Advertisement

Baseline Predictors of 12-Month Treatment Response to Ranibizumab in Patients With Wet Age-Related Macular Degeneration

Open AccessPublished:July 28, 2015DOI:https://doi.org/10.1016/j.ajo.2015.07.034

      Purpose

      To identify baseline characteristics predictive of visual acuity (VA) outcomes at month 12 (M12) and treatment frequency in the first 12 months of the phase III HARBOR study.

      Design

      Retrospective, exploratory analysis of multicenter randomized controlled trial data.

      Methods

      setting: Randomized, multicenter. study population: Patients aged ≥50 years with subfoveal wet age-related macular degeneration (AMD) who had best-corrected VA (BCVA) values measured at baseline and M12. intervention: Intravitreal ranibizumab 0.5 mg administered monthly (n = 249) or as needed (PRN) after 3 monthly loading doses (n = 251). main outcome measures: BCVA change from baseline at M12, percentage of patients who gained ≥15 letters (3 lines) in BCVA from baseline at M12, and percentage of patients who achieved ≥20/40 vision (Snellen) at M12 served as the basis for analyzing baseline predictors of observed VA outcomes in the monthly and PRN groups. Total number of ranibizumab PRN injections in the first 12 months was also evaluated. Only variables that were statistically significant (P < .05) remained in the final statistical models.

      Results

      Baseline predictors of BCVA change from baseline at M12 and/or percentage of 3-line gainers included lower BCVA, younger age, smaller total choroidal neovascularization (CNV) leakage area, smaller area of occult CNV, and presence of subretinal fluid (SRF). Baseline predictors of ≥20/40 vision at M12 included higher BCVA, smaller total CNV leakage area, and presence of SRF. SRF thickness >118.25 μm at baseline predicted requiring more ranibizumab injections in the first 12 months of treatment.

      Conclusions

      Select baseline characteristics have predictive value for visual prognosis and treatment frequency in ranibizumab-treated patients with wet AMD.
      Although most patients with neovascular age-related macular degeneration (wet AMD) experience improvements in visual and anatomic outcomes with anti–vascular endothelial growth factor (anti-VEGF) therapy, a subset of patients do not respond optimally to treatment. For example, despite significant visual improvements in the majority of patients treated with ranibizumab (Lucentis; Genentech, Inc, South San Francisco, California, USA) in the ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration)
      • Brown D.M.
      • Kaiser P.K.
      • Michels M.
      • et al.
      for the ANCHOR Study Group
      Ranibizumab versus verteporfin for neovascular age-related macular degeneration.
      • Brown D.M.
      • Michels M.
      • Kaiser P.K.
      • Heier J.S.
      • Sy J.P.
      • Ianchulev T.
      ANCHOR Study Group
      Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study.
      and MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD)
      • Rosenfeld P.J.
      • Brown D.M.
      • Heier J.S.
      • et al.
      for the MARINA Study Group
      Ranibizumab for neovascular age-related macular degeneration.
      trials, ∼10% of patients in ANCHOR and ∼8%–10% of patients in MARINA lost ≥15 letters in best-corrected visual acuity (BCVA) from baseline at month 24.
      • Brown D.M.
      • Kaiser P.K.
      • Michels M.
      • et al.
      for the ANCHOR Study Group
      Ranibizumab versus verteporfin for neovascular age-related macular degeneration.
      • Brown D.M.
      • Michels M.
      • Kaiser P.K.
      • Heier J.S.
      • Sy J.P.
      • Ianchulev T.
      ANCHOR Study Group
      Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study.
      • Rosenfeld P.J.
      • Brown D.M.
      • Heier J.S.
      • et al.
      for the MARINA Study Group
      Ranibizumab for neovascular age-related macular degeneration.
      Findings from several retrospective studies suggest that certain demographic and choroidal neovascularization (CNV) lesion characteristics at baseline may increase the likelihood of having better or worse treatment outcomes.
      • Kaiser P.K.
      • Brown D.M.
      • Zhang K.
      • et al.
      Ranibizumab for predominantly classic neovascular age-related macular degeneration: subgroup analysis of first-year ANCHOR results.
      • Kaiser P.K.
      • Blodi B.A.
      • Shapiro H.
      • Acharya N.R.
      MARINA Study Group
      Angiographic and optical coherence tomographic results of the MARINA study of ranibizumab in neovascular age-related macular degeneration.
      • Ying G.-s.
      • Huang J.
      • Maguire M.G.
      • et al.
      on behalf of the Comparison of Age-related Macular Degeneration Treatments Trials Research Group
      Baseline predictors for one-year visual outcomes with ranibizumab or bevacizumab for neovascular age-related macular degeneration.
      The elucidation of demographic, anatomic/imaging, and functional characteristics at baseline that can be used as predictive biomarkers of response to anti-VEGF treatments will be helpful for the successful development of next-generation treatments for wet AMD.
      Historically, smaller CNV lesion sizes at baseline are generally associated with better visual acuity (VA) outcomes at month 24 in patients with subfoveal wet AMD, as shown in the TAP (Treatment of Age-Related Macular Degeneration With Photodynamic Therapy) and VIP (Verteporfin in Photodynamic Therapy) trials.
      • Blinder K.J.
      • Bradley S.
      • Bressler N.M.
      • et al.
      Treatment of Age-related Macular Degeneration with Photodynamic Therapy Study Group; Verteporfin in Photodynamic Therapy Study Group
      Effect of lesion size, visual acuity, and lesion composition on visual acuity change with and without verteporfin therapy for choroidal neovascularization secondary to age-related macular degeneration: TAP and VIP report no. 1.
      Retrospective analyses of 12-month data from ANCHOR
      • Kaiser P.K.
      • Brown D.M.
      • Zhang K.
      • et al.
      Ranibizumab for predominantly classic neovascular age-related macular degeneration: subgroup analysis of first-year ANCHOR results.
      and 24-month data from MARINA
      • Kaiser P.K.
      • Blodi B.A.
      • Shapiro H.
      • Acharya N.R.
      MARINA Study Group
      Angiographic and optical coherence tomographic results of the MARINA study of ranibizumab in neovascular age-related macular degeneration.
      demonstrated that lower baseline BCVA, smaller baseline CNV lesion size, and younger baseline age were predictive of better VA outcomes in ranibizumab-treated patients with wet AMD.
      • Kaiser P.K.
      • Brown D.M.
      • Zhang K.
      • et al.
      Ranibizumab for predominantly classic neovascular age-related macular degeneration: subgroup analysis of first-year ANCHOR results.
      • Kaiser P.K.
      • Blodi B.A.
      • Shapiro H.
      • Acharya N.R.
      MARINA Study Group
      Angiographic and optical coherence tomographic results of the MARINA study of ranibizumab in neovascular age-related macular degeneration.
      These baseline predictors of visual outcomes were also observed in a retrospective analysis of ranibizumab- or bevacizumab-treated patients with wet AMD who completed the first year of CATT (Comparison of Age-Related Macular Degeneration Treatments Trials).
      • Kaiser P.K.
      • Brown D.M.
      • Zhang K.
      • et al.
      Ranibizumab for predominantly classic neovascular age-related macular degeneration: subgroup analysis of first-year ANCHOR results.
      • Kaiser P.K.
      • Blodi B.A.
      • Shapiro H.
      • Acharya N.R.
      MARINA Study Group
      Angiographic and optical coherence tomographic results of the MARINA study of ranibizumab in neovascular age-related macular degeneration.
      The HARBOR (Phase III, Double-Masked, Multicenter, Randomized, Active treatment-controlled Study of the Efficacy and Safety of 0.5 mg and 2.0 mg Ranibizumab Administered Monthly or on an As-needed Basis [PRN] in Patients With Subfoveal Neovascular Age-Related Macular Degeneration) trial provides a large prospective data set on ranibizumab-treated patients with wet AMD.
      • Busbee B.G.
      • Ho A.C.
      • Brown D.M.
      • et al.
      for the HARBOR Study Group
      Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration.
      At the end of the first year of HARBOR (the primary endpoint), clinically meaningful and similar improvements in BCVA were observed across all treatment groups.
      • Busbee B.G.
      • Ho A.C.
      • Brown D.M.
      • et al.
      for the HARBOR Study Group
      Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration.
      The mean change from baseline in BCVA at month 12, based on the last-observation-carried-forward method, was +10.1 letters (0.5 mg monthly; n = 275), +8.2 letters (0.5 mg PRN; n = 275), +9.2 letters (2.0 mg monthly; n = 274), and +8.6 letters (2.0 mg PRN; n= 273).
      • Busbee B.G.
      • Ho A.C.
      • Brown D.M.
      • et al.
      for the HARBOR Study Group
      Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration.
      These improvements were achieved with a mean of 7.7 and 6.9 injections in the 0.5 mg and 2.0 mg PRN groups, respectively, and a mean of 11.3 and 11.2 injections in the 0.5 mg and 2.0 mg monthly groups, respectively.
      • Busbee B.G.
      • Ho A.C.
      • Brown D.M.
      • et al.
      for the HARBOR Study Group
      Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration.
      Although the prespecified superiority and noninferiority comparisons were not met at year 1, the HARBOR study 1-year results demonstrated that ranibizumab 0.5 mg administered on a monthly or PRN regimen, guided by VA and strict spectral-domain optical coherence tomography (SD-OCT) re-treatment criteria, resulted in clinically meaningful VA gains in patients with wet AMD.
      • Busbee B.G.
      • Ho A.C.
      • Brown D.M.
      • et al.
      for the HARBOR Study Group
      Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration.
      This retrospective, exploratory analysis of data from the HARBOR study investigated demographic and baseline characteristics predictive of VA outcomes at month 12 in the ranibizumab 0.5 mg monthly and 0.5 mg PRN groups, and treatment frequency in the first 12 months in the ranibizumab 0.5 mg PRN group. The ranibizumab 0.5 mg dose was chosen because it is the approved dosage for the treatment of wet AMD,
      and is thus the most useful to clinicians in the context of evaluating baseline predictors of treatment response. Understanding which demographic and ocular characteristics at baseline can be used as predictive biomarkers of response to anti-VEGF treatment may help retina specialists design optimal treatment plans tailored from the start of therapy to individual patients with wet AMD.

      Methods

       Study Design and Patient Eligibility

      The methods for the HARBOR study have been reported previously.
      • Busbee B.G.
      • Ho A.C.
      • Brown D.M.
      • et al.
      for the HARBOR Study Group
      Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration.
      Briefly, HARBOR was a 24-month, phase III, randomized, multicenter, double-masked, active-treatment controlled study that evaluated the efficacy and safety of intravitreal ranibizumab 0.5 mg and 2.0 mg administered monthly or PRN after 3 monthly loading doses in treatment-naïve patients (n = 1097) aged ≥50 years with active subfoveal wet AMD (predominantly classic, minimally classic, or purely occult CNV) and baseline BCVA of 20/40–20/230 (Snellen equivalent).
      • Busbee B.G.
      • Ho A.C.
      • Brown D.M.
      • et al.
      for the HARBOR Study Group
      Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration.
      Re-treatment in the PRN groups was based on BCVA using Early Treatment Diabetic Retinopathy (ETDRS) charts and SD OCT criteria. The study was conducted in accordance with Good Clinical Practice guidelines (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use E6), applicable US Food and Drug Administration regulations, and the Health Insurance Portability and Accountability Act. The study protocol was approved by institutional review boards at each location prior to study initiation, and all participants provided written informed consent. The HARBOR study is registered at ClinicalTrials.gov (no. NCT00891735).

       Outcome Measures

      The primary endpoint of the HARBOR study was the mean change from baseline in BCVA at month 12.
      • Busbee B.G.
      • Ho A.C.
      • Brown D.M.
      • et al.
      for the HARBOR Study Group
      Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration.
      In this retrospective, exploratory analysis of multicenter, randomized, controlled data from the HARBOR trial, the main outcome measures that served as a basis for baseline predictors of VA outcomes at month 12 were BCVA change from baseline at month 12, the proportion of patients with a BCVA gain of ≥15 ETDRS letters from baseline at month 12, and the proportion of patients with a Snellen equivalent of 20/40 or better at month 12 in the ranibizumab 0.5 mg monthly and 0.5 mg PRN groups. A post hoc analysis of the total number of injections in the first 12 months in patients receiving ranibizumab 0.5 mg PRN was also performed.

       Statistical Methods

      These exploratory analyses were performed on observed data from patients in the ranibizumab 0.5 mg monthly (n = 249) and 0.5 mg PRN (n = 251) treatment groups who had BCVA values measured at both baseline and month 12. A multivariate linear regression model was performed to determine baseline predictors for BCVA change from baseline at month 12. Multivariate analysis using logistic regression models was performed to determine baseline predictors for BCVA gain of ≥15 letters from baseline at month 12 and baseline predictors for Snellen equivalent of 20/40 or better at month 12. Proportional odds and linear regression models were used to determine baseline predictors for the total number of injections in the 0.5 mg PRN group during the first 12 months of the study. Final models included only significant (P < .05) predictors selected by stepwise selection methods. All analyses were exploratory in nature and no multiplicity adjustment was made. All analyses were conducted using SAS software version 9.2 (SAS Institute, Inc, Cary, North Carolina, USA).
      To better facilitate interpretation of the data and illustrate the trends graphically, a Classification and Regression Tree (CART) analysis
      • Breiman L.
      • Friedman J.H.
      • Olshen R.A.
      • Stone C.J.
      Classification and Regression Trees.
      was used to dichotomize values for continuous baseline predictors from the final models where appropriate. All cutoff values were derived using CART v6.0 (Salford Systems, San Diego, California, USA). A total of 44 variables (demographic parameters, baseline characteristics, and assessments) were included in the statistical modeling; for predictors of visual outcome, regimen (monthly vs PRN) was also included in the candidate list.

      Results

      Patient demographics and baseline ocular characteristics for the study eye, previously reported, were well balanced among the ranibizumab treatment arms.
      • Busbee B.G.
      • Ho A.C.
      • Brown D.M.
      • et al.
      for the HARBOR Study Group
      Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration.
      In the 0.5 mg monthly and 0.5 mg PRN groups, mean VA at baseline was 54.2 and 54.5 letters (approximate Snellen equivalent of 20/80), respectively, and the mean age at baseline was approximately 79 years. Overall, approximately 46% of patients in the 0.5 mg monthly and 0.5 mg PRN groups had minimally classic CNV lesions, 16% had predominantly classic lesions, and 37% had purely occult CNV. Total area of CNV leakage and total area of CNV in the 2 treatment groups ranged from 3.31 to 3.48 disc area (DA) and from 3.04 to 3.27 DA, respectively.
      • Busbee B.G.
      • Ho A.C.
      • Brown D.M.
      • et al.
      for the HARBOR Study Group
      Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration.
      The mean baseline area of occult CNV in the 0.5 mg monthly and 0.5 mg PRN arms were 2.81 DA and 2.59 DA, respectively. Approximately 76% of all patients had subretinal fluid (SRF) present at baseline, and the average baseline SRF thickness (including patients with no SRF) was 120.0 μm and 129.7 μm (median, 109.5 μm and 111.0 μm) in the 0.5 mg monthly and 0.5 mg PRN groups, respectively. In these retrospective, exploratory analyses of the HARBOR study, 6 of 44 variables were found to be significant baseline predictors of visual outcomes and/or injection frequency (Table).
      TablePatient Demographics, Baseline Characteristics, and Assessments Included in the Statistical Modeling of Baseline Predictors of 12-Month Treatment Response to Ranibizumab in Patients with Wet Age-Related Macular Degeneration
      Variables that were baseline predictors of visual outcomes at month 12
      Age; BCVA; area of occult CNV with no classic component; total CNV leakage area; subretinal fluid presence
      Baseline predictors are variables that were statistically significant (P < .05) in the final model.
      Variables that were baseline predictors of treatment frequency in the first 12 months
      Subretinal fluid thickness
      Baseline predictors are variables that were statistically significant (P < .05) in the final model.
      Variables that were NOT baseline predictors of visual outcomes or treatment frequency
      Sex

      Race

      Ethnicity

      Current smoking status

      Lens status

      Treatment regimen (monthly vs PRN)

      Central foveal thickness

      Central subfield thickness

      Area of classic CNV

      Percentage of classic CNV area

      CNV classification

      Evidence of fluid from CNV

      Percentage of total CNV area

      Area of subretinal fibrous tissue

      Percentage of subretinal fibrous tissue
      Greatest linear dimension of lesion

      Percentage of occult CNV with no classic component

      Area of other lesion component with no CNV

      PED

      PED thickness

      Presence of blood

      Presence of classic CNV

      Presence of fibrous tissue

      Presence of neovascular AMD

      Presence of occult CNV

      Presence of photocoagulation scar

      Presence of serous PED
      Total macular volume

      Total area of CNV

      Total area of lesion

      Macula dry
      See Appendix (Supplemental Material available at AJO.com) for definition, as provided by the Digital Angiography Reading Center (DARC).


      Macula dry-2
      See Appendix (Supplemental Material available at AJO.com) for definition, as provided by the Digital Angiography Reading Center (DARC).


      Macula totally dry
      See Appendix (Supplemental Material available at AJO.com) for definition, as provided by the Digital Angiography Reading Center (DARC).


      Macula totally dry-2
      See Appendix (Supplemental Material available at AJO.com) for definition, as provided by the Digital Angiography Reading Center (DARC).


      Retina dry
      See Appendix (Supplemental Material available at AJO.com) for definition, as provided by the Digital Angiography Reading Center (DARC).


      Retina dry-2
      See Appendix (Supplemental Material available at AJO.com) for definition, as provided by the Digital Angiography Reading Center (DARC).


      Retinal fluid atrophy (none, extrafoveal, remote, subfoveal)

      RPE rip (none, outside,
      See Appendix (Supplemental Material available at AJO.com) for definition, as provided by the Digital Angiography Reading Center (DARC).
      remote,
      See Appendix (Supplemental Material available at AJO.com) for definition, as provided by the Digital Angiography Reading Center (DARC).
      subfoveal)
      AMD = age-related macular degeneration; BCVA = best-corrected visual acuity; CNV = choroidal neovascularization; PED = pigment epithelial defect; RPE = retinal pigment epithelium.
      a Baseline predictors are variables that were statistically significant (P < .05) in the final model.
      b See Appendix (Supplemental Material available at AJO.com) for definition, as provided by the Digital Angiography Reading Center (DARC).

       Baseline Predictors for Best-Corrected Visual Acuity Change at Month 12

      Significant baseline predictors for BCVA change at month 12 in patients who had both baseline and month 12 BCVA values included baseline BCVA, age, and total CNV leakage area and area of occult CNV.
      Lower (ie, worse) BCVA at baseline predicted greater mean gains in BCVA at month 12 (Figure 1). Patients with baseline BCVA ≤44 letters (approximate Snellen equivalent of 20/125; n = 103; gray circles) gained an average of 15.3 letters at month 12 compared with a mean gain of 8.2 letters in patients with baseline BCVA >44 letters (approximate Snellen equivalent of 20/125 or better; n = 397; black circles). Younger age at baseline also predicted greater mean gain in BCVA at month 12 (Figure 2). Patients aged ≤73 years at baseline (n = 116; gray circles) gained a mean of 13.1 letters at month 12 compared with a mean gain of 8.6 letters in patients aged >73 years at baseline (n = 384; black circles).
      Figure thumbnail gr1
      Figure 1Lower (ie, worse) best-corrected visual acuity at baseline predicted, on average, greater mean gain in best-corrected visual acuity at month 12 in patients treated with ranibizumab for wet age-related macular degeneration. Data shown are for patients in the ranibizumab 0.5 mg monthly and 0.5 mg as-needed groups who had best-corrected visual acuity measured at both baseline and month 12. Dashed line = fitted simple linear regression line. BCVA = best-corrected visual acuity.
      Figure thumbnail gr2
      Figure 2Younger age at baseline predicted, on average, greater mean gain in best-corrected visual acuity at month 12 in patients treated with ranibizumab for wet age-related macular degeneration. Data shown are for patients in the ranibizumab 0.5 mg monthly and 0.5 mg as-needed groups who had best-corrected visual acuity measured at both baseline and month 12. Dashed line = fitted simple linear regression line. BCVA = best-corrected visual acuity.
      Smaller total CNV leakage area at baseline and area of occult CNV were also predictive of greater mean gains in BCVA at month 12 (Figure 3). Patients with baseline total CNV leakage area ≤5.24 DA and baseline area of occult CNV ≤5.47 DA at baseline (n = 415; Left panel) had a greater mean gain in BCVA at month 12 (+10.7 letters) than did patients with total CNV leakage area >5.24 DA and area of occult CNV >5.47 DA (n = 51; +8.9 letters; Middle panel). Patients with smaller total CNV leakage area ≤5.24 DA and area of occult CNV ≤5.47 DA at baseline also had greater mean gains than did patients with total CNV leakage area >5.24 DA and area of occult CNV ≤5.47 DA (n = 34; −3.0 letters; Right panel).
      Figure thumbnail gr3
      Figure 3Smaller total choroidal neovascularization leakage area at baseline and area of occult choroidal neovascularization predicted, on average, greater mean gain in best-corrected visual acuity at month 12 in patients treated with ranibizumab for wet age-related macular degeneration. Data shown are for patients in the ranibizumab 0.5 mg monthly and 0.5 mg as-needed groups who had best-corrected visual acuity measured at both baseline and month 12. Vertical bars are ±1 standard error of the mean. BCVA = best-corrected visual acuity; CNV = choroidal neovascularization; DA = disc area.

       Baseline Predictors for Best-Corrected Visual Acuity Gain ≥15 Letters at Month 12

      Significant baseline predictors for BCVA gain ≥15 letters at month 12 in patients who had both baseline and month 12 BCVA values included BCVA and total CNV leakage area with SRF present.
      Lower (ie, worse) BCVA at baseline predicted a greater likelihood of gaining ≥15 letters at month 12 (Figure 4). Among patients with baseline BCVA ≤68 letters (approximate Snellen equivalent of 20/40 or worse; n = 438), 37% gained ≥15 letters at month 12 vs 11% of patients with baseline BCVA >68 letters (approximate Snellen equivalent better than 20/40; n = 62; odds ratio [OR], 4.6; 95% confidence interval [CI] 2.1–10.5; from logistic regression model with baseline BCVA, baseline total CNV leakage area, and SRF presence at baseline as covariates).
      Figure thumbnail gr4
      Figure 4Lower (ie, worse) best-corrected visual acuity at baseline predicted, on average, a greater likelihood of gaining ≥15 letters at month 12 in patients treated with ranibizumab for wet age-related macular degeneration. Data analyzed for patients in the ranibizumab 0.5 mg monthly and 0.5 mg as-needed groups who had best-corrected visual acuity measured at both baseline and month 12. Odds ratio, 4.6 (95% confidence interval 2.1–10.5) from logistic regression model with baseline best-corrected visual acuity, baseline total choroidal neovascularization leakage area, and subretinal fluid presence at baseline as covariates. BCVA = best-corrected visual acuity.
      Smaller total CNV leakage area with SRF present at baseline also predicted a greater likelihood of BCVA gain ≥15 letters at month 12 (Figure 5). In patients with SRF present at baseline, 41% of those with baseline total CNV leakage area ≤4.51 DA (n = 282) gained ≥15 letters at month 12 vs 22% of patients with baseline total CNV leakage area >4.51 DA (n = 99; OR, 2.5; 95% CI 1.5–4.3; from logistic regression model with baseline BCVA, baseline total CNV leakage area, and SRF presence at baseline as covariates). In patients who did not have SRF present at baseline, total CNV leakage area at baseline was not predictive of BCVA gain ≥15 letters at month 12.
      Figure thumbnail gr5
      Figure 5Smaller total choroidal neovascularization leakage area with subretinal fluid present at baseline predicted, on average, a greater likelihood of best-corrected visual acuity gain ≥15 letters at month 12 in patients treated with ranibizumab for wet age-related macular degeneration. Data analyzed for patients in the ranibizumab 0.5 mg monthly and 0.5 mg as-needed groups who had best-corrected visual acuity measured at both baseline and month 12. Odds ratio, 2.5 (95% confidence interval 1.5–4.3) from logistic regression model with baseline best-corrected visual acuity, baseline total choroidal neovascularization leakage area, and subretinal fluid presence at baseline as covariates. BCVA = best-corrected visual acuity; CNV = choroidal neovascularization; DA = disc area; SRF = subretinal fluid.

       Baseline Predictors for Snellen Equivalent of 20/40 or Better at Month 12

      Significant baseline predictors for Snellen equivalent of 20/40 or better at month 12 for patients who had both baseline and month 12 BCVA values included BCVA, total CNV leakage area, and presence of SRF.
      Higher (ie, better) BCVA at baseline predicted a greater likelihood of achieving a Snellen equivalent of 20/40 or better at month 12 (Figure 6). Patients who achieved 20/40 or better at month 12 (n = 260; gray circles) had a mean baseline BCVA of 60.7 letters (approximate Snellen equivalent of 20/62.5) vs a mean baseline BCVA of 48.3 letters (approximate Snellen equivalent of 20/100) in patients who did not achieve 20/40 at month 12 (n = 240; black circles). Each letter increase in baseline BCVA increased the odds of achieving 20/40 or better by 1.11-fold (95% CI 1.09–1.13) at month 12.
      Figure thumbnail gr6
      Figure 6Higher (ie, better) best-corrected visual acuity at baseline predicted, on average, a greater likelihood of achieving a Snellen equivalent of 20/40 or better at month 12 in patients treated with ranibizumab for wet age-related macular degeneration. Data shown are for patients in the ranibizumab 0.5 mg monthly and 0.5 mg as-needed groups who had best-corrected visual acuity measured at both baseline and month 12. Dashed line = fitted simple linear regression line. BCVA = best-corrected visual acuity.
      Smaller total CNV leakage area at baseline also predicted a greater likelihood of achieving a Snellen equivalent of 20/40 or better at month 12 (Figure 7). Patients who achieved 20/40 or better at month 12 (n = 260; gray circles) had a smaller mean total area of CNV leakage at baseline (3.00 DA) compared with patients who did not achieve 20/40 at month 12 (n = 240; 3.69 DA). Each DA decrease in total area of CNV leakage at baseline increased the odds of achieving 20/40 or better by 1.2-fold (95% CI 1.1–1.3) at month 12.
      Figure thumbnail gr7
      Figure 7Smaller total choroidal neovascularization leakage area at baseline predicted, on average, a greater likelihood of achieving 20/40 or better at month 12 in patients treated with ranibizumab for wet age-related macular degeneration. Data shown are for patients in the ranibizumab 0.5 mg monthly and 0.5 mg as-needed groups who had best-corrected visual acuity measured at both baseline and month 12. Dashed line = fitted simple linear regression line. BCVA = best-corrected visual acuity; CNV = choroidal neovascularization; DA = disc area.
      The presence of SRF at baseline was also predictive of a greater likelihood of achieving a Snellen equivalent of 20/40 or better at month 12 (Figure 8). Overall, 56% of patients with SRF present at baseline (n = 381) achieved 20/40 or better at month 12 compared with 40% of patients with SRF absent at baseline (n = 119). Patients with SRF present at baseline had 2-fold greater odds of achieving 20/40 or better at month 12 compared with patients who did not have SRF present at baseline (OR, 2.0; 95% CI 1.2–3.3; from logistic regression model with baseline BCVA, baseline total CNV leakage area, and SRF presence at baseline as covariates).
      Figure thumbnail gr8
      Figure 8Subretinal fluid presence at baseline predicted, on average, a greater likelihood of achieving 20/40 or better at month 12 in patients treated with ranibizumab for wet age-related macular degeneration. Data shown for patients in the ranibizumab 0.5 mg monthly and 0.5 mg as-needed groups who had best-corrected visual acuity measured at both baseline and month 12. Odds ratio, 2.0 (95% confidence interval 1.2–3.3) derived from logistic regression model with baseline best-corrected visual acuity, baseline total choroidal neovascularization leakage area, and subretinal fluid presence at baseline as covariates. SRF = subretinal fluid.

       Baseline Predictors for Total Number of Injections Over 12 Months

      A post hoc analysis of the total number of injections over 12 months in ranibizumab 0.5 mg PRN patients with baseline and month 12 BCVA values found that greater SRF thickness at baseline predicted a greater likelihood of receiving more ranibizumab injections in the first 12 months of the HARBOR study (Figure 9). Patients with SRF thickness >118.25 μm (n = 117; black circles) required a mean of 8.9 injections over 12 months vs a mean of 7.3 injections for patients with SRF ≤118.25 μm (n = 134; gray circles). Similar results were obtained when the number of injections was evaluated as a continuous variable.
      Figure thumbnail gr9
      Figure 9Greater subretinal fluid thickness at baseline predicted requiring, on average, a greater number of ranibizumab injections in the first 12 months of study treatment in patients with wet age-related macular degeneration. Data shown for patients in the ranibizumab 0.5 mg monthly and 0.5 mg as-needed groups who had best-corrected visual acuity measured at both baseline and month 12. Dashed line = fitted simple linear regression line. SRF = subretinal fluid.

      Discussion

      Anti-VEGF therapy was the first treatment approved for wet AMD that showed a possibility of VA restoration in a previously poorly treatable disease.
      • Brown D.M.
      • Kaiser P.K.
      • Michels M.
      • et al.
      for the ANCHOR Study Group
      Ranibizumab versus verteporfin for neovascular age-related macular degeneration.
      • Brown D.M.
      • Michels M.
      • Kaiser P.K.
      • Heier J.S.
      • Sy J.P.
      • Ianchulev T.
      ANCHOR Study Group
      Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study.
      • Rosenfeld P.J.
      • Brown D.M.
      • Heier J.S.
      • et al.
      for the MARINA Study Group
      Ranibizumab for neovascular age-related macular degeneration.
      Despite the great advancement in wet AMD treatment with anti-VEGF molecules, there is a need to develop additional approaches for those wet AMD patients who demonstrate suboptimal response to anti-VEGF therapy. Identification of predictive biomarkers of anti-VEGF response would enable the selection of those patients who will most benefit from novel therapies. In addition, validated objective biomarkers predictive of injection frequency with anti-VEGF molecules may enable retina specialists to individualize dosing regimens at the time of a patient's first treatment.
      A variety of baseline patient and ocular characteristics predictive of treatment response have been explored in previous wet AMD studies.
      • Kaiser P.K.
      • Brown D.M.
      • Zhang K.
      • et al.
      Ranibizumab for predominantly classic neovascular age-related macular degeneration: subgroup analysis of first-year ANCHOR results.
      • Kaiser P.K.
      • Blodi B.A.
      • Shapiro H.
      • Acharya N.R.
      MARINA Study Group
      Angiographic and optical coherence tomographic results of the MARINA study of ranibizumab in neovascular age-related macular degeneration.
      • Ying G.-s.
      • Huang J.
      • Maguire M.G.
      • et al.
      on behalf of the Comparison of Age-related Macular Degeneration Treatments Trials Research Group
      Baseline predictors for one-year visual outcomes with ranibizumab or bevacizumab for neovascular age-related macular degeneration.
      In the current study, we performed a retrospective exploratory analysis of the large 12-month HARBOR data set to evaluate the correlation of baseline characteristics that could serve as potential predictive biomarkers of anti-VEGF response. Our focus was on the anatomic/imaging and demographic characteristics present at baseline and the potential associations of these characteristics with visual function outcomes at month 12 in patients receiving ranibizumab 0.5 mg monthly or PRN.
      Significant baseline predictors of better VA outcomes at month 12 in the ranibizumab 0.5 mg monthly and 0.5 mg PRN groups included lower baseline BCVA, younger age at baseline, and smaller total area of CNV leakage at baseline. These findings provide further confirmation of baseline predictors of visual outcomes in wet AMD patients treated with ranibizumab,
      • Kaiser P.K.
      • Brown D.M.
      • Zhang K.
      • et al.
      Ranibizumab for predominantly classic neovascular age-related macular degeneration: subgroup analysis of first-year ANCHOR results.
      • Ying G.-s.
      • Huang J.
      • Maguire M.G.
      • et al.
      on behalf of the Comparison of Age-related Macular Degeneration Treatments Trials Research Group
      Baseline predictors for one-year visual outcomes with ranibizumab or bevacizumab for neovascular age-related macular degeneration.
      • Boyer D.S.
      • Antoszyk A.N.
      • Awh C.C.
      • Bhistkul R.B.
      • Shapiro H.
      • Acharya N.R.
      for the MARINA Study Group
      Subgroup analysis of the MARINA study of ranibizumab in neovascular age-related macular degeneration.
      • Rosenfeld P.J.
      • Shapiro H.
      • Tuomi L.
      • Webster M.
      • Elledge J.
      • Blodi B.
      MARINA Study Group; ANCHOR Study Group
      Characteristics of patients losing vision after 2 years of monthly dosing in the phase III ranibizumab clinical trials.
      particularly in the PRN group, where only the CATT data
      • Ying G.-s.
      • Huang J.
      • Maguire M.G.
      • et al.
      on behalf of the Comparison of Age-related Macular Degeneration Treatments Trials Research Group
      Baseline predictors for one-year visual outcomes with ranibizumab or bevacizumab for neovascular age-related macular degeneration.
      exist in such a large cohort. Additionally, the CATT subanalysis identified total foveal thickness and retinal pigment epithelium elevation on time-domain OCT as baseline anatomic predictors of VA outcomes at month 12.
      • Ying G.-s.
      • Huang J.
      • Maguire M.G.
      • et al.
      on behalf of the Comparison of Age-related Macular Degeneration Treatments Trials Research Group
      Baseline predictors for one-year visual outcomes with ranibizumab or bevacizumab for neovascular age-related macular degeneration.
      Although these anatomic variables were included in the current HARBOR subanalysis, they were not identified as significant covariates for treatment response, possibly owing to differences in the way the variables were defined or measured (SD OCT was used in HARBOR, whereas time-domain OCT was used in year 1 of CATT), or owing to differences in how the statistical modeling was conducted between studies.
      In an effort to reduce the treatment burden associated with frequent anti-VEGF injections, many retina specialists individualize treatment for their patients using variable dosing regimens such as PRN and treat-and-extend.
      • Haller J.A.
      Current anti-vascular endothelial growth factor dosing regimens: benefits and burden.
      • Lally D.R.
      • Gerstenblith A.T.
      • Regillo C.D.
      Preferred therapies for neovascular age-related macular degeneration.
      PRN treatment regimens with VEGF inhibitors resulted in visual outcomes similar to monthly treatment when VA and OCT criteria were used to assess the need for re-treatment.
      • Busbee B.G.
      • Ho A.C.
      • Brown D.M.
      • et al.
      for the HARBOR Study Group
      Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration.
      • Fung A.E.
      • Lalwani G.A.
      • Rosenfeld P.J.
      • et al.
      An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration.
      • Lalwani G.A.
      • Rosenfeld P.J.
      • Fung A.E.
      • et al.
      A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO Study.
      • The CATT Research Group
      Ranibizumab and bevacizumab for neovascular age-related macular degeneration.
      • Martin D.F.
      • Maguire M.G.
      • Fine S.L.
      • et al.
      for the Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group
      Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results.
      • Chakravarthy U.
      • Harding S.P.
      • Rogers C.A.
      • et al.
      the IVAN Study Investigators
      Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial.
      • Chakravarthy U.
      • Harding S.P.
      • Rogers C.A.
      • et al.
      on behalf of the IVAN Study Investigators
      Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial.
      • Heier J.S.
      • Brown D.M.
      • Chong V.
      • et al.
      VIEW 1 and VIEW 2 Study Groups
      Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration.
      In this subanalysis of the HARBOR study, SRF thickness >118.25 μm at baseline predicted requiring, on average, 1.6 more injections in year 1 of HARBOR compared with patients whose SRF thickness was ≤118.25 μm at baseline. These data suggest that greater SRF thickness at baseline may require more-frequent injections in the first year of treatment.
      A retrospective, exploratory, post hoc analysis of pooled ranibizumab 0.5 mg data from 4 ranibizumab trials in wet AMD patients (ANCHOR,
      • Brown D.M.
      • Kaiser P.K.
      • Michels M.
      • et al.
      for the ANCHOR Study Group
      Ranibizumab versus verteporfin for neovascular age-related macular degeneration.
      MARINA,
      • Rosenfeld P.J.
      • Brown D.M.
      • Heier J.S.
      • et al.
      for the MARINA Study Group
      Ranibizumab for neovascular age-related macular degeneration.
      HARBOR,
      • Busbee B.G.
      • Ho A.C.
      • Brown D.M.
      • et al.
      for the HARBOR Study Group
      Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration.
      and PIER [Phase IIIb, Multicenter, Randomized, Double-Masked, Sham Injection-Controlled Study of the Efficacy and Safety of Ranibizumab in Subjects With Subfoveal Choroidal Neovascularization With or Without Classic CNV Secondary to Age-Related Macular Degeneration study]
      • Regillo C.D.
      • Brown D.M.
      • Abraham P.
      • et al.
      PIER Study Group
      Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1.
      ) also demonstrated that patients who required ≥10 injections in the first 12 months of ranibizumab treatment (n = 76) had significantly greater mean SRF thickness at baseline compared with patients who required <10 injections (n = 175). (Adamis AP et al. Presented at the 2012 Retina Society Annual Meeting, October 4–7, 2012; Washington, DC). In this HARBOR subanalysis, the presence of SRF at baseline was also associated with a greater likelihood of achieving a Snellen equivalent of 20/40 or better at month 12, as well as a greater likelihood of gaining ≥15 letters when total CNV leakage area ≤4.51 DA was also present. It is possible that SRF presence and/or thickness at baseline contributed to poor baseline VA, and these patients had a greater likelihood of achieving 20/40 vision with more-frequent treatment compared with patients who started with a better VA at baseline. It may also be possible that SRF provides photoreceptors access to nutrients, allowing for better functioning with continued anti-VEGF therapy over time. Further study is warranted to confirm and help elucidate the potential mechanism for this baseline characteristic leading to beneficial functional outcomes with treatment.
      In summary, this retrospective exploratory analysis of the HARBOR study identified several baseline predictors associated with VA outcomes at month 12 with ranibizumab treatment in patients with wet AMD. Consistent with other published reports, lower baseline BCVA, younger age, and smaller total CNV leakage area and area of occult CNV at baseline were identified as being predictive of more VA gain, as was SRF presence at baseline. Understanding which biomarkers are predictive of visual and treatment frequency response to anti-VEGF treatment may help retina specialists manage patient expectations and guide treatment decisions from the start of therapy.
      Funding/Support: Genentech, Inc, South San Francisco, CA provided support for the study and participated in the study design; conducting the study; and data collection, management, and interpretation. Financial disclosures: Carl D. Regillo serves as a consultant for Allergan (Irvine, CA), Genentech (South San Francisco, CA), GlaxoSmithKline (Brentford, United Kingdom), Regeneron (Tarrytown, NY), and Thrombogenics (Leuven, Belgium); and receives research funding from Allergan, Genentech, GlaxoSmithKline, Ophthotech (New York, NY), Regeneron, and Thrombogenics. Brandon G. Busbee serves as a consultant for Genentech, Regeneron, and Synergetics (O'Fallon, MO); and receives royalties from AKORN (Lake Forest, IL). Allen C. Ho serves as a consultant for Alcon (Fort Worth, TX), Allergan, Genentech, Janssen (Titusville, NJ; Raritan, NJ), Ophthotech, and Regeneron; receives research funding from Alcon, Allergan, Genentech, Janssen, NEI/NIH, Ophthotech, and Regeneron; and is a member of the speakers bureau for Alcon, Genentech, and Regeneron. Beiying Ding, and Zdenka Haskova are employees of Genentech, Inc. All authors attest that they meet the current ICMJE criteria for authorship.
      The authors would like to thank Linda Yau, PhD, of Genentech, Inc, for her contributions to the statistical analyses. Support for third-party writing assistance for this manuscript, furnished by Michelle Kelly, PhD, CMPP, of Envision Scientific Solutions, was provided by Genentech, Inc.

      Appendix

      Definitions as Derived From the Digital Angiography Reading Center (DARC, New York, USA)
      Macula dry: If at least 2 graders say that subretinal fluid (SRF) thickness is not present and cystoid spaces = “No” and intraretinal fluid = “No” and at least 2 graders say that pigment epithelial thickness is not present, then this is set to Yes; otherwise it is set to No.
      Macula dry-2: If cystoid spaces = “No” and central subfield thickness average <275 μm and at least 2 graders say that SRF thickness is not present, then this is set to Yes; otherwise it is set to No.
      Macula totally dry: If at least 2 graders say that SRF thickness is not present and cystoid spaces = “No” and intraretinal fluid = “No” and at least 2 graders say that pigment epithelial thickness is not present and central subfield thickness average is <275 μm, then this is set to Yes; otherwise it is set to No.
      Macula totally dry-2: If cystoid spaces = “No” and central subfield thickness average <275 μm and at least 2 graders say that SRF thickness is not present and at least 2 graders say that pigment epithelial thickness is not present, then this is set to Yes; otherwise it is set to No.
      Retina dry: If at least 2 graders say that SRF thickness is not present and cystoid spaces = “No” and intraretinal fluid = “No” then this is set to Yes; otherwise it is set to No.
      Retina dry-2: If cystoid spaces = “No” and central subfield thickness average <275 μm, then this is set to Yes; otherwise it is set to No.
      Retinal pigment epithelium (RPE) rip outside: Anything not under the fovea but within 3000 μm of the fovea.
      RPE rip remote: Anything farther than 3000 μm from the fovea.
      SRF presence: Indicates whether SRF is present or not.
      SRF thickness: The numeric value of the thickness; a thickness of 0 means that SRF is not present.

      References

        • Brown D.M.
        • Kaiser P.K.
        • Michels M.
        • et al.
        • for the ANCHOR Study Group
        Ranibizumab versus verteporfin for neovascular age-related macular degeneration.
        N Engl J Med. 2006; 355: 1432-1444
        • Brown D.M.
        • Michels M.
        • Kaiser P.K.
        • Heier J.S.
        • Sy J.P.
        • Ianchulev T.
        • ANCHOR Study Group
        Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study.
        Ophthalmology. 2009; 116: 57-65.e5
        • Rosenfeld P.J.
        • Brown D.M.
        • Heier J.S.
        • et al.
        • for the MARINA Study Group
        Ranibizumab for neovascular age-related macular degeneration.
        N Engl J Med. 2006; 355: 1419-1431
        • Kaiser P.K.
        • Brown D.M.
        • Zhang K.
        • et al.
        Ranibizumab for predominantly classic neovascular age-related macular degeneration: subgroup analysis of first-year ANCHOR results.
        Am J Ophthalmol. 2007; 144: 850-857
        • Kaiser P.K.
        • Blodi B.A.
        • Shapiro H.
        • Acharya N.R.
        • MARINA Study Group
        Angiographic and optical coherence tomographic results of the MARINA study of ranibizumab in neovascular age-related macular degeneration.
        Ophthalmology. 2007; 114: 1868-1875
        • Ying G.-s.
        • Huang J.
        • Maguire M.G.
        • et al.
        • on behalf of the Comparison of Age-related Macular Degeneration Treatments Trials Research Group
        Baseline predictors for one-year visual outcomes with ranibizumab or bevacizumab for neovascular age-related macular degeneration.
        Ophthalmology. 2013; 120: 122-129
        • Blinder K.J.
        • Bradley S.
        • Bressler N.M.
        • et al.
        • Treatment of Age-related Macular Degeneration with Photodynamic Therapy Study Group; Verteporfin in Photodynamic Therapy Study Group
        Effect of lesion size, visual acuity, and lesion composition on visual acuity change with and without verteporfin therapy for choroidal neovascularization secondary to age-related macular degeneration: TAP and VIP report no. 1.
        Am J Ophthalmol. 2003; 136: 407-418
        • Busbee B.G.
        • Ho A.C.
        • Brown D.M.
        • et al.
        • for the HARBOR Study Group
        Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration.
        Ophthalmology. 2013; 120: 1046-1056
      1. Lucentis® (ranibizumab) injection package insert. Genentech, Inc., South San Francisco, CA2014
        • Breiman L.
        • Friedman J.H.
        • Olshen R.A.
        • Stone C.J.
        Classification and Regression Trees.
        Chapman & Hall/CRC, New York1993: 1-368
        • Boyer D.S.
        • Antoszyk A.N.
        • Awh C.C.
        • Bhistkul R.B.
        • Shapiro H.
        • Acharya N.R.
        • for the MARINA Study Group
        Subgroup analysis of the MARINA study of ranibizumab in neovascular age-related macular degeneration.
        Ophthalmology. 2007; 114: 246-252
        • Rosenfeld P.J.
        • Shapiro H.
        • Tuomi L.
        • Webster M.
        • Elledge J.
        • Blodi B.
        • MARINA Study Group; ANCHOR Study Group
        Characteristics of patients losing vision after 2 years of monthly dosing in the phase III ranibizumab clinical trials.
        Ophthalmology. 2011; 118: 523-530
        • Haller J.A.
        Current anti-vascular endothelial growth factor dosing regimens: benefits and burden.
        Ophthalmology. 2013; 120: S3-7
        • Lally D.R.
        • Gerstenblith A.T.
        • Regillo C.D.
        Preferred therapies for neovascular age-related macular degeneration.
        Curr Opin Ophthalmol. 2012; 23: 182-188
        • Fung A.E.
        • Lalwani G.A.
        • Rosenfeld P.J.
        • et al.
        An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration.
        Am J Ophthalmol. 2007; 143: 566-583
        • Lalwani G.A.
        • Rosenfeld P.J.
        • Fung A.E.
        • et al.
        A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO Study.
        Am J Ophthalmol. 2009; 148: 43-58.e1
        • The CATT Research Group
        Ranibizumab and bevacizumab for neovascular age-related macular degeneration.
        N Engl J Med. 2011; 364: 1897-1908
        • Martin D.F.
        • Maguire M.G.
        • Fine S.L.
        • et al.
        • for the Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group
        Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results.
        Ophthalmology. 2012; 119: 1388-1398
        • Chakravarthy U.
        • Harding S.P.
        • Rogers C.A.
        • et al.
        • the IVAN Study Investigators
        Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial.
        Ophthalmology. 2012; 119: 1399-1411
        • Chakravarthy U.
        • Harding S.P.
        • Rogers C.A.
        • et al.
        • on behalf of the IVAN Study Investigators
        Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial.
        Lancet. 2013; 382: 1258-1267
        • Heier J.S.
        • Brown D.M.
        • Chong V.
        • et al.
        • VIEW 1 and VIEW 2 Study Groups
        Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration.
        Ophthalmology. 2012; 119: 2537-2548
        • Regillo C.D.
        • Brown D.M.
        • Abraham P.
        • et al.
        • PIER Study Group
        Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1.
        Am J Ophthalmol. 2008; 145: 239-248

      Biography

      Dr Carl D. Regillo is Professor of Ophthalmology at Thomas Jefferson University and Director of the Retina Service of Wills Eye Hospital in Philadelphia. He has authored >100 publications and eight major books. He is an investigator on numerous major clinical trials for retinal diseases. He is invited to lecture worldwide and is a recipient of many prestigious awards including AAO Achievement, Senior Achievement, and Secretariat Awards and the ASRS Honor and Senior Honor Awards.