From the editors of Review of Ophthalmology and Retina Specialist
THE LATEST PUBLISHED RESEARCH
WELCOME to Review of Ophthalmology's Retina Online newsletter. Each month, Medical Editor Philip Rosenfeld, MD, PhD, and our editors provide you with this timely and easily accessible report to keep you up to date on important information affecting the care of patients with vitreoretinal disease.
Anti-VEGF Therapy for Persistent Neovascularization Following Complete Panretinal Photocoagulation in PDR
Researchers reported the rate of new vessel regression after monthly injections of bevacizumab in laser treated proliferative diabetic retinopathy eyes with persistent neovascularization, as part of a prospective cohort study.
Eyes with PDR with incomplete response to prior complete panretinal photocoagulation were included in the study. Ninety eyes of 80 individuals with persistent PDR despite adequate PRP were prospectively followed on a monthly basis with anti-VEGF injections when needed and stereo fundus images looking at the regression of NVs. The main outcome measure included regression of new vessels. Here are some of the findings:
• Seventy out of 90 (77.8 percent) eyes had regression of NV.
• The mean number of injections to reach quiescence was 9 ±3 for pPDR in the high-risk characteristics group (80 eyes), and 3 ±1 for the PDR-without-HRC group (10 eyes) (p<0.001).
• All individuals with PDR without HRC responded to the adjuvant therapy, while 75 percent of eyes with PDR with HRC responded.
• Eyes with initial retinal neovascularization all responded to the adjuvant treatment.
• Eyes without a vitreous hemorrhage at study entry were more likely to respond (OR=5.43, CI, 1.37 to 21.44, p<0.01).
• In some eyes, therapy was found to be unsuccessful because of the continuous growth of the NV despite treatment (three eyes), the development of traction (five eyes) and development of a dense vitreous hemorrhage (six eyes).
Researchers wrote that anti-VEGF rescue therapy has a potential role in select cases of laser treated PDR with persistent new vessels, and no evidence of traction to achieve regression of neovascularization.
SOURCE: Mehanna C-J, Fattah MA, Haddad S, et al. Anti-VEGF therapy for persistent neovascularization following complete panretinal photocoagulation in proliferative diabetic retinopathy. Ophthalmology Retina 2019; Feb 8. [Epub ahead of print].
Detection of Clinically Unsuspected Retinal Neovascularization
Scientists evaluated widefield optical coherence tomography angiography for detection of clinically unsuspected neovascularization in diabetic retinopathy, as part of a prospective, observational, single-center study including adult patients with a clinical diagnosis of nonproliferative DR.
Participants underwent a clinical exam, standard 7-field color photography, and OCTA with commercial and prototype swept-source devices. Widefield OCTA was achieved by montaging five 6 × 10-mm scans from a prototype device into a 25 × 10-mm image and three 6 × 6-mm scans from a commercial device into a 15 × 6-mm image. A masked grader determined retinopathy severity from color photographs. Two trained readers examined conventional and widefield OCTA images for the presence of NV. Here were some of the results:
• Of 27 participants, photographic grading found 13 mild, seven moderate and seven severe nonproliferative DR cases. (p=0.867).
• Conventional 6 × 6-mm OCTA detected NV in two eyes (7 percent) and found none with 3 × 3-mm scans.
• Prototype and commercial widefield OCTA detected NV in two additional eyes.
• The mean area of NV was 0.38 mm2 (range: 0.17 to 0.54 mm2).
• All eyes with OCTA-detected NV were photographically graded as severe nonproliferative DR.
Scientists reported that widefield OCTA could detect small NV not seen on clinical examinations or color photographs, and might improve the clinical evaluation of DR.
SOURCE: You QS, Guo Y, Wang J, et al. Detection of clinically unsuspected retinal neovascularization with wide-field optical coherence tomography angiography. Retina 2019; Mar. 4. [Epub ahead of print].
Deep Learning Predicts OCT Measures of Diabetic Macular Thickening
Researchers developed deep learning (DL) models for the automatic detection of optical coherence tomography measures of diabetic macular thickening from color fundus photographs (CFPs).
The retrospective analysis included 17,997 CFPs and their associated OCT measurements from the Phase III RIDE/RISE diabetic macular edema studies. Researchers applied DL with transfer-learning cascades on CFPs to predict time-domain OCT-equivalent measures of macular thickening, including central subfield thickness and central foveal thickness. They defined MT by using two OCT cutoff points: 250 μm and 400 μm. And they developed a DL regression model to directly quantify the actual CST and CFT from CFPs. The following were some of the findings:
• The best DL model was able to predict CST ≥250 μm with an area under the curve of 0.97 (CI, 0.89 to 1) and CFT ≥250 μm with an area under the curve of 0.91 (CI, 0.76 to 0.99).
• The best DL model was able to predict CST ≥400 μm with an AUC of 0.94 (CI, 0.82 to 1.00) and CFT ≥400 μm with an AUC of 0.96 (CI, 0.88 to 1).
• The best deep convolutional neural network regression model to quantify CST had an R2 of 0.74 (CI, 0.49 to 0.91) and to quantify CFT had an R2 of 0.54 (CI, 0.20 to 0.87).
• The performance of the DL models declined when CFPs were of poor quality or contained laser scars.
Researchers concluded that DL was capable of predicting key quantitative TD-OCT measurements related to MT from CFPs. They added that DL models presented in the study could enhance the efficiency of DME diagnosis in tele-ophthalmology programs, which might promote better visual outcomes. However, researchers wrote that future research would be needed to validate DL algorithms for MT in the real world.
SOURCE: Arcadu F, Benmansour F, Maunz A, et al. Deep learning predicts OCT measures of diabetic macular thickening from color fundus photographs. IOVS 2019;60:852-7.
Topical Interferon Α2b as a Complementary Treatment of ME in DR
Researchers evaluated the effect of the topical interferon α2b as an adjunctive therapy in the treatment of diabetic macular edema, as part of a randomized controlled clinical trial.
Fifty eyes of 50 DME patients (one eye/person) receiving therapy (the primary treatment for the DME wasn't specified in the abstract) were randomly assigned to get topical IFNα2b 1 MU/mL or artificial tear eye drops as adjunctive therapy. Primary measure outcomes were best-corrected visual acuity and central macular thickness; secondary goals were to assess the effect of topical IFNα2b on intraocular pressure and potential side effects. Here are some of the findings:
• Baseline demographic data of the two groups were similar.
• By the end of the fourth week, individuals on IFN experienced greater VA improvement, with more (6.85) Early Treatment Diabetic Retinopathy Study letters gained than individuals on artificial tears (1.45 ETDRS letters) (p=0.001); by the eighth week, individuals on IFN gained more ETDRS letters (6.75) than individuals on artificial tears (1.05 ETDRS letters) (p=0.005).
• Central macular thickness also decreased by the end of the fourth week (53.1 ±153 µm for individuals on IFN and 26.6 ±119.1 µm for individuals on artificial tears, p=0.497) and eighth week (27.9 ±67.7 for individuals on IFN and 29.2 ±98 µm for individuals on artificial tears, p=0.957), though the reduction wasn’t statistically significant.
• IOP was decreased on the fourth week in the IFN group (1.7 mmHg ±3) and increased in the artificial tear group (0.1 mmHg ±2.3) (p=0.018).
• No significant side effects were detected with topical IFN drops.
Researchers found topical IFNα2b 1 MU/mL was well-tolerated and might help improve BCVA in individuals with DME. They also reported an IOP lowering effect in the study eyes, but suggested that further studies would be needed to confirm this finding.
SOURCE: Afarid M, Meshksar A, Salehi A. Evaluation of the effect of topical interferon α2b as a complementary treatment of macular edema of patients with diabetic retinopathy. Retina 2019; Feb 6. [Epub ahead of print].
Impact of Baseline Retinal Nonperfusion and Macular Retinal Capillary Nonperfusion on Outcomes in COPERNICUS & GALILEO Studies
Investigators looked at the impact of baseline retinal nonperfusion (RNP) and macular retinal capillary nonperfusion (MNP) status on visual and anatomic outcomes at week 24, as part of a post hoc analyses of two Phase III, randomized, double-masked, multicenter, sham-controlled studies.
Participants included 366 individuals with macular edema secondary to central retinal vein occlusion randomized in COPERNICUS and GALILEO. Investigators randomized individuals 3:2 to receive intravitreal aflibercept 2 mg every four weeks or sham injections until W24. RNP and MNP were assessed by a masked independent reading center.
Main outcome measures included the proportion of individuals with ≥10 disc areas of RNP and any degree of MNP at W24, relative risks of developing ≥10 DA RNP or any degree of MNP at W24, change from baseline in best-corrected visual acuity and central retinal thickness by baseline RNP and MNP status, relationship between baseline RNP and MNP status. Here were some of the findings:
• At baseline, 24.6 percent of all individuals had ≥10 DA RNP and 72.6 percent had MNP, irrespective of baseline RNP status.
• At W24, the pooled proportions of individuals with ≥10 DA RNP were: in the intravitreal aflibercept group: 11.6 percent; and in the sham group: 29 percent (p=0.0001); the respective proportions with any degree of MNP were 61.2 percent and 79.5 percent (p=0.0008).
• Relative risks and CI for intravitreal aflibercept vs. sham were 0.4 (0.25 to 0.62) for ≥10 DA RNP and 0.8 (0.68 to 0.90) for MNP, indicating a lower risk for these outcomes in intravitreal aflibercept than sham-treated cases.
• Mean BCVA change was greater in intravitreal aflibercept vs. sham-treated eyes with <10 and ≥10 DA RNP at baseline (+17.5 vs. -4.1 and +18.3 vs. +0.8 letters, respectively), and with and without baseline MNP (+15.7 vs. +0.3 and +17.1 vs. +0.4 letters, respectively).
• Agreement between baseline RNP and MNP status was low (κ=0.12).
• The proportion of individuals with ≥1 ocular serious adverse events in the intravitreal aflibercept group was 3.2 percent and in the sham-treated group was 11.3 percent.
Investigators found that, at week 24, visual and anatomic improvements, including perfusion status, were greater in eyes treated with intravitreal aflibercept than with sham, regardless of baseline RNP or MNP status.
Source: Feltgen N, Ogura Y, Boscia F, et al. Impact of baseline retinal nonperfusion and macular retinal capillary nonperfusion on outcomes in the COPERNICUS and GALILEO studies. Ophthalmology Retina Feb 26. [Epub ahead of print].
Characteristics of Type 3 Neovascularization Lesions
Investigators evaluated the incidence of multifocal lesions and distribution of lesion location in type 3 neovascularization, as part of a retrospective, observational study including 148 eyes of 148 people diagnosed with type 3 neovascularization.
Investigators counted the number of type 3 neovascularization lesions and estimated the incidence of multiple lesions in an eye. In addition, they estimated the distance from the fovea to the lesion, and the geographic location of the lesion.
Investigators also compared pseudodrusen incidence between eyes with and without multifocal lesions. Here were some of the findings:
• Investigators reported a total of 169 type 3 neovascularization lesions.
• They found a single lesion in 130 eyes (87.8 percent), and two or three multifocal lesions in the remaining 18 eyes (12.2 percent).
• The mean distance from the fovea to the lesion was 898.8 ±324.9 µm.
• The distribution of lesion locations exhibited a fovea-sparing pattern.
• No lesions were located within 200 µm of the fovea; 20 lesions (11.8 percent) were located >200 and ≤500 µm away from the fovea; 89 lesions (52.7 percent) were located >500 and ≤1,000 µm away from the fovea; and 60 lesions (35.5 percent) were located >1,000 µm away from the fovea.
• Pseudodrusen incidence was significantly higher in eyes with multifocal lesions (p=0.024).
Investigators reported two or more multifocal lesions in 12.2 percent of eyes with type 3 neovascularization, and they noted that pseudodrusen incidence was higher in eyes with multifocal lesions. In addition, investigators found that lesion distribution exhibited a fovea-sparing pattern—characteristics that they said might be associated with the distinct pathophysiology of type 3 neovascularization.
SOURCE: Kim JH, Chang Y, Kim JW, et al. Characteristics of type 3 neovascularization lesions. Retina 2019; Feb. 28. [Epub ahead of print].
Prophylactic Laser Treatment to Decrease Incidence of Retinal Detachment in Fellow Eyes of Idiopathic Giant Retinal Tears
Scientists evaluated the effectiveness of prophylactic 360-degree-laser treatment in the fellow eye of individuals with unilateral idiopathic giant retinal tear to prevent the occurrence of a macula-off retinal detachment, as part of a retrospective, nonrandomized case-control study.
They analyzed clinical data of consecutive patients undergoing surgery for idiopathic GRT, between 2003 and 2015. The data collected included GRT, retinal detachment and retinal tears in the fellow eye. Scientists included 129 individuals who underwent surgery for an idiopathic GRT, with a mean follow-up period of 107 months.
In the observation group, a retinal detachment developed in the fellow eye in 22/51 individuals (43.1 percent), leading to a macula-off detachment in 9/51 individuals (17.6 percent). By contrast, in the prophylactic 360-degree laser group, only 10/78 (12.8 percent) individuals developed a retinal detachment, leading to a macula-off detachment in 1 out of 78 patients (1.3 percent). This difference was statistically significant.
Scientists wrote that the study suggested that prophylactic 360-degree laser treatment in the fellow eye of individuals with an idiopathic GRT decreased the incidence of retinal detachment, lowering the high risk of visual loss due to a macula-off retinal detachment.
SOURCE: Verhoekx JSN, van Etten PG, Wubbels RJ, et al. Prophylactic laser treatment to decrease the incidence of retinal detachment in fellow eyes of idiopathic giant retinal tears. Ophthalmology Retina 2019; March 6. [Epub ahead of print].
Macular Perfusion Changes Assessed with OCTA after Vitrectomy for RRD
Investigators explored whether macular perfusion changes in individuals with rhegmatogenous retinal detachment involved the macula following successful surgery, and evaluated the correlation between macular blood flow density and visual outcomes using optical coherence tomography angiography.
This retrospective study included 14 eyes (14 individuals) with macula-off RRD that underwent a standard three-port 23-gauge pars plana vitrectomy and intraocular gas tamponade combined with phacoemulsification, aspiration and intraocular lens implantation. OCTA was used to evaluate the macular perfusion changes throughout the postoperative 12 weeks in the superficial capillary plexus, deep capillary plexus and choriocapillary plexus. The fellow unaffected eyes were used as controls for comparison. Here were some of the findings:
• Investigators observed a significant increase in the superficial capillary plexus flow density (SCPFD) (p=0.000) over time in RRD eyes with successful PPV, as well as in the deep capillary plexus (DCPFD) (p=0.000) and choriocapillary plexus flow densities (CCPFD)(p=0.000).
• Final best-corrected visual acuity was positively associated with CCPFD (r=- 0.577; p=0.031), and non-correlated with SCPFD and DCPFD (p>0.05).
Investigators determined that macular perfusion gradually recovered after successful RRD repair by PPV. They added that OCTA provided a noninvasive method to explore the underlying reasons for different postoperative visual outcomes in macular-off RRD individuals.
SOURCE: Wang H, Xu X, Sun X, et al. Macular perfusion changes assessed with optical coherence tomography angiography after vitrectomy for rhegmatogenous retinal detachment. Graefes Arch Clin Exp Ophthalmol 2019; Feb. 22. [Epub ahead of print].
New Research in Familial Exudative Vitreoretinopathy
Investigators quantitatively detected the macular microvascular alterations of eyes with familial exudative vitreoretinopathy, and analyzed associations with the severity and visual acuity of FEVR.
They conducted a case-control study including 62 individuals (62 eyes) with FEVR and 21 age-matched healthy individuals (21 eyes) with normal vision. In addition, they measured parafoveal vascular density using optical coherence tomography angiography, and recorded visual acuity, intraocular pressure and axial length. Here were some of the findings:
• Parafoveal vascular density of eyes with FEVR was lower than that of controls (p<0.05).
• Parafoveal vascular density decreased with increasing FEVR stages (p<0.05).
• Decreased vascular density in the superficial capillary plexus was independently correlated with FEVR severity (OR: 1.558, p<0.001) after controlling for other confounding variables.
• Vascular density in eyes with FEVR and decreased vascular density were lower than eyes with FEVR and normal VA (SCP, p<0.001; deep capillary plexus, p=0.001).
• Vascular density loss was independently associated with visual loss in FEVR (SCP: OR: 0.817, p=0.019; deep capillary plexus: OR: 0.763, p=0.016).
Investigators wrote that parafoveal microvascular defects in FEVR were a possibility and that vascular density loss in SCP might be correlated with FEVR severity. They added that VD loss in SCP and deep capillary plexus might be associated with visual loss in FEVR.
SOURCE: Zhang J, Jiang C, Ruan Lu, et al. Macular capillary dropout in familial exudative vitreoretinopathy and its relationship with visual acuity and disease progression. Retina 2019; March 6. [Epub ahead of print].
ROCHE AND GENENTECH INITIATE TWO PHASE III STUDIES IN WET AMD FOR FARICIMAB; STUDY SHOWS EVIDENCE AI CAN DETECT DME SEVERITY
Roche and Genentech initiated two Phase III clinical trials investigating the bispecific molecule faricimab, which simultaneously binds to and inactivates Angiopoietin-2 and vascular endothelial growth factor A, to treat retinal eye diseases. By targeting Ang-2 and VEGF-A, faricimab may lead to sustained efficacy at longer treatment intervals, thereby improving vision outcomes for patients. The identically designed, multicenter, randomized, double-masked, active comparator-controlled Phase III TENAYA and LUCERNE studies will evaluate the efficacy, safety and durability of faricimab compared with aflibercept for the treatment of wet age-related macular degeneration. The primary endpoint of each study is the change in best-corrected visual acuity at week 48 from baseline.
Read more about TENAYA.
Read more about LUCERNE.
In addition, a study published as part of Roche/Genentech's Ophthalmology Personalized Healthcare initiative in Investigative Ophthalmology and Visual Science
suggests that artificial intelligence could be used to provide widespread, cost-effective eye screenings via telemedicine to assist ophthalmologists in improving vision outcomes for diabetics who may not be getting regular eye exams. The research assessed how deep learning can automatically view color fundus photographs to accurately detect DME and determine its severity.
SOURCE: Genentech, March 2019
ReNeuron Clinical Trial Progresses to Next Stage
ReNeuron Group began dosing of the second cohort of three Phase II subjects, as part of an ongoing Phase I/II clinical trial in the United States of its hRPC cell therapy candidate for retinitis pigmentosa. Following a positive Data Safety Monitoring Board review of clinical data from the first Phase II patient cohort, the first subject in the latest cohort was treated at Massachusetts Eye and Ear in Boston. The company previously reported that all three of the first cohort of subjects reported a rapid and significant improvement in vision, on average equivalent to reading an additional three lines of five letters on the EDTRS eye chart. The clinical program was granted U.S. FDA Fast Track designation. Read more.
SOURCE: ReNeuron Group, March 2019
PROQR DOSES FIRST PATIENT IN PHASE I/II STELLAR TRIAL OF QR-421A FOR USHER SYNDROME TYPE 2
ProQR Therapeutics announced the first patient was dosed in the Phase I/II STELLAR clinical trial for QR-421a in Usher syndrome type 2 or non-syndromic retinitis pigmentosa. Interim data from the study are expected to be announced in mid-2019. Read more.
SOURCE: ProQR Therapeutics, March 2019
Aerpio TIME-2b Study of AKB-9778 in DR Doesn’t Meet Primary Endpoint
Aerpio Pharmaceuticals announced that the company’s TIME-2b study, a Phase IIb clinical trial designed to assess the efficacy and safety of its lead candidate, AKB-9778, for moderate to severe non-proliferative diabetic retinopathy didn’t meet the primary endpoint. Administration of AKB-9778 twice daily didn’t increase the percentage of patients with an improvement of two or more steps in the study eye diabetic retinopathy severity score compared with placebo. Read more.
Source: Aerpio Pharmaceuticals, March 2019
Théa and OliX Collaborate to Develop Therapies for AMD
OliX Pharmaceuticals signed a license and collaboration agreement with Théa Open Innovation, an independent pharmaceutical company in Europe, to develop and commercialize OLX301A, an investigational treatment for dry and wet AMD. Théa was granted licensing rights for the OLX301A program in EU countries, the Middle East and Africa, while OliX continues to hold the rights of the OLX301A program for the United States and Asia. Read more.
SOURCE: OliX Pharmaceuticals, March 2019
ROCHE ENTERS INTO MERGER AGREEMENT TO ACQUIRE SPARK
Roche and Spark Therapeutics announced that they entered into a definitive merger agreement for Roche to fully acquire Spark for approximately $4.3 billion. Spark Therapeutics was the first company to receive FDA approval for a gene therapy for a genetic disease in 2017 with Luxturna (voretigene neparvovec-rzyl). Luxturna, which is marketed by Spark, is a one-time gene therapy product indicated for the treatment of individuals with confirmed biallelic RPE65 mutation-associated retinal dystrophy. The company is also developing SPK-1001 for CLN2 disease (a form of Batten disease) as well as additional preclinical programs for Stargardt’s disease. Read more.
Source: Roche, February 2019
BIOGEN TO ACQUIRE NIGHTSTAR THERAPEUTICS
Biogen entered into an agreement to acquire Nightstar Therapeutics, a London-based, clinical-stage gene therapy company focused on adeno-associated virus treatments for inherited retinal disorders. Nightstar’s lead asset is NSR-REP1 for the treatment of choroideremia, composed of an AAV vector administered by subretinal injection that provides a functioning CHM gene and expression of the REP-1 protein to restore membrane trafficking. NSR-REP1 is being evaluated in the ongoing Phase III STAR trial. NST’s second clinical program is NSR-RPGR for the treatment of X-linked retinitis pigmentosa. Biogen expects to complete the acquisition by mid-2019. Read more.
SOURCE: Biogen, February 2019
EYEPOINT LAUNCHES DEXYCU IN THE UNITED STATES
EyePoint Pharmaceuticals has officially launched the anti-inflammatory DEXYCU (dexamethasone intraocular suspension) 9%. The company says the drug is the first and only FDA-approved intraocular steroid for the treatment of postoperative inflammation, administered as a single dose at the end of cataract surgery, in the United States. The Centers for Medicare and Medicaid Services assigned a specific, permanent reimbursement J-code for DEXYCU, J1095, which became effective Jan. 1. The J-code will replace the previously issued C-code for DEXYCU (C9034) that became effective on Oct. 1, 2018. Read more.
SOURCE: EyePoint Pharmaceuticals, March 2019
B+L GETS FDA NOD FOR LOTEMAX SM
The FDA approved Bausch + Lomb’s Lotemax SM (loteprednol etabonate ophthalmic gel) 0.38%, a new gel formulation for the treatment of postoperative inflammation and pain following ocular surgery. The company says Lotemax SM uses novel SubMicron (SM) technology to control ocular pain and inflammation after all ocular surgeries. Compared with Lotemax Gel (loteprednol etabonate ophthalmic gel) 0.5%, the company says Lotemax SM delivers a submicron particle size for faster drug dissolution in tears and provides two times greater penetration to the aqueous humor. The company developed SM technology to adhere to the ocular surface and then penetrate key ocular tissues, B+L says. Read more.
SOURCE: Bausch + Lomb, February 2019
LUMITHERA RECEIVES NOTICE OF $2.5 MILLION NEI GRANT AWARD
LumiThera is a recipient of a small business innovative research Phase II grant from the National Institutes of Health and the National Eye Institute to support a prospective, randomized, multicenter human clinical trial in U.S. subjects diagnosed with dry age-related macular degeneration. The LIGHTSITE III trial, which is subject to FDA Investigational Device Exemption approval, will test vision and examine disease pathology in eyes following PBM treatments using the company's Valeda Light Delivery System. Subjects will be followed for up to two years. Read more.
SOURCE: LumiThera, February 2019
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