Lisa Tuomi

Characteristics of patients losing vision after 2 years of monthly dosing in the phase III ranibizumab clinical trials.

PURPOSE To investigate the cause of visual acuity (VA) loss in patients with neovascular age-related macular degeneration (AMD) receiving monthly ranibizumab injections in the pivotal ranibizumab phase III trials. DESIGN Retrospective analysis. PARTICIPANTS The Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab In the treatment of Neovascular AMD (MARINA) and Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR) trials. METHODS Demographics and lesion characteristics at baseline and month 24 were compared in patients with ≥15 letters VA loss and patients with ≥15 letters VA gain from baseline to month 24. Additional evaluations of fundus photographs from these patients were performed to assess features of non-exudative AMD, such as geographic atrophy (GA) and retinal pigment epithelium (RPE) abnormalities. MAIN OUTCOME MEASURES Differences in lesion characteristics between patients who lost versus gained ≥15 letters of VA from baseline to month 24. RESULTS At month 24, 9% of ranibizumab-treated patients from MARINA and 10% of ranibizumab-treated patients from ANCHOR had lost ≥15 letters VA; 30% of ranibizumab-treated patients from MARINA and 38% of ranibizumab-treated patients from ANCHOR had gained ≥15 letters VA. Baseline characteristics associated with VA loss at month 24 included older age, better VA, and larger lesions. At month 24, an increased area of RPE abnormality was associated with VA loss in both the MARINA (P = 0.0008) and ANCHOR (P = 0.0046) trials. Increased total lesion area at month 24 was associated with VA loss in both trials. In MARINA, the increase in total lesion area was attributable to an increase in the angiographic designation of atrophic scar among VA losers (P = 0.0043), but in ANCHOR it was attributable to an increased area of choroidal neovascularization (CNV) (P = 0.039) but not an increased area of leakage (P = 0.17). Increased areas of GA, fibrosis, and hemorrhage were not associated with VA loss. CONCLUSIONS Vision loss after 2 years of monthly ranibizumab therapy was associated with lesion characteristics commonly associated with suppressed CNV, such as pigmentary abnormalities, atrophic scar, and the absence of leakage. Future VA improvements in patients receiving ranibizumab therapy may require preservation of photoreceptor and RPE function rather than strategies that target CNV.

Ranibizumab Combined With Verteporfin Photodynamic Therapy in Neovascular Age-related Macular Degeneration (FOCUS): Year 2 Results

PURPOSE To assess the efficacy and adverse-events profile of combined treatment with ranibizumab and verteporfin photodynamic therapy (PDT) in patients with predominantly classic choroidal neovascularization (CNV) secondary to neovascular age-related macular degeneration. DESIGN Two-year, multicenter, randomized, single-masked, controlled study. METHODS Patients received monthly intravitreal injections of ranibizumab 0.5 mg (n = 106) or sham injections (n = 56). All patients received PDT on day zero, then quarterly as needed. Efficacy assessment included changes in visual acuity (VA) and lesion characteristics and PDT frequency. Adverse events were summarized by incidence and severity. RESULTS At month 24, 88% of ranibizumab + PDT patients had lost <15 letters from baseline VA (vs 75% for PDT alone), 25% had gained >or=15 letters (vs 7% for PDT alone), and the two treatment arms differed by 12.4 letters in mean VA change (P < .05 for all between-group differences). The VA benefit of adding ranibizumab to PDT in year one persisted through year two. On average, ranibizumab + PDT patients exhibited less lesion growth and greater reduction of CNV leakage and subretinal fluid accumulation, and required fewer PDT retreatments, than PDT-alone patients (mean = 0.4 vs 3.0 PDT retreatments). Endophthalmitis and serious intraocular inflammation occurred, respectively, in 2.9% and 12.4% of ranibizumab + PDT patients and 0% of PDT-alone patients. Incidences of serious nonocular adverse events were similar in the two treatment groups. CONCLUSIONS Through two years, ranibizumab + PDT was more effective than PDT alone and had a low rate of associated adverse events.

Incidence of Retinal Pigment Epithelial Tears after Intravitreal Ranibizumab Injection for Neovascular Age-Related Macular Degeneration

OBJECTIVE To explore the association between treatment for neovascular age-related macular degeneration (AMD) and incidence and timing of retinal pigment epithelium (RPE) tears in ranibizumab-treated patients versus control treatment. DESIGN Results from 3 phase III clinical trials (ANti-VEGF antibody for the treatment of predominantly classic CHORoidal neovascularization in age-related macular degeneration [ANCHOR], Minimally classic/occult trial of the Anti-VEGF antibody Ranibizumab In the treatment of Neovascular Age-related macular degeneration [MARINA], and A Phase IIIb, Multicenter, Randomized, Double-Masked, Sham Injection-Controlled Study of the Efficacy and Safety of Ranibizumab in Subjects with Subfoveal Choroidal Neovascularization [CNV] with or without Classic CNV Secondary to Age-Related Macular Degeneration [PIER]) were retrospectively reviewed to identify patients who developed RPE tears during the study period, detected on fluorescein angiography performed at prespecified intervals. PARTICIPANTS Patients with baseline and post-baseline angiographic assessments. METHODS Patients received intravitreal ranibizumab (0.3 or 0.5 mg) or control treatment (verteporfin photodynamic therapy [PDT] in ANCHOR and sham intravitreal injections in ANCHOR, MARINA, and PIER). MAIN OUTCOME MEASURES Incidence and timing of RPE tears during the treatment period. RESULTS Data from 1298 patients were analyzed. No statistically significant differences in RPE tear incidence were observed. The pooled rate of RPE tears was 1.8% with 0.5 mg ranibizumab, 3.0% with 0.3 mg ranibizumab, and 1.6% in the control group. Most (76%; 16/21) RPE tears in ranibizumab-treated patients were identified within 3 months of initiating treatment, whereas the majority (80%; 4/5) of late-onset RPE tears occurred in control patients. In patients who developed RPE tears, better visual acuity (VA) outcomes were observed in those treated with ranibizumab versus control treatment. CONCLUSIONS As studied in these trials, no statistically significant differences in the incidence of RPE tears within a 2-year treatment period were observed in patients who received ranibizumab (0.5 or 0.3 mg) versus control treatment, although most RPE tears with ranibizumab occurred within 3 months of initiating treatment. Mean VA was better in patients who developed RPE tears while receiving ranibizumab than in those who received control treatment, suggesting a potential benefit of continued ranibizumab therapy in patients with neovascular AMD who developed RPE tears. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Anatomical measures as predictors of visual outcomes in ranibizumab-treated eyes with neovascular age-related macular degeneration.

Purpose: To investigate if anatomical characteristics of eyes undergoing ranibizumab therapy were predictive of best-corrected visual acuity (BCVA) outcomes over 2 years. Methods: Post hoc analyses of patients with age-related macular degeneration from PIER studies, defined by fundus fluorescein angiography, quantitative optical coherence tomography (OCT), and qualitative OCT, were performed to determine if associations with BCVA outcomes could be found. Results: Ranibizumab-treated subgroups defined by baseline fundus fluorescein angiography lesion size and composition did not differ in BCVA outcomes at Month 24 (P = 0.13–1.0). Inactivity on fundus fluorescein angiography at Month 3 was associated with a 12-letter gain by Month 12 (P < 0.01), whereas inactivity on Month 3 qualitative OCT was not (P > 0.05). Qualitative OCT inactivity at Month 5 and separately at Month 8 was associated with greater BCVA gains by Month 24 (7.1 and 9.5 letters, respectively; P ⩽ 0.045) versus eyes with OCT activity. Conclusion: When assessed separately, eyes with qualitative OCT (Months 5 and 8) or fundus fluorescein angiography (Months 3 and 5) inactivity maintained vision gain from baseline at Month 24, while those with leakage not only lost initial vision gains achieved by intraocular ranibizumab but also had net vision losses from baseline at Month 24. The PIER infrequent dosing regimen likely exaggerated and accelerated the deleterious effects of retinal fluid on BCVA, and it is not known whether these findings are applicable to treatment regimens that use more frequent monitoring and dosing of ranibizumab.

Influence of Glycosylated Hemoglobin on the Efficacy of Ranibizumab for Diabetic Macular Edema: A Post Hoc Analysis of the RIDE/RISE Trials

PURPOSE To investigate the influence of glycosylated hemoglobin (HbA1c) on treatment outcomes in patients with diabetic macular edema (DME) receiving intravitreal ranibizumab. DESIGN Post hoc analysis of 2 identical phase III clinical trials assessing the efficacy and safety of intravitreal ranibizumab in DME over 36 months (RIDE: NCT00473382/RISE: NCT00473330). PARTICIPANTS A total of 483 adults with vision loss from DME treated with ranibizumab were included in this analysis from RIDE/RISE. Participants received monthly intravitreal ranibizumab (0.3 or 0.5 mg). MAIN OUTCOME MEASURES Differences in visual and anatomic outcomes, and diabetic retinopathy (DR) severity score, between subgroups of patients with baseline HbA1c ≤7% versus HbA1c >7% at 36 months. RESULTS There were 195 patients in RIDE/RISE who were treated with ranibizumab with a baseline HbA1c ≤7% and 288 patients with a baseline HbA1c >7% included in this analysis. The mean improvement in visual acuity (VA) at 36 months was +13 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in patients with baseline HbA1c ≤7% compared with +11 ETDRS letters in the patients with a baseline HbA1c >7% (P = 0.17). After adjustment for baseline central foveal thickness (CFT) and duration of diabetes, the mean CFT reduction was -268 μm in patients with a baseline HbA1c ≤7% and -269 μm in patients with a baseline HbA1c >7% (P = 0.98; 95% confidence interval, -22.93 to 23.54). The proportion of patients with a ≥2-step improvement in DR severity score was 38% in patients with baseline HbA1c ≤7% compared with 41% in the patients with a baseline HbA1c >7% (P = 0.53). There was no correlation of baseline HbA1c with any visual or anatomic parameter. CONCLUSIONS The improvement in VA, anatomic reduction of macular edema, and improvement in DR severity score with ranibizumab treatment seem to be independent of baseline HbA1c.

Pharmacokinetics of Ranibizumab after Intravitreal Administration in Patients with Retinal Vein Occlusion or Diabetic Macular Edema

OBJECTIVE To describe the systemic pharmacokinetics of ranibizumab after intravitreal administration in patients with retinal vein occlusion (RVO) or diabetic macular edema (DME). DESIGN A population approach of nonlinear mixed-effect pharmacokinetics modeling based on serum concentrations of ranibizumab measured at various times after intravitreal administration. PARTICIPANTS Patients with RVO (n = 441) and DME (n = 435) from 4 large, randomized, phase 3 clinical trials of monthly ranibizumab intravitreal administration. METHODS A 1-compartment pharmacokinetics model with first-order absorption and elimination rate constants previously developed in patients with age-related macular degeneration (AMD) was fitted separately to RVO and DME data. Population pharmacokinetic parameters and interindividual variability were estimated for each model. Baseline covariates were evaluated for potential effects on systemic pharmacokinetics. Model performance was validated using general diagnostic plots and a visual predictive check. MAIN OUTCOME MEASURES Ranibizumab disposition was determined in RVO and DME patients and compared with that previously seen in AMD patients. RESULTS The AMD pharmacokinetics model correctly predicted the measured serum ranibizumab concentration data for RVO and DME patients. Most observed data points were within the simulated 90% confidence interval, indicating that systemic ranibizumab concentrations were comparable among AMD, RVO, and DME patients. No disease-related covariates were identified by the population pharmacokinetics analysis. CONCLUSIONS The systemic pharmacokinetics of ranibizumab were similar among patients with AMD, RVO, or DME. Disease-related differences and patient demographics, measured in this study, did not lead to variability in ocular elimination or in systemic exposure of ranibizumab after intravitreal administration. In all disease processes tested, ranibizumab exits the eye slowly and then is eliminated rapidly from the circulation, thus minimizing systemic exposure.

Fixed Monthly versus Less Frequent Ranibizumab Dosing and Predictors of Visual Response in Exudative Age-Related Macular Degeneration

Purpose. To examine temporal patterns of visual acuity (VA) response to pooled 0.3 mg/0.5 mg ranibizumab treatment in patients with age-related macular degeneration and identify potential baseline predictors of response. Design. Retrospective analysis. Methods. Results from 1824 ranibizumab-treated patients receiving fixed monthly, quarterly, or as-needed dosing after three monthly loading doses in four phase III/IIIb trials (ANCHOR, MARINA, PIER, and SAILOR) were analyzed. Results. At month 3, 14.9% to 29.4% of patients had gained ≥15 letters. Not all patients achieved peak gains at month 3; many continued to have VA increases throughout treatment. After three monthly loading doses, continued monthly dosing resulted in further gains, as there were more delayed 15-letter responders at month 12 (14.7–16.1%) than with less frequent dosing (5.0–6.0%). Monthly dosing also resulted in more patients maintaining VA gains at later time points. Early 15-letter responders had lower baseline mean VA than delayed 15-letter responders in ANCHOR and MARINA; no other differences in baseline characteristics were noted. Conclusions. Although some patients have rapid improvements in VA, others do not experience peak VA until later during treatment. Continued monthly dosing resulted in a greater percentage of patients gaining ≥15 letters than with switching to less frequent dosing regimens.

Patterns of Early and Delayed Visual Response to Ranibizumab Treatment for Neovascular Age-Related Macular Degeneration

IMPORTANCE Understanding the range of temporal responses to ranibizumab is critical for the assessment of individualized treatment regimens for neovascular age-related macular degeneration. OBJECTIVE To examine patterns of visual and anatomical response to ranibizumab treatment. DESIGN, SETTING, AND PARTICIPANTS This study is a retrospective subanalysis of HARBOR (a phase 3, 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). A total of 1097 patients with neovascular age-related macular degeneration were randomized to intravitreal ranibizumab, 0.5 or 2.0 mg, administered monthly or as needed (PRN) with monthly monitoring. Of the 1097 patients, 1057 were included in the analysis for early responders (best-corrected visual acuity [BCVA] obtained at baseline and month 3), and 988 patients were included in the analysis for delayed responders (BCVA obtained at baseline, month 3, and month 12). The HARBOR study began July 7, 2009, with the primary 12-month end point completed on August 5, 2011, ongoing to 24 months. Data analysis for the subgroup was performed from January 4, 2013, through December 17, 2015. INTERVENTIONS Patients were categorized based on BCVA outcomes as early 15-letter responders (gained ≥15 letters from baseline at month 3) or delayed 15-letter responders (did not gain ≥15 letters from baseline at month 3 but did so at month 12). MAIN OUTCOMES AND MEASURES Changes from baseline in BCVA and central foveal thickness (CFT). RESULTS In total, 266 early and 135 delayed 15-letter responders were identified. In the 0.5-mg monthly, 0.5-mg PRN, 2.0-mg monthly, and 2.0-mg PRN treatment groups, 63 (24.0%) of 263, 65 (24.6%) of 264, 68 (25.7%) of 265, and 70 (26.4%) of 265 patients were early responders, respectively, and 40 (16.3%) of 246, 31 (12.6%) of 247, 35 (14.1%) of 248, and 29 (11.7%) of 247 patients were delayed responders, respectively. By month 12, early vs delayed responders in the PRN treatment groups received 7.5 vs 7.4 ranibizumab injections, respectively (P = .84). More than 80% of early responders receiving PRN treatment maintained 15-letter or greater gains at month 24. At baseline, early vs delayed responders had worse BCVA (49.8 vs 55.4 letters; P < .001) and greater CFT (374.9 vs 339.0 µm; P = .02), although anatomical results were comparable by month 3 (CFT, 187.7 vs 188.9 µm). CONCLUSIONS AND RELEVANCE Improvement of 15 letters or more from baseline occurred in 266 (25.2%) of 1057 patients within 3 months of beginning ranibizumab treatment, whereas an additional 135 (13.7%) of 988 patients achieved this gain by 12 months. The 2 cohorts had similar anatomical temporal response patterns. PRN treatment with monthly monitoring was effective in maintaining early vision gains and allowing delayed vision gains. These results suggest that vision improvement can continue in some patients after macular edema resolves and CFT decreases stabilize.

An observational retrospective subgroup analysis of verteporfin photodynamic therapy-naive and previously treated patients in the focus trial.

Purpose: To perform a retrospective post hoc subgroup analysis of the FOCUS trial to assess the visual acuity outcomes and treatment benefits for patients receiving combination therapy who, at the time of enrollment, were naive to verteporfin photodynamic therapy (PDT) or had previously received PDT. Methods: In this retrospective post hoc analysis of 24-month data from the FOCUS trial, PDT-naive and previously PDT-treated patients (n = 162) were included. Patients were randomized in a 2:1 ratio to receive 0.5 mg of ranibizumab monthly plus PDT or PDT alone. We retrospectively identified patients who had or had not received prior PDT for a post hoc subgroup analysis of 12- and 24-month outcomes. Results: For the PDT-naive patients, mean change in the visual acuity at 24 months was +4.1 letters for the ranibizumab plus PDT group and −11.5 letters for the PDT monotherapy group, a treatment benefit over control group of 15.6 letters (95% confidence interval: 7.1-24.2). For the previously treated patients, mean change in the visual acuity at 24 months was +5.2 letters for the ranibizumab plus PDT group and −4.3 letters for the PDT monotherapy group, a treatment benefit over control group of 9.5 letters (95% confidence interval: 2.3-16.8). Conclusion: In the FOCUS subanalysis, the PDT-naive patients showed a trend toward greater treatment benefit over control subjects compared with patients previously treated with PDT. However, this study was not designed to address this question, and the confidence intervals were wide. Furthermore, the mean change in the visual acuity from baseline to 24 months was similar for both the PDT-naive and previously treated patients receiving combination therapy.