Compound Name:RanibizumabMolecular Target:VEGF-AMolecular Structure:humanized IgG1? Fab fragmentLicensed Indication:neovascular (wet) age-related macular degenerationManufacturer and/or Distributor:Genentech; (XOMA)Initial FDA Approval:2006Summary:Ranibizumab (Lucentis) is a Fab fragment (approximate M.W. 48 KDa) of a humanized IgG1 kappa murine monoclonal antibody that binds activated forms of vascular endothelial growth factor (VEGF-A). This prevents binding of VEGF-A to its receptors (VEGFR1 and VEGFR2) on vascular endothelium and thereby prevents vascular endothelial proliferation, vascular leakage and neo-vascularization. The usual treatment schedule consists of intra-vitreal monthly injections for at least 3 months. The drug was originally approved in 2006 for treatment of “wet” (or neo-vascular) age-related macular degeneration (AMD). In 2010, the indication for macular edema after retinal vein occlusion was added. In 2012 approval was also given for treatment of diabetic macular edema. Treatment with Lucentis has been effective in preventing visual loss and improving visual acuity in patients with AMD1. In December 2014, the FDA granted breakthrough therapy designation to ranibizumab for the treatment of diabetic retinopathy. The potential serious adverse effects are endophthalmitis, retinal detachments, hemorrhage, increased intraocular pressure and arterial thrombotic events. An increase in fatalities over two years was observed in pivotal clinical trials with diabetic patients treated with Ranibizumab. Each study group had 250 patients; there were 3 fatalities in the control group; 11 fatalities in the higher-dose ranibizumab group; and 7 fatalities in the standard (approved) dose group. The relationship of these events to the drug is not clear; in each arm of the study the drug was administered by intra-vitreal injection. A recent review has concluded that many of the adverse events are related to the injection procedure. A Cochrane Database Review of 18 studies of patients with diabetic macular edema concluded that anti-angiogenic drugs provided clinical benefits that were superior to laser photocoagulation. Ranibizumab was derived from the same murine monoclonal antibody as Bevacizumab (Avastin). It differs in that it is a Fab fragment rather than the intact IgG molecule. It is not glycosylated because is produced by E.coli rather than a mammalian cell line. Ranibizumab contains five mutations that increase its affinity for VEGF-A. Although Bevacizumab has been studied for treatment of macular degeneration and found to be effective, it is not approved for this indication. Ranibizumab is expensive and clinical trials may suggest alternatives.References

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1. Steinbrook R. The price of sight--ranibizumab, bevacizumab, and the treatment of macular degeneration. N Engl J Med. 2006 Oct 5;355(14):1409-1412. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17021315

2. Stone EM. A very effective treatment for neovascular macular degeneration. N Engl J Med. 2006 Oct 5;355(14):1493-1495. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17021326

3. Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006 Oct 5;355(14):1432-1444. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17021319

4. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006 Oct 5;355(14):1419-1431.

5. Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011 May 19;364(20):1897-1908. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21526923

6. Nguyen Q, Brown D, Marcus D, Boyer D, Patel S, Feiner L, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119(4):789-801. http://dx.doi.org/10.1016/j.ophtha.2011.12.039

7. Shikari H, Silva PS, Sun JK. Complications of intravitreal injections in patients with diabetes. Semin Ophthalmol 2014; 29(5-6):276-289. http://www.ncbi.nlm.nih.gov/pubmed/25325853

8. Virgili G, Parravano M, Menchini F, Evans JR. Anti-vascular endothelial growth factor for diabetic macular edema. Cochrane Database Syst Rev 2014; Oct 24;10:CD007419. http://www.ncbi.nlm.nih.gov/pubmed/25342124

9.  Diabetic Retinopathy Clinical Research Network. Aflibercept, Bevacizumab,orRanibizumabfor Diabetic  Macular Edema.NEJM 2015; 372:1193 – 1203. http://www.nejm.org/doi/full/10.1056/NEJMoa1414264#t=articleDiscussion

10. Wells, J.A., Glassman, A.R., Ayala, A.R. et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology. 2016; 123 (1351-1359) http://www.aaojournal.org/article/S0161-6420(16)00206-2/fulltext

11. The Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015; 372 (1193-1203) http://www.nejm.org/doi/full/10.1056/NEJMoa1414264#t=article