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03-21-2017 | Retinopathy | Review | Article

A Review of Ranibizumab for the Treatment of Diabetic Retinopathy

Journal: Ophthalmology and Therapy

Author: Michael W. Stewart

Publisher: Springer Healthcare

Abstract

Introduction

Laser photocoagulation has been the standard treatment for diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) for several decades. The discovery of vascular endothelial growth factor (VEGF) and the subsequent determination of its critical role in the development DME and PDR has led to the development of VEGF inhibitory drugs. Ranibizumab was the first anti-VEGF drug approved for the treatment of both DME and diabetic retinopathy in eyes with DME.

Methods

Medline searches with the keywords "ranibizumab," "diabetic macular edema," and "proliferative diabetic retinopathy" were performed to identify pertinent pre-clinical studies and clinical trials. Top-line data, with emphasis on pivotal trials, was identified and incorporated into this manuscript. Findings from small uncontrolled trials were generally not used unless they filled important gaps in our understanding of anti-VEGF therapy.

Results

Ranibizumab is a recombinant humanized antibody fragment that binds all isoforms of VEGF-A with high affinity. Three parallel lines of clinical research have produced level I evidence supporting the superiority of ranibizumab over laser photocoagulation for the treatment of DME. Regular injections also lead to improvement in diabetic retinopathy severity scores in a large minority of eyes. Ranibizumab is effective for PDR and produces less visual field loss than laser photocoagulation. It has an excellent safety profile, with low incidence of ocular and systemic adverse events.

Conclusions

Ranibizumab has become a frequently used first-line therapy for the treatment of DME. Emerging data suggest that it may become an important treatment for DR and PDR.
Literature
1.
Congdon N, O’Colmain B, Klaver CC, et al. Eye Diseases Prevalence Research Group. Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol. 2004;122(4):477–85.CrossRefPubMed
2.
Roy MS, Janal MN. High caloric and sodium intakes as risk factors for progression of retinopathy in type 1 diabetes mellitus. Arch Ophthalmol. 2010;128:33–9.CrossRefPubMed
3.
Alwakeel JS, Sulimani R, Al-Asaad H, et al. Diabetes complications in 1952 type 2 diabetes mellitus patients managed in a single institution in Saudi Arabia. Ann Saudi Med. 2008;28:260–6.CrossRefPubMed
4.
Borchers AT, Uibo R, Gershwin ME. The geoepidemiology of type 1 diabetes. Autoimmun Rev. 2010;9:A355–65.CrossRefPubMed
5.
Stuckler D, Basu S, McKee M. Drivers of inequality in Millennium Development Goal progress: a statistical analysis. PLoS Med. 2010;7:e1000241.CrossRefPubMedPubMedCentral
6.
Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study Research Group report number 1. Arch Ophthalmol. 1985;103(12):1796–806.CrossRef
7.
The Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy: the second report of diabetic retinopathy study findings. Trans Am Acad Ophthalmol Otolaryngol. 1978;85:82.
8.
Early Treatment Diabetic Retinopathy Study Research Group. Early photocoagulation for diabetic retinopathy: ETDRS report number 9. Ophthalmology. 1991;98(Suppl):766–85.
9.
Michaelson IC. The mode of development of the vascular system of the retina with some observations on its significance for certain retinal disorders. Trans Ophthalmol Soc UK. 1948;68:1625–710.
10.
Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182–6.CrossRefPubMed
11.
Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983;12:983–5.CrossRef
12.
Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun. 1989;161:851–8.CrossRefPubMed
13.
Connolly DT, Heuvelman DM, Nelson R, et al. Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest. 1989;84:1470–8.CrossRefPubMedPubMedCentral
14.
Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331:1480–7.CrossRefPubMed
15.
Roberts WG, Palade GE. Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J Cell Sci. 1995;108:2369–79.PubMed
16.
Qaum T, Xu Q, Joussen AM, et al. VEGF-initiated blood-retinal barrier breakdown in early diabetes. Invest Ophthalmol Vis Sci. 2001;42:2408–13.PubMed
17.
Tolentino MJ, McLeod DS, Taomoto M, Otsuji T, Adamis AP, Lutty GA. Pathologic features of vascular endothelial growth factor-induced retinopathy in the nonhuman primate. Am J Ophthalmol. 2002;133:373–85.CrossRefPubMed
18.
Ferrara N, Damico L, Shams N, Lowman H, Kim R. Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina. 2006;26:859–70.CrossRefPubMed
19.
Lowe J, Araujo J, Yang J, et al. Ranibizumab inhibits multiple forms of active vascular endothelial growth factor in vitro and in vivo. Exp Eye Res. 2007;85(4):425–30.CrossRefPubMed
20.
Papadopoulos N, Martin J, Ruan Q, et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis. 2012;15(2):171–85.CrossRefPubMedPubMedCentral
21.
Gaudreault J, Fei D, Rusit J, Suboc P, Shiu V. Preclinical pharmacokinetics of ranibizumab (rhuFabV2) after a single intravitreal administration. Invest Ophthalmol Vis Sci. 2005;46:726–33.CrossRefPubMed
22.
Bakri SJ, Snyder MR, Reid JM, Pulido JS, Ezzat MK, Singh RJ. Pharmacokinetics of intravitreal ranibizumab (Lucentis). Ophthalmology. 2007;114:2179–82.CrossRefPubMed
23.
Christofordis JB, Carlton MM, Knopp MV, Hinkle GH. Pet/CT imaging of I-124-radiolabeled bevacizumab and ranibizumab after intravitreal injection in a rabbit model. Invest Ophthalmol Vis Sci. 2011;52:5899–903.CrossRef
24.
Mordenti J, Cuthbertson RA, Ferrara N, et al. Comparisons of the intraocular tissue distribution, pharmacokinetics, and safety of 125I-labeled full-length and Fab antibodies in rhesus monkeys following intravitreal administration. Toxicol Pathol. 1999;27:536–44.CrossRefPubMed
25.
Krohne TU, Liu Z, Holz FG, Meyer CH. Intraocular pharmacokinetics of ranibizumab following a single intravitreal injection in humans. Am J Ophthalmol. 2012;154(4):682–6.CrossRefPubMed
26.
Xu L, Lu T, Tuomi L, et al. Pharmacokinetics of ranibizumab in patients with neovascular age-related macular degeneration: a population approach. Invest Ophthalmol Vis Sci. 2013;54(3):1616–24.CrossRefPubMed
27.
Avery RL, Castellarin AA, Steinle NC, et al. Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD. Br J Ophthalmol. 2014;98(12):1636–41.CrossRefPubMedPubMedCentral
28.
Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;334:1432–44.CrossRef
29.
Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for age-related macular degeneration. N Engl J Med. 2006;355:1419–31.CrossRefPubMed
30.
Nguyen QD, Tatlipinar S, Shah SM, et al. Vascular endothelial growth factor is critical stimulus for diabetic macular edema. Am J Ophthalmol. 2006;142:961–9.CrossRefPubMed
31.
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. 2006;113:1706–12.CrossRefPubMed
32.
Nguyen QD, Shah SM, Heier JS, et al. Primary end point (six months) results of the ranibizumab for edema of the macula in diabetes (READ-2) study. Ophthalmology. 2009;116:2175–81.CrossRefPubMed
33.
Nguyen QD, Shah SM, Khwaja AA, et al. Two-year outcomes of the ranibizumab for edema of the macula in diabetes (READ-2) study. Ophthalmology. 2010;117:2146–51.CrossRefPubMed
34.
Do DV, Nguyen QD, Khwaja AA, et al. Ranibizumab for edema of the macula in diabetes study: 3-year outcomes and the need for prolonged frequent treatment. JAMA Ophthalmol. 2013;131(2):139–45.CrossRefPubMed
35.
Busbee BG, Ho AC, Brown DM, et al. HARBOR Study Group. Twelve-month efficacy and safety of 0.5 mg or 2 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration. Ophthalmology. 2013;120(5):1046–56.CrossRefPubMed
36.
Do DV, Sepah YJ, Boyer D, et al. Month-6 primary outcomes of the READ-3 study (Ranibizumab for Edema of the mAcula in Diabetes-Protocol 3 with high dose). Eye (Lond). 2015;29(12):1538–44.CrossRef
37.
Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119:789–801.CrossRefPubMed
38.
Brown DM, Nguyen QD, Marcus DM, et al. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials. Ophthalmology. 2013;120:2013–22.CrossRefPubMed
39.
Boyer DS, Nguyen QD, Brown DM, et al. Outcomes with as-needed ranibizumab after initial monthly therapy: long-term outcomes of the phase III RIDE and RISE trials. Ophthalmology. 2015;122:2504–13.CrossRefPubMed
40.
Massin P, Bandello F, Garweg JG, et al. Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12-month, randomized, controlled, double-masked, multicenter phase II study. Diabetes Care. 2010;33:2399–405.CrossRefPubMedPubMedCentral
41.
Mitchell P, Bandello F, Schmidt-Erfurth U, et al. On behalf of the RESTORE study group. The RESTORE Study. Ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118(4):615–25.CrossRefPubMed
42.
Lang GE, Berta A, Eldem BM, et al. On behalf of the RESTORE Extension Study Group. Two-year safety and efficacy of ranibizumab 0.5 mg in diabetic macular edema. Interim analysis of the RESTORE extension study. Ophthalmology. 2013;120(10):2004–12.CrossRefPubMed
43.
Schmidt-Erfurth U, Lang GE, Holz FG, et al. RESTORE extension study group. Three-year outcomes of individualized ranibizumab treatment in patients with diabetic macular edema: the RESTORE extension study. Ophthalmology. 2014;121:1045–53.CrossRefPubMed
44.
Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117:1064–77.CrossRef
45.
Diabetic Retinopathy Clinical Research Network Writing Committee, Elman MJ, Bressler NM, Qin H, et al. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2011;118:609–14.CrossRef
46.
Diabetic Retinopathy Clinical Research Network Writing Committee, Elman MJ, Qin H, Aiello LP, et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment. Three-year randomized trial results. Ophthalmology. 2012;119(11):2312–8.CrossRef
47.
Elman MJ, Ayala A, Bressler NM, et al. For the Diabetic Retinopathy Clinical Research Network. Intravitreal ranibizumab for diabetic macular edema with prompt vs. deferred laser treatment: 5-year randomized trial results. Ophthalmology. 2015;122(2):375–81.CrossRefPubMed
48.
Prünte C, Fajnkuchen F, Mahmood S, et al. Ranibizumab 0.5 mg treat-and-extend regimen for diabetic oedema: the RETAIN study. Br J Ophthalmol. 2016;100(6):787–95.CrossRefPubMed
49.
Nepomuceno AB, Takaki E, Paes de Almeida FP, et al. A prospective randomized trial of intravitreal bevacizumab versus ranibizumab for the management of diabetic macular edema. Am J Ophthalmol. 2013;156:502–10.CrossRefPubMed
50.
Diabetic Retinopathy Clinical Research Network, Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372(13):1193–203.CrossRef
51.
Wells JA, Glassman AR, Ayala AR, et al. Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology. 2016;123(6):1351–9.CrossRefPubMed
52.
Bressler SB, Ayala AR, Bressler NM, et al. Diabetic Retinopathy Clinical Research Network. Persistent macular thickening after ranibizumab treatment for diabetic macular edema with vision impairment. JAMA Ophthalmol. 2016;134(3):278–85.CrossRefPubMedPubMedCentral
53.
Ferris FL 3rd, Maguire MG, Glassman AR, Ying GS, Martin DF. Evaluating effects of switching anti-vascular endothelial growth factor drugs for age-related macular degeneration and diabetic macular edema. JAMA Ophthalmol. 2016 [Epub ahead of print].
54.
Filho JA, Messias A, Almeida FP, et al. Panretinal photocoagulation (PRP) versus PRP plus ranibizumab for high-risk proliferative diabetic retinopathy. Acta Ophthalmol. 2011;89:e567–72.CrossRefPubMed
55.
Writing Committee for the Diabetic Retinopathy Clinical Research Network, Gross JG, Glassman AR, Jampol LM, et al. Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy. A randomized clinical trial. JAMA. 2015;314(20):2137–46.CrossRef

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