benjamin R. Yerxa.
Envisia Therapeutics, Research Triangle Park, NC.
Program Number: 410 Poster Board Number: A0276
Presentation Time: 1:30 PM–3:15 PM
Prophylactic Ranibizumab for Exudative age-related macular
degeneration (AMD) in Vulnerable Eyes with Non-Exudative
AMD Trial (PREVENT): A prospective controlled clinical trial
Maziar Lalezary1, 2, Steven G. Lin1, Clement K. Chan1,
Bansal S. Alok3, Rahul N. Khurana3, Mark Wieland3, Louis K. Chang3,
James Palmer3, Prema Abraham5, Michael J. Elman6,
Brandon J. Lujan3, Glenn Yiu4. 1Southern California Desert Retina
Consultants, Palm Desert, CA; 2Doctor Retina, P.C., Beverly Hills,
CA; 3Northern California Retina Vitreous Associates, Mountain View,
CA; 4Ophthalmology, UC Davis, Davis, CA; 5Black Hills Regional
Eye Institute, Rapid City, SD; 6Elman Retina Group, Baltimore, MD.
Purpose: To report interim baseline demographics and results of the
Prophylactic Ranibizumab for Exudative AMD in Vulnerable Eyes
with Non-Exudative AMD Trial (PREVENT).
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ARVO 2017 Annual Meeting Abstracts
Methods: PREVENT is a multicenter, prospectively randomized,
single-masked and controlled, interventional investigator sponsored
phase I/II study of subjects with non-exudative AMD (NE-AMD)
treated with 0.5 mg intravitreal ranibizumab (IVR) every 3 months
for prophylaxis of exudative AMD (Ex-AMD) over 2 years.
One-hundred eyes of 100 patients with high-risk NE-AMD in one
eye (study eye) and history of Ex-AMD in the fellow eye will be
randomized (1:1) to observation (OBS) or treatment (IVR). At
baseline, all participants undergo evaluation by a retina specialist
with ETDRS best-corrected visual acuity, intraocular pressure, exam,
fundus photography, autofluorescence, fluorescein angiography (FA),
spectral-domain optical coherence tomography (Cirrus SD-OCT, Carl
Zeiss Meditec, Inc.) and genetic testing. Patients return every
3 months for exam and testing, adverse event monitoring and IVR
only in the treatment group. The primary outcome measure is
conversion to Ex-AMD as detect by examination, FA and/or OCT.
Reading center evaluation of OCT parameters including drusen
volume will be analyzed.
Results: Thirty-two (32) eyes with, 13 (40.6%) IVR and 19 (59.3%)
OBS group, are reported in this interim analysis. All patients are
Caucasian, 17 female, with mean age 77 and average baseline
vision logMAR 0.14 (Snellen 20/25, 78 ETDRS letters). Baseline
characteristics (age, gender, vision) were balanced between the two
groups. Ten patients have completed the 2 year study. Three patients,
all in the OBS group, converted to Ex-AMD at 1, 8 and 18 months.
Seven patients (3 IVR, 4 OBS group) withdrew early from the study;
2 opted out by choice (OBS group), 1 relocated (IVR group) and
4 due to medical issues (2 OBS group). No ocular complications or
adverse events were reported.
Conclusions: Interim analysis of PREVENT suggests that
prophylactic anti-VEGF therapy (IVR) is tolerated well and may
reduce the risk of Ex-AMD. This trend reinforces the hypothesis
and warrants continued investigation as enrollment of the study is
not complete and attrition has occurred. Continued follow-up of this
cohort should provide further insight into the role of prophylactic
IVR.
Commercial Relationships: Maziar Lalezary, None;
Steven G. Lin, Acucela (F), Genentech-Roche (F), NEI
(F), Ophthotec (F), Regeneron (F), Pfizer (F), Allergan (F);
Clement K. Chan, Acucela (F), NEI (F), Regeneron (F), Pfizer (F),
Allergan (F), Genentech-Roche (F), Ophtotech (F), Allergan (C);
Bansal S. Alok, None; Rahul N. Khurana, Santen (F), Regeneron
(F), Clearside (F), Digisight (F), Allergan (F), Santen (C),
Genentech-Roche (F), Genentech-Roche (C), Regeneron (C),
Allergan (C); Mark Wieland, Novartis (C), Compact Imaging
(C), Zeiss (C), Genentech-Roche (C), Alcon (C), Allergan (C);
Louis K. Chang, None; James Palmer, None; Prema Abraham,
Regeneron (F), Allergan (F), Lexitas (F), Janssen Research and
Development (F), Alcon (F), Ophthotech (F), Apellis (F),
Genentech/Roche (F), OHR Pharmaceuticals (F), Thrombogenics (F);
Michael J. Elman, None; Brandon J. Lujan, Genentech-Roche (F),
UC Berkeley (P), Genentech-Roche (C); Glenn Yiu, Alcon (F), Carl
Zeiss Meditec (C), Allergan (C)
Support: Genentech IST Grant
Clinical Trial: NCT02140151
Program Number: 411 Poster Board Number: A0277
Presentation Time: 1:30 PM–3:15 PM
Aflibercept outcomes in AMD at 3 years: maintains vision but
significant decline in follow up
Julia Vig1, James Talks1, Sobha Sivaprasad2. 1Eye Centre, Newcastle
upon Tyne Hospitals NHS Foundation Trust, Newcastle upon
Tyne, United Kingdom; 2Moorfields Eye Hospital, London, United
Kingdom.
Purpose: Aflibercept was approved for use in the UK for neovascular
macular degeneration in July 2013. Treatment requires regular, often
long-term follow up, putting strain on patients and services. We
aimed to assess outcomes and maintenance of follow up in clinical
practice of patients treated for three years by analysing data from a
multicentre cohort.
Methods: Visual acuity and injection numbers were collected from
an electronic medical record on treatment naive patients, who had
started treatment 3 years before the data cut off in November 2016.
Data was collected from the 17 centres contributing to the UK
Aflibercept Users Group.
Results: 722 eyes had potential to have data three years from
baseline. 246 eyes from 226 patients were still under follow up. Mean
age 78.2, 149 were female. In those with 3 years follow up the mean
baseline visual acuity was 56.5 letters increasing to 62.8 letters at
12 months (+6.3), 61.3 letters at 24 months (+4.8) and 59.4 letters
at 36 months (+2.9, median 3, SD 17.8). Those seeing >70 letters at
three years increased from 18.5% to 32%, 26% gained ≥15 letters.
Visual loss of ≥15 letters was recorded in 4.5% after the first year,
11.5% at 2 years and 14.7% at 3 years. Mean injection numbers were
6.9 during year 1, 4.1 during year 2, 4 in year 3. For those no longer
under follow up the mean change in last vision was -2.1 (median 0,
SD 18.7), 19% had lost >15 letters, 15% gained ≥ 15 letters. 21%
could see ≥ 70 letters. Follow up percentages at three years varied
between centres from 60% to 10%.
Conclusions: Only 34% of eyes were still under follow up at three
years reflecting the age related nature of the condition but possibly
the difficulties of maintaining the therapy. Patients that were still
being monitored showed significant standard deviation with a third of
eyes seeing more than 70 letters and one in seven losing 15 or more
letters from baseline. Visual acuity of those no longer under followup also showed significant variations with 1 in 5 eyes seeing more
than 70 letters and another 1 in 5 losing more than 15 letters at last
follow-up.
Commercial Relationships: Julia Vig, Bayer (R); James Talks,
Bayer (C), Bayer (R), Bayer (F); Sobha Sivaprasad, Bayer (C),
Bayer (R), Bayer (F)
Program Number: 412 Poster Board Number: A0278
Presentation Time: 1:30 PM–3:15 PM
Influence of OCT-examination during ranibizumab treatment of
AMD patients in a real-life setting (OCEAN study)
Frederic Gunnemann1, Jessica Voegeler2, Steffen SchmitzValckenberg3, Georg Spital1, Sandra Liakopoulos4, Focke Ziemssen5.
1
Augenärzte am St. Franziskus-Hospital Münster, Münster,
Germany; 2Novartis Pharma GmbH, Novartis Pharma
GmbH, Germany; 3Universitätsaugenklinik Bonn, Bonn,
Germany; 4Universitätsaugenklinik Köln, Köln, Germany;
5
Universitätsaugenklinik Tübingen, Tübingen, Germany.
Purpose: Randomized controlled trials have proven the beneficial
effect of vascular endothelial growth factor (VEGF) inhibition
with ranibizumab in neovascular age-related macular degeneration
(nAMD). The non-interventional, prospective OCEAN trial
(NCT02194803) was initiated to evaluate ranibizumab treatment
patterns in real-life conditions and to allow for a better understanding
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ARVO 2017 Annual Meeting Abstracts
of challenges. The study evaluated the impact and use of optical
coherence tomography (OCT) imaging, the key monitoring tool to
guide retreatment in nAMD, which was newly implemented in local
guidelines at the beginning of the observational period.
Methods: 5.779 patients are observed in a prospective manner over
24 months. The 12-month interim-analysis evaluated the number of
visits, visual acuity, number of injections, the use of diagnostic tools
and adverse events of 3.630 patients diagnosed with nAMD
(61% female/39% male) with an average age of 77.9 years.
Results: The mean baseline BCVA was 52.0 ETDRS letters. During
the first year, patients received an average of 4.5 injections and
gained 3.8 respectively 4.2 letters (by injecting ophthalmologists)
after 12 months (55.8 ± 23.4 ETDRS letter). 37.9% of patients gained
≥ 5 letters, while 21.1% even gained ≥ 15 letters.
The average time between the first visual acuity assessment and the
first ranibizumab treatment was 22.4 days. A subgroup of patients
treated with a delay of less than 14 days showed notably higher
BCVA gains.
Patients underwent 9.5 BCVA assessments and 4.0 OCT
examinations. When OCT imaging was performed at ≥ 4 visits, a
higher number of patients achieved ≥ 10 letters (31.1%) compared
with patients receiving only one or none OCTs (23.1%). The
proportion of patients discontinuing the trial does not show any
correlation to patient’s baseline VA. No new safety signals were
identified.
An update of 24-month data will be presented.
Conclusions: This interim analysis of the non-interventional OCEAN
trial shows a beneficial effect of ranibizumab after 12 months for
nAMD patients when observed in a real-life setting. The presented
data implies that there might be an association of improvement of VA
and number of OCT-examinations. Our data show that better VA gain
can be achieved with a higher number of visits using OCT scans for
(re-)treatment decisions in a real-life setting.
Commercial Relationships: Frederic Gunnemann, None;
Jessica Voegeler, Novartis (E); Steffen Schmitz-Valckenberg,
Allergan (F), Alcon (C), Formycon (F), Optos (F), Allergan (R),
Carl Zeiss MediTec (F), Novartis (C), Heidelberg Engineering (F),
Genentech/Roche (R), Bayer (R), Novartis (F), Alcon (F), Heidelberg
Engineering (R), Genentech/Roche (C), Genentech/Roche (F), Bayer
(F); Georg Spital, Allergan (R), Heidelberg engineering (R), Pfizer
(R), Novartis (R), Bayer (R), Novartis (F); Sandra Liakopoulos,
Novartis (C), Allergan (R), Heidelberg Engineering (R), Novartis
(R), Bayer (R); Focke Ziemssen, Alcon (R), Novartis (C), Novartis
(R), Bayer Healthcare (R), Boehringer-Ingelheim (C), Alimera (C),
Allergan (R), Biogen (R), Allergan (C), Bayer Healthcare (C)
Clinical Trial: NCT02194803
Program Number: 413 Poster Board Number: A0279
Presentation Time: 1:30 PM–3:15 PM
Genetic markers within the Vascular Endothelial Growth Factor
(VEGF) pathway as predictors of the response to the treatment of
the Age Related Macular Degeneration (ARMD)
Irina Balikova1, 2, Laurence Postelmans2, Brigitte Pasteels2,
Pascale Coquelet2, Jeanette Catherine2, Azra Efendic2,
Bernard Thienpont3, Dieter Lambrechts3. 1Ophtalmology, UZ Ghent,
Gent, Belgium; 2Ophtalmology, Brugmann University Hospital,
Brussels, Belgium; 3Flemish Biotechnology Institute VIB, Leuven,
Belgium.
Purpose: Age-related macular degeneration (ARMD) is a leading
cause of visual impairment in the adult population in industrialized
countries. The anti-Vascular Endothelial Growth Factor (VEGF)
antibodies ranibizumab (Lucentis ) and bevacizumab (Avastin)
together with the recently developed anti VEGF protein, Aflibercept
(Eylea) have become the standard treatment for the wet form of
ARMD. While most patients respond favourably to treatment,
some do not. The difference seen in the responses suggests patientspecific factors influencing drug efficacy. We hypothesize that single
nucleotide polymorphisms (SNPs) in genes encoding VEGF pathway
members contribute to response.
The aim of our study is to evaluate the association between a panel
of 138 selected polymorphic markers in the VEGF pathway and the
response to therapy with anti VEGF antibody for ARMD.
Methods: This is retrospective study. We collected genetic material
and clinical information for 281 patients treated with anti VEGF
antibodies with 3 loading injections and PRN treatment regiment for
wet ARMD. For each patient, DNA from blood and demographic
information were collected along with their visual acuity (VA) at
baseline, after 3 loading injections and at 12 months; the number
of injections received at 12 months and the changes in the retinal
morphology. The latter included the central foveal thickness (CFT)
at baseline, after 3 loading injections and at 12 months, as well as
the presence or absence of intraretinal cysts, serous detachment of
the neuroepithelium and pigment epithelial detachment at baseline
and after 3 loading injections. Patients were classified as responders
and non responders based on the VA, CFT and morphological signs
of activity. DNA samples were genotyped using Sequenom for 158
tagging SNPs in the VEGF pathway. Association of SNPs to therapy
response was assessed by binomial logistic regression.
Results: We found significant association between SNPs within the
FLT4 (p=2.22E-06) and VEGFA (p=0.007283342) genes and the
response to anti VEFG antibodies.
Conclusions: Defining the factors important for the treatment
response has important consequences. It can help to develop
individualized approach towards the treatment of ARMD and can
point towards new therapeutic targets.
Commercial Relationships: Irina Balikova, Novartis (F);
Laurence Postelmans, None; Brigitte Pasteels, None;
Pascale Coquelet, None; Jeanette Catherine, None; Azra Efendic,
None; Bernard Thienpont, None; Dieter Lambrechts, None
Support: NCT02762188
Clinical Trial: NCT02762188
Program Number: 414 Poster Board Number: A0280
Presentation Time: 1:30 PM–3:15 PM
Five-year results of a population treated in “real life” with PRN
regimen for an exudative age-related macular degeneration:
ELOUAN 2 registry
Frederic Queguiner, Maud Righini, Jean Christophe Courjaret.
Ophtalmology, hopital saint joseph, Marseille, France.
Purpose: Exudative AMD, a frequent disease related to the
population aging, is one of the leading causes of legal blindness and
represents today a major public health problem. In the literature few
long-term results (> 5 years) are available for this type of population.
We aimed to present the results of a population of patients treated in
real life for 5 years.
Methods: In this retrospective, monocentric registry, patients with
exudative AMD treated in real life with intravitreal injections of antiVEGF (Ranibizumab) were followed by PRN regimen with monthly
control visits (CV). The primary objective was to study changes in
visual acuity (VA) over time (initial VA, and VA at: 6, 12, 18, 24, 30,
36, 42, 48 months). The secondary objective was to assess whether
the number of CV and Injection visits (IV) throughout follow-up
were good predictor of VA evolution over time.
Results: The studied population (109 patients and 131 eyes) had a
usual female prevalence (64%) and a mean age of 78.4 ± 7.7 years.
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ARVO 2017 Annual Meeting Abstracts
VA significantly increased during the first 6 months, with a delta
ETDRS of 4.2 ± 15.2 letters (p = 0.0288). VA declined thereafter
until the end of the follow-up, but without any statistical significance
between the different controls (table 1).
The mean number of CV and IV decreased all along the follow-up
and this decrease was significant most of the time (table 2).
Conclusions: Anti-VEGFs IVTs represent a reliable treatment for
exudative AMD, even in the long term (at 5 years). PRN regimen
with regular follow-up and treatment is necessary to stabilize
patients’ AV over time. The follow-up should be adapted by the
ophthalmologist to the progress of each patient, in order to avoid over
or under treatment, which, in both cases, could deleterious to the final
result.
Table 1: Statistical analysis of visual acuity (ETDRS an SNELLEN)
at each time of the follow-up compared to the previous time
Table 2: Statistical analysis of mean number of control and injection
visits for each year of follow-up compared to previous year
Commercial Relationships: Frederic Queguiner, None;
Maud Righini, None; Jean Christophe Courjaret, None
Support: Grant support from Novartis france SAS
Program Number: 415 Poster Board Number: A0281
Presentation Time: 1:30 PM–3:15 PM
Visual and anatomical outcomes in NVAMD patients with
subfoveal hemorrhage (SFH) treated with anti-VEGF agents
Saleema Kherani, Adrienne W. Scott, Adam Wenick,
Ingrid E. Zimmer-Galler, Christopher Brady, Akrit Sodhi,
Catherine Meyerele, Rimsha Shaukat, Olukemi Adeyemo,
Roomasa Channa, James T. Handa, Tahreem A. Mir,
Peter A. Campochiaro. Ophthalmology, Wilmer Eye Institute, Johns
Hopkins University, Baltimore, MD.
Purpose: To assess visual and anatomic outcomes in patients with
NVAMD complicated by SFH treated with intraocular injections of
anti-VEGF agents.
Methods: Screening of patients with NVAMD seen by a co-author
between January and December 2014 identified 222 (265 eyes) with
good follow up; 15 patients had SFH ≥1 disc area (DA) in one eye
treated with injections of an anti-VEGF agent.
Results: Baseline visual acuity (VA) was 20/50-20/100,
20/125-20/160, 20/200-20/400, or ≤20/500 in 2, 2, 8, 3 patients.
The number of patients with final VA ≥20/40, 20/50-20/100,
20/125-20/160, 20/200-20/400, or ≤20/500 was 2, 3, 1, 3, 6. Change
from baseline VA at final visit was a gain ≥3, ≥2, ≥1 lines in 4, 5, 7,
no change in 3, and loss of ≥3, ≥2, ≥1 lines in 4, 4, 4 patients. The
duration between anti-VEGF injections was 4-6 weeks in 6, relatively
frequent PRN in 2, and PRN with long treatment-free intervals in
7 patients. Two (13.3%) patients developed subfoveal (SF) atrophy
without fibrosis and 8 (53.3%) developed SF fibrosis, 5 out of which
developed atrophy within the area of fibrosis during follow-up.
Patients receiving frequent injections (every 4-6 weeks; n=6) had VA
gain >3 lines in 2, gain of 1-3 lines in 2, no change in 1 and loss of
1-3 lines in 1; received 20.5±4.8 injections over a mean of 26.6±7.8
months, and developed SF fibrosis in 2, SF atrophy in 1 and neither
in 3. Those receiving PRN injections with long intervals without
treatment (n=7) had VA gain >3 lines in 1, 1-3 lines in 1, no change
in 2 and loss of >3 lines in 3; received 10.7±2.6 injections over mean
duration of 40.0±4.4 months and developed SF fibrosis in 71.4% and
SF atrophy in 28.6%.
Patients who developed SF fibrosis or atrophy (n=10) versus those
that did not (n=5) had mean SRH size of 13.3±2.0 vs 4.3±1.7 DA,
received 9.8±1.8 vs 23.8±4.4 anti-VEGF injections over a mean of
31.7±5.4 vs 32.8±6.5 months; had a VA gain >3 lines in 10.0% vs
60.0%, 1-3 lines in 10.0% vs 40.0%, no change in 30.0% vs 0, loss of
1-3 lines 10.0% vs 0, loss of >3 lines in 40.0% vs 0.
Conclusions: SFH does not preclude good visual outcomes in
patients with NVAMD and there is an association of good outcomes
with smaller area of SFH and more frequent anti-VEGF injections.
Commercial Relationships: Saleema Kherani, None;
Adrienne W. Scott, None; Adam Wenick, None;
Ingrid E. Zimmer-Galler, None; Christopher Brady, None;
Akrit Sodhi, None; Catherine Meyerele, None; Rimsha Shaukat,
None; Olukemi Adeyemo, None; Roomasa Channa,
None; James T. Handa, None; Tahreem A. Mir, None;
Peter A. Campochiaro, None
Program Number: 416 Poster Board Number: A0282
Presentation Time: 1:30 PM–3:15 PM
Efficacy and safety of ranibizumab 0.5 mg treat and extend
versus monthly regimen in patients with neovascular age-related
macular degeneration: 12-month results from the TREND study
Rufino Silva1, Michael Larsen2, Chrystel Feller3, Wayne Macfadden3.
1
Department of Ophthalmology, Faculty of Medicine, University of
Coimbra (FMUC); Centro Hospitalar e Universitário de Coimbra
(CHUC); Association for Innovation and Biomedical Research
on Light and Image (AIBILI), Coimbra, Portugal; 2Department of
Ophthalmology, Rigshospitalet and Faculty of Health and Medical
Sciences, University of Copenhagen, Copenhagen, Denmark;
3
Department of Ophthalmology, Novartis Pharma AG, Basel,
Switzerland.
Purpose: To assess the efficacy and safety of ranibizumab 0.5 mg
treat and extend (T&E) versus a monthly regimen in patients with
neovascular age-related macular degeneration (nAMD) from the
TREND study.
Methods: TREND was a phase IIIb, visual acuity (VA)
assessor-masked, multicenter, interventional, 12-month study
(NCT01948830). Treatment-naïve patients aged ≥50 years (N=650)
were randomized (1:1) to receive ranibizumab T&E (n=323) or
monthly (n=327). Patients on the T&E regimen received 2 initial
monthly injections at baseline and Month 1; thereafter, the treatment
interval was lengthened or shortened by 2 weeks (treatment intervals
were ≥4 and ≤12 weeks). The primary objective was to demonstrate
the non-inferiority of ranibizumab T&E to a monthly regimen, as
assessed by the change in best-corrected VA (BCVA) from baseline
to the end of study at one year. Key secondary objectives included
assessment of change in central subfield retinal thickness (CSFT)
from baseline to the end of study, treatment exposure, and safety.
Results: Overall, 89.8% (T&E) and 90.2% (monthly) patients
completed the study. Patient demographic and baseline characteristics
were well balanced across treatment groups. The T&E regimen was
non-inferior (p<0.001) to the monthly regimen with a least squares
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ARVO 2017 Annual Meeting Abstracts
(LS) mean BCVA change of 6.2 versus 8.1 letters from baseline to
the end of study, respectively. Mean change in CSFT from baseline
to the end of study was −172.1 µm (T&E) and −173.3 µm (monthly).
Fewer injections were required in patients receiving T&E (8.7) versus
monthly (11.1) regimen. The most common ocular adverse events
(AEs) were increase in intraocular pressure (T&E: 8.4%; monthly:
8.6%) and conjunctival hemorrhage (T&E: 4.3%; monthly: 5.8%).
Ocular serious AEs (SAEs) were similar between groups (1.2%
each). In general, ocular and non-ocular AEs and SAEs reported were
comparable between groups.
Conclusions: Ranibizumab 0.5 mg administered according to the
T&E regimen was statistically non-inferior and clinically comparable
to the monthly regimen in improving BCVA from baseline to the
end of study with no new safety findings. Therefore, T&E treatment
may provide comparable benefits to monthly treatment with fewer
injections, thereby reducing treatment burden for patients, clinicians,
and health care systems.
Commercial Relationships: Rufino Silva, Alcon (R), THEA (R),
Allergan (R), Novartis (R), Bayer (R), Alimera (R); Michael Larsen,
Alcon (R), Roche (R), Novartis (R), Roche (F), Allergan (F),
Novartis (F), Allergan (R), Alcon (F); Chrystel Feller, Novartis (E);
Wayne Macfadden, Novartis (E)
Clinical Trial: NCT01948830
Program Number: 417 Poster Board Number: A0283
Presentation Time: 1:30 PM–3:15 PM
Anti-Vascular Endothelial Growth Factor Monotherapy for
Thick Submacular Hemorrhage Associated With Retinal Pigment
Epithelial Detachment in Age-Related Macular Degeneration
Jeffrey G. Gross1, Freda Yin1, W. Riley Stroman2. 1Carolina Retina
Center, Columbia, SC; 2University of South Carolina School of
Medicine, Columbia, SC.
Purpose: Thick submacular hemorrhage in age-related macular
degeneration (AMD) is often managed by vitrectomy with pneumatic
displacement using injected tissue plasminogen activator (TPA)
and/or air into the subretinal space. Retinal pigment epithelial
detachment (PED) beneath the subretinal hemorrhage may pose risks
associated with the subretinal injection. A retrospective, observational
clinical study was performed to assess the efficacy of anti-vascular
endothelial growth factor (anti-VEGF) injections for the treatment
of thick submacular hemorrhages associated with retinal PED
complicating AMD.
Methods: Retrospective consecutive case series of six eyes with
AMD and acute onset thick submacular hemorrhage associated with
underlying retinal PED and vision loss. Eyes received intravitreal
anti-VEGF monotherapy using bevacizumab, ranibizumab or
aflibercept every 4 weeks. After resolution of the subfoveal
hemorrhage component the interval was extended using a treat and
extend schedule.
Results: Optical coherence tomography (OCT) central thickness
of the subretinal hemorrhage was greater than 450 microns in each
eye at baseline (range 467 – 1177 microns). All eyes demonstrated
resolution of the subfoveal portion of submacular hemorrhage
between 3 to 4 months. Snellen visual acuity at baseline ranged
between 20/100 and 2/200 (mean 20/567). Maximum Snellen visual
acuity ranged from 20/25 to 20/400 (mean 20/143) and 67% were
20/50 or better. Following a minimum follow up of 4 months (range
4 - 47 months) the final visual acuity ranged from 20/30 to 20/400
(mean 20/156). Complications included subfoveal RPE atrophy 1 eye
and an RPE tear in one eye. None of the eyes had recurrent subretinal
hemorrhage, injection related complications or endophthalmitis.
Conclusions: Anti-VEGF monotherapy resulted in improved visual
and anatomic outcomes and may be an effective treatment alternative
to vitrectomy with pneumatic displacement for submacular
hemorrhage associated with retinal PED complicating AMD.
Thick submacular hemorrhage. Vision 5/100, OCT 770 micron
thickness.
Submacular hemorrhage resolved after anti-VEGF monotherapy.
Vision 20/25, OCT 276 micron thickness.
Commercial Relationships: Jeffrey G. Gross, Acucela (F),
Regeneron (F), Ohr Pharmaceuticals (F), Genentech (F); Freda Yin,
None; W. Riley Stroman, None
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ARVO 2017 Annual Meeting Abstracts
Program Number: 418 Poster Board Number: A0284
Presentation Time: 1:30 PM–3:15 PM
Long-term real world outcomes in younger (under 60yrs) patients
receiving anti-VEGF therapy for choridal neovascular membrane
(CNVM)
Lyudmila Kishikova, Yewande Babalola, Maged S. Habib,
Deepali Varma, David Steel, Jonathan Smith, Maria T. Sandinha,
Ajay Kumar Kotagiri. Ophthalmology, Sunderland Eye Infirmary,
Sunderland, United Kingdom.
Purpose: Intravitreal anti-vascular endothelial growth factor
(anti-VEGF) therapy has revolutionised the management of CNVM
due to neovascular Age related Macular Degeneration (nAMD),
myopic macular degeneration as well as secondary causes.
However no long-term real life data is available with regard to their
effectiveness in myopic CNVM, nAMD and secondary CNVM
diagnosed in younger age group (<60 years).
The aim of the project is to evaluate the visual and anatomical
outcomes in younger (<60 years) patients with CNVM receiving
intra-vitreal anti-VEGF therapy.
Methods: Retrospective audit of consecutive younger patients
(<60yrs), receiving intra-vitreal anti-VEGF injections for the
treatment of CNVM between January 2014 and January 2016 at a
single regional centre (Sunderland Eye Iinfirmary). Visual acuity,
OCT features, follow up period and number of treatments received
was noted.
Results: 65 eyes receiving treatment for nAMD, myopic CNVM and
secondary CNVM were included. Mean age of patients was 52 years.
Diagnosis of nAMD was made in 50.77% of eyes, Myopic CNVM
in 24.62% and secondary CNVM in 24.62 eyes. Mean follow up
period was 29.1 months. Visual acuity stabilised in 80% of patients
with 15.4% gaining >15 letters. On average, patients received 8.5
injections. There was significant reduction in the central macular
thickness (mean change of -68.5 um) with 37.9% being dry on OCT
at last follow up.
Conclusions: This audit confirmed the effectiveness of anti VEGF
therapy in younger age group diagnosed with CNVM. Limitations
include small number of patients and varied follow up.
Commercial Relationships: Lyudmila Kishikova, None;
Yewande Babalola, None; Maged S. Habib, Bayer (R), Novatis
(R); Deepali Varma, Bayer (R), Novatis (R); David Steel, Bayer
(R), Novatis (R); Jonathan Smith, Bayer (R), Novatis (R);
Maria T. Sandinha, Bayer (R); Ajay Kumar Kotagiri, Bayer (R)
Support: Travel grants from Bayer and Novartis
Program Number: 419 Poster Board Number: A0285
Presentation Time: 1:30 PM–3:15 PM
Prospective evaluation of different subtypes of exudative
maculopathy under an as-needed treatment regimen with
aflibercept
Adrian Reumueller, Sandra Rezar, Katharina Eibenberger,
Wolf Buehl, Ursula Schmidt-Erfurth, Stefan Sacu. Department of
Ophthalmology and Optometry, Medical University of Vienna,
Vienna, Austria.
Purpose: To prospectively evaluate the response to intravitreal
aflibercept monotherapy with an as-needed treatment regimen in
patients with specific subtypes of exudative maculopathy beyond the
standard label.
Methods: Thirty-eight eyes of treatment-naïve patients with
polypoidal choroidal vasculopathy (PCV, n=11), hemorrhagic
choroidal neovascularization (hCNV, n=10), pigment epithelium
detachment (PED, n=9) and retinal angiomatous proliferation (RAP,
n=8) were included in this prospective analysis. All patients received
three initial aflibercept 2mg/0.05ml injections (Eylea®) in monthly
intervals (loading phase) and were subsequently treated with an
as-needed regimen until month 12. Retreatment criteria included
evidence of sub/intraretinal fluid, intraretinal cysts, hemorrhage or
a disease-activity related decrease in visual acuity (VA). Outcome
measures were the functional and morphological response to
treatment and the number of injections over the study period.
Results: Mean baseline VA was 61±21 ETDRS letters (60±24 letters
in patients with PCV; 51±26 in hCNV; 72±8 in PED and 61±5 in
RAP). After three initial monthly aflibercept injections VA increased
to 68±18 letters (p=0.2). After 6 months, a VA of 68±19 letters
(p=0.2) and after 12 months, a VA of 67±19 letters (p=0.3) was
achieved (58±28 letters in patients with PCV; 72±11 in hCNV; 69±15
in PED and 70±10 in RAP at month 12). Final VA improved or was
stable in 80% of the patients. Mean central retinal thickness (CRT)
was 547±192µm at baseline (456±124µm in patients with PCV;
361±140µm in hCNV; 685±232µm in PED and 579±110µm in RAP).
After the initial loading phase CRT decreased to 438µm (p=0.2),
after 6 months to 378µm and after 12 months to 338µm (p<0.001)
(300±63µm in patients with PCV; 291±47µm in hCNV; 470±155µm
in PED and 302±40µm in RAP at month 12). During the study
period, the patients received a mean of 6±2 intravitreal aflibercept
injections (7±2 in patients with PCV; 6±3 in hCNV; 6±2 in PED and
6±2 in RAP). Bimonthly or monthly treatment was necessary in 28%
of the patients. After 12 months, disease activity was still observed in
one third of the study population.
Conclusions: Aflibercept monotherapy with an as-needed treatment
regimen was effective regarding anatomical and visual outcome in
patients with specific subtypes of exudative maculopathy beyond the
classic indication.
Commercial Relationships: Adrian Reumueller, None;
Sandra Rezar, None; Katharina Eibenberger, None; Wolf Buehl,
None; Ursula Schmidt-Erfurth, Novartis (C), Boehringer (C),
Bayer (C), Alcon (C); Stefan Sacu, Bayer (F)
Clinical Trial: 2014-002384-15
Program Number: 420 Poster Board Number: A0286
Presentation Time: 1:30 PM–3:15 PM
Incidence of New Choroidal Neovascularization in Fellow Eyes
of Patients Treated with Intravitreal Aflibercept Injection or
Ranibizumab in the VIEW studies
Robert L. Avery. California Retina Consultants, Santa Barbara, CA.
Purpose: To evaluate incidence of new choroidal neovascularization
(CNV) in fellow eyes of patients treated for neovascular age-related
macular degeneration (AMD) with intravitreal aflibercept injection
(IAI) or ranibizumab in two similarly designed phase 3 clinical
studies (VIEW1 and VIEW2).
Methods: Patients in both studies were randomized to ranibizumab
0.5 mg every 4 weeks (Rq4), IAI 2 mg every 4 weeks (2q4), IAI 0.5
mg every 4 weeks (0.5q4), or IAI 2 mg every 8 weeks following 3
initial monthly doses (2q8) over 52 weeks. From Weeks 52 to 96,
patients were dosed at least quarterly with more frequent dosing
allowed based on prespecified retreatment criteria. In this post hoc
sub analysis, only fellow eyes lacking signs of neovascular AMD
at baseline were included. Development of new CNV was based on
adverse event reporting, concomitant medications, and fluorescein
angiographic determination by an independent reading center.
Kaplan-Meier methodology was employed to evaluate incidence of
first observation of new CNV over 96 weeks. In addition, effect of
select baseline factors (age, gender, and study eye characteristics
[central retinal thickness, CNV lesion size, and intraretinal fluid])
were evaluated on incidence of new CNV in fellow eyes. Data from
integrated VIEW studies are reported.
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ARVO 2017 Annual Meeting Abstracts
Results: Proportions of fellow eyes at baseline without evidence of
CNV in the Rq4, 2q4, 0.5q4, and 2q8 groups were 67.1%, 63.1%,
64.4%, and 63.6%, respectively. At Week 96, cumulative incidences
of new CNV in these fellow eyes were similar across all treatment
groups: 32.2%, 28.2%, 26.2%, 29.0% in the Rq4, 2q4, 0.5q4, and
2q8 groups, respectively. Baseline demographics associated with the
occurrence of new CNV in fellow eyes were increasing age and being
female. Larger CNV lesion size and presence of intraretinal fluid at
baseline in the study eye was also associated with higher rates of new
CNV in fellow eyes.
Conclusions: During two years of follow-up in the VIEW studies,
incidence of new CNV in fellow eyes of patients treated with IAI
or ranibizumab were similar across treatment groups indicating that
treatment in the study eye was not a factor. The rate of new CNV
development was higher in fellow eyes of patients whose study eyes
presented with a larger CNV size and intraretinal fluid.
Commercial Relationships: Robert L. Avery
Clinical Trial: NCT00509795
Program Number: 421 Poster Board Number: A0287
Presentation Time: 1:30 PM–3:15 PM
A Meta-Analysis of Baseline Characteristics and Anti-VEGF
Frequency for Neovascular AMD: Visual Acuity Gains are
Influenced by Injection Frequency
Rehan M. Hussain, Thomas A. Ciulla. Ophthalmology, Indiana
University School of Medicine, Indianapolis, IN.
Purpose:
To examine how baseline patient characteristics and frequency
of anti-vascular endothelial growth factor (anti-VEGF) therapy
influence visual acuity (VA) outcomes in patients with neovascular
age-related macular degeneration (nAMD).
Methods: A meta-analysis of studies employing various injection
frequency regimens with bevacizumab or ranibizumab for nAMD
was performed. Only studies that measured VA with ETDRS letters
were included. Four treat-and-extend studies (LUCAS, TREXAMD, Abedi et al, Oubraham et al) were compared to randomized
prospective trials employing monthly treatment (ANCHOR,
MARINA, CATT, IVAN, VIEW), quarterly treatment (PIER and
EXCITE), and PRN treatment (PRONTO, SAILOR, SUSTAIN,
HARBOR, CATT, IVAN). Multiple linear regression was performed
on the dependent variable of 12 month mean ETDRS letters gained
versus the independent variables of mean 12-month injection count
and multiple mean baseline characteristics (baseline ETDRS VA,
age, central subfield thickness (CSFT), % classic CNV (choroidal
neovascularization), and lesion size).
Results:
From the clinical trials above, 23 treatment arms were analyzed.
Multiple linear regression revealed that the best fit model included
only mean 12-month injection count as the dependent variable.
Number of injections showed a linear correlation with number of
letters gained at 1 year (r=0.68, R2=0.39). Mean letters gained
did not increase beyond a mean of 9 or more injections in the first
year. When all studies with fewer than 9 injections in 1 year were
analyzed, there was greater linear correlation (r = 1.69, R2 = 0.52),
suggesting that 52% of the variability in letters gained in the first year
is related to injection frequency.
Conclusions:
AntiVEGF injection frequency plays a much greater role in 12-month
VA outcomes than mean baseline features of the patient population,
such as baseline ETDRS VA, age, CSFT, % classic CNV, and lesion
size. There is a ceiling effect, highlighting a limitation of antiVEGF therapy for nAMD. Fewer than 9 injections in the first year is
associated with worse VA outcomes, highlighting treatment burden as
a limitation of antiVEGF therapy for nAMD.
Commercial Relationships: Rehan M. Hussain, None;
Thomas A. Ciulla, Ophthotech (E)
Program Number: 422 Poster Board Number: A0288
Presentation Time: 1:30 PM–3:15 PM
TWO-YEAR DATA COMPAIRING THE EFFICACY OF
AFLIBERCEPT IN WET AGE-RELATED MACULAR
DEGENERATION IN TREATMENT NAÏVE AND
SWITCHOVER PATIENTS
Michael McKenna, Javid Suleman, Darren S. Ting,
Sreekumari Pushpoth, Philip Severn. James Cook University Hospital
Ophthalmology, NHS, Middlesbrough, United Kingdom.
Purpose: Purpose: To examine the two year efficacy of intravitreal
aflibercept (Eylea) in patients with wet age-related macular
degeneration (AMD), and the efficacy of intravitreal Afilbercept
in patients that were previously non-responsive to intravitreal
Ranibizumab (Lucentis).
Methods: Methods: This is an on-going, comparative, interventional
case series comparing two years of data. All cases of wet AMD were
treated with Aflibercept (Eylea), one group treated from the outset
and the other, that were previously non-responsive to intravitreal
Ranibizumab were switched to intravitreal aflibercept.
Results: Results: Approximately 234 eyes were treated with anti
VEGF. In the first cohort 135 eyes, were from the start, treated with
purely Aflibercept (Eylea) during the study period (July 2013 to
December 2016). The mean age was 77.0±8.1years. In the treatment
‘naïve’ group (Eylea only) - at presentation the mean baseline (pretreatment) BCVA was 55.4 ± 15.1 letters, with a mean gain of 1.1
± 11.4 letters at 12th months (p=0.320). Twenty-four month data is
currently being collated and analysed.
The mean pre-treatment central macular thickness (CMT) was
333.6 ± 113.3 µm with a mean reduction of 83.3±94.3 µm at
12 months (p<0.001) and a reduction of 50±42.6 µm at 24 months
(provisional two-year data - currently in progress).
In the switched group (initially on Ranibizumab then switched to
Eylea) approximately 94 patients were treated. The mean age was
75.5 ± 7.3 years. An average of 13.9 ± 8.3 intravitreal ranibizumab
injections (Lucentis) were given before switching to intravitreal
Aflibercept (Eylea). The baseline best-corrected visual acuity
(BCVA) on first presentation was 60.9 ± 11.6 letter. Initial mean
central macular thickness (CMT) pre-aflibercept was
343 ± 127 μm. The BCVA on switching from ranibizumab to
aflibercept was 55.6 ± 14.6 letters, with a mean change of -5.8 letters
(p<0.001). At 12-month post aflibercept, there was a mean change
of -0.3 letters (p=0.82). Central macula thickness was reduced by
approximately 75 μm at 12 months (p<0.001) and 63 μm at 24months
(provisional data).
No complications were noted during the study period.
Conclusions: Conclusions: Our study demonstrates that aflibercept
serves as an effective and safe alternative treatment of wet AMD and
offers good efficacy over an extended period of time.
Commercial Relationships: Michael McKenna,
None; Javid Suleman, None; Darren S. Ting, None;
Sreekumari Pushpoth, None; Philip Severn, None
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ARVO 2017 Annual Meeting Abstracts
Program Number: 423 Poster Board Number: A0289
Presentation Time: 1:30 PM–3:15 PM
Real life long term outcomes of patients receiving intra-vitreal
Aflibercept for Neo-vascular age related macular degeneration
(nAMD): three years follow up
Yewande Babalola, Lyudmila Kishikova, Maged S. Habib,
Deepali Varma, Jonathan Smith, Maria T. Sandinha, David Steel,
Ajay Kotagiri. Sunderland Eye Infirmary, Stockton on Tees, United
Kingdom.
Purpose: Multi-centre trials have demonstrated the efficacy of
Aflibercept in the management of nAMD. There is no long term real
life data available, on patient’s outcomes 3 years after the initiation
of treatment. We carried out a retrospective study of visual and
anatomical outcomes 3 years after initiating Aflibercept therapy.
Methods: Retrospective analysis of 100 consecutive treatment naive
eyes receiving intravitreal Aflibercept for the treatment of nAMD
(April 2013-Nov 2016), at a single specialised ophthalmic centre in
the north east of England, UK. In the first year, fixed dosing regimen
was adhered to, with three monthly loading doses and a bimonthly
regimen thereafter. Pro re nata (PRN) dosing regimen was followed
after the first year. Visual acuity, OCT features, follow-up period and
number of treatments received were noted.
Results: One hundred eyes (96 patients) receiving Aflibercept
treatment for nAMD were included. Mean age at presentation was
79.6 years with 60% diagnosed as Occult choroidal neo-vascular
membrane. Mean follow up period was 142.9wks (48.4-174.4wks).
Ten patients (10 eyes) had died at the time of this analysis. Seven
eyes were switched to Ranibizumab. Stability of vision was achieved
by 82% of patients with 12% of patients gaining >15letters. 79% of
patients maintained the vision they attained at 12months. On average,
patients received 11 injections. 66% of OCT’s were noted to be dry at
last follow up.
Conclusions: The real life outcomes confirm the long term
effectiveness of Aflibercept in the treatment of nAMD after three
years of treatment.
Commercial Relationships: Yewande Babalola, None;
Lyudmila Kishikova, None; Maged S. Habib, Novartis (R), Bayer
(R); Deepali Varma, novartis (R), bayer (R); Jonathan Smith,
Novartis (R), Bayer (R); Maria T. Sandinha, Bayer (R);
David Steel, Novartis (R), Bayer (R); Ajay Kotagiri, Bayer (R)
Program Number: 425 Poster Board Number: A0291
Presentation Time: 1:30 PM–3:15 PM
Regularity of treatment in nAMD: 12-month results of the
PERSEUS and RAINBOW studies
Carsten Framme1, Laurent KODJIKIAN2. 1Ophthalmology,
Medizinische Hochschule Hannover, Hannover, Germany;
2
Ophthalmology, Hopital de la Croix-Rousse, Lyon, France.
Purpose: PERSEUS and RAINBOW are the first studies to analyze
the real-life use of intravitreal aflibercept injections (IAI) in
neovascular macular degeneration (nAMD) in Germany and France,
respectively. The aim of these analyses was to assess the impact of
regular treatment approach (PERSEUS; loading dose of 2 mg IAI
once a month for 3 months, followed by 2 mg IAI every 2 months)
and loading doses (RAINBOW; 3 IAI within 120 days) on visual
acuity (VA) after 12 months of treatment in 2 different healthcare
systems.
Methods: PERSEUS is a prospective observational study in
Germany. Inclusion criteria were patients diagnosed with nAMD
who received treatment with IAI in accordance with European IAI
product labeling. In total, 874 patients were included in the 12-month
analysis. The 12-month results from the anti-VEGF treatment-naïve
cohort (n=451) stratified based on the regularity of treatment (regular
cohort [loading doses, followed by 2 mg IAI every 2 months] and
irregular cohort [patients who didn’t meet the criteria for regular
cohort]) are presented. RAINBOW is a retrospective and prospective
observational study in France. Inclusion criteria were patients
diagnosed with nAMD receiving treatment with 2 mg IAI as first-line
therapy. An interim analysis was performed after 12 months for 196
patients. Furthermore, the subgroup who received 3 loading doses
within 120 days (n=179) was analyzed.
Results: PERSEUS: baseline mean age was 77.4±7.7 years and
VA was 53.1±18.2 letters. Patients in the regular cohort (33%)
showed mean±SD VA improvement of 8.1±17.7 letters (irregular
cohort [67%]: 4.2±17.0; all naïve patients combined: 5.5±17.3).
Mean number of injections was 5.8±2.2, mean number of visits was
8.9±4.1.
RAINBOW: baseline mean age was 78.8±7.7 years and VA was
57.7±18.3 letters. Mean VA improvement was 6.2±16.8 in all
patients. In the subgroup receiving the loading doses, mean VA gain
was 7.4±15.8. In all patients, the mean number of injections was
6.3±2.0, mean number of visits was 9.9±1.7.
In PERSEUS and RAINBOW, respectively, treatment-related
treatment-emergent adverse events (TEAEs) occurred in 3.4% and
2.6% of patients. No endophthalmitis cases were observed in either
study.
Conclusions: In both healthcare systems within a 12-month treatment
period, patients benefited most when receiving 3 IAI loading doses or
when such was combined with IAI in regular injection intervals, as
opposed to irregular treatment.
Commercial Relationships: Carsten Framme, Heidelberg
Engineering (R), Allergan (R), Zeiss (R), Novartis (R), Bayer (C),
Bayer (R), Novartis (F); Laurent KODJIKIAN, Novartis (C), Bayer
(C), Théa (C), Allergan (C), Alcon (C)
Clinical Trial: NCT01914380
Program Number: 426 Poster Board Number: A0292
Presentation Time: 1:30 PM–3:15 PM
Effect of intravitreal anti-vascular endothelial growth factor
injection in drusenoid pigment epithelium detachment progressed
to wet age-related macular degeneration
Kwang-Soo Kim, Jung Yeob Han. Ophthalmology, Keimyung Univ
Dongsan Medical Ctr, Daegu, Korea (the Republic of).
Purpose: To evaluate the effect of intravitreal anti-vascular
endothelial growth factor (anti-VEGF) injection in eyes with wet agerelated macular degeneration (AMD) secondary to drusenoid pigment
epithelium detachment (PED).
Methods: Nineteen eyes (nineteen patients) which had drusenoid
PED with choroidal nevascularization were included in this study.
Eyes had undergone intravitreal anti-VEGF injection on pro re nata
schedule and followed-up for over 12 months. Best corrected visual
acuity (BCVA) check and optical coherence tomography (OCT) for
central macular thickness (CMT), height of subfoveal subretinal
fluid (sSRF) and subfoveal drusenoid PED (sPED) were done at each
visit. Factors which influenced final findings were analyzed using
Wilcoxon signed rank test and multiple regression test. The eyes were
divided into 3 groups according to the macular morphology by OCT:
with intraretinal cystic edema (Group A, 4 eyes), with SRF (Group
B, 8 eyes) and with mixed type (Group C, 7 eyes). Also the eyes
were divided into 2 groups: continuous treatment group (9 eyes) and
late observation group (10 eyes). Subgroup analysis was done using
Kruskal-Wallis test.
Results: The mean age of the patients was 67.84±7.35years. The
mean follow-up period was 48.16±35.92months and the mean
number of injections was 7.68±5.61. The initial BCVA(logMAR)
was 0.56±0.30, and the mean pre-injection CMT, sSRF and sPED
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ARVO 2017 Annual Meeting Abstracts
height was 129.95±35.13, 84.63±108.19μm and 172.21±121.83μm,
respectively. The post-injection sSRF height showed a significant
decrease (p=0.049), but there was no significant change in postinjection VA, sPED and CMT. Final BCVA was better when the
number of injection was high (p=0.010) and the initial VA was better
(p=0.047). Improvement of VA was greater in younger age (p=0.017)
and with high number of injection (p=0.003). In subgroup analysis,
VA improvement showed greatest in group C and less in group
B (p=0.009). Continuous treatment group showed greater initial
PED height (p=0.035) and mean change of CMT (p=0.043) than late
observation group.
Conclusions: Wet AMD secondary to drusenoid PED showed better
outcomes in eyes with better intial VA and showed relatively good
response to anti-VEGF injection. OCT morphologically different
types affect prognosis of the disease. When initial PED height is
higher, there is tendency to maintain treatment.
Commercial Relationships: Kwang-Soo Kim, None; Jung
Yeob Han, None
Program Number: 427 Poster Board Number: A0293
Presentation Time: 1:30 PM–3:15 PM
Italian multicenter real-life experience in anti VEGF treatments
for maculopathies: what is the best clinical pathway?
Claudio Azzolini1, Alfredo Pece2, Simone Donati1. 1Morphological &
Surgical Sci, Clinica Oculistica - Universita’ Insubria, Varese, Italy;
2
Ophthalmology, Melegnano Hospital, Melegnano, Italy.
Purpose: To evaluate the best clinical approach on real-life for the
treatment with antiVEGF in different maculopathies.
Methods: Eighty-five ophthalmologists coming from thirty-five
Retina Centers around Italy were involved in this project. Twelve
county meetings were organized to collect and discuss experiences
and methodologies on antiVEGF treatments. Meeting leaders
presented the following topics: 1-Induction phase: application and
modalities, 2- Individualized therapy during follow up. Literature
data were presented for each topic before discussion. A questionnaire
was completed to investigate main technical and practical issues
in patients management. All data coming from discussion and
questionnaires were collected and analyzed.
Results: The following statements were shared: (topic 1) the time
of diagnosis and therapy are the keys; the “loading phase” modality
has to be changed into “treatment until stabilization” modality; the
treatment interval must not be more than one month. (topic 2): aim of
the follow up is to maintain the results of induction phase, treatment
could be applied according to Pro Re Nata or Treat and Extend
regimen; the participants agreed to apply different clinical approaches
and systemic monitoring according to the pathology.
The questionnaire underlined the real life aspects of the management:
mean time between diagnosis and treatment less than 10 days in 40%
centers; about 53% of involved clinician perform induction phase of
three injection for AMD and DME; the personalized PRN is applied
by 52% ophthalmologists in AMD and by 62% in DME, a monthly
control and PRN by 38% and 27% respectively.
The questionnaire underlined the difficulties on economical and
administrative aspects for drugs management and lack of medical
staff. A final document was prepared to ameliorate clinical approach,
follow up and management of patients.
Conclusions: The project and the consensus coming from the
meeting discussion underlined the new phase of antiVEGF treatment
procedure: the induction and follow up phases of the treatment must
be tailored on patients responsivity. A key moment is the beginning
of the therapy but its continuation its crucial in all the considered
pathologies. The creation of Maculopathies Centers could be a
new dimension, to control cost and to ameliorate significantly the
management of these pathologies.
Commercial Relationships: Claudio Azzolini, None; Alfredo Pece,
None; Simone Donati, None
Program Number: 428 Poster Board Number: A0294
Presentation Time: 1:30 PM–3:15 PM
Use of discrete event simulation (DEM) to evaluate the clinical
practices in neovascular age-related macular degeneration
Patricio G. Schlottmann1, Jose D. Luna Pinto2, Santiago Palma3,
Juan Pablo Real3. 1Ophthalmology, Organizacion Medica de
Investigacion, Buenos Aires, Argentina; 2Fundacion Ver, Cordoba,
Argentina; 3Farmacia, Facultad de Ciencias Quimicas UNC, Cordoba,
Argentina.
Purpose: To evaluate the outcomes and direct medical cost of
different treatment regimens in managing nAMD.
Methods: A discrete event simulation model was developed
reproducing the long-term evolution of 5000 patients with nAMD.
The model allows calculation the cost-effectiveness of treatment of
AMD with Ranibizumab in two different therapeutic regimens: pro
re nata (PRN) and Treat and Extend (TAE). Ranibizumab at the price
of Lucentis (U$2000) and Ranibizumab at the price of Accentix
(U$380). Data on effectiveness, rate of visual loss without treatment,
the vision-related quality of life, time with VEGF suppression and
time to functional recurrence were identified through a systematic
literature searches.
Time horizons were 10 years. A third-party-payer perspective was
employed. A discount rate of 3% per annum was considered for both
costs and outcomes benefits.
Results: Over ten years of simulated treatment show us that the
use of TAE scheme implies a higher number of intravitreal doses, a
smaller number of consultations and savings in the accomplishment
of studies of OCT. Effectiveness associated with the RNB regimens,
Treat and extend (TAE) and as-needed (PRN), were 4.83 and
4.71QALY, respectively. The cost associated with LUCENTIS
TAE and PRN were U$149.722 and U$ 125.200. When the price of
Ranibizumab is that of Accentix, the cost associated is U$56.540 and
U$60.000. The sensitivity analysis shows that TAE can be considered
cost-effective compared to PRN when the price of RNB is less than
U$900.
Conclusions: DEM is a useful tool in the analysis of clinical
practices For this case, TAE is the most effective régimen and is cost
effective when Accentix is used.
Commercial Relationships: Patricio G. Schlottmann, None;
Jose D. Luna Pinto, None; Santiago Palma, None; Juan
Pablo Real, None
Program Number: 429 Poster Board Number: A0295
Presentation Time: 1:30 PM–3:15 PM
Exudative AMD lesion components predicting microperimetric
retinal sensitivity during anti-VEGF treatment
Henrik Bygglin1, Asta Hautamäki1, Arto Luoma2, Ilkka J. Immonen1.
1
Ophthalmology, Helsinki University Central Hospital, Helsinki,
Finland; 2Univertsity of Tampere, Tampere, Finland.
Purpose: To find exudative AMD lesion components correlating
with retinal sensitivity in patients treated with pro-re-nata (PRN)
bevacizumab for 2 years.
Methods: Fifty patients were prospectively analyzed in a 2-year
study of bevacizumab treatment for exudative AMD. Visual
acuity, fluorescein and indocyanine green (ICG) angiographies
and autofluorescence images as well as microperimetry and OCTs
recorded with Spectral OCT/SLO (OPKO/OTI) were analyzed.
Reliable microperimetries and good quality OCTs from visits at
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ARVO 2017 Annual Meeting Abstracts
baseline and at 1 and 2 years were available from 24 eyes of 24
patients and were included in the current analysis.
The microperimetries were automatically aligned with the OCTs
and manually aligned with the angiographies and autofluorescence
images. Thicknesses of the neuroretina, pigment epithelial (RPE)
elevation (PEE), neuroepithelial detachment (NED), subretinal
tissue (SRT) and cystoid spaces were manually measured under each
stimulus site, and areas of classic and occult CNVs, ICG plaque,
hemorrhage and RPE atrophy were identified.
Multivariate mixed linear models for repeated measurements
were built to estimate the effects of lesion components on retinal
sensitivity and to find the best predictors of retinal sensitivity during
PRN treatment.
Results: Retinal sensitivity increased during the first year (mean,
baseline, 9.7 dB, 1 year, 10.7 dB, p<0.0001), but decreased during
the second year (2 years, 10.5 dB, p=0.028). In the combined data of
all visits the lesion components affecting retinal sensitivities were in
a decreasing order of effect sizes (ES): the presences of RPE atrophy
(ES 6.7), SRT (2.6), hemorrhage (2.4), cystoid spaces (2.4), classic
(2.2) and occult CNVs (1.5) and neuroretinal thinning (1.2). The
effects of PEE (0.96) and ICG plaque (0.69) were less pronounced.
Baseline components associating with decreased retinal sensitivity
at both 1 and 2 years were: the RPE atrophy, the area of classic
CNV, presence of cystoid spaces, haemorrhage and occult CNV.
Neuroretinal thickening, PEE and NED had lesser effects. Increasing
age of the patient had a negative effect on the retinal sensitivities
during the treatment.
Conclusions: The most powerful predictors of retinal sensitivity loss
during 2 years anti-VEGF treatment were the RPE atrophy, classic
CNV, cystoid spaces and SRT. The occult CNV, PEE and NED had
lesser effects.
Commercial Relationships: Henrik Bygglin, None;
Asta Hautamäki, None; Arto Luoma, None; Ilkka J. Immonen,
None
Support: Personal grants for research by the Finnish Eye-Society
(Silmäsäätiö),
Clinical Trial: ACTRN12608000223336
Program Number: 430 Poster Board Number: A0296
Presentation Time: 1:30 PM–3:15 PM
Correlation between visual outcomes and anti-vegf injection
frequency in neovascular age-related macular degeneration
(nAMD) in Observe and Plan Regimen
Charlotte Rohart, Loic Granados, Sophie Navarre, Sandrine Allieu.
ophthalmology, Clinique Beausoleil, Montpellier, France.
Purpose: To compare visual acuity and morphologic features
according to anti-vegf injection frequency in real-life in Observe and
Plan Regimen after at least two years treatment period.
Methods: This was a french monocentrique retrospective study that
included 80 eyes with nAMD. For all eyes, a personalized treatment
regimen considering the recurrence interval was planned.
Study eyes were divided into two groups according the intravitreal
anti-vegf injection frequency. Forty eyes were included in the group
1 with high injection frequency (4 to 7 weeks), and 40 eyes were
included in the group 2 with low injection frequency (8 to 12 weeks).
Best corrected visual acuity (BCVA) and morphologic features at
baseline and at recurrence were collected for all patients in each
group.
Results: Patients characteristics were similar for two groups. The
follow up was 37 months in group 1 and 39 months in group 2.
There was a significant difference between initial BCVA and final
BCVA in each group (p < 0.05). The initial BCVA and the final
BCVA were better in group 1 with high injection frequency (p<0.05).
The final BCVA was 76 letters (ETDRS) in group 1 and 69 letters
(ETDRS) in group 2. Morphologic features at baseline and at
recurrence were different between two groups with subretinal fluid
presence in 90 % in group 1 versus 60 % in group 2. In group 1, eyes
were divided and analyzed into 2 subgroups : eyes with persistant
fluid (23 eyes) and eyes with recurrence fluid (17 eyes).
Conclusions: In nAMD with Observe and Plan regimen, eyes with
high injection frequency had better visual outcomes but needed
intravitreal injection more frequently. More than 50% of these eyes
with high injection frequency were associated with persistant fluid.
In aggreement with others studies, subretinal fluid was associated
with better visual acuity.
Commercial Relationships: Charlotte Rohart; Loic Granados,
None; Sophie Navarre, None; Sandrine Allieu, None
Program Number: 431 Poster Board Number: A0297
Presentation Time: 1:30 PM–3:15 PM
Twelve-Month Outcomes of Aflibercept vs. Ranibizumab for Wet
Macular Degeneration
Hussein Almuhtaseb1, 2, Luke Michaels2, Thanos Vardarinos3,
Andrew J. Lotery1, 2. 1Eye Unit, University Hospital Southampton,
Southampton, United Kingdom; 2Clinical and Experimental Sciences,
University of Southampton, Southampton, United Kingdom; 3Eye
Unit, West Suffolk Hospital, Suffolk, United Kingdom.
Purpose: To compare visual acuity (VA) outcomes in year 1 of
treatment with aflibercept vs. ranibizumab for eyes with wet macular
degeneration (nAMD) treated in two centres by two different
treatment regimens.
Methods: Retrospective analysis from an electronic medical record
(EMR). 100 Treatment-naïve eyes with nAMD received therapy with
aflibercept or ranibizumab intravitreal injections (IVI)s. In Group
A (University Hospital Southampton: 51 eyes) aflibercept was used
per VIEW modified protocol. In Group B (West Suffolk Hospital: 49
eyes) ranibizumab was used per Treat and Extend (T&E) protocol.
Group A received Aflibercept per VIEW protocol (Q8W) with a total
of 3 Clinic Visits (3 OCTs) during a year of treatment.
Group B received Lucentis per T&E protocol: after a loading of 3
IVIs, inter-IVI interval was extended/shortened by 2 weeks based on
disease activity.
Mean change in best-corrected visual acuity (BCVA) and central
retinal thickness (CRT) at year 1 compared to baseline, mean number
of injections and visits were collected. Economic analysis was
performed based on data from the coding department.
Results: Baseline parameters were well matched (Age, baseline
BCVA). The mean VA of Group A eyes improved from 0.49 LogMar
at baseline to 0.34 LogMar (+7.5 ETDRS L gain [P = 0.0010]) at
end of year 1 (Y1), compared with 0.48 LogMar at baseline to 0.32
LogMar (+8.3 ETDRS L gain [P < 0.0001]) for Group B. Mean
BCVA Group A vs mean BCVA Group B (P=0.1550). The mean CRT
of Group A improved from 296 μm at baseline to 214 at Y 1. The
mean CRT of Group B improved from 428 μm at baseline to 272
at Y1. In Group A vs. Group B comparisons, the mean numbers of
IVIs were 7 vs. 7.75 (P < 0.0001) and Clinic Visits were 3 vs. 5.75
(P=0.0001). In the T&E group IVI and Clinic Visit numbers ranged
from 5-11. Economic analysis revealed the total mean cost per patient
per annum was £6919.00 for aflibercept per Southampton protocol,
£7395.00 for ranibizumab per the T&E protocol.
Conclusions: Visual gains were significant and comparable for both
Aflibercept (Q8W) and Ranibizumab (T&E) used proactively in
year 1. Differences between the 2 regimens were significant when
mean numbers of IVIs and Clinic Visits were compared. From an
economic point of view, Southampton protocol for Aflibercept is
more cost effective compared to T&E for Ranibizumab in Y1 of
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ARVO 2017 Annual Meeting Abstracts
treatment. Larger case series AND/OR RCTs are needed to give
further evidence.
Commercial Relationships: Hussein Almuhtaseb, Novartis (R),
Bayer (R); Luke Michaels, None; Thanos Vardarinos, Novartis (R),
Bayer (R); Andrew J. Lotery, Roche (R), Bayer (R)
Program Number: 432 Poster Board Number: A0298
Presentation Time: 1:30 PM–3:15 PM
Real life evidence data on intravitreal usage of/treatment with
intravitreal aflibercept in Germany: 12-months results of an
observational study in nAMD (PERSEUS)
Nicole Eter1, Claudia Jochmann2, Peter M. Wiedemann2,
Joachim Wachtlin3, Helmut G. Sachs4, Harald Schilling5,
Zoran Hasanbasic6, Carsten Framme7. 1Ophthalmology,
University of Muenster Medical Center, Muenster, Germany;
2
Universitätsklinikum Leipzig, Leipzig, Germany; 3St. GertraudenKrankenhaus, Berlin, Germany; 4Städtisches Klinikum DresdenFriedrichstadt, Dresden, Germany; 5St.-Johannes-Hospital,
Dortmund, Germany; 6Bayer Vital GmbH, Leverkusen, Germany;
7
Medizinische Hochschule Hannover, Hannover, Germany.
Purpose: To evaluate the effectiveness of intravitreal aflibercept
injections (IAI) for the total study population as well as the
subgroups of treatment-naïve and pretreated patients (who received
any pretreatment for neovascular age-related macular degeneration
[nAMD]), and to describe follow-up as well as treatment patterns in
patients with nAMD for up to 24 months in routine clinical practice
in Germany.
Methods: The study enrolled 988 patients and was conducted in
ophthalmology clinics and practices throughout Germany to inform
on outcomes potentially representative of the current real life
treatment patterns. In order to be included in the study, patients had to
be diagnosed with nAMD and be treated with IAI in accordance with
the European IAI label.
Outcomes following 12 months of treatment are reported here for the
whole study cohort (N=847) as well as for subgroups of treatmentnaïve (n=451) and pretreated patients (n=396).
Results: Analyzed data at 12 months showed significant
improvement in visual acuity (VA), although injection numbers
were lower than what would be expected during treatment in strict
accordance to the European IAI label.
3.5% of all patients experienced non-ocular treatment-emergent
adverse events (TEAE), 8.9% experienced ocular TEAEs. Of all
patients, 1.9% had a cataract, 1.1% had conjunctival hemorrhage, and
0.7% had corneal erosion. No cases of endophthalmitis were reported
(5211 injections).
Conclusions: After 12 months of treatment with IAI, both
treatment-naïve and pretreated patients demonstrated VA gains. VA
improvement was higher in treatment naïve patients.
Table 1: Analyzed data after 12 months of treatment with IVA.
* Clinical (i.e. visit for injection only) + Monitoring (i.e. visit without
injection) + Combined visits (i.e. injection and monitoring visit)
Commercial Relationships: Nicole Eter, Novartis (C), Roche (C),
Novartis (R), Bayer (C), Roche (F), Bayer (R), Allergan (F), Novartis
(F), HeidelbergEngineering (R), Alimera (C), Alimera (F), Bayer (F),
Allergan (C); Claudia Jochmann, Alcon (R), Allergan (R), Novartis
(R), Bayer (R), Alimera (R); Peter M. Wiedemann, Acucela (F),
pSivida (F), Second Sight (F), Bioeq GmbH (F), Novartis (F),
Hoffmann - La Roche (F), Allergan (F), Alcon (F), Ophthotech (F),
Alimera (F), Bayer (F), Thrombogenics (F); Joachim Wachtlin,
Alcon (R), Allergan (R), Novartis (R), Bayer (R); Helmut G. Sachs,
Retina Implant (R), Novartis (C), Retina Implant (C), Novartis (R),
Bayer (C), Bayer (R), Allergan (R), Allergan (C); Harald Schilling,
Allergan (R), Novartis (R), Bayer (R); Zoran Hasanbasic, Bayer
(E); Carsten Framme, Heidelberg Engineering (R), Allergan (R),
Zeiss (R), Novartis (R), Bayer (C), Bayer (R), Novartis (F)
Clinical Trial: NCT01914380
Program Number: 433 Poster Board Number: A0299
Presentation Time: 1:30 PM–3:15 PM
Twenty Four-Month Outcomes of Aflibercept for Neovascular
Age-Related Macular Degeneration: Different Treatment
Regimens in Year Two based on the Macular Status at the End of
Year One
Luke Michaels2, Hussein Almuhtaseb1, 2, Adham Youssef1,
Christina A. Rennie1, Andrew J. Lotery2, 1. 1Eye Unit, University
Hospital Southampton, Southampon, United Kingdom; 2Clinical and
Experimental Sciences, University of Southampton, Southampon,
United Kingdom.
Purpose: To compare clinical outcomes in year 2 of treatment
with aflibercept for eyes with neovascular age-related macular
degeneration (nAMD).
Methods: A single centre retrospective analysis from an electronic
medical record system identified 105 treatment-naïve eyes with
nAMD that completed 2 years of treatment with aflibercept..
In year 1 (Y1), eyes were treated per VIEW study protocol. At end
of Y1, eyes were classified into Inactive-Dry or Active-Wet based on
evidence of exudation and were assigned to 3 treatment regimens in
Y2. Wet Maculae received intravitreal injections (IVIs) bi-monthly
(Q8W) with only 2 follow-up visits at months 17 and 23 [GROUP
A] (n=30). Dry Maculae received aflibercept in 2 ways: Capped
PRN: bi-monthly OCTs with mandatory “capped” IVIs at an interval
of 12 weeks since the previous treatment [GROUP B] (n=25) or by
Treat and Extend (T&E) [GROUP C] (n=23). In a seperate subgroup
of wet maculae, aflibercept was administered at a greater frequency
Q6W/Q4W in Y2 [GROUP D] (n=27).
Mean change in best corrected visual acuity (BCVA) and central
retinal thickness (CRT) at Y2 compared to Y1 and to baseline, mean
number of injections and of follow-up visits in Y2 were assessed.
Results: Mean LogMar BCVA and CRT of GROUPS A-C were
comparable at baseline. The mean LogMar BCVA of GROUPS A-C
improved to 0.45 [+9 ETDRS L gain], 0.54 [+6 ETDRS L gain] and
0.50 [+7 ETDRS L gain] respectively at the end of Y1.
Mean LogMar BCVA of GROUPS A-C were 0.4 [+3 ETDRS L
gain], 0.54 [maintained VA gain] and 0.50 [maintained VA gain]
respectively at the end of Y2.
Mean LogMar BCVA of GROUP D pre- and post-switch into
aflibercept Q6W/Q4W was 0.40 and 0.44 respectively (P=0.4). Mean
CRT pre- and post-switch was 210 and 229 (P=0.11) respectively.
The average number of IVIs in Y2 was 6, 4 and 5 in GROUPS A-C
respectively.
The average number of Clinic Visits in Y2 was 2, 6 and 5 in
GROUPS A-C respectively.
Conclusions: Gains at the end of Y1 were maintained throughout the
2-year treatment plan in all treated groups. Q8W, CPRN and T&E
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ARVO 2017 Annual Meeting Abstracts
are proactive regimens that appear to guarantee maintainance of Y1
gains. Shortening the inter-IVI interval down to Q6W/Q4W might not
guarantee better clinical outcomes. Aflibercept Q8W in Y2 is a costeffective treatment regimen as it maintains Y1 gains with the lowest
number of follow-up visits.
Commercial Relationships: Luke Michaels, None;
Hussein Almuhtaseb, Novartis (R), Bayer (R); Adham Youssef,
None; Christina A. Rennie, Novartis (R), Bayer (R);
Andrew J. Lotery, Roche (R), Bayer (R)
Program Number: 434 Poster Board Number: A0300
Presentation Time: 1:30 PM–3:15 PM
Silicone oil microdroplets in repackaged bevacizumab syringes:
Identification, quantification, and strategies for reducing clincal
impact
John D. Pitcher1, 2, Christopher N. Roybal1, 2. 1Eye Associates of New
Mexico, Albuquerque, NM; 2Ophthalmology, University of New
Mexico, Albuquerque, NM.
Purpose: Bevacizumab (BEV) is an anti-VEGF agent that is used
for off-label treatment of retinal diseases. Most BEV intravitreal
injections given in the US are repackaged by a third party
compounding pharmacy. The low dead space present in insulin-style
syringes minimizes drug overfill and thus reduces cost. Silicone oil
(SO) microdroplets have been identified in the vitreous of patients
following injection with such syringes. These patients may report
persistent floaters that are visually significant and, in severe cases,
require vitrectomy. The incidence of symptomatic patients has
escalated, prompting statements from professional organizations
including AAO, ASRS, and OMIC. The purpose of this study is to
develop a method for identification and quantification of SO droplets
in repackaged BEV syringes and investigate possible strategies for
reducing their clinical impact.
Methods: BEV pre-filled 31g syringes (BD, Franklin Lakes, NJ)
were purchased from Avella Pharmacy (Phoenix, AZ). The syringes
were taken from a lot number used in patient care. All syringe
manipulations were performed by a retina specialist. Four groups
were studied: 1) PBS control (n=12), 2) First half injection (0.025
mL, n=12), 3) Second half injection (0.025 mL, n=12), and 4)
Complete evacuation (0.05 mL plus air to clear the hub and needle,
n=12). The contents of each group were labeled with hydrophobic
BODIPY® 493/503 on a hemacytometer and imaged with EVOS FL
auto cell imaging system (Invitrogen, Carlsbad, CA). SO droplets of
four 1mm2 areas were counted in a masked fashion.
Results: SO was adherent to the syringe wall and not suspended in
solution (Figure 1A). BODIPY staining allowed differentiation of SO
bubbles from air. Stained SO bubbles were of variable size
(Figure 1B and 1C). The first half of expelled BEV volume contained
0.1 bubbles/mm2, vs 8.6 bubbles/mm2 in the second half (p=0.01),
and 17.3 bubbles/mm2 in the complete evaucation group.
Conclusions: SO is present on the wall of insulin-style syringes prefilled with BEV. SO bubbles expelled during injection can be labeled
and counted. There is significantly more SO expressed during the
latter portions of the injection process, presumably due to squeegee
effect of the plunger along the walls of the syringe. Small volume
overfill with incomplete evacuation may be a mechanism to reduce
the clinical impact of this phenomenon.
Commercial Relationships: John D. Pitcher, Genentech (C),
Allergan (C); Christopher N. Roybal, None
Program Number: 435 Poster Board Number: A0301
Presentation Time: 1:30 PM–3:15 PM
Morphologic parameters of the macula as a prognostic factors for
visual outcome in patients with age related macular degeneration
Ivan Georgiev, Petja I. Vassileva. Eye Hospital “Prof. Pashev”, Sofia,
Bulgaria.
Purpose: To study the association of macular morphology and
visual outcome in patients with neovascular age-related macular
degeneration (nARMD) receiving intravitreal aflibercept.
Methods: Data of 65 consecutive patients with nARMD receiving
three monthly injections of aflibercept 2 mg starting in april 2015
till may 2016, was analyzed. BCVA was measured using the Early
Treatment Diabetic Retinopathy protocol and retinal morphology
was assessed every two months by OptoVue OCT. The morphologic
parameters included: intraretinal cystoid fluid (IRC), subretinal fluid
(SRF) and pigment epithelial detachment (PED). The correlations
between baseline retinal morphologic parameters and best-corrected
visual acuity (BCVA) change were assessed two months after the
third injection. Statistical analysis of covariance was conducted to
evaluate the influence of the studied morphologic features on BCVA
change after the loading phase of the treatment.
Results: Sixty five patients with mean age 76.1 (range 56-87) were
included. Subretinal fluid was present in 72% of patients, IRC in
51% of patients and PED in 78%. The mean change in BCVA after
the loading phase as a function of SRF, IRC and PED status was
evaluated. Relevant predictive factors for BCVA change after the
loading phase were baseline SRF (P = 0.05) and IRC (P = 0.05).
Conclusions: Presence of SRF, IRC and PED may be used as an
important biomarker for prognosing the therapeutical result and to
monitor treatment efficacy. Patients with IRC and SRF may require
more frequent injections for maintenance of vision. This finding
may have implications in clinical practice by helping to tailor an
individualized re-treatment pattern in nARMD patients.
Commercial Relationships: Ivan Georgiev, None;
Petja I. Vassileva, None
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ARVO 2017 Annual Meeting Abstracts
Program Number: 436 Poster Board Number: A0302
Presentation Time: 1:30 PM–3:15 PM
Same-day bilateral intravitreal injections of anti-VEGF
Verena Juncal1, Carolina Francisconi2, 1, Alan Berger2, 1,
Rajeev Muni2, 1, Louis Giavedoni2, 1, Filiberto Altomare2, 1,
David Chow2, 1, David Wong2, 1. 1St. Michael’s Hospital, Toronto,
ON, Canada; 2Department of Ophthalmology and Vision Sciences,
University of Toronto, Toronto, ON, Canada.
Purpose: Intravitreal injections are one of the most common
ophthalmic procedures and bilateral injections are frequently
necessary in clinical practice, since many retinal diseases requiring
this treatment occur bilaterally. This study evaluated the outcomes
and complications of bilateral same-day intravitreal anti-vascular
endothelial growth factor (anti-VEGF) injections.
Methods: This is a retrospective case series of 118 eyes of 59
patients who received concomitant bilateral intravitreal anti-VEGF
injections in the office between September 2011 and November
2016. The medical records were reviewed for diagnosis, anti-VEGF
agent used, pre and post injection visual acuity (VA) and intraocular
pressure (IOP), post injection complications, newly developed
systemic conditions throughout follow-up or any patient’s intolerance
of simultaneous bilateral injections. All intravitreal injections had a
separate povidone-iodine preparation, speculum, needle and syringe
for each eye.
Results: A total of 1217 injections were performed bilaterally,
with a mean of 20.63±12.56 injections per patient (range=2 to
56) throughout a follow-up period of 31.46±17.38 months. The
indications for anti-VEGF therapy were especially wet age-related
macular degeneration (83.1%) and diabetic macular edema (11.9%).
Ranibizumab was the initiating anti-VEGF agent in 91.5% of the
patients, aflibercept in 8.5% and none received bevacizumab. The
mean logMAR VA pre and post bilateral treatment were minimally
changed (0.65±0.59 and 0.64±0.62, respectively, p=0.819), as well
as the pre and post IOP (15.28±3.07 and 14.90±3.68, respectively,
p=0.189). However, 44.1% of the eyes required a total of 252
anterior chamber paracentesis (mean per eye= 4.85±3.99, range=1
to 19) at the moment of intravitreal injection due to an acute IOP
rise. One patient had a mild vitreous hemorrhage not explained by
the underlying ocular disease. Only one patient called the office
complaining of a painless subconjunctival hemorrhage. No cases of
endophthalmitis, ocular inflammation, retinal tear, retinal detachment
or systemic side effects were identified. No patients requested to
switch to alternating unilateral injections.
Conclusions: Same-day bilateral intravitreal anti-VEGF injections
are safe and well tolerated by patients. Evidence of its good
acceptance and safety profile is important on supporting the use
of this strategy, which may help reduce the treatment burden
experienced by these patients.
Commercial Relationships: Verena Juncal, None;
Carolina Francisconi, None; Alan Berger, None; Rajeev Muni,
None; Louis Giavedoni, None; Filiberto Altomare, None;
David Chow, None; David Wong, None
Program Number: 437 Poster Board Number: A0303
Presentation Time: 1:30 PM–3:15 PM
Long-Term Follow-Up of Polypoidal Choroidal Vasculopathy
Treated with Intravitreal Bevacizumab
Maxwell Wagner1, Nathaniel Tracer2, Edmund Tsui2,
Jesse T. McCann2, Irene A. Barbazetto2. 1Eastern Virginia Medical
School, Virginia Beach, VA; 2Ophthalmology, New York University
School of Medicine, New York, NY.
Purpose: To evaluate the long-term outcomes of patients with
polypoidal choroidal vasculopathy (PCV) receiving regular
intravitreal bevacizumab injections as treatment.
Methods: A retrospective review of 21 eyes from 18 patients
diagnosed with PCV was performed to assess longitudinal outcomes
including best-corrected visual acuity (BCVA), central foveal
thickness (CFT) and number of intravitreal injections. The mean
BCVA and mean CFT at 1 month, 3 months, 6 months, 12 months,
18 months, and 24 months follow-up were compared to baseline
using paired t-tests.
Results: The patients had a mean age of 68.9±7.1 years, a mean
follow-up time of 23.9±20.5 months, and received a mean number
of 9.3±6.9 injections. The mean baseline BCVA was 1.19±0.84
in LogMAR units and the mean baseline CFT was 389.2±127.9
µm. At 1 month, 3 months, 6 months, 12 months, 18 months, and
24 months follow-up the mean BCVA was 1.15±0.9, 1.02±0.76,
1.11±0.76, 1.11±0.82, 1±0.88, 0.83±0.58, and 1±0.52 LogMAR units,
respectively (P=0.09, P=0.06, P=0.13, P=0.22, P=0.13, P=0.34).
The mean CFT at 1 month, 3 months, 6 months, 12 months, 18
months, and 24 months of follow-up were 376±94.7, 364.79±122.63,
380.1±156.95, 351.88±126.46, 357.17±88.22, and 350.25±62.32
µm, respectively (P=0.07, P=0.002, P=0.001, P=0.002, P=0.01,
P=0.19). In addition, 9 eyes showed no regression of the polyps, 11
eyes showed partial regression of the polyps, and 1 eye showed total
regression as ascertained by the presence of subretinal or intraretinal
fluid on optical coherence tomography (OCT).
Conclusions: At 1 month, 3 months, 6 months, 12 months,
18 months, and 24 months of follow-up the mean BCVA and
mean CFT showed consistent improvement. The BCVA, while not
significant, was improved at all follow-up visits relative to baseline.
The CFT showed significant improvement at all follow-up visits
except at 24 months compared to baseline. For both BCVA and
CFT, at the 24-month follow-up the least significant improvement
was seen. These results support the regular use of intravitreal
bevacizumab injections in the treatment of PCV. However, they may
indicate that the improved outcomes of injections are only observed
within a year and deterioration may ensue in the long term.
Commercial Relationships: Maxwell Wagner, None;
Nathaniel Tracer, None; Edmund Tsui, None; Jesse T. McCann,
None; Irene A. Barbazetto, None
Program Number: 438 Poster Board Number: A0304
Presentation Time: 1:30 PM–3:15 PM
Intravitreal injections lead to vitreous body contamination due to
injection of cellular content of ocular tissues cut by the needle tip
Lyubomyr Lytvynchuk1, 2. 1Ophthalmology Department, University
Hospital Giessen Marburg GmbH, Giessen, Germany; 2Karl
Landsteiner Institute for Retinal Research and Imaging, Vienna,
Austria.
Purpose: Intravitreal injections (IVI) of different medications have
associated risk of intraocular inflammation, and considered to be the
main cause of intraocular septic and aseptic reaction. The mechanism
of vitreous contamination remains unclear. We aimed to discover
the cellular content in needle tip aspirates after standard IVI, and to
compare it between different needle types.
Methods: Thirty Wistar white outbred albino rats (age: 6 months,
weight: ≈700 g) and human cadaver eye were used for IVI with
hypodermic 27 gauge (G) and 30G needles, and spinal anesthesia
Pencan 27G needles, with 10 injections pro one needle type. After
transscleral penetration during IVI, an aspiration of vitreous was
applied for quantitative morphological and cell cultivation analysis of
needle tip aspirates, as well as cyto-histological analysis of aspirates
and entry sites were performed. The results were analyzed using
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ARVO 2017 Annual Meeting Abstracts
descriptive statistics, frequency tables, correlation matrices and t-test
(p <0.05 considered statistically significant).
Results: All aspirates showed a marked amount of cells presented
with following morphological cell types: conjunctival, ciliary
body non-pigmented epithelial, and sclerocyte-like cells and
granular proteins (marker of cellular damage). Aspirates from 27G
hypodermic needles (rat and cadaver eyes study) showed significantly
higher amount of granulated proteins compared to 30G hypodermic
and 27G Pencan needles (p<0.05). Study of entry sites of hypodermic
needles showed marked trauma in all layers of the eye wall (rat and
cadaver eyes study) associated with cellular destruction, compared
to 27G Pencan needle, where partial reposition of sclerocytes after
IVI was noticed. After 4 weeks of cultivation of aspirates in medium
(cadaver eye study), adherent or gravitationally immobile proliferated
conjunctival cells could be detected.
Conclusions: Our results support the hypothesis that vitreous can
be contaminated with cellular content cut by sharp inner edge of the
tip of hypodermic needle which have been used routinely for IVI.
Smaller gauge needle (30 G) causes less trauma leading to smaller
amount of cells in the needle tip potentially injected into the eye. The
alternative needle design and the possible consequences of cellular
content being injected into the vitreous cavity need to be considered
accordingly.
Commercial Relationships: Lyubomyr Lytvynchuk, None
Program Number: 439 Poster Board Number: A0305
Presentation Time: 1:30 PM–3:15 PM
Interspecies Comparison of Small Molecule Distribution Into the
Anterior Chamber Following Intravitreal Administration
Jennifer Seal, Werhner Orilla, Edward Chow, James A. Burke,
Jie Shen. Allergan, Irvine, CA.
Purpose: Drug delivery of small molecules via intravitreal (IVT)
administration has been beneficial for the treatment of retinal
diseases. Besides rabbit studies, the nonclinical pharmacokinetics
(PK) and safety of such therapeutics are often characterized in a
higher species (dog or monkey). The species selection may be based
on several factors including drug distribution pattern into the anterior
chamber (AC). The purpose of these studies was to understand
interspecies differences in distribution of IVT small molecules to the
AC and to determine which species best represented human.
Methods: Following IVT injection of 0.05% sodium fluorescein
(NaFl), 300 µg beclamethasone dipropionate (BDP) suspension,
or 4 mg triamcinolone acetonide (TA) suspension to rabbit, dog,
monkey, and pig (TA only), aqueous humor (AH) concentrations
were measured up to 6 months post dose using a Fluorotron (NaFl)
or liquid chromatography tandem mass spectrometry (BDP and TA).
Nonclinical AH TA concentrations were compared to human AH
concentrations obtained from a published clinical study following
IVT dose of 4 mg TA.
Results: 1) Maximal AH concentrations (Cmax) of NaFl in dogs were
9x and 30x higher than in monkey and rabbit, respectively.
2) The AH Cmax for BDP in dogs was 1500x and 11,000x higher than
in monkey and rabbit, respectively. Concentrations in dogs reached
~10 µg/mL and remained above the BDP solubility limit (0.2 µg/mL)
for ~14 days.
3) The AH Cmax for TA in dogs was 2x, 4x, 40x, and 70x higher than
human, monkey, pig, and rabbit, respectively. However, TA was more
rapidly cleared from the dog AH than in the other species. Due to
this rapid clearance, AH AUC rank ordering was human > monkey >
dog > pig > and rabbit. Overall, monkey AH TA concentrations most
closely approximated human exposure (Cmax and AUC).
Conclusions: Following IVT administration of all tested molecules
the AH Cmax rank ordering was dog > monkey > rabbit, though
the relative magnitude of exposure varied. For TA, the dog data
overestimated human AH Cmax but underestimated AUC. These
studies indicate that while rabbit is a common animal model for PK
evaluation of IVT drugs, interpretation of drug distribution to the
AC needs caution especially if AC exposure is an important safety
concern. Overall, monkey may be the more appropriate higher
species for IVT drug development.
Commercial Relationships: Jennifer Seal, Allergan (E);
Werhner Orilla, Allergan (E); Edward Chow, Allergan (E);
James A. Burke, Allergan (E); Jie Shen, Allergan (E)
Program Number: 424 Poster Board Number: A0290
Presentation Time: 1:30 PM–3:15 PM
Targeting SRPK1 with novel potent and selective small molecule
inhibitors inhibits choroidal neovascularisation through
modulating VEGF-A alternative splicing
David O. Bates1, 2, Hamish Toop1, James Daubney1,
Elizabeth Stewart1, Jonathan Morris3, 1, Jennifer Batson1. 1Exonate
Ltd, Nottingham, United Kingdom; 2Cancer Biology, Division
of Cancer and Stem Cells, School of Medicine, Univerity of
Nottingham, Nottingham, United Kingdom; 3School of Chemistry,
University of New South Wales, Sydney, United Kingdom.
Purpose:
Purpose: Anti-angiogenic VEGF inhibitors are the standard of
care for wAMD but must be administered by intraocular injection
and non-specifically inhibit all VEGF-A isoforms. Pathological
angiogenesis occurs when the balance between pro-angiogenic
VEGF-A165a and anti-angiogenic VEGF-A165b is switched by
differential splicing of VEGF-A mRNA to the proangiogenic
form. Small molecule inhibitors were identified that target SRPK1,
the kinase promoting VEGF-A165a splicing, thereby selectively
inhibiting pro-angiogenic VEGF-A without inhibiting endogenous,
cytoprotective, antiangiogenic VEGF-A165b. Here we describe novel
SRPK1 inhibitors that specifically inhibit pro-angiogenic VEGF-A
isoform-driven angiogenesis underlying wAMD.
Methods:
Methods: Novel compounds, synthesized based on the structure
of SRPK1, were tested in kinase assays, immunoprecipitation,
immunoblotting and immunofluorescent assays. Alternative splicing
and VEGF-A isoform expression was evaluated by RT-PCR and
ELISA. Selectivity was analysed using kinome screens, differential
scanning fluorimetry and kinome immunoprecipitation. Compounds
were evaluated for toxicity in vitro and hERG inhibition. Efficacy
was evaluated by laser-CNV in vivo in C57/Bl6 mice.
Results:
Novel compounds selectively bind to SRPK1 and dosedependently inhibit SRPK1 kinase activity (IC50s<10 nM),
SRSF1 phosphorylation and nuclear localization. The balance of
anti-angiogenic VEGF-A165b:pro-angiogenic VEGF-A165a levels
was specifically increased at the mRNA and protein level. Novel
compounds were identified that were highly specific for SRPK1
over closely related kinases and in kinome screens. These SRPK1
inhibitors were not toxic to RPE cells and had improved hERG IC50s
>1 mM. Novel compounds potently inhibited laser-CNV following
eye drop administration in mice (EC50s<0.5µM, n=6-8, P<0.05, Oneway ANOVA).
Conclusions:
We developed highly potent and selective SRPK1 inhibitors that
specifically target pro-angiogenic VEGF-A-driven choroidal
neovascularization following eye drop administration. These
compounds potentially offer more specific, efficacious and safer
therapeutics for patients with wAMD.
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ARVO 2017 Annual Meeting Abstracts
Commercial Relationships: David O. Bates, Exonate Ltd
(P), Exonate Ltd (F), Exonate Ltd (I); Hamish Toop, Exonate
Ltd (P), Exonate Ltd (E); James Daubney, Exonate Ltd (E);
Elizabeth Stewart, Exonate Ltd (E); Jonathan Morris, Exonate
Ltd (P), Exonate Ltd (C), Exonate Ltd (F), Exonate Ltd (I);
Jennifer Batson, Exonate Ltd (P), Exonate Ltd (I), Exonate Ltd (E)
Program Number: 440 Poster Board Number: A0306
Presentation Time: 1:30 PM–3:15 PM
Long term visual and anatomic outcomes of switching to
Aflibercept for neovascular AMD : 2 years results
David Sayag1, 2, Mayer Srour1, 2, Oudy Semoun1, 2, Neda Abraham3,
Vincent Pierre-Kahn3, 2. 1Ophthalmology Eye Clinic, Creteil Eye
Clinic Univ Hospital, Paris, France; 2Paris Retina Vision, Paris,
France; 3Foch Hospital, Suresnes, France.
Purpose: To report interim 2-year visual and anatomic outcomes
of intravitreal aflibercept for neovascular age-related macular
degeneration (AMD) in patients recurrent or refractory to
ranibizumab.
Methods: This is a retrospective review of eyes with neovascular
AMD with at least 2 years of follow-up after the switch. All Patients
has had a minimum of 3 injections of ranibizumab before the
switch. Aflibercept was used in recurrent or refractory patients to
ranibizumab. Changes in best corrected visual acuity (BVCA), fluid,
central retinal thickness, anatomic outcome of ellipsoid (, retinal
pigment epithelium (RPE) and external limiting membrane (ELM) on
optical coherence tomography (OCT) were described .Frequency of
injections were also analyzed
Results: 125 eyes on110 patients were studied. Mean age of patients
was 79 years. Before switching, patients had received a mean of 7,7
injections of ranibizumab (3-30). At baseline BCVA was 49,9 letters
and the mean CRT 388,3 µm. 153 (87%) eyes showed a pigment
epithelial detachment. Intraretinal fluid (IFR) was present in 59 %
of eyes. Sub-retinal fluid was present in 65% of eyes. mean follow
up duration after the first injection of aflibercept was 24 months.
One year after the switch, an interim analysis shows a nonsignificant
increase of + 2,3 letters (p=0,454) with a mean number of 3,9
Aflibercept injections (65 eyes analyzed) and a mean change in CRT
of -59,5 µm (p<0,0001 ; 145 eyes analyzed). Two years after the
switch, an interim analysis shows a mean change in visual acuity of
-0,3 letters (p=0,633) with a mean of 6,1 injections of aflibercept and
a mean change in CRT of -76,1 µm (p<0,0001 ; 55 eyes analyzed). At
24 months, ELM and RPE disruption were shown in 75% and 63%
without correlation with final BVCA.
Conclusions: Two years after a switch to aflibercept for nAMD in
patients recurrent or refractory to ranibizumab, an interim analysis
shows that visual acuity was stabilized and CRT had a significant
improvement (p<0,0001). Moreover ELM and RPE disruption are
frequent after long term switching clinical practice
Commercial Relationships: David Sayag; Mayer Srour, None;
Oudy Semoun, None; Neda Abraham, None;
Vincent Pierre-Kahn, None
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