FEATURED ARTICLE
Pipeline therapies for neovascular age-related macular degeneration
Int J Retina Vitreous.2021 Oct 1;7(1):55.
Sruthi Arepalli, Peter K Kaiser
Abstract
Age related macular degeneration (AMD) is the most common cause of vision loss in the elderly population. Neovascular AMD comprises 10% of all cases and can lead to devastating visual loss due to choroidal neovascularization (CNV). There are various cytokine pathways involved in the formation and leakage from CNV. Prior treatments have included focal laser therapy, verteporfin (Visudyne, Bausch and Lomb, Rochester, New York) ocular photodynamic therapy, transpupillary thermotherapy, intravitreal steroids and surgical excision of choroidal neovascular membranes. Currently, the major therapies in AMD focus on the VEGF-A pathway, of which the most common are bevacizumab (Avastin; Genentech, San Francisco, California), ranibizumab (Lucentis; Genentech, South San Francisco, California), and aflibercept (Eylea; Regeneron, Tarrytown, New York). Anti-VEGF agents have revolutionized our treatment of wet AMD; however, real world studies have shown limited visual improvement in patients over time, largely due to the large treatment burden. Cheaper alternatives, including ranibizumab biosimilars, include razumab (Intas Pharmaceuticals Ltd., Ahmedabad, India), FYB 201 (Formycon AG, Munich, Germany and Bioeq Gmbh Holzkirchen, Germany), SB-11 (Samsung Bioepsis, Incheon, South Korea), xlucane (Xbrane Biopharma, Solna, Sweden), PF582 (Pfnex, San Diego, California), CHS3551 (Coherus BioSciences, Redwood City, California). Additionally, aflibercept biosimilars under development include FYB203 (Formycon AG, Munich, Germany and Bioeq Gmbh Holzkirchen, Germany), ALT-L9 (Alteogen, Deajeon, South Korea), MYL1710 (Momenta Pharamaceuticals, Cambridge, MA, and Mylan Pharmacueticals, Canonsburg, PA), CHS-2020 (Coherus BioSciences, Redwood City, California). Those in the pipeline of VEGF targets include abicipar pegol (Abicipar; Allergan, Coolock, Dublin), OPT-302 (Opthea; OPTHEA limited; Victoria, Melbourne), conbercept (Lumitin; Chengdu Kanghong Pharmaceutical Group, Chengdu, Sichuan), and KSI-301 (Kodiak Sciences, Palo Alto, CA). There are also combination medications, which target VEGF and PDGF, VEGF and tissue factor, VEGF and Tie-2, which this paper will also discuss in depth. Furthermore, long lasting depots, such as the ranibizumab port delivery system (PDS) (Genentech, San Francisco, CA), as well as others are under evaluation. Gene therapy present possible longer treatments options as well and are reviewed here. This paper will highlight the past approved medications as well as pipeline therapies for neovascular AMD.
DOI: 10.1186/s40942-021-00325-5
DRUG TREATMENT
Efficacy and safety of Aflibercept for the treatment of idiopathic choroidal neovascularization in young patients: the INTUITION study
Retina.2021 Sep 27.
Laurent Kodjikian, Ramin Tadayoni, Eric H Souied, Stéphanie Baillif, Solange Milazzo, Stéphane Dumas, Joël Uzzan, Lorraine Bernard, Evelyne Decullier, Laure Huot, Thibaud Mathis
Purpose: To evaluate mean change in visual acuity at 52-weeks in patients with idiopathic choroidal neovascularization (iCNV) treated with aflibercept.
Methods: We conducted a prospective non-comparative open-label phase-II trial. The dosage regimen evaluated in this study was structured into two periods: (1) from inclusion to 20-weeks: a treat-and-extend period composed of three mandatory intravitreal injections, and complementary intravitreal injections performed if needed; (2) from 21-weeks to 52-weeks: a pro re nata period composed of intravitreal injections performed only if needed.
Results: A total of 19 patients were included and 16 completed the 52-weeks study. At baseline, mean BCVA was 66.56 (±20.72) letters (≈20/50 Snellen equivalent), and mean CRT was 376.74µm (±93.77). At 52-week, the mean change in BCVA was +19.50 (±19.36) letters [95%CI=+9.18-+29.82]. None of the patients included lost ≥15-letters at 24-weeks or 52-weeks. Mean change in CRT was -96.78µm (±104.29) at 24-weeks and -86.22µm (±112.27) at 52-weeks. The mean number of intravitreal injections was 5.4 (±3.0) at 52-weeks. No ocular serious adverse events related to the treatment were reported.
Conclusions: The present analysis shows clinically significant functional and anatomical treatment effect of aflibercept in case of iCNV. The treat-and-extend regimen proposed after the first injection seems adequate to treat the majority of neovessels.
DOI: 10.1097/IAE.0000000000003310
Disease-modifying effects of ranibizumab for central retinal vein occlusion
Graefes Arch Clin Exp Ophthalmol.2021 Oct 6.
Jason M Huang, Rahul N Khurana, Avanti Ghanekar, Pin-Wen Wang, Bann-Mo Day, Barbara A Blodi, Amitha Domalpally, Carlos Quezada-Ruiz, Michael S Ip
Purpose: To identify anatomic endpoints altered by intravitreal ranibizumab in central retinal vein occlusion (CRVO) to determine any potential underlying disease modification that occurs with anti-vascular endothelial growth factor (anti-VEGF) therapy beyond best-corrected visual acuity and central optical coherence tomography outcomes.
Methods: A post hoc analysis of a double-masked, multicenter, randomized clinical trial was performed. A total of 392 patients with macular edema after CRVO were randomized 1:1:1 to receive monthly intraocular injections of 0.3 or 0.5 mg of ranibizumab or sham injections. Central reading center-read data were reviewed to explore potential anatomic endpoints altered by therapy.
Results: At 6 months, there was a reduction in the ranibizumab groups compared with sham groups with respect to total area of retinal hemorrhage (median change from baseline in disc areas: – 1.17 [sham], – 2.37 [ranibizumab 0.3 mg], – 1.64 [ranibizumab 0.5 mg]), development of disc neovascularization (prevalence: 3% [sham], 0% [ranibizumab 0.3 mg], 0% [ranibizumab 0.5 mg]), and presence of papillary swelling (prevalence: 22.9% [sham], 8.0% [ranibizumab 0.3 mg], 8.3% [ranibizumab 0.5 mg], p < 0.01). There was no difference between groups in collateral vessel formation. Analysis of vitreous and preretinal hemorrhage could not be performed due to low frequency of events in both treated and sham groups.
Conclusions: Ranibizumab for CRVO resulted in beneficial disease-modifying effects through a reduction in retinal hemorrhage, neovascularization, and papillary swelling. These findings may form the basis for future work in the development of a treatment response or severity scale for eyes with CRVO.
DOI: 10.1007/s00417-021-05224-x
OTHER TREATMENT
One-Year Follow-Up in a Phase 1/2a Clinical Trial of an Allogeneic RPE Cell Bioengineered Implant for Advanced Dry Age-Related Macular Degeneration
Transl Vis Sci Technol.2021 Aug 12;10(10):13.
Amir H Kashani, Jane S Lebkowski, Firas M Rahhal, Robert L Avery, Hani Salehi-Had, Sanford Chen, Clement Chan, Neal Palejwala, April Ingram, Wei Dang, Chih-Min Lin, Debbie Mitra, Britney O Pennington, Cassidy Hinman, Mohamed A Faynus, Jeffrey K Bailey, Sukriti Mohan, Narsing Rao, Lincoln V Johnson, Dennis O Clegg, David R Hinton, Mark S Humayun
Purpose: To report 1-year follow-up of a phase 1/2a clinical trial testing a composite subretinal implant having polarized human embryonic stem cell (hESC)-derived retinal pigment epithelium (RPE) cells on an ultrathin parylene substrate in subjects with advanced non-neovascular age-related macular degeneration (NNAMD).
Methods: The phase 1/2a clinical trial included 16 subjects in two cohorts. The main endpoint was safety assessed at 365 days using ophthalmic and systemic exams. Pseudophakic subjects with geographic atrophy (GA) and severe vision loss were eligible. Low-dose tacrolimus immunosuppression was utilized for 68 days in the peri-implantation period. The implant was delivered to the worst seeing eye with a custom subretinal insertion device in an outpatient setting. A data safety monitoring committee reviewed all results.
Results: The treated eyes of all subjects were legally blind with a baseline best-corrected visual acuity (BCVA) of ≤ 20/200. There were no unexpected serious adverse events. Four subjects in cohort 1 had serious ocular adverse events, including retinal hemorrhage, edema, focal retinal detachment, or RPE detachment, which was mitigated in cohort 2 using improved hemostasis during surgery. Although this study was not powered to assess efficacy, treated eyes from four subjects showed an increased BCVA of >5 letters (6-13 letters). A larger proportion of treated eyes experienced a >5-letter gain when compared with the untreated eye (27% vs. 7%; P = not significant) and a larger proportion of nonimplanted eyes demonstrated a >5-letter loss (47% vs. 33%; P = not significant).
Conclusions: Outpatient delivery of the implant can be performed routinely. At 1 year, the implant is safe and well tolerated in subjects with advanced dry AMD.
Translational relevance: This work describes the first clinical trial, to our knowledge, of a novel implant for advanced dry AMD.
One-year outcome of cystoid macular degeneration in central serous chorioretinopathy
Eur J Ophthalmol.2021 Oct 7
Niroj Kumar Sahoo, Marco Lupidi, Abhilash Goud, Sankeert Gangakhedkar, Felice Cardillo Piccolino, Jay Chhablani
Purpose: To study structural and functional outcomes of cystoid macular degeneration (CMD) in chronic central serous chorioretinopathy (CSCR).
Methods: This retrospective study included 26 eyes having chronic CSCR with CMD who underwent either observation, photodynamic therapy (PDT), micropulse laser, or eplerenone therapy. Various optical coherence tomography parameters were analyzed at baseline and 1 year.
Results: Number of eyes that maintained or gained vision after treatment was 63.1%, compared to a loss of 2.1 ± 1.1 lines in observation group. Sub-foveal large choroidal vessel responded to PDT (p = 0.03); while CMT (p = 0.035) and intra-retinal cystoid spaces (0.037) responded to eplerenone. Longer duration of the symptoms and round cystoid spaces were associated with a decrease in CMT (p = 0.03) and decrease in cystoid spaces size (p = 0.02) respectively on follow up.
Conclusion: Treatment of eyes with CMD prevents further deterioration of vision. Round configuration of intra-retinal cystoid space has a better anatomical outcome.
DOI: 10.1177/11206721211046497
Management of submacular massive haemorrhage in age-related macular degeneration: comparison between subretinal transplant of human amniotic membrane and subretinal injection of tissue plasminogen activator
Acta Ophthalmol.2021 Oct 5.
Tomaso Caporossi, Daniela Bacherini, Lorenzo Governatori, Leandro Oliverio, Laura Di Leo, Ruggero Tartaro, Stanislao Rizzo
Purpose: Macular neovascularization (MNV) can complicate age-related macular degeneration (AMD) and lead to severe visual acuity reduction. Massive submacular haemorrhage (SMH) is a sight-threatening complication of MNV and a challenge in the management of complications related to MNV in AMD since the effects of anti-vascular endothelial growth factor treatment alone are insufficient. Here, we evaluate the different postoperative outcomes of patients affected by MNV complicated by SMH that underwent subretinal implant of human amniotic membrane (hAM) or subretinal injection of tissue plasminogen activator (tPA).
Methods: This is a retrospective, consecutive, comparative, non-randomized interventional study. We included 44 eyes of 44 patients affected by AMD complicated by MNV and SMH. Twenty-two eyes underwent a pars plana vitrectomy (PPV), SMH and neovascular membrane removal, with a subretinal implant of hAM and silicone oil, and 22 eyes underwent PPV, subretinal injection of tPA, and 20% sulphur hexafluoride. The primary study outcome was visual acuity improvement. Secondary outcomes were postoperative complications, and MNV recurrence and optical coherence tomography (OCT)-Angiography parameters correlated with best-corrected visual acuity (BCVA).
Results: Mean preoperative BCVA was 1.9 logarithm of the minimal angle of resolution (logMAR) in the amniotic membrane-group and 2 logMAR in the tPA-group. The mean final BCVA values were 1.25 and 1.4 logMAR, respectively, with a statistically significant difference. Optical coherence tomography (OCT)-Angiography scan was be used to evaluate the retinal vascularization in the treated eye.
Conclusion: Both techniques report similar VA improvements and postoperative complications. However, transplantation of hAM seems to have a significant benefit in inhibiting MNV recurrence.
DOI: 10.1111/aos.15045
DIAGNOSIS & IMAGING
Increased Systemic C-Reactive Protein Is Associated with Choroidal Thinning in Intermediate Age-Related Macular Degeneration
Transl Vis Sci Technol.2021 Oct 4;10(12):7.
Rachel C Chen, Alan G Palestine, Anne M Lynch, Jennifer L Patnaik, Brandie D Wagner, Marc T Mathias, Naresh Mandava
Purpose: C-reactive protein (CRP) and decreased choroidal thickness (CT) are risk factors for progression to advanced age-related macular degeneration (AMD). We examined the association between systemic levels of CRP and CT in patients with intermediate AMD (iAMD).
Methods: Patients with iAMD in the Colorado AMD Registry were included. Baseline serum samples and multimodal imaging including spectral domain-optical coherence tomography (SD-OCT), fundus photography, and autofluorescence were obtained. Medical and social histories were surveyed. CT was obtained by manual segmentation of OCT images. High-sensitivity CRP levels were quantified in serum samples. Univariate and multivariable linear regression models accounting for the intrasubject correlation of two eyes were fit using log-transformed CT as the outcome.
Results: The study included 213 eyes from 107 patients with a mean age of 76.8 years (SD, 6.8). Median CT was 200.5 µm (range, 86.5-447.0). Median CRP was 1.43 mg/L (range, 0.13-17.10). Higher CRP was associated with decreased CT in the univariate model (P = 0.01). Older age and presence of reticular pseudodrusen (RPD) were associated with decreased CT (P < 0.01), whereas gender, body mass index, and smoking were not associated with CT. Higher CRP remained significantly associated with decreased CT after adjustment for age and RPD (P = 0.01).
Conclusions: Increased CRP may damage the choroid, leading to choroidal thinning and increased risk of progression to advanced AMD. Alternatively, CRP may be a marker for inflammatory events that mediate ocular disease. The results of this study further strengthen the association between inflammation and AMD.
Translational relevance: Increased CRP is associated with choroidal thinning, a clinical risk factor for AMD.
DOI: 10.1167/tvst.10.12.7
Optical coherence tomography predictors of progression of non-exudative age-related macular degeneration to advanced atrophic and exudative disease
Graefes Arch Clin Exp Ophthalmol.2021 Oct 4.
Sohani Amarasekera, Anindya Samanta, Mahima Jhingan, Supriya Arora, Sumit Singh, Davide Tucci, Marco Lupidi, Jay Chhablani, Age Related Macular Degeneration study group
Purpose: To study the natural history of optical coherence tomography (OCT) imaging-based findings seen in non-exudative age-related macular degeneration (neAMD) and model their relative likelihood in predicting development of incomplete retinal pigment epithelium and outer retinal atrophy (iRORA), complete retinal pigment epithelium and outer retinal atrophy (cRORA), and neovascular AMD (nAMD).
Methods: Retrospective chart review was performed at two academic practices. Patients diagnosed with neAMD for whom yearly OCT scans were obtained for at least 4 consecutive years were included. Baseline demographic, visual acuity, AREDS staging, and OCT data were collected. OCTs were assessed for the presence or absence of eleven features previously individually associated with progression of neAMD, both at baseline, and on all subsequent follow-up scans. Likewise, charts were reviewed to assess visual acuity and staging of NEAMD at all follow-up visits. A multivariate regression analysis was constructed to determine predictors of iRORA, cRORA, and nAMD.
Results: A total of 107 eyes of 88 patients were evaluated. Follow-up included yearly OCTs obtained over at least 4 consecutive years follow-up (range: 50-94 months). During the follow-up period, 17 eyes progressed to iRORA while 25 progressed to cRORA and 16 underwent conversion to nAMD. Predictors of conversion to iRORA and cRORA included integrity of the external limiting membrane (p = 0.02), the ellipsoid zone (p = 0.01), and the cone outer segment line (p = 0.003) and the presence of intraretinal hyporeflective spaces (p = 0.009), drusen ooze (p = 0.05), and drusen collapse (p = 0.001). OCT features predictive of conversion to nAMD included outer nuclear layer (ONL) loss (p = 0.01), presence of intraretinal (p = 0.001) and subretinal (p = 0.005) hyporeflective spaces, and drusen collapse (p = 0.003).
Conclusion: Of these multiple factors predictive of progression of neAMD, the OCT feature most strongly correlated to progression to iRORA/cRORA was drusen collapse, and the feature most predictive of conversion to nAMD was the presence of intraretinal hyporeflective spaces.
DOI: 10.1007/s00417-021-05419-2
REVIEWS
Review of intravitreal VEGF inhibitor toxicity and report of collapsing FSGS with TMA in a patient with age-related macular degeneration
Clin Kidney J.2021 Mar 23;14(10):2158-2165.
Gautam Phadke, Ramy M Hanna, Antoney Ferrey, Everardo Arias Torres, Anjali Singla, Amit Kaushal, Kamyar Kalantar-Zadeh, Ira Kurtz, Kenar D Jhaveri
Abstract
Intravitreal vascular endothelial growth factor (VEGF) receptor blockade is used for a variety of retinal pathologies. These include age-related macular degeneration (AMD), diabetic macular edema (DME) and central retinal vein obstruction. Reports of absorption of intravitreal agents into systemic circulation have increased in number and confirmation of depletion of VEGF has been confirmed. Increasingly there are studies and case reports showing worsening hypertension, proteinuria, renal dysfunction and glomerular disease. The pathognomonic findings of systemic VEGF blockade, thrombotic microangiopathies (TMAs), are also being increasingly reported. One lesion that occurs in conjunction with TMAs that has been described is collapsing focal segmental glomerulosclerosis (cFSGS). cFSGS has been postulated to occur due to TMA-induced chronic glomerular hypoxia. In this updated review we discuss the mechanistic, pharmacological, epidemiological and clinical evidence of intravitreal VEGF toxicity. We review cases of biopsy-proven toxicity presented by our group and other investigators. We also present the third reported case of cFSGS in the setting of intravitreal VEGF blockade with a chronic TMA component that was crucially found on biopsy. This patient is a 74-year-old nondiabetic male receiving aflibercept for AMD. Of the two prior cases of cFSGS in the setting of VEGF blockade, one had AMD and the other had DME. This case solidifies the finding of cFSGS and its association with chronic TMA as a lesion that may be frequently encountered in patients receiving intravitreal VEGF inhibitors.
DOI: 10.1093/ckj/sfab066
