Ranibizumab Therapy Research Articles

The Efficacy of Ranibizumab for Choroidal Neovascularization in Age-related Macular Degeneration

Purpose: To report 1-year clinical changes in visual acuity (VA) after intravitreal ranibizumab therapy for choroidal neovascularization (CNV) due to age-related macular degeneration (AMD), and to determine differences in treatment effects according to the CNV subtype. Methods: Forty six patients (46 eyes) with subfoveal CNV were treated with intravitreal ranibizumab (0.5 mg) injections as needed. Visual acuity, fluorescein angiography, and macular OCT were examined after 12 months. The patients were divided into two groups: Classic CNV and occult CNV. The VA of the two groups was compared 12 months after the initial injections. Results: The average VA and mean central retinal thickness (CRT) before ranibizumab treatment was 1.0110.408 logMAR and 335.3 , respectively, and the VA and mean CRT 12 months after the initial injections was 0.9280.357 logMAR and 246.2 , respectively (p=0.042, p＜0.001). Out of 46 eyes, 13 eyes (28.3%) had a VA that improved by more than 0.1 logMAR, 33 eyes (71.7%) had VA that changed less than 0.1 logMAR, and 40 eyes (86.6%) had a VA that changed by less than 0.3 logMAR. The VA improved to 0.084 logMAR in classic CNV (18 eyes) and to 0.081 logMAR in occult CNV (28 eyes) after 12 months, though the difference between groups was not significant (p=0.910). Conclusions: Intravitreal injection of ranibizumab is an effective treatment for patients with subfoveal CNV secondary to AMD to improve or stabilize VA, and the effect of treatment on VA is not significantly different according to the CNV subtype.

Ranibizumab versus Verteporfin Photodynamic Therapy for Neovascular Age-Related Macular Degeneration: Two-Year Results of the ANCHOR Study

The 2-year, phase III trial designated Anti-vascular endothelial growth factor (VEGF) Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization (CNV) in Age-related Macular Degeneration (ANCHOR) compared ranibizumab with verteporfin photodynamic therapy (PDT) in treating predominantly classic CNV. Multicenter, international, randomized, double-masked, active-treatment-controlled clinical trial. Patients with predominantly classic, subfoveal CNV not previously treated with PDT or antiangiogenic drugs. Patients were randomized 1:1:1 to verteporfin PDT plus monthly sham intraocular injection or to sham verteporfin PDT plus monthly intravitreal ranibizumab (0.3 mg or 0.5 mg) injection. The need for PDT (active or sham) retreatment was evaluated every 3 months using fluorescein angiography (FA). The primary, intent-to-treat efficacy analysis was at 12 months, with continued measurements to month 24. Key measures included the percentage losing <15 letters from baseline visual acuity (VA) score (month 12 primary efficacy outcome measure), percentage gaining >or=15 letters from baseline, and mean change over time in VA score and FA-assessed lesion characteristics. Adverse events were monitored. Of 423 patients (143 PDT, 140 each in the 2 ranibizumab groups), the majority (>or=77% in each group) completed the 2-year study. Consistent with results at month 12, at month 24 the VA benefit from ranibizumab was statistically significant (P<0.0001 vs. PDT) and clinically meaningful: 89.9% to 90.0% of ranibizumab-treated patients had lost <15 letters from baseline (vs. 65.7% of PDT patients); 34% to 41.0% had gained >or=15 letters (vs. 6.3% of PDT group); and, on average, VA was improved from baseline by 8.1 to 10.7 letters (vs. a mean decline of 9.8 letters in PDT group). Changes in lesion anatomic characteristics on FA also favored ranibizumab (all comparisons P<0.0001 vs. PDT). Overall, there was no imbalance among groups in rates of serious ocular and nonocular adverse events. In the pooled ranibizumab groups, 3 of 277 (1.1%) patients developed presumed endophthalmitis in the study eye (rate per injection = 3/5921 [0.05%]). In this 2-year study, ranibizumab provided greater clinical benefit than verteporfin PDT in patients with age-related macular degeneration with new-onset, predominantly classic CNV. Rates of serious adverse events were low. Proprietary or commercial disclosure may be found after the references.

Ranibizumab for neovascular age-related macular degeneration

The pharmacology, pharmacokinetics, clinical efficacy, safety, pharmacoeconomics, and place in therapy of ranibizumab are reviewed. Ranibizumab is the humanized fragment of the murine monoclonal antibody that binds all the active forms of the vascular endothelial growth factor, leading to the inhibition of the neovascular process underlying age-related macular degeneration (AMD). In animal studies, intravitreal administration of ranibizumab resulted in penetration of the drug into all layers of the retina and subsequent slow absorption into the systemic circulation. Improvement in visual acuity by 15 or more letters has been observed in 33.8-40.3% of patients treated with ranibizumab in pivotal clinical trials, compared with 5% of patients treated with sham injections and photodynamic therapy (PDT). The addition of PDT to ranibizumab has not been shown to offer any benefit in terms of efficacy and has been found to worsen ocular adverse reactions. The most common adverse ocular reactions reported in patients receiving ranibizumab during clinical trials include conjunctival hemorrhage, eye pain, vitreous floaters, increased intraocular pressure, and intraocular inflammation. Ranibizumab's efficacy in the treatment of neovascular AMD is well established; however, questions remain regarding the drug's optimal dosing strategy, duration of therapy, and combined therapy with other agents. While ranibizumab has been defined as the best available weapon against AMD, it is also the most expensive. The efficacy of ranibizumab in the treatment of AMD is well established, but more studies are needed to determine ranibizumab's optimal dosage interval, duration of therapy, and combined use with other agents.

Toxoplasmosis-Associated Neovascular Lesions Treated Successfully With Ranibizumab and Antiparasitic Therapy

Joseph D. Benevento, MD1, Rama D. Jager, MD, MBA1, A. Gwendolyn Noble, MD, PhD2, Paul Latkany, MD1,3, William F. Mieler, MD1, Mari Sautter, BA1, Sanford Meyers, MD1, Marilyn Mets, MD2, Michael A. Grassi, MD1, Peter Rabiah, MD1, Kennneth Boyer, MD4, Charles Swisher, MD2, and Rima McLeod, MD1,* other members of the Toxoplasmosis Study Group† 1University of Chicago Pritzker School of Medicine, Chicago, IL 2Children’s Memorial Hospital, Chicago, IL 3St. Luke’s Roosevelt Hospital, The New York Eye & Ear Infirmary, New York, NY 4Rush University Medical Center, Chicago, IL

Time Course of Morphologic Effects on Different Retinal Compartments after Ranibizumab Therapy in Age-related Macular Degeneration

To analyze the effect of ranibizumab therapy on retinal and subretinal compartments in age-related macular degeneration and to compare the time course of compartment specific effects to visual function. Prospective noncomparative case series. Fourteen patients with changes in 3 major compartments owing to neovascular age-related macular degeneration. Standard treatment with 3 monthly doses of intravitreal ranibizumab was performed. Eyes were examined at baseline and weeks 1, 4, and 12 using a standardized protocol. Manual segmentation was applied to all 128 B-scans contained in a macular raster scan (MRS). Morphology and time course of different retinal and subretinal compartments. High-definition optical coherence tomography and manual segmentation allowed for precise identification of volumes within individual compartments. All morphologic parameters responded positively to therapy, but demonstrated a specific time course. Subretinal fluid was identified as the most relevant factor for visual function, whereas changes in retinal and subpigment epithelial volumes did not correlate with the time course of functional rehabilitation. Analysis of MRS identified a characteristic impact of therapy on retinal and subretinal morphology.

Quantitative Subanalysis of Optical Coherence Tomography after Treatment with Ranibizumab for Neovascular Age-Related Macular Degeneration

To investigate the effects of ranibizumab on retinal morphology in patients with neovascular age-related macular degeneration (AMD) using optical coherence tomography (OCT) quantitative subanalysis. Data from 95 patients receiving intravitreal ranibizumab for neovascular AMD were collected. StratusOCT images were analyzed using custom software that allows precise positioning of prespecified boundaries on every B-scan. Changes in thickness/volume of the retina, subretinal fluid (SRF), subretinal tissue (SRT), and pigment epithelial detachments (PEDs) at week 1 and at months 1, 3, 6, and 9 after treatment were calculated. Total retinal volume reached its nadir at month 1, with an average reduction of 0.43 mm(3) (P < 0.001). By month 9, this initial change had been reduced to a mean reduction of 0.32 mm(3) (P = 0.0011). Total SRF volume reached its lowest level by month 1, with an average reduction of 0.24 mm(3) (P < 0.001). This reduction lessened subsequently, to 0.18 mm(3), by month 9. There was an average 0.3-mm(3) decrease in total PED volume by month 1 (P < 0.001), and this later declined further, to 0.45 mm(3), by month 9 (P = 0.0014). Total SRT volume was reduced by an average of 0.07 mm(3) at month 1 (P = 0.0159) and subsequently remained constant. Although neurosensory retinal edema and SRF showed an early reduction to nadir after the initiation of ranibizumab therapy, the effect on the retina was attenuated over time, suggesting possible tachyphylaxis. PED volume showed a slower but progressive reduction. Manual quantitative OCT subanalysis may allow a more precise understanding of anatomic outcomes and their correlation with visual acuity.

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

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. Two-year, multicenter, randomized, single-masked, controlled study. 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. 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. Through two years, ranibizumab + PDT was more effective than PDT alone and had a low rate of associated adverse events.

Treatment of age-related macular degeneration: focus on ranibizumab

Ranibizumab, a humanized antigen-binding fragment (Fab) that binds all isoforms of VEGF-A, significantly slows down loss of vision and causes significant visual improvement in many patients with choroidal neovascularization (CNV) due to exudative age-related macular degeneration (AMD). These benefits of intravitreal ranibizumab apply to all angiographic subtypes of neovascular AMD and across all lesion sizes when the drug is injected at monthly intervals as shown in two pivotal phase III trials (ANCHOR and MARINA). The results from the PrONTO study suggest that less frequent treatment with ranibizumab through a variable dosing regimen dependent on optical coherence tomography (OCT) findings is a treatment option that results in comparably favorable visual outcomes. Currently, it is unclear whether combination therapy of ranibizumab with photodynamic therapy (PDT) provides any significant advantage over ranibizumab monotherapy (FOCUS trial); however, the combination of PDT and ranibizumab may decrease the need for frequent retreatment. This question will be addressed in the SUMMIT trial. Therapy with ranibizumab is generally very well tolerated with a low rate of seriously adverse ocular events or systemic side-effects. The advent of vascular endothelial growth factor (VEGF) inhibitors has revolutionized the therapy of neovascular AMD. Ranibizumab at the moment appears to be the most effective approved treatment for neovascular AMD.

Ranibizumab Combined With Low-Dose Sorafenib for Exudative Age-Related Macular Degeneration

Ranibizumab Combined With Low-Dose Sorafenib for Exudative Age-Related Macular Degeneration

Ranibizumab Combined With Low-Dose Sorafenib for Exudative Age-Related Macular Degeneration

Angiogenesis is a common factor in the pathogenesis of cancer and in exudative age-related macular degeneration (AMD). Therefore, angiogenesis inhibition has been developed as a therapeutic strategy. We report 2 cases of recurrent exudative AMD in which oral sorafenib, a tyrosine kinase inhibitor approved for cancer, was added to intravitreal ranibizumab, an antibody to vascular endothelial growth factor. These 2 patients were followed up by determination of visual acuity, fluorescein angiography, fundoscopy, and optical coherence tomography. The visual acuity of 1 patient improved from 20/70 to 20/60 while he was receiving sorafenib therapy; that of the other did not. Marked improvement was noted in both patients on optical coherence tomography. Additionally, both patients appeared to receive some benefit when low-dose oral sorafenib was used as monotherapy after its initial addition to ranibizumab therapy. Randomized trials of adding sorafenib to standard therapy for patients with neovascular AMD should be considered.

Ranibizumab: the evidence of its therapeutic value in neovascular age-related macular degeneration

Neovascular age-related macular degeneration (AMD) is the leading cause of severe, irreversible visual impairment in people over 60 years of age. Neovascular AMD is characterized by abnormal growth of blood vessels under the retina, specifically the macula. These vessels leak blood and fluids, damaging the retina and its photoreceptors, resulting in permanent loss of central vision. Vascular endothelial growth factor-A (VEGF-A) has been shown to play a critical role in the pathogenesis of neovascular AMD. In the US, ranibizumab, a VEGF-A blocker, is approved and indicated for the treatment of patients with neovascular AMD. To review the clinical evidence for ranibizumab in the treatment of neovascular AMD. Phase III clinical trial data have established ranibizumab as a safe and well-tolerated treatment for neovascular AMD. Monthly intravitreal injections of ranibizumab result in a statistically significantly greater proportion of patients losing <15 letters of visual acuity (VA) and statistically significant increases in the mean number of letters gained compared with controls. Anatomically, ranibizumab results in stabilization in the mean area of choroidal neovascularization (CNV) and statistically significant reductions in the mean area of leakage compared with controls. Although there is limited economic evidence available, ranibizumab therapy for neovascular AMD appears to deliver a significant degree of value gain in terms of quality of life when compared with other neovascular AMD interventions. Clinical evidence establishes ranibizumab as a first-line therapy option for virtually all treatable neovascular AMD patients. Updating neovascular AMD treatment guidelines to reflect the evidence base for ranibizumab as a preferred first-line therapy would be beneficial for physicians in making informed treatment choices and ultimately helping to ensure the best care for patients.

RANIBIZUMAB FOR TREATMENT OF CHOROIDAL NEOVASCULARIZATION SECONDARY TO AGE-RELATED MACULAR DEGENERATION

To evaluate the short-term outcomes after intravitreal ranibizumab (Lucentis; Genentech, Inc., South San Francisco, CA) injection in patients with neovascular age-related macular degeneration. A review of data for consecutive patients who received intravitreal ranibizumab injection was conducted. The main outcome measures were mean visual acuity and central macular thickness at 3 months compared with those at baseline. Response to ranibizumab therapy was evaluated with particular attention to prior treatment with bevacizumab (Avastin; Genentech, Inc.). Mean baseline visual acuity of 231 eyes of 231 patients was 20/152, and 189 patients (81.8%) had undergone prior treatment, with 153 (65.4%) having received intravitreal bevacizumab. Mean visual acuity at 3 months, available for 203 patients (88%), was 20/126 (P = 0.004). Mean visual acuity for 98 patients treated with bevacizumab within 3 months before ranibizumab injection was 20/100 at baseline and 20/98 at 3 months (P = 0.35). Mean baseline central macular thickness was 278 microm for all patients and improved to 211 microm at 3 months (P < 0.001). Macular thickness decrease was noted irrespective of previous bevacizumab therapy. Ranibizumab therapy was associated with significant improvements in mean visual acuity and central macular thickness for the group of all patients. Patients who had received bevacizumab treatment within 3 months before initiating ranibizumab treatment had stability of, but no improvement in, visual acuity.

Retinal pigment epithelium tears following intravitreal ranibizumab therapy

Two patients with choroidal neovascularization secondary to age-related macular degeneration (AMD) developed a retinal pigment epithelial (RPE) tear following intravitreal injection of ranibizumab. One patient developed the RPE tear within 2 weeks of the injection, the other within 6 weeks of a second injection. Both patients presented with vision loss of one line at diagnosis of the RPE tear. During long-term follow-up, visual acuity improved in one patient by one line and deteriorated in the second patient by three lines. RPE tears may occur after intravitreal injection of ranibizumab in patients with neovascular AMD, probably because of the rapid regression of the fibrovascular membrane.

Retinal Pigment Epithelial Tear after Ranibizumab Therapy for Subfoveal Fibrovascular Pigment Epithelial Detachment

To describe the unusual complication of retinal pigment epithelial (RPE) tear after intravitreal ranibizumab (Lucentis) for subfoveal fibrovascular pigment epithelial detachment (PED) and its effective management. Chart review for case report of RPE tear after ranibizumab. An inferior RPE tear was documented by fluorescein angiography, fundus photography, and optical coherence tomography (OCT) 1 month after receiving repeat ranibizumab injection in the right eye of a patient with bilateral subfoveal fibrovascular PED. He had undergone multiple bevacizumab followed by ranibizumab injections for neovascular age-related macular degeneration (AMD) in both eyes, starting 6 months previously. Subsequent antivascular endothelial growth factor (VEGF) therapy improved vision of right eye from 20/200 to 20/40, despite RPE tear. RPE tear may form after anti-VEGF therapy, including ranibizumab injection. Further anti-VEGF therapy may preserve or improve vision. To the authors' knowledge, this is first case report of effective suppression of neovascular activity with bevacizumab after an RPE tear following ranibizumab therapy.

Value-based medicine and interventions for macular degeneration

The aim of this article is to review the patient value conferred by interventions for neovascular macular degeneration. Value-based medicine is the practice of medicine based upon the patient value (improvement in quality of life and length of life) conferred by an intervention. For ophthalmologic interventions, in which length-of-life is generally unaffected, the value gain is equivalent to the improvement in quality of life. Photodynamic therapy delivers a value gain (improvement in quality of life) of 8.1% for the average person with classic subfoveal choroidal neovascularization, while laser photocoagulation for the same entity confers a 4.4% improvement in quality of life. Preliminary data suggest the value gain for the treatment of occult/minimally classic choroidal neovascularization with ranibizumab is greater than 15%. The average value gain for statins for the treatment of hyperlipidemia is 3.9%, while that for the use of biphosphonates for the treatment of osteoporosis is 1.1% and that for drugs to treat benign prostatic hyperplasia is 1-2%. Interventions, especially ranibizumab therapy, for neovascular macular degeneration appear to deliver an extraordinary degree of value compared with many other interventions across healthcare.

Management of diabetic macular edema with antiangiogenic therapy

Evaluation of: Chun DW, Heier JS, Topping TM, Duker JS, Bankert JM. A pilot study of multiple intravitreal injections of ranibizumab in patients with center-involving clinically significant diabetic macular edema. Ophthalmology 113, 1706–1712 (2006).Macular edema is the leading cause of blindness in diabetic patients. Laser photocoagulation has been the standard therapy for several decades. Recently, vascular endothelial growth factor (VEGF) has been implicated as an important factor in the occurrence of vascular permeability in this disease. Thus, anti-VEGF therapy has been used to treat this condition. The paper under evaluation offers the preliminary results of a pilot study assessing the role of intravitreal injections of ranibizumab to treat center-involving clinically significant diabetic macular edema. This study demonstrates that ranibizumab therapy has the potential to maintain or improve visual acuity and reduce retinal thickness in patients with this disorder.

Ranibizumab versus Verteporfin for Neovascular Age-Related Macular Degeneration

We compared ranibizumab--a recombinant, humanized, monoclonal antibody Fab that neutralizes all active forms of vascular endothelial growth factor A--with photodynamic therapy with verteporfin in the treatment of predominantly classic neovascular age-related macular degeneration. During the first year of this 2-year, multicenter, double-blind study, we randomly assigned patients in a 1:1:1 ratio to receive monthly intravitreal injections of ranibizumab (0.3 mg or 0.5 mg) plus sham verteporfin therapy or monthly sham injections plus active verteporfin therapy. The primary end point was the proportion of patients losing fewer than 15 letters from baseline visual acuity at 12 months. Of the 423 patients enrolled, 94.3% of those given 0.3 mg of ranibizumab and 96.4% of those given 0.5 mg lost fewer than 15 letters, as compared with 64.3% of those in the verteporfin group (P<0.001 for each comparison). Visual acuity improved by 15 letters or more in 35.7% of the 0.3-mg group and 40.3% of the 0.5-mg group, as compared with 5.6% of the verteporfin group (P<0.001 for each comparison). Mean visual acuity increased by 8.5 letters in the 0.3-mg group and 11.3 letters in the 0.5-mg group, as compared with a decrease of 9.5 letters in the verteporfin group (P<0.001 for each comparison). Among 140 patients treated with 0.5 mg of ranibizumab, presumed endophthalmitis occurred in 2 patients (1.4%) and serious uveitis in 1 (0.7%). Ranibizumab was superior to verteporfin as intravitreal treatment of predominantly classic neovascular age-related macular degeneration, with low rates of serious ocular adverse events. Treatment improved visual acuity on average at 1 year. (ClinicalTrials.gov number, NCT00061594 [ClinicalTrials.gov].).

A Pilot Study of Multiple Intravitreal Injections of Ranibizumab in Patients with Center-Involving Clinically Significant Diabetic Macular Edema

To evaluate the biologic activity of multiple intravitreal injections of ranibizumab in patients with center-involving clinically significant diabetic macular edema (DME) and to report any associated adverse events. Single-center, open-label, dose-escalating pilot study. A total of 10 eyes of 10 patients (mean age, 69.3 years [range, 59-81]) with DME involving the center of the macula and best-corrected visual acuity (BCVA) in the study eye between 20/63 and 20/400. Three intravitreal injections of ranibizumab (0.3 mg or 0.5 mg each injection) administered on day 0, month 1, and month 2, and observation until month 24. Primary end points were the frequency and severity of ocular and systemic adverse events. Secondary end points were BCVA and measurement of retinal thickness by optical coherence tomography. Of the 10 patients enrolled, 5 received 0.3-mg and 5 received 0.5-mg ranibizumab. Intravitreal injections of ranibizumab were well tolerated. No systemic adverse events were reported. Five occurrences of mild to moderate ocular inflammation were reported. At month 3, 4 of 10 patients gained > or =15 letters, 5 of 10 gained > or =10 letters, and 8 of 10 gained > or =1 letters. At month 3, the mean decrease in retinal thickness of the center point of the central subfield was 45.3+/-196.3 microm for the low-dose group and 197.8+/-85.9 microm for the high-dose group. Ranibizumab appears to be a well-tolerated therapy for patients with DME. This pilot study demonstrates that ranibizumab therapy has the potential to maintain or improve BCVA and reduce retinal thickness in patients with center-involved clinically significant DME.

Therapie der neovaskulären altersbedingten Makuladegeneration mit Ranibizumab/Lucentis™

Vascular endothelial growth factor (VEGF) is considered to play an essential role in the pathogenesis of age-related macular degeneration due to its vascular permeability-inducing and angiogenic properties. Ranibizumab, a small antibody fragment designed to competitively bind all VEGF isoforms, passes after intravitreal injection all retinal layers reaching the retinal pigment epithelium-choroid complex. Experimental animal models showed the drug to be safe and effective. Subsequently, Phase I/II clinical trials conducted in patients with neovascular AMD demonstrated a good safety profile, and a significant functional benefit. Ranibizumab therapy repeated every four weeks for the treatment of neovascular AMD is currently in Phase III clinical trials. Combination therapy trials aiming for improved treatment durability and effectiveness are currently ongoing as well as new treatment strategies using intermittent, optical coherence tomography (OCT) guided therapy. Anti-VEGF therapy using Ranibizumab is a promising new treatment option for neovascular AMD.