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Age-Related Macular Degeneration Drug Delivery
Published in Glenn J. Jaffe, Paul Ashton, P. Andrew Pearson, Intraocular Drug Delivery, 2006
Kourous A. Rezaei, Sophie J. Bakri, Peter K. Kaiser
Study FVF2128g, a Phase IB/II randomized, controlled, single-agent trial of two different rhuFabV doses given as multiple intravitreal injections was conducted (76). Sixty-four patients were enrolled in a single-agent, multicenter trial. The mean age of the treated patients was 78 years (range 63–87), 56% were female, and 92% were Caucasian. In the drug-treated group (n = 53), intravitreal rhuFab V2 injections (either 300 or 500 μg) were administered to one eye every four weeks for four weeks. Control eyes (n = 11) were treated with standard of care (no ranibizumab). Three different groups of subjects were enrolled in the study based on disease pattern as determined by fluorescein angiography (predominantly classic or minimally classic) and prior treatment: minimally classic (48% of treated patients), predominantly classic (28% of treated patients), and patients previously treated with PDT (24% of treated patients). Patients were monitored for safety and visual acuity. Visual acuity was defined as change from baseline in total number of letters read correctly (gained or lost) on the ETDRS chart. Baseline visual acuity of the enrolled patients ranged from 20/50 to 20/400, with a median of 20/125. There were no drug-related serious adverse events, and only two of 25 had transient vitreal inflammation. By day 98, after four injections, the visual acuity increased by three lines or greater in eight of 24, was stable in 14 of 24, and decreased by three lines or greater in two of 24 patients. The results from the first cohort of treated patients suggest that ranibizumab is well tolerated and visual acuity results were promising.
Treatment of neovascular age-related macular degeneration with ranibizumab
Published in A Peyman MD Gholam, A Meffert MD Stephen, D Conway MD FACS Mandi, Chiasson Trisha, Vitreoretinal Surgical Techniques, 2019
Ranibizumab is an antibody fragment (Fab) derived from a full-length recombinant anti-VEGF monoclonal murine antibody, A4.6.1, that binds all VEGF-A isoforms. The Fab of A4.6.1 was humanized by grafting the specific antigen-binding regions (i.e. the complementarity-determining regions) onto a wholly human Fab framework to generate the Fab MB1.6, and this Fab was then further affinity matured in multiple steps to generate the Fab variant ranibizumab (formerly known as rhuFab V2) with increased affinity to VEGF (compared to the first-generation Fabs, such as rhuFab V1, as well as bevacizumab).32 Bevacizumab (Avastin, Genentech, Inc.), a humanized anti-VEGF monoclonal full-length antibody, has been demonstrated clinically to effectively inhibit tumor-associated angiogenesis33 and was recently approved in the USA for treatment of metastatic colorectal cancer. (For further discussion on the use of bevacizumab in the treatment of ocular disease, see Chapters 66 and 67). Although ranibizumab and bevacizumab share the same parent molecule (A4.6.1), ranibizumab is not the Fab of bevacizumab, as ranibizumab was derived from the Fab variant MB1.6, whereas bevacizumab was derived from a different humanized Fab variant of A4.6.1, Fab-12. Ranibizumab was designed for ocular administration; it consists of the antigen-binding portion without the Fc region and was developed for treatment of retinal/ choroidal neovascularization because the molecular size of full-length antibodies limits the extent of retinal penetration that can be achieved with intravitreal administration. The molecular weight of ranibizumab is 48 kDa, compared with 150 kDa for bevacizumab. It appears that the upper limit of size for a molecule that can penetrate the retina in a healthy eye is between 100 and 150 Å (an angstrom [Å], 0.1 nm, is about the size of one atom). In a rhesus monkey model, it was demonstrated that the small size (48 kDa) of an earlier Fab variant of ranibizumab (rhuFab V1) enabled penetration of the molecule through all layers of the retina.34 A study in rabbits has confirmed that ranibizumab penetrates all retinal layers.35 Because ranibizumab is humanized, induction of antibodies against ranibizumab, which theoretically could neutralize the therapeutic activity of the Fab and/or reduce its tolerability, is not expected to be clinically important. As noted earlier, confirmation of the in vivo anti-VEGF activity of ranibizumab in a primate model of CNV suggested that this molecule was a promising candidate for the treatment of ARMD-related CNV.31
The Spectrum of Ocular Manifestations in Patients with Waldenström’s Macroglobulinemia
Published in Ocular Immunology and Inflammation, 2022
Rosanna Dammacco, Walter Lisch, Tero T. Kivelä, Evangelos Terpos, Efstathios Kastritis, Dario Sisto, Alberto Mavilio, Roberto Ria, Giovanni Alessio, Angelo Vacca, Franco Dammacco
A central retinal vein occlusion with secondary macular edema was diagnosed in the left eye of patient #11. As vascular endothelial growth factor-A (VEGF-A) is an important regulator of angiogenesis and therefore an anti-angiogenic target in retinal diseases,34 the patient was treated with ranibizumab (Lucentis®). Intravitreal injection of 0.5 mg ranibizumab monthly for three consecutive months resulted in a clinically meaningful gain in BCVA from baseline. After no response to six cycles of R-CD, the patient was switched to an R-CHOP regimen, which led to a complete response that was maintained for 3 years. A subsequent relapse was treated with the same R-CHOP regimen and induced a durable very good partial response, maintained until the end of follow-up. The ophthalmological improvement remained unchanged.
Safety review of anti-VEGF therapy in patients with myopic choroidal neovascularization
Published in Expert Opinion on Drug Safety, 2022
Danny S. C. Ng, Mary Ho, Lawrence P.L. Iu, Timothy Y.Y. Lai
Ocular serious adverse event was reported in one (0.93%) patient in the treatment-naïve group. Two (1.14%) patients in the prior ranibizumab-treated group developed ocular serious adverse events, which included one patient each with subretinal fibrosis and retinal detachment. The subretinal fibrosis is unlikely to be treatment-related as fibrosis is not uncommonly seen as part of the natural course of myopic CNV. Non-ocular adverse events were encountered in 11 (10.19%) patients in the treatment-naïve group, which included one (0.93%) patient who developed myalgia suspected to be ranibizumab-associated [33]. Ocular adverse events were reported in 11 (10.19%) treatment-naïve patients, with increased intraocular pressure (IOP) (1.9%; n = 2) being the most common. Eighteen (10.29%) prior-ranibizumab treated patients also developed ocular adverse events and the most common adverse events included 3 (1.71%) patients with glaucoma, and 2 (1.14%) patients each with cataract, increased IOP, conjunctival hemorrhage, and reduced visual acuity.
Ranibizumab for the treatment of diabetic retinopathy
Published in Expert Opinion on Biological Therapy, 2021
Of note, the systemic pharmacokinetics of ranibizumab after intravitreal administration were similar among patients with age-related macular degeneration, DME and retinal vein occlusion. In all diseases, ranibizumab exits the eye slowly and then it presents fast systemic clearance due to lack of the Fc receptor [54,55]; this might theoretically enhance its systemic safety for intraocular use, minimizing systemic exposure [55]. Specifically, the serum half-life of ranibizumab is around 9 days following a single intravitreal injection and the systemic concentration was estimated to be 90,000 times lower than in the vitreous [52]. The routes of elimination of ranibizumab from the eye are mainly through the choroidal vessels or aqueous humor outflow [47]. Once ranibizumab enters the systemic circulation, it is excreted via the renal filtration system [52].