Systemic Safety in Ranibizumab-Treated Patients with Neovascular Age-Related Macular Degeneration: A Patient-Level Pooled Analysis

Topic This study evaluated the cardiovascular/cerebrovascular safety profile of ranibizumab 0.5 mg versus sham ± verteporfin in patients with neovascular age-related macular degeneration (nAMD). In addition, comparisons of ranibizumab 0.3 mg with sham and ranibizumab 0.5 mg to 0.3 mg were performed. Clinical Relevance Intravitreal anti–vascular endothelial growth factor (VEGF) agents carry potential increased systemic risks, including cardiovascular or cerebrovascular events. Pooled safety analyses allow better interpretation of safety outcomes seen in individual clinical trials, especially for less common events. To our knowledge, this is the largest patient-level pooled analysis of patients with nAMD treated with ranibizumab. Methods Patient-level pooled analysis of data from 7 Genentech- and Novartis-sponsored phase II, III, and IV studies in nAMD that were completed by December 31, 2013. Pairwise comparisons (primary comparison: ranibizumab 0.5 mg [globally approved dose for nAMD] vs. sham or verteporfin) were performed using Cox proportional hazard regression (hazard ratios [HRs], 95% confidence intervals [CIs]) and rates per 100 patient-years. Standardized Medical Dictionary for Regulatory Activities queries (SMQs) and extended searches were used to identify relevant safety endpoints, including arterial thromboembolic events (ATEs), myocardial infarction (MI), stroke or transient ischemic attack (TIA), stroke (excluding TIA), vascular deaths, and major vascular events as defined by the Antiplatelet Trialists' Collaboration (APTC). Results The HRs (95% CIs) for the primary comparison of ranibizumab 0.5 mg (n=480) versus sham or verteporfin (n=462) were 1.16 (0.72–1.88) for ATE, 1.33 (0.59–2.97) for MI, 1.43 (0.54–3.77) for stroke excluding TIA, 1.25 (0.61–2.55) for stroke or TIA, 0.57 (0.18–1.78) for vascular death, and 1.12 (0.64–1.98) for APTC events. Hazard ratio 95% CIs included 1, indicating no significant treatment differences, for all endpoints for comparison of ranibizumab 0.5 mg versus sham or verteporfin. Conclusions The rates of cardiovascular and cerebrovascular events were low in these patients with nAMD and not clinically meaningfully different for patients treated with ranibizumab 0.5 mg versus sham or verteporfin, which supports the favorable benefit–risk profile of ranibizumab in the patient population with nAMD. Pooling these studies allows an analysis with higher power and precision compared with individual study analyses

MACUSTAR: Development and Clinical Validation of Functional, Structural, and Patient-Reported Endpoints in Intermediate Age-Related Macular Degeneration

Purpose: Currently, no outcome measures are clinically validated and accepted as clinical endpoints by regulatory agencies for drug development in intermediate age-related macular degeneration (iAMD). The MACUSTAR Consortium, a public-private research group funded by the European Innovative Medicines Initiative intends to close this gap. Procedures: Development of study protocol and statistical analysis plan including predictive modelling of multimodal endpoints based on a review of the literature and expert consensus. Results: This observational study consists of a cross-sectional and a longitudinal part. Functional outcome measures assessed under low contrast and low luminance have the potential to detect progression of visual deficit within iAMD and to late AMD. Structural outcome measures will be multimodal and investigate topographical relationships with function. Current patient-reported outcome measures (PROMs) are not acceptable to regulators and may not capture the functional deficit specific to iAMD with needed precision, justifying development of novel PROMs for iAMD. The total sample size will be n = 750, consisting mainly of subjects with iAMD (n = 600). Conclusions: As clinical endpoints currently accepted by regulators cannot detect functional loss or patient-relevant impact in iAMD, we will clinically validate novel candidate endpoints for iAMD

Synthese et photobiologie de phtalocyanines sulfonees absorbant a plus de 700 nm, dans une perspective de therapie photodynamique de cancers

SIGLEAvailable from INIST (FR), Document Supply Service, under shelf-number : T 80307 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Epidemiological and Clinical Baseline Characteristics as Predictive Biomarkers of Response to Anti-VEGF Treatment in Patients with Neovascular AMD

Purpose. To review the current literature investigating patient response to antivascular endothelial growth factor-A (VEGF) therapy in the treatment of neovascular age-related macular degeneration (nAMD) and to identify baseline characteristics that might predict response. Method. A literature search of the PubMed database was performed, using the keywords: AMD, anti-VEGF, biomarker, optical coherence tomography, treatment outcome, and predictor. The search was limited to articles published from 2006 to date. Exclusion criteria included phase 1 trials, case reports, studies focusing on indications other than nAMD, and oncology. Results. A total of 1467 articles were identified, of which 845 were excluded. Of the 622 remaining references, 47 met all the search criteria and were included in this review. Conclusion. Several baseline characteristics correlated with anti-VEGF treatment response, including best-corrected visual acuity, age, lesion size, and retinal thickness. The majority of factors were associated with disease duration, suggesting that longer disease duration before treatment results in worse treatment outcomes. This highlights the need for early treatment for patients with nAMD to gain optimal treatment outcomes. Many of the identified baseline characteristics are interconnected and cannot be evaluated in isolation; therefore multivariate analyses will be required to determine any specific relationship with treatment response

Photodynamic Therapy with Verteporfin in a Rabbit Model of Corneal Neovascularization

PURPOSE. To determine the efficacy of photodynamic therapy (PDT) with verteporfin (Visudyne; Novartis AG, Basel, Switzerland) for treatment of corneal neovascularization in a rabbit eye model. METHODS. Corneal neovascularization was induced in Dutch belted rabbits by placing an intrastromal silk suture near the limbus. Verteporfin was administered by intravenous injection at a dose of 1.5 mg/kg, and the pharmacokinetics of verteporfin distribution in the anterior segment or PDT-induced (laser energy levels 17, 50, and 150 J/cm 2 ) regression of corneal blood vessels were then determined. To assess PDT-induced toxicity of the anterior segment, corneal and iris/ciliary body histology, and IOP were evaluated after PDT. RESULTS. Verteporfin accumulation in vascularized regions of the cornea and the iris/ciliary body tissue were time dependent and maximum levels achieved at 60 minutes after injection. In rabbits, PDT of corneal vessels using laser energy of 17 or 50 J/cm 2 resulted in 30% to 50% regression of corneal neovascularization; however, in these animals, a rapid regrowth of new blood vessels occurred between 3 and 5 days. In the rabbits receiving PDT using laser energies of 150 J/cm 2 , the mean vessel regression was 56%. During the nine days of the laser therapy follow-up period, no vessel regrowth was observed in these rabbits. Histologic examination of the anterior segment after PDT (150 J/cm 2 ) showed localized degeneration of the corneal blood vessels without observable change in other anterior segment structures. CONCLUSIONS. These results provide evidence that PDT can produce significant regression of neovascular corneal vessels with no observable toxicity to the anterior segments. However, the optimal laser energy necessary to induce long-term regression (150 J/cm 2 ) was three times that used to treat choroidal neovascularization. (Invest Ophthalmol Vis Sci. 2003;44: 2954 -2958) DOI:10.1167/iovs.02-0572 C orneal neovascularization affects an estimated 1.4 million Americans and is a major cause of blindness worldwide. 1 Several corneal disorders including infections, chemical burns, immunologic diseases, degenerative disorders, and prior trauma can induce corneal neovascularization. In the United States, the most frequently associated etiology is long-time contact lens wear, especially that of soft hydrogel lenses. The primary treatment for actively proliferating corneal vessels is topical corticosteroids. 2 However, in corneas where vessels have been established for an extended period, corticosteroid treatment is often ineffective. Recently, angiogenic inhibitors have also been used to treat corneal neovascularization. 3,4 Photodynamic treatment (PDT) offers another potential treatment for corneal neovascularization. In PDT, systemically administered porphyrin derivatives accumulate in proliferating endothelial cells. Laser energy is then used to activate the porphyrin derivates 2,5-9 liberating cytotoxic oxygen free radicals. The ensuing cytotoxic response results in occlusion of neovascular vessels. Photodynamic treatment using verteporfin (Visudyne; Novartis AG, Basel, Switzerland), a benzoporphyrin derivative monoacid ring A, has been recently approved for the treatment of subfoveal choroidal neovascularization. -12 The purpose of this study was to evaluate the efficacy of the FDA-approved verteporfin formulation and dose and laser treatment for corneal neovascularization. These studies examined the pharmacokinetic characteristics of verteporfin in the anterior segment of rabbit eyes with corneal neovascularization, the PDT-induced toxicity of adjacent ocular structures (e.g., the corneal endothelium and iris/ciliary body), and the optimal laser parameters for treatment of corneal neovascularization. Our results demonstrate that significant amounts of verteporfin can be found in vascularized areas of the cornea as early as 15 minutes after drug injection and that PDT is efficacious in producing and maintaining regression of corneal blood vessels up to 9 days after PDT. However, the optimal laser energy necessary to induce long-term regression (150 J/cm 2 ) was three times that used to treat choroidal neovascularization. MATERIALS AND METHODS Dutch-belted rabbits, weighing 1.5 to 2 kg were maintained in a standard 12-hour light-dark cycle with free access to food and water. Corneal neovascularization was induced using a modified technique described by Schmidt-Erfurth et al. To determine the area of corneal neovascularization, slit-lamp photographs in a standardized magnification were taken on days 1, 4, 7