Macular Degeneration: Shams N

Ferrara N, Damico L, Shams N, Lowman H, Kim R. · Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. · Retina. · Pubmed #17031284 No free full text.

Abstract: BACKGROUND: Angiogenesis is a key aspect of the wet form of age-related neovascular (AMD), the leading cause of blindness in the elderly population. Substantial evidence indicated that vascular endothelial growth factor (VEGF)-A is a major mediator of angiogenesis and vascular leakage in wet AMD. VEGF-A is the prototype member of a gene family that includes also PlGF, VEGF-B, VEGF-C, VEGF-D and the orf virus-encoded VEGF-E. Several isoforms of VEGF-A can be generated due to alternative mRNA splicing. Various VEGF inhibitors have been clinically developed. Among these, ranibizumab is a high affinity recombinant Fab that neutralizes all isoforms of VEGF-A. The article briefly reviews the biology of VEGF and then focuses on the path that led to clinical development of ranibizumab. RESULTS: The safety and efficacy of ranibizumab in the treatment of neovascular AMD have been evaluated in two large phase III, multicenter, randomized, double-masked, controlled pivotal trials in different neovascular AMD patient populations. Combined, the trial results indicate that ranibizumab results not only in a slowing down of vision loss but also in a significant proportion of patients experiencing a clinically meaningful vision gain. The visual acuity benefit over control was observed regardless of CNV lesion type. Furthermore, the benefit was associated with a low rate of serious adverse events. CONCLUSIONS: Ranibizumab represents a novel therapy that, for the first time, appears to have the potential to enable many AMD patients to obtain a meaningful and sustained gain of vision. On June 30 2006, ranibizumab was approved by the US Food and Drug Administration for the treatment of wet AMD.

Shams N, Ianchulev T. · Ophthalmic Medicine, Genentech, One DNA Way, South San Francisco, CA 94080-4990, USA. · Ophthalmol Clin North Am. · Pubmed #16935208 No free full text.

Abstract: VEGF-A is a critical regulator of ocular angiogenesis and vascular permeability and is involved in the pathogenesis of several ocular diseases involving neovascularization or increased vascular permeability, such as neovascular AMD, diabetic ME, and diabetic retinopathy. Currently available therapies for neovascular AMD, such as laser photocoagulation, PDT with verteporfin, and pegaptanib sodium, slow visual loss but do not improve vision for most patients. In contrast, an emerging anti-VEGF agent, ranibizumab, improved vision in 25% to 34% of treated patients in one clinical trial, rather than slowing visual loss and is the first treatment for neovascular AMD to demonstrate visual improvement in a substantial number of patients. This represents a major advance in the treatment of ocular diseases involving neovascularization or increased vascular permeability and provides hope to patients with these debilitating diseases. Since the submission of this article, ranibizumab was approved by the FDA for the treatment of neovascular AMD.

Regillo CD, Brown DM, Abraham P, Yue H, Ianchulev T, Schneider S, Shams N. · Retina Service, Wills Eye Institute, 840 Walnut Street, Philadelphia, PA 19107, USA. · Am J Ophthalmol. · Pubmed #18222192 No free full text.

Abstract: PURPOSE: To evaluate the efficacy and safety of ranibizumab administered monthly for three months and then quarterly in patients with subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). DESIGN: Phase IIIb, multicenter, randomized, double-masked, sham injection-controlled trial in patients with predominantly or minimally classic or occult with no classic CNV lesions. METHODS: Patients were randomized 1:1:1 to 0.3 mg ranibizumab (n = 60), 0.5 mg ranibizumab (n = 61), or sham (n = 63) treatment groups. The primary efficacy endpoint was mean change from baseline visual acuity (VA) at month 12. RESULTS: Mean changes from baseline VA at 12 months were -16.3, -1.6, and -0.2 letters for the sham, 0.3 mg, and 0.5 mg groups, respectively (P < or = .0001, each ranibizumab dose vs sham). Ranibizumab arrested CNV growth and reduced leakage from CNV. However, the treatment effect declined in the ranibizumab groups during quarterly dosing (e.g., at three months the mean changes from baseline VA had been gains of 2.9 and 4.3 letters for the 0.3 mg and 0.5 mg doses, respectively). Results of subgroups analyses of mean change from baseline VA at 12 months by baseline age, VA, and lesion characteristics were consistent with the overall results. Few serious ocular or nonocular adverse events occurred in any group. CONCLUSIONS: Ranibizumab administered monthly for three months and then quarterly provided significant VA benefit to patients with AMD-related subfoveal CNV and was well tolerated. The incidence of serious ocular or nonocular adverse events was low.

Rosenfeld PJ, Heier JS, Hantsbarger G, Shams N. · Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami, Miami, Florida 33136, USA. · Ophthalmology. · Pubmed #16581423 No free full text.

Abstract: PURPOSE: To investigate whether multiple intravitreal doses of up to 2 mg of an antigen-binding fragment known as ranibizumab, derived from a humanized anti-vascular endothelial growth factor antibody, can be tolerated and are biologically active when injected using a dose-escalating strategy in eyes of patients with neovascular age-related macular degeneration (AMD). DESIGN: Open-label, 2-center, uncontrolled, randomized clinical study of 3 different dose-escalating regimens of ranibizumab. PARTICIPANTS: Thirty-two patients with primary or recurrent subfoveal choroidal neovascularization secondary to AMD were enrolled. Baseline best-corrected visual acuity (VA) in the study eye was from 20/40 to 20/640 (Snellen equivalent). METHODS: Treatment regimens consisted of 5, 7, or 9 intravitreal injections of ranibizumab at 2- or 4-week intervals for 16 weeks, with escalating doses ranging from 0.3 to 2.0 mg. Patients were evaluated through day 140, 4 weeks after their last injection. MAIN OUTCOME MEASURES: Safety was assessed based on ocular and nonocular adverse events, changes in VA, changes in intraocular pressure (IOP), slit-lamp ocular examination, changes in lesion characteristics based on fluorescein angiography and color fundus photography, and the presence of anti-ranibizumab antibodies. RESULTS: Twenty-nine patients received an injection at baseline, and 27 patients completed the study through day 140. Results were similar across the 3 treatment groups. All patients experienced ocular adverse events, most of which were mild. The most common ocular adverse events were iridocyclitis (83%) and injection-site reactions (72%). Inflammation did not increase with repeated injections, despite the increasing ranibizumab doses. Transient mild IOP elevations were common after ranibizumab injection. No serum anti-ranibizumab antibodies were detected. Overall, median and mean VAs in the study eyes improved by day 140 in all 3 groups. Only 3 of the 27 patients lost significant vision. There was no significant lesion growth, and a decrease in area of leakage from choroidal neovascularization was detected through day 140. CONCLUSIONS: Multiple intravitreal injections of ranibizumab at escalating doses ranging from 0.3 to 2.0 mg were well tolerated and biologically active in eyes with neovascular AMD through 20 weeks. Mild transient ocular inflammation was the most common postinjection adverse event.

Heier JS, Antoszyk AN, Pavan PR, Leff SR, Rosenfeld PJ, Ciulla TA, Dreyer RF, Gentile RC, Sy JP, Hantsbarger G, Shams N. · Ophthalmic Consultants of Boston, Boston, Massachusetts 02114, USA. · Ophthalmology. · Pubmed #16483659 No free full text.

Abstract: OBJECTIVE: To assess safety of repeated intravitreal injections of ranibizumab in treating neovascular age-related macular degeneration (AMD), and to assess changes in visual acuity (VA) and AMD lesion characteristics. DESIGN: Multicenter, controlled, open-label, clinical trial. PARTICIPANTS: Sixty-four patients with subfoveal predominantly or minimally classic AMD-related choroidal neovascularization. METHODS: In part 1, subjects were randomized to monthly intravitreal ranibizumab for 3 months (4 injections of 0.3 mg or 1 injection of 0.3 mg followed by 3 injections of 0.5 mg; n = 53) or usual care (UC; n = 11). In part 2, subjects could continue their regimen for 3 additional months or cross over to the alternative treatment. MAIN OUTCOME MEASURES: Adverse events (AEs), intraocular pressure (IOP), VA, and lesion characteristics assessed by fluorescein angiography and fundus photography. RESULTS: Of the 64 randomized subjects, 62 completed the 6-month study. Twenty of 25 subjects (80%) randomized to 0.3 mg, and 22 of 28 subjects (79%) randomized to 0.5-mg ranibizumab in part 1 continued on that treatment in part 2; 9 of 11 (82%) subjects randomized to UC in part 1 crossed over to ranibizumab treatment in part 2. The most common AEs with ranibizumab were reversible inflammation and minor injection-site hemorrhages. Serious AEs were iridocyclitis, endophthalmitis, and central retinal vein occlusion (1 subject each). Postinjection, IOP increased transiently in 22.6% of ranibizumab-treated eyes in parts 1 and 2. After 4 ranibizumab injections (day 98), mean (+/- standard deviation) VA had increased 9.4+/-13.3 and 9.1+/-17.2 letters in the 0.3- and 0.5-mg groups, respectively, but had decreased 5.1+/-9.6 letters with UC. In part 2 (day 210), VA increased from baseline 12.8+/-14.7 and 15.0+/-14.2 letters in subjects continuing on 0.3 and 0.5 mg, respectively. Visual acuity improved from baseline > or =15 letters in 26% (day 98) and 45% (day 210) of subjects initially randomized to and continuing on ranibizumab, respectively, and areas of leakage and subretinal fluid decreased. No UC subject had a > or =15-letter improvement at day 98. CONCLUSIONS: Repeated intravitreal injections of ranibizumab had a good safety profile and were associated with improved VA and decreased leakage from choroidal neovascularization in subjects with neovascular AMD.

Rosenfeld PJ, Schwartz SD, Blumenkranz MS, Miller JW, Haller JA, Reimann JD, Greene WL, Shams N. · Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami, Miami, Florida 33136, USA. · Ophthalmology. · Pubmed #15885778 No free full text.

Abstract: PURPOSE: To investigate the maximum tolerated dose of ranibizumab administered as a single intravitreal injection. DESIGN: Open-label, 5-center, uncontrolled, prospective, dose-ranging, interventional case series. PARTICIPANTS: Twenty-seven patients with subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) with best-corrected Snellen equivalent visual acuity (VA) of 20/100 or worse and considered ineligible for laser photocoagulation or photodynamic therapy. METHODS: A single intravitreal injection of ranibizumab was to be administered at 1 of 6 escalating doses (50, 150, 300, 500, 1000, and 2000 microg), with escalation to the next dose level occurring only after the safety and tolerability of the lower dose level was established through postinjection day 14. Follow-up examinations were performed on postinjection days 1, 3, 7, 14, 42, and 90. Enrollment was stopped if > or =2 patients experienced dose-limiting toxicity. MAIN OUTCOME MEASURES: The primary safety measures were changes from baseline in VA, intraocular pressure (IOP), intraocular inflammation, and production of antiranibizumab antibody. Dose-limiting toxicity was defined by intraocular inflammation, elevated IOP, reduced VA, or hemorrhage within 90 days after injection. RESULTS: All patients completed this single intravitreal injection study, and 500 microg of ranibizumab was the maximum tolerated dose. At the higher dose of 1000 microg, significant intraocular inflammation was noted. All adverse events were self-limited, and no infectious endophthalmitis occurred. Aqueous or vitreous ocular inflammation occurred in 12 subjects, with complete resolution within 42 days. In 9 of the subjects, the inflammation was graded as trace to 1+ and required no treatment; in 3 of the subjects, the inflammation was graded as 2+ or 3+, and 2 of the 3 were treated with topical 1% prednisolone acetate. No serum antiranibizumab antibodies were detected. All patients had VA similar or improved compared with baseline values. CONCLUSION: The maximum tolerated single dose of ranibizumab in neovascular AMD patients was 500 microg. Single intravitreal injections of ranibizumab up to a dose of 500 microg were safe and well tolerated in this small group of patients.