Non-Response to Anti-VEGF in Patients with Wet-Form (Neovascular) Age-Related Macular Degeneration, Treatment Resistance and Switch of Anti-VEGF Agents

Response To Treatment ◽

Similar Response ◽

Anti Vegf ◽

Age Related ◽

Age-related macular degeneration (AMD) is a chronic and degenerative disease that causes vision loss. Although anti-vascular endothelial growth factor (Anti-VEGF) drugs are the mainstay of treatment in cases of age-related AMD, there is no similar response to treatment in each patient. In the case of non-response, the treatment approach for the cause must be regulated. Although there is no consensus on the concept of response to treatment, the use of alternative anti-VEGF in cases where drug efficacy is weak is quite common.

Current and upcoming anti-VEGF therapies and dosing strategies for the treatment of neovascular AMD: a comparative review

BMJ Open Ophthalmology ◽

10.1136/bmjophth-2019-000398 ◽

2019 ◽

Vol 4 (1) ◽

pp. e000398 ◽

Cited By ~ 14

Author(s):

Saira Khanna ◽

Rahul Komati ◽

David A Eichenbaum ◽

Ishani Hariprasad ◽

Thomas A Ciulla ◽

...

Keyword(s):

Macular Degeneration ◽

Vision Loss ◽

Disease Process ◽

Anti Vegf ◽

Age Related ◽

Optimal Dosing ◽

Comparative Review ◽

Dosing Strategies ◽

Age-related macular degeneration is the leading cause of vision loss in the developed world, with the expected number of affected elderly individuals reaching 17.8 million. Antivascular endothelial growth factor (anti-VEGF) injection therapy has been instrumental in treating a disease process that was previously thought to be untreatable. Over the past two decades, landmark studies have demonstrated the efficacy of different anti-VEGF medications and investigated the optimal dosing regimen and delivery mechanism to increase overall vision and minimise patient burden. In this review, we outline landmark neovascular age-related macular degeneration clinical trials that have demonstrated level 1 evidence for its usage or have contributed to the understanding of how to dose these agents.

Microvascular abnormalities secondary to radiation therapy in neovascular age-related macular degeneration: findings from the INTREPID clinical trial

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2018-311865 ◽

2018 ◽

Vol 103 (4) ◽

pp. 469-474 ◽

Cited By ~ 6

Author(s):

Florentina Joyce Freiberg ◽

Stephan Michels ◽

Alyson Muldrew ◽

Jason Slakter ◽

Denis O’Shaughnessy ◽

...

Keyword(s):

Clinical Trial ◽

Macular Degeneration ◽

Vision Loss ◽

Visual Outcome ◽

Retinal Vessel ◽

Controlled Clinical Trial ◽

Anti Vegf ◽

Age Related ◽

PurposeTo report the incidence and features of retinal microvascular abnormalities (MVAs) occurring secondary to stereotactic radiotherapy (SRT) in a randomised double-masked sham-controlled clinical trial at 21 European sites.MethodsTwo hundred and thirty participants with neovascular age-related macular degeneration (AMD) treated with at least three intravitreal antivascular endothelial growth factor (anti-VEGF) injections prior to enrolment, and demonstrating a continuing need for re-treatment. Interventions: 16 Gy, 24 Gy or sham SRT. All three groups received pro re nata anti-VEGF injections if the lesion was judged to be active at review visits. Colour fundus images from baseline and 6 months and fluorescein angiograms from baseline and annual visits were graded for measures of morphological outcome and safety using a prespecified protocol with accompanying definitions to distinguish RT-related MVA from non-specific retinal vessel abnormalities that are known to occur in neovascular AMD. The main outcome measure was MVA detected by months 12, 24 and 36 after enrolment.ResultsThe frequency of MVAs in the combined SRT arms was 0% in year 1, 13.1% in year 2 and 30.3% in year 3. The area of MVA was small and the mean change in visual acuity in year 2 was similar in a subset of SRT eyes with MVAs, versus those without MVAs. MVA was considered to have possibly contributed to vision loss in 2 of 18 cases with MVA in year 2, and 5 of 37 cases in year 3.ConclusionTreatment with SRT is associated with development of subtle MVAs that have little or no impact on visual outcome. These findings can help clinicians recognise the retinal MVAs that occur in response to SRT.

Changes оf vascular endothelial growth factor concentration in patients with exudative age related macular degeneration and primary open-angled glaucoma on the anti-VEGF therapy

POINT OF VIEW EAST – WEST ◽

10.25276/2410-1257-2018-2-59-62 ◽

2018 ◽

pp. 59-62

Author(s):

O.А. Zhabina ◽

◽

I.V. Andreeva ◽

A.S. Rudko ◽

A.A. Plyukhova ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Macular Degeneration ◽

Vascular Endothelial ◽

Anti Vegf ◽

Age Related ◽

Endothelial Growth Factor ◽

Factor Concentration

Mingjing granule, a traditional Chinese medicine in the treatment of neovascular age-related macular degeneration: study protocol for a randomized controlled trial

Trials ◽

10.1186/s13063-021-05025-x ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Yamin Li ◽

Lina Liang ◽

Torkel Snellingen ◽

Kai Xu ◽

Yun Gao ◽

...

Keyword(s):

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Macular Degeneration ◽

Vision Loss ◽

Case Report Form ◽

Link Type ◽

Anti Vegf ◽

Age Related ◽

Function Test

Abstract Background Neovascular age-related macular degeneration (nAMD) is the most common cause of irreversible vision loss and blindness among the older people aged 50 and over. Although anti-vascular endothelial growth factor (anti-VEGF) therapies have resulted in improving patient outcomes, there are limitations associated with these treatments. In China, traditional Chinese medicine (TCM) has been used to treat eye diseases for more than 2000 years. Previous studies have shown that TCM may be beneficial for nAMD patients. However, explicit evidence has not been obtained. The purpose of the present trial is to examine the efficacy and safety of the Mingjing granule, a compound Chinese herbal medicine, for nAMD patients. Methods/design This is a double-blind, placebo-controlled, randomized trial of Mingjing granule as an add-on to intravitreous ranibizumab for nAMD. One hundred eighty nAMD patients from six hospitals in China will be enrolled according to the inclusion and exclusion criteria and randomly allocated into two groups, 90 in each. All participants will receive a 24-week treatment and then be followed up for another 24 weeks. The primary outcome is the mean change of best-corrected visual acuity at week 24 and 48 as compared to the baseline. The secondary outcomes include mean change in central retinal thickness, area of retinal hemorrhage and exudation, and TCM syndrome score, mean number of intravitreal ranibizumab injection, and total cost of the treatment. Indexes of safety include blood regular test, urine regular test, liver function test, renal function test, and electrocardiogram from baseline to weeks 24 and 48. Qualitative control and some standard operating processes will be formed throughout the trial. Any ocular or systemic adverse events will be treated suitably, and related data will be recorded accurately and completely in the case report form. Discussion Based on previous empirical and animal laboratory studies, this study will address the question of whether Mingjing granule could contribute to improving efficacy, safety, and efficiency with need for fewer intravitreal injections of anti-VEGF, improving compliance and visual outcomes in the management of persons with nAMD. Trial registration Chinese Clinical Trial Registry (http://www.chictr.org.cn), ChiCTR2000035990. Registered on 21 August 2020.

Introduction to the multi-author review on macular degeneration

Cellular and Molecular Life Sciences ◽

10.1007/s00018-019-03418-5 ◽

2020 ◽

Vol 77 (5) ◽

pp. 779-780 ◽

Cited By ~ 1

Author(s):

Anu Kauppinen

Keyword(s):

Macular Degeneration ◽

Vision Loss ◽

The Elderly ◽

Developed Countries ◽

Age Related ◽

Severe Vision Loss ◽

Author Review ◽

Dry Amd ◽

AbstractProlonged life expectancies contribute to the increasing prevalence of age-related macular degeneration (AMD) that is already the leading cause of severe vision loss among the elderly in developed countries. In dry AMD, the disease culminates into vast retinal atrophy, whereas the wet form is characterized by retinal edema and sudden vision loss due to neovascularization originating from the choroid beneath the Bruch’s membrane. There is no treatment for dry AMD and despite intravitreal injections of anti-vascular endothelial growth factor (VEGF) that suppress the neovessel formation, also wet AMD needs new therapies to prevent the disease progression and to serve patients lacking of positive response to current medicines. Knowledge on disease mechanisms is a prerequisite for the drug development, which is hindered by the multifactorial nature of AMD. Numerous distinguished publications have revealed AMD mechanisms at the cellular and molecular level and in this multi-author review, we take a bit broader look at the topic with some novel aspects.

Long-term outcome of neovascular age-related macular degeneration: association between treatment outcome and major risk alleles

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2021-319054 ◽

2021 ◽

pp. bjophthalmol-2021-319054

Author(s):

Brice Nguedia Vofo ◽

Gala Beykin ◽

Jaime Levy ◽

Itay Chowers

Keyword(s):

Macular Degeneration ◽

Vision Loss ◽

Long Term Outcome ◽

Risk Alleles ◽

Macular Atrophy ◽

Anti Vegf ◽

Age Related

AimsTo evaluate the long-term functional and anatomical outcomes of neovascular age-related macular degeneration (nvAMD) treated with intravitreal anti-vascular endothelial growth factor (anti-VEGF) for up to 10 years, and to identify associated risk factors.MethodsClinical and optical coherence tomography findings were retrieved for nvAMD cases treated with intravitreal anti-VEGF compounds using a treat-and-extend protocol. In addition, the major risk alleles for AMD in the CFH (rs1061170), HTRA1 (rs1200638) and C3 (rs2230199) genes were genotyped.ResultsFrom 276 eligible eyes in 206 patients, 80 eyes (29%) in 66 patients (32.0%) had a follow-up period of ≥8 years and were included in this study. Over a 10-year period, 73.3±28.0 (mean±SD) anti-VEGF injections were administered. Best-corrected visual acuity (BCVA; LogMAR) deteriorated from 0.55±0.53 at baseline to 1.00±0.73 at 10 years (p<0.0005). Central subfield thickness (CST) decreased from 415.8±162.1 µm at baseline to 323±113.6 µm (p<0.0005) after three monthly injections and remained lower than baseline throughout the follow-up period. Visual outcome was associated with BCVA and intraretinal fluid (IRF) at baseline, macular atrophy, and macular thinning at follow-up. The decrease in CST was inversely correlated with the number of CFH and/or C3 risk alleles carried by the patient (Pearson’s r: −0.608; p=0.003).ConclusionsPatients with nvAMD who received anti-VEGF therapy for 10 years developed substantial vision loss associated with the presence of IRF at baseline and macular atrophy. Major risk alleles for AMD in two complement genes were associated with a reduced long-term reduction in macular thickness.

Pegaptanib Sodium in the Treatment of Neovascular Age-Related Macular Degeneration

Clinical Medicine Insights Therapeutics ◽

10.4137/cmt.s2393 ◽

2010 ◽

Vol 2 ◽

pp. CMT.S2393

Author(s):

Giuseppe Querques

Keyword(s):

Macular Degeneration ◽

Macular Edema ◽

Single Agent ◽

Ocular Neovascularization ◽

Pegaptanib Sodium ◽

Anti Vegf ◽

Age Related ◽

Favorable Safety ◽

Pegaptanib sodium is a polyethylene-glycolated, 28-nucleotide RNA aptamer that binds selectively to vascular endothelial growth factor (VEGF)165 but not smaller isoforms. Preclinical studies identified VEGF165 as an especially potent promoter of ocular neovascularization and inflammation. Following the pivotal clinical trials demonstrating the efficacy of intravitreal pegaptanib in treating all angiographic subtypes of neovascular age-related macular degeneration (NV-AMD), pegaptanib became the first anti-VEGF therapy to receive regulatory approval for this condition. In view of the importance of VEGF in a variety of tissues, including the cardiovascular system and the retina, concerns have been raised as to the risks that might accompany VEGF inhibition. It is thus of particular note that pegaptanib has proved to have a favorable safety record in treating NV-AMD, with no ocular or systemic safety signals having emerged over more than 4 years of clinical studies. Accordingly, in addition to its use as a single agent, pegaptanib has demonstrated promise in combinatorial regimens that employ nonselective anti-VEGF agents as an initial treatment followed by maintenance therapy with pegaptanib. Pegaptanib has also shown encouraging preliminary results in the treatment of diabetic macular edema, proliferative diabetic retinopathy, and macular edema secondary to retinal venous occlusive conditions.

Ten-year survival trends of neovascular age-related macular degeneration at first presentation

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2020-317161 ◽

2020 ◽

pp. bjophthalmol-2020-317161

Author(s):

Cristina Arpa ◽

Hagar Khalid ◽

Shruti Chandra ◽

Siegfried Wagner ◽

Katrin Fasler ◽

...

Keyword(s):

Macular Degeneration ◽

Visual Outcomes ◽

Anti Vegf ◽

Kaplan Meier ◽

Age Related ◽

Treatment Naïve ◽

Mean Trend ◽

Endothelial Growth Factor ◽

Good Vision

BackgroundTo describe 10-year trends in visual outcomes, anatomical outcomes and treatment burden of patients receiving antivascular endothelial growth factor (anti-VEGF) therapy for neovascular age-related macular degeneration (nAMD).MethodsRetrospective cohort study of treatment-naïve, first-affected eyes with nAMD started on ranibizumab before January 1, 2009. The primary outcome was time to best-corrected visual acuity (BCVA) falling ≤35 ETDRS letters after initiating anti-VEGF therapy. Secondary outcomes included time to BCVA reaching ≥70 letters, proportion of eyes with BCVA ≥70 and ≤35 letters in 10 years, mean trend of BCVA and central retinal thickness over 10 years, and mean number of injections.ResultsFor our cohort of 103 patients, Kaplan-Meier analyses demonstrated median time to BCVA reaching ≤35 and ≥70 letters were 37.8 (95% CI 22.2 to 65.1) and 8.3 (95% CI 4.8 to 20.9) months after commencing anti-VEGF therapy, respectively. At the final follow-up, BCVA was ≤35 letters and ≥70 letters in 41.1% and 21%, respectively, in first-affected eyes, while this was the case for 5.4% and 48.2%, respectively, in a patient’s better-seeing eye. Mean injection number was 37.0±24.2 per eye and 53.6±30.1 at patient level (63.1% of patients required injections in both eyes).ConclusionsThe chronicity of nAMD disease and its management highlights the importance of long-term visual prognosis. Our analyses suggest that one in five patients will retain good vision (BCVA ≥70 ETDRS letters) in the first-affected eye at 10 years after starting anti-VEGF treatment; yet, one in two patients will have good vision in their better-seeing eye. Moreover, our data suggest that early treatment of nAMD is associated with better visual outcomes.

Antivascular Endothelial Growth Factor Treatment Might Be Continued Even After Vitrectomy for Endophthalmitis in Neovascular Age-Related Macular Degeneration

Journal of VitreoRetinal Diseases ◽

10.1177/2474126419883561 ◽

2019 ◽

Vol 4 (1) ◽

pp. 6-12

Author(s):

Zofia Michalewska ◽

Jerzy Nawrocki

Keyword(s):

Growth Factor ◽

Macular Degeneration ◽

Visual Outcome ◽

Anti Vegf ◽

Endothelial Growth Factor ◽

Mean Time

Purpose: This article studies visual outcome and frequency of antivascular endothelial growth factor (anti-VEGF) injections continued in patients with neovascular age-related macular degeneration (AMD) who had an earlier vitrectomy for postinjection endophthalmitis. Methods: A retrospective interventional study was conducted reviewing our database for patients with a diagnosis of endophthalmitis in the course of anti-VEGF injections. Endophthalmitis diagnosis was made on clinical examination of pain, rapid decrease in visual acuity (VA), conjunctival hyperemia, hypopyon, and vitritis. In all eyes, core vitrectomy with intravitreal antibiotics was performed. Spectral-domain optical coherence tomography was performed monthly before and after surgery during follow-up. Anti-VEGF injections were continued after surgery in all cases. Results: Eight eyes with postinjection endophthalmitis were included. Mean VA immediately before endophthalmitis was 20/50 Snellen with a mean of 19 intravitreal anti-VEGF injections ( P = .45). At time of endophthalmitis diagnosis, mean VA was 20/1000 (range, 20/2000-20/200). Mean time from injection to when the patient noted first symptoms was 4.3 days (range, 1-8 days). Mean time from first symptoms to surgery was 12 hours (range, 2.5-26 hours). Final mean VA at the end of follow-up (range, 12-84 months) did not statistically differ from VA at the visit immediately before endophthalmitis diagnosis ( P = .69). Mean frequency of injections after vitrectomy did not significantly differ from the presurgical course of treatment ( P =.97). Conclusions: Anti-VEGF treatment might be continued after vitrectomy for endophthalmitis and results in satisfactory anatomical and visual outcome. Surgery did not influence the frequency of anti-VEGF injections for neovascular AMD.

Tie2 activation promotes choriocapillary regeneration for alleviating neovascular age-related macular degeneration

Science Advances ◽

10.1126/sciadv.aau6732 ◽

2019 ◽

Vol 5 (2) ◽

pp. eaau6732 ◽

Cited By ~ 6

Author(s):

Jaeryung Kim ◽

Jang Ryul Park ◽

Jeongwoon Choi ◽

Intae Park ◽

Yoonha Hwang ◽

...

Keyword(s):

Macular Degeneration ◽

Therapeutic Strategy ◽

Vascular Leakage ◽

Vascular Endothelial ◽

Medical Needs ◽

Anti Vegf ◽

Age Related ◽

Angiopoietin 2 ◽

Choriocapillary loss is a major cause of neovascular age-related macular degeneration (NV-AMD). Although vascular endothelial growth factor (VEGF) blockade for NV-AMD has shown beneficial outcomes, unmet medical needs for patients refractory or tachyphylactic to anti-VEGF therapy exist. In addition, the treatment could exacerbate choriocapillary rarefaction, necessitating advanced treatment for fundamental recovery from NV-AMD. In this study, Tie2 activation by angiopoietin-2–binding and Tie2-activating antibody (ABTAA) presents a therapeutic strategy for NV-AMD. Conditional Tie2 deletion impeded choriocapillary maintenance, rendering eyes susceptible to NV-AMD development. Moreover, in a NV-AMD mouse model, ABTAA not only suppressed choroidal neovascularization (CNV) and vascular leakage but also regenerated the choriocapillaris and relieved hypoxia. Conversely, VEGF blockade degenerated the choriocapillaris and exacerbated hypoxia, although it suppressed CNV and vascular leakage. Together, we establish that angiopoietin-Tie2 signaling is critical for choriocapillary maintenance and that ABTAA represents an alternative, combinative therapeutic strategy for NV-AMD by alleviating anti-VEGF adverse effects.