Angiopoietins as Targets for Diabetic Retinopathy Treatment

2021 ◽  
Author(s):  
Lauren M. Ciulla ◽  
Nimesh A. Patel ◽  
Nicolas A. Yannuzzi ◽  
Rehan M. Hussain
Keyword(s):  
Diabetic Retinopathy ◽  
Phase 1 ◽  
Developed Countries ◽  
Significant Treatment ◽  
Alternative Pathways ◽  
Anti Vegf ◽  
Primary Endpoints ◽  
Vascular Stability ◽  
Prospective Trials ◽  
Favorable Safety

Diabetic eye diseases, such as diabetic retinopathy (DR) and diabetic macular edema (DME) are among the leading causes of blindness in developed countries. Anti-VEGF therapies such as, ranibizumab, aflibercept and off-label bevacizumab have become first-line treatment for DME. While randomized controlled trials show significant improvement in vision, these anti-VEGF agents have limited durability leading to a significant treatment burden, as reflected in real-world studies, which generally demonstrate under-treatment and less favorable visual acuity outcomes than observed in prospective trials. Alternative pathways, such as the Tie-2 angiopoietin pathway may address unmet needs, with potential for greater efficacy or durability when compared to anti-VEGF monotherapy. While some Tie-2 angiopoietin therapeutic agents, such as nesvacumab, ARP-1536 or AKB-9778, did not meet primary endpoints in clinical trials, other agents have shown promise. One such agent is faricimab, a bispecific antibody inhibiting both VEGF-A and Ang-2. The phase 3 DME trials (YOSEMITE and RHINE) demonstrated favorable safety, visual, and durability outcomes; patients receiving faricimab injection every 4 months achieved similar visual gains as those receiving aflibercept injection every 2 months. Another agent, AXT107 is a peptide that inhibits VEGFR2 and modifies Ang-2 to behave more similarly to Ang-1, promoting vascular stability. This drug is currently undergoing phase 1/2a trials for safety and bioactivity to be completed in May 2022.

Nivolumab (nivo) in sorafenib (sor)-naive and -experienced pts with advanced hepatocellular carcinoma (HCC): CheckMate 040 study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4013-4013 ◽  
Author(s):  
Todd S. Crocenzi ◽  
Anthony B. El-Khoueiry ◽  
Thomas Cheung Yau ◽  
Ignacio Melero ◽  
Bruno Sangro ◽  
...  
Keyword(s):  
Phase 1 ◽  
Advanced Hepatocellular Carcinoma ◽  
Term Survival ◽  
Advanced Hcc ◽  
Primary Endpoints ◽  
Secondary Endpoints ◽  
Pre Treatment ◽  
Favorable Safety ◽  
Tumor Types

4013 Background: Many pts with advanced HCC progress on SOC therapy. Nivo is a fully human anti–PD-1 IgG4 mAb that demonstrated durable responses (20% ORR with a median DOR of 9.9 mo; 9-mo OS rate was 74%) in pts with advanced HCC in the dose-expansion (EXP) phase of the CheckMate 040 study (NCT01658878; Melero et al. 2017). Here we present survival and durability of response data in both sor-naive and -experienced pts with advanced HCC in CheckMate 040. Methods: Pts naive to or previously treated with sor received nivo in phase 1/2 dose-escalation (ESC; 0.1–10 mg/kg) and -EXP (3 mg/kg) cohorts Q2W regardless of PD-L1 status. Primary endpoints were safety/tolerability (ESC) and ORR (EXP; ORR by investigator [INV] and blinded independent central review [BICR]) using RECIST v1.1. Secondary endpoints included DOR, DCR, and OS. Biomarkers were assessed using pre-treatment tumor samples. Results: Overall, pts (N=262) had a median follow-up of 12.9 mo, and 98% had Child-Pugh scores 5–6. In sor-naive pts (n=80), the ORR (INV) was 23%, with 44% of responses (8/18) ongoing (Table). The DCR was 63%; 40% of pts had stable disease ≥6 mo. In sor-experienced pts (n=182; 91% progressed on sor), the ORRs (INV) were 16%–19%. Overall, responses occurred regardless of etiology or tumor cell PD-L1 expression. Nivo had a manageable safety profile consistent with that reported in other tumor types. Updated data with additional 4 mo of follow-up will be presented. Conclusions: Nivo demonstrated durable responses with long-term survival and favorable safety in both sor-naive and -experienced pts with advanced HCC. Clinical trial information: NCT01658878. [Table: see text]

Anti-VEGF Deficiency, Treatment Resistance, Pharmaceutical Changes and Combined Treatments in Diabetic Macular Edema

2018 ◽  
pp. 165-169
Keyword(s):  
Diabetic Retinopathy ◽  
Combination Therapy ◽  
Visual Impairment ◽  
Macular Edema ◽  
Diabetic Macular Edema ◽  
Treatment Resistance ◽  
Developed Countries ◽  
Combined Treatments ◽  
Anti Vegf ◽  
Treatment Switch

Diabetic retinopathy is the most important cause of blindness in developed countries today. The most important cause of visual impairment is complications related to diabetic macular edema (DME) and proliferative retinopathy. Intravitreal anti-VEGF agents are the first treatment option for central involvement in diabetic macular edema (DME). Despite anti-VEGF agents, some cases are refractory (persistent) to multiple anti-VEGF treatments. In this review, unresponsiveness to anti-VEGF treatment, switch, and combination therapy in DME is mentioned.

Aflibercept for the Treatment of Diabetic Retinopathy and Diabetic Macular Edema

2018 ◽  
pp. 147-154
Keyword(s):  
Diabetic Retinopathy ◽  
Growth Factor ◽  
Macular Edema ◽  
Diabetic Macular Edema ◽  
Vision Loss ◽  
Developed Countries ◽  
Inhibitory Effect ◽  
Duration Of Action ◽  
Anti Vegf ◽  
Working Age

Diabetic macular edema (DME) is a common complication of diabetic retinopathy (DR) and is a leading cause of vision loss in developed countries during the working age. Understanding the role of vascular endothelial growth factor (VEGF) in the pathogenesis of DME has emphasized the importance of using anti-VEGF agents in treatment. Anti-VEGF drugs such as pegaptanib, ranibizumab, bevacizumab, and aflibercept have been studied in the treatment of DME. Aflibercept is a recombinant fusion protein with an inhibitory effect on VEGF-A, VEGF-B, placental growth factor (PIGF) 1 and 2. It is believed that this agent has a longer duration of action than other anti-VEGF molecules due to its high-affinity binding to the VEGF molecule. This review summarizes the pharmacological properties of aflibercept in terms of clinical efficacy, use, and tolerability in the treatment of DME.

Treatment Patterns and Clinical Outcomes for Branch Retinal Vein Occlusion: An 8-Year Experience at a Tertiary Eye Center

2021 ◽  
pp. 247412642097887
Author(s):  
Terry Lee ◽  
Cason B. Robbins ◽  
Akshay S. Thomas ◽  
Sharon Fekrat
Keyword(s):  
Visual Acuity ◽  
Diabetic Retinopathy ◽  
Retinal Vein Occlusion ◽  
Real World ◽  
Early Treatment ◽  
Branch Retinal Vein Occlusion ◽  
Treatment Patterns ◽  
Vein Occlusion ◽  
Anti Vegf ◽  
Treatment Naïve

Purpose: This work aims to investigate real-world treatment patterns and outcomes in eyes with branch retinal vein occlusion in the antivascular endothelial growth factor (anti-VEGF) era. Methods: A retrospective, nonrandomized, comparative study was conducted on eyes diagnosed with branch retinal vein occlusion at a single tertiary center between 2009 and 2017. Medical history, treatment patterns, and visual acuity outcomes were examined. Subanalysis was performed for eyes that met the eligibility criteria for the BRAVO (Ranibizumab for the Treatment of Macular Edema Following Branch Retinal Vein Occlusion) trial. Results: A total of 315 eyes were included, of which 244 were treatment naive. In all eyes, the most common first treatment was the following: intravitreal bevacizumab (38.4%), aflibercept (15.1%), ranibizumab (8.1%), sectoral scatter laser (6.2%), and triamcinolone (3.1%). At 1 year, treatment-naive eyes had received an average of 2.43 anti-VEGF injections. During follow-up, treatment-naive eyes gained an average of 0.21 Early Treatment Diabetic Retinopathy Study lines. Forty eyes that met BRAVO trial criteria received an average of 5.05 anti-VEGF injections in the first year and gained an average of 1.83 Early Treatment Diabetic Retinopathy Study lines. Conclusions: This real-world cohort received fewer anti-VEGF injections at year 1 and experienced less improvement in visual acuity during the course of treatment than clinical trial participants. Trial-eligible patients received more injections and had greater visual gains than those who would not have been eligible for the trial.

scholarly journals Diabetic Retinopathy Prediction by Ensemble Learning Based on Biochemical and Physical Data

Sensors ◽  
2021 ◽  
Vol 21 (11) ◽  
pp. 3663
Author(s):  
Zun Shen ◽  
Qingfeng Wu ◽  
Zhi Wang ◽  
Guoyi Chen ◽  
Bin Lin
Keyword(s):  
Diabetic Retinopathy ◽  
Prediction Model ◽  
Ensemble Learning ◽  
Positive Impact ◽  
Reduction Rate ◽  
Developed Countries ◽  
Small Sample ◽  
Feature Reduction ◽  
Physical Data ◽  
Diabetes Retinopathy

(1) Background: Diabetic retinopathy, one of the most serious complications of diabetes, is the primary cause of blindness in developed countries. Therefore, the prediction of diabetic retinopathy has a positive impact on its early detection and treatment. The prediction of diabetic retinopathy based on high-dimensional and small-sample-structured datasets (such as biochemical data and physical data) was the problem to be solved in this study. (2) Methods: This study proposed the XGB-Stacking model with the foundation of XGBoost and stacking. First, a wrapped feature selection algorithm, XGBIBS (Improved Backward Search Based on XGBoost), was used to reduce data feature redundancy and improve the effect of a single ensemble learning classifier. Second, in view of the slight limitation of a single classifier, a stacking model fusion method, Sel-Stacking (Select-Stacking), which keeps Label-Proba as the input matrix of meta-classifier and determines the optimal combination of learners by a global search, was used in the XGB-Stacking model. (3) Results: XGBIBS greatly improved the prediction accuracy and the feature reduction rate of a single classifier. Compared to a single classifier, the accuracy of the Sel-Stacking model was improved to varying degrees. Experiments proved that the prediction model of XGB-Stacking based on the XGBIBS algorithm and the Sel-Stacking method made effective predictions on diabetes retinopathy. (4) Conclusion: The XGB-Stacking prediction model of diabetic retinopathy based on biochemical and physical data had outstanding performance. This is highly significant to improve the screening efficiency of diabetes retinopathy and reduce the cost of diagnosis.

scholarly journals Rho-Kinase Inhibitors for the Treatment of Refractory Diabetic Macular Oedema

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1683
Author(s):  
Milagros Mateos-Olivares ◽  
Luis García-Onrubia ◽  
Fco. Javier Valentín-Bravo ◽  
Rogelio González-Sarmiento ◽  
Maribel Lopez-Galvez ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Macular Oedema ◽  
Standard Therapy ◽  
Vision Loss ◽  
Therapeutic Potential ◽  
Rho Kinase ◽  
Diabetic Macular Oedema ◽  
New Drugs ◽  
Anti Vegf

Diabetic macular oedema (DMO) is one of the leading causes of vision loss associated with diabetic retinopathy (DR). New insights in managing this condition have changed the paradigm in its treatment, with intravitreal injections of antivascular endothelial growth factor (anti-VEGF) having become the standard therapy for DMO worldwide. However, there is no single standard therapy for all patients DMO refractory to anti-VEGF treatment; thus, further investigation is still needed. The key obstacles in developing suitable therapeutics for refractory DMO lie in its complex pathophysiology; therefore, there is an opportunity for further improvements in the progress and applications of new drugs. Previous studies have indicated that Rho-associated kinase (Rho-kinase/ROCK) is an essential molecule in the pathogenesis of DMO. This is why the Rho/ROCK signalling pathway has been proposed as a possible target for new treatments. The present review focuses on the recent progress on the possible role of ROCK and its therapeutic potential in DMO. A systematic literature search was performed, covering the years 1991 to 2021, using the following keywords: “rho-Associated Kinas-es”, “Diabetic Retinopathy”, “Macular Edema”, “Ripasudil”, “Fasudil” and “Netarsudil”. Better insight into the pathological role of Rho-kinase/ROCK may lead to the development of new strategies for refractory DMO treatment and prevention.

scholarly journals Situational analysis of diabetic retinopathy treatment Services in Ghana

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Agatha Mensah-Debrah ◽  
Kwesi Nyan Amissah Arthur ◽  
David Ben Kumah ◽  
Kwadwo Owusu Akuffo ◽  
Isaiah Osei Duah ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Vitreoretinal Surgery ◽  
Health Facilities ◽  
Service Utilisation ◽  
Eye Care ◽  
Treatment Service ◽  
Treatment Services ◽  
Disadvantaged Population ◽  
Anti Vegf ◽  
Geographical Regions

Abstract Background Although the equitable distribution of diabetic retinopathy (DR) services across Ghana remains paramount, there is currently a poor understanding of nationwide DR treatment services. This study aims to conduct a situation analysis of DR treatment services in Ghana and provide evidence on the breadth, coverage, workload, and gaps in service delivery for DR treatment. Methods A cross-sectional study was designed to identify health facilities which treat DR in Ghana from June 2018 to August 2018. Data were obtained from the facilities using a semi-structured questionnaire which included questions identifying human resources involved in DR treatment, location of health facilities with laser, vitreoretinal surgery and Anti–vascular endothelial growth factor therapy (Anti-VEGF) for DR treatment, service utilisation and workload at these facilities, and the average price of DR treatment in these facilities. Results Fourteen facilities offer DR treatment in Ghana; four in the public sector, seven in the private sector and three in the Christian Health Association of Ghana (CHAG) centres. There was a huge disparity in the distribution of facilities offering DR services, the eye care cadre, workload, and DR treatment service (retinal laser, Anti-VEGF, and vitreoretinal surgery). The retinal laser treatment price was independent of all variables (facility type, settings, regions, and National Health Insurance Scheme coverage). However, settings (p = 0.028) and geographical regions (p = 0.010) were significantly associated with anti-VEGF treatment price per eye. Conclusion Our results suggest a disproportionate distribution of DR services in Ghana. Hence, there should be a strategic development and implementation of an eye care plan to ensure the widespread provision of DR services to the disadvantaged population as we aim towards a disadvantaged population as we aim towards a universal health coverage.

scholarly journals Foslevodopa/Foscarbidopa Is Well Tolerated and Maintains Stable Levodopa and Carbidopa Exposure Following Subcutaneous Infusion

2021 ◽  
pp. 1-8
Author(s):  
Matthew Rosebraugh ◽  
Wei Liu ◽  
Melina Neenan ◽  
Maurizio F. Facheris
Keyword(s):  
Steady State ◽  
Phase 1 ◽  
The United States ◽  
Therapeutic Window ◽  
Fixed Dose ◽  
Advanced Parkinson’S Disease ◽  
Subcutaneous Infusion ◽  
Study Results ◽  
Wide Range ◽  
Favorable Safety

Background: Foslevodopa/foscarbidopa, formerly known as ABBV-951, is a formulation of levodopa/carbidopa prodrugs with solubility that allows for subcutaneous (SC) infusion and is in development for the treatment of motor complications for patients with advanced Parkinson’s disease (aPD). Objective: The current work characterizes the levodopa (LD) and carbidopa (CD) pharmacokinetics (PK) following SC infusions of foslevodopa/foscarbidopa delivered at four different infusion rates in PD patients. Methods: This was a Phase 1, single ascending dose, single-blind study conducted in 28 adult male and female subjects at seven sites in the United States. Foslevodopa/foscarbidopa was administered via abdominal SC infusion in PD patients over 72 hours. Patients were stratified in 4 groups and received a fixed dose of foslevodopa/foscarbidopa based on their oral daily LD intake. Serial plasma PK samples were collected to assay for LD and CD concentrations. Safety and tolerability were assessed throughout the study. Results: LD exposure quickly reached steady state and remained stable with minimal fluctuations. Foslevodopa/foscarbidopa infusion provides stable LD and CD exposures compared to oral LD/CD dosing with the average steady-state exposure ranging from 747-4660 ng/mL for the different groups. Conclusion: Foslevodopa/foscarbidopa was able to provide stable LD and CD exposures in PD patients over 72 hours via SC route of delivery with very low fluctuation in LD concentration level across a wide range of clinically relevant exposures. Foslevodopa/foscarbidopa had a favorable safety profile. The low PK fluctuation following foslevodopa/foscarbidopa infusion is expected to maintain LD exposure to treat aPD patients within a narrow therapeutic window.

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