Carol Chung

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.

Rituximab versus an alternative TNF inhibitor in patients with rheumatoid arthritis who failed to respond to a single previous TNF inhibitor: SWITCH-RA, a global, observational, comparative effectiveness study

Objectives To compare the effectiveness of rituximab versus an alternative tumour necrosis factor (TNF) inhibitor (TNFi) in patients with rheumatoid arthritis (RA) with an inadequate response to one previous TNFi. Methods SWITCH-RA was a prospective, global, observational, real-life study. Patients non-responsive or intolerant to a single TNFi were enrolled ≤4 weeks after starting rituximab or a second TNFi. Primary end point: change in Disease Activity Score in 28 joints excluding patients global health component (DAS28-3)–erythrocyte sedimentation rate (ESR) over 6 months. Results 604 patients received rituximab, and 507 an alternative TNFi as second biological therapy. Reasons for discontinuing the first TNFi were inefficacy (n=827), intolerance (n=263) and other (n=21). A total of 728 patients were available for primary end point analysis (rituximab n=405; TNFi n=323). Baseline mean (SD) DAS28-3–ESR was higher in the rituximab than the TNFi group: 5.2 (1.2) vs 4.8 (1.3); p<0.0001. Least squares mean (SE) change in DAS28-3–ESR at 6 months was significantly greater in rituximab than TNFi patients: −1.5 (0.2) vs −1.1 (0.2); p=0.007. The difference remained significant among patients discontinuing the initial TNFi because of inefficacy (−1.7 vs −1.3; p=0.017) but not intolerance (−0.7 vs −0.7; p=0.894). Seropositive patients showed significantly greater improvements in DAS28-3–ESR with rituximab than with TNFi (−1.6 (0.3) vs −1.2 (0.3); p=0.011), particularly those switching because of inefficacy (−1.9 (0.3) vs −1.5 (0.4); p=0.021). The overall incidence of adverse events was similar between the rituximab and TNFi groups. Conclusions These real-life data indicate that, after discontinuation of an initial TNFi, switching to rituximab is associated with significantly improved clinical effectiveness compared with switching to a second TNFi. This difference was particularly evident in seropositive patients and in those switched because of inefficacy.

Multiple Courses of Rituximab Produce Sustained Clinical and Radiographic Efficacy and Safety in Patients with Rheumatoid Arthritis and an Inadequate Response to 1 or More Tumor Necrosis Factor Inhibitors: 5-Year Data from the REFLEX Study

Objective. This 5-year observational posthoc analysis of the REFLEX study and its open-label extension assessed clinical efficacy, radiographic response, and safety of rituximab (RTX) in patients with rheumatoid arthritis (RA) who had an inadequate response to tumor necrosis factor (TNF) inhibitors. Methods. Patients in REFLEX were originally randomized to placebo (PBO) + methotrexate (MTX; PBO-randomized) or RTX + MTX (RTX-randomized). PBO-randomized patients were rescued with RTX as appropriate. Patients responding to initial RTX treatment could receive further RTX courses. For clinical efficacy and safety analyses, PBO-randomized patients were re-baselined prior to first RTX treatment and the data were pooled with RTX-randomized patient data. Efficacy outcomes 24 weeks after each course were calculated relative to first RTX pretreatment baseline. Radiographic outcomes were assessed relative to randomization baseline for both PBO-randomized and RTX-randomized groups. Results. A total of 480 patients received ≥ 1 RTX course. At 24 weeks, American College of Rheumatology 20/50/70 responses were 62.0%, 30.8%, and 13.0%, respectively at course 1 (n = 400) and 70.3%, 41.8%, and 22.0% at course 5 (n = 91). European League Against Rheumatism good/moderate responses were 77.2% and 84.4% at courses 1 (n = 390) and 5 (n = 90). Rates of adverse events (AE), serious AE, and infections generally remained stable. Rate of progressive joint damage (PJD; change in mean Total Sharp Score) decreased over time in both PBO-randomized (n = 79) and RTX-randomized (n = 105) groups. Mean change from baseline in PJD over 5 years was greater in PBO-randomized versus RTX-randomized patients (5.51 vs 3.21). Conclusion. RTX re-treatment over 5 years is associated with maintained or improved efficacy, continued inhibition of PJD, and a safety profile consistent with that previously reported. A delay in initiating RTX treatment may result in increased PJD.

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.

Composite Indices Using 3 or 4 Components of the Core Data Set Have Similar Predictive Ability to Measure Disease Activity in RA: Evidence from the DANCER and REFLEX Studies

Background. Understanding how disease-assessment indices perform in rheumatoid arthritis (RA) clinical trials can inform their use in routine practice. The study objective was to assess the capacity of combinations of RA Core Data Set measures to distinguish rituximab from control treatment. Methods. Post hoc analysis of two randomised clinical trials was used. Composite Efficacy Indices were derived by combining three or four RA Core Data Set measures from three possible sources: physician, patient, and laboratory. Results. All 105 Composite Efficacy Indices evaluated significantly distinguished rituximab from control treatment (P < 10−7). Generally, indices containing measures from three different sources had a greater capacity to distinguish rituximab from control treatment than indices containing three measures from one source. Composite Efficacy Indices performed as well as validated indices such as DAS28, RAPID3, and CDAI. Conclusions. All indices composed of three or four RA Core Data Set measures have a similar capacity to detect treatment differences. These results suggest that the precise measurement used is less important than whether any measurement is performed, although selection should be consistent for each patient. Therefore, the choice of assessment tool should not be limited to a prescribed list and should instead be left to the clinicians discretion.

FRI0200 Relative effectiveness of rituximab versus an alternative TNF inhibitor in patients with rheumatoid arthritis and an inadequate response to a single previous TNF inhibitor: Results from switch-RA, a global, comparative-effectiveness, observational study

Background Recent studies indicate that RA patients (pts) with an inadequate response (IR) to a tumor necrosis factor inhibitor (TNFi) may achieve greater clinical benefit from switching to rituximab (RTX) than to an alternative TNFi.1 SWITCH-RA, a global, multicentre, prospective, observational, clinical practice study, evaluated the relative effectiveness of RTX vs an alternative TNFi in pts with an IR to a single previous TNFi. Methods The primary endpoint was 6-month change from baseline in DAS28 based on DAS28(3)-ESR, whichexcludes patient’s global health component. Analysis of covariance adjusting for unbalanced baseline characteristics was used for treatment cohort comparisons, with missing DAS28(3)-ESR valuesimputed with investigator-reported and nearest-timepoint values. “As observed” analysis was performedto validate the results’robustness. Results Of 1107 eligible pts (mean age 55.5 yrs; 79.0% women), 602 switched to RTX and 505 to an alternative TNFi. The RTX pts (vs alternative TNFi pts) had a mean RA disease duration of 8.9 yrs (vs 7.6, p=0.056) and a mean initial TNFi duration of 25.4 months (vs 25.2, p=0.227). At time of switch, RTX pts had greater mean baseline DAS28(3)-ESRfor the study overall (5.5 vs 5.0, p<0.001), for the sub-cohort (n=824) who discontinued initial TNFi due to inefficacy (5.3 vs 4.7, p<0.001)and for the sub-cohort (n=264) who discontinued due to intolerance (5.0 vs 4.5, p=0.019). The study had a high incidence of missing data (similar between treatment cohorts). Data for 530 (observed) and 703 (imputed) pts were available for the primary endpoint analysis. At 6 months, there were greater decreases in DAS28(3)-ESR (least squares means) in RTX than in alternative TNFi pts for overall (-1.5 vs -1.1, p=0.008) and the “inefficacy” sub-cohort (-1.5 vs -1.0, p=0.007), but not the “intolerance” sub-cohort (-1.0 vs -0.9, p=0.877). “As observed” analysis showed similar results. A greater decrease in ESR was also noted in the RTX vs the alternative TNFi group, both overall (-15.2 vs -9.2; p=0.009) and the “inefficacy” sub-cohort (-12.8 vs -6.8; p=0.035). Rates of AEs and serious AEs were similar between the treatment cohorts. Conclusions These data from SWITCH-RA indicate that, following discontinuation of a first TNFi, pts starting treatment with RTX achieved improved effectiveness as demonstrated by significantly greater decreases in DAS28-ESR, in particular those switched for inefficacy, over 6 months compared with pts switching to an alternative TNFi. References Finckh, et al. Ann Rheum Dis 2010;69:387. Disclosure of Interest P. Emery Consultant for: Pfizer, Merck, Abbott, BMS, Roche, Novartis, J.-E. Gottenberg Consultant for: Abbott, BMS, Pfizer, Roche, Schering-Plough, P. Sarzi-Puttini Grant/Research support from: Roche, Pfizer, UCB, Abbott, R. Moots Grant/Research support from: Roche, UCB, MSD, D. Choquette Consultant for: Roche, Speakers Bureau: Roche, A. Finckh Grant/Research support from: Pfizer, Abbott, Roche, Consultant for: Roche, Pfizer, BMS, Speakers Bureau: Roche, A. Östör Consultant for: Roche, Chugai, Schering-Plough/MSD, Abbott, Wyeth/Pfizer, BMS, GSK, MerckSorono, UCB, A. Andrianakos Speakers Bureau: Roche, L. Barile-Fabris Consultant for: Roche, Pfizer, MSD, BMS, M.-L. Desjuzeur Employee of: F. Hoffmann-La Roche Ltd, L. Hinsch-Gylvin Employee of: F. Hoffmann-La Roche Ltd, C. Chung Employee of: Genentech, Inc, C. Mpofu Employee of: F. Hoffmann-La Roche Ltd