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.
Effect of Ciliary Neurotrophic Factor on Retinal Neurodegeneration in MacTel 2
Researchers tested the effects of an encapsulated cell-based delivery of a neuroprotective agent, ciliary neurotrophic factor, on progression of macular telangiectasia type 2, in a randomized, sham-controlled clinical trial.
Ninety-nine study eyes of 67 eligible participants were enrolled. As part of a single-masked, randomized clinical trial of 24 months' duration conducted from May 2014 through April 2017, in 11 clinical centers of retinal specialists in the United States and Australia, participants were randomized 1:1 to surgical implantation of intravitreal sustained delivery of human CNTF versus a sham procedure.
The primary outcome was the difference in the area of neurodegeneration as measured in the area of the ellipsoid zone disruption (or photoreceptor loss) measured on spectral-domain optical coherence tomography images at 24 months from baseline between the treated and untreated groups. Secondary outcomes included comparison of visual function changes between treatment groups. Here were some of the findings:
• Among the 67 participants who were randomized (mean age: 62 ±8.9 years; 41 women [61 percent]; 58 white persons [86 percent]), 65 (97 percent) completed the study. Two participants (three study eyes) died and three participants (four eyes) were found ineligible.
• The eyes receiving sham treatment had 31 percent greater progression of neurodegeneration than the CNTF-treated eyes.
• The difference in mean area of photoreceptor loss was 0.05 ±0.03 mm2 (p=0.04) at 24 months. Retinal sensitivity changes, measured using microperimetry, were correlated highly with the changes in the area of photoreceptor loss (r=0.86; p<0.0001).
• The mean retinal sensitivity loss of the sham group was 45 percent greater than that of the treated group (decrease: 15.81 ±8.93 dB; p=0.07).
• Reading speed deteriorated in the sham group (-13.9 words per minute) with no loss in the treated group (p=0.02).
• Serious adverse ocular effects were found in two of 51 individuals (4 percent) in the sham group and two of 48 persons (4 percent) in the treated group.
Researchers determined that, in individuals with macular telangiectasia type 2 compared with a sham procedure, a surgical implant that released CNTF into the vitreous cavity slowed the progression of retinal degeneration. They added that further research would be needed to assess longer-term clinical outcomes and safety.
SOURCE: Chew EY, Clemons TE, Jaffe GJ, et al. Effect of ciliary neurotrophic factor on retinal neurodegeneration in patients with macular telangiectasia type 2: A randomized clinical trial. Ophthalmology 2018; Oct 4. [Epub ahead of print].
Treat-and-extend Trial with Ranibizumab in nAMD: CANTREAT Study
Researchers compared the efficacy of ranibizumab using a treat-and-extend regimen to monthly dosing in treatment-naïve subjects with neovascular age-related macular degeneration, as part of a prospective, randomized, open-label, multicenter, non-inferiority, post-authorization study.
Participants included treatment-naïve subjects with choroidal neovascularization secondary to AMD. Subjects with nAMD were randomized 1:1 to receive intravitreal ranibizumab at a dose of 0.5 mg in a T&E or monthly dosing regimen. The non-inferiority of T&E compared with the monthly dosing regimen was shown using a margin of five letters in best-corrected visual acuity improvement.
The main outcome measure was mean change in BCVA Early Treatment Diabetic Retinopathy Study letters from baseline to month 12. Baseline and 12-month visual acuity data were available for 526 individuals (T&E: n=268; monthly: n=258). Below are some of the results:
• At baseline, mean age was 78.8 ±7.8 years: 60.3 percent were females and 94.3 percent were Caucasian. No significant between-group baseline differences were observed.
• The primary outcome of non-inferiority regarding visual acuity was met with mean BCVA improvement of 8.4 ±11.9 letters in the T&E group and 6 ±11.9 letters in the monthly group (p=0.017), with a between-group mean difference of 2.38 (CI, 0.32 to 4.45).
• Per protocol, a secondary analysis was performed to test for superiority of number of injections received up to month 12. This analysis demonstrated significantly fewer injections with T&E (9.4) vs. monthly (11.8) dosing, with a mean difference of -2.46 (CI, -2.68 to -2.23).
Researchers determined that 12-month results of the two-year study revealed that, with regard to visual outcomes, the T&E regimen was non-inferior to a monthly dosing regimen. They added that similar visual outcomes in the T&E group as in the monthly dosing group were achieved with significantly fewer injections.
SOURCE: Kertes PJ, Galic IJ, Greve M, et al. Canadian treat and extend analysis trial with ranibizumab in patients with neovascular age-related macular disease: 1-year results of the randomized CANTREAT study. Ophthalmology 2019; Jan 21. [Epub ahead of print].
Simulating an Anti-VEGF Switch in nAMD: HARBOR Subanalysis
Researchers conducted a post hoc analysis of the Phase III HARBOR clinical trial—a simulated switching study that assessed the effects of continuing the same anti-vascular endothelial growth factor treatment among individuals who were typically considered for a therapy switch.
Individuals with neovascular age-related macular degeneration who demonstrated a suboptimal response after three or six months of ranibizumab treatment were identified as switching candidates. Rather than switching, however, patients continued on ranibizumab treatment, and researchers examined visual/anatomic outcomes from the time of the “hypothetical” switch.
Subjects were included in the three-month “switcher” analysis if they received three of three initial monthly ranibizumab doses, and six-month switcher analysis if they received five of six initial monthly ranibizumab doses, and achieved: ≤5-letter gain from baseline; best-corrected visual acuity 20/40 or worse; and intraretinal or subretinal fluid with central foveal thickness ≥central subfield thickness.
Researchers examined subject data at months three and six to identify those who met predetermined switching criteria. They examined BCVA and CFT from the point at which switching criteria were met through months six, 12, 18 and 24 of HARBOR, and compared them with those who didn’t meet the criteria. Main outcome measures included mean BCVA and CFT change over time from the point at which switching criteria were met (month three or six). Here were some of the findings:
• By month three, only 44 of 1,059 (4.2 percent) met inclusion criteria for hypothetical switching; and by month six, 37 of 769 (4.8 percent) individuals did.
• Individuals who met switching criteria at month three gained, on average, 5.3 letters from months three to 12, and 2.7 letters from months three to 24.
• Month-six switchers gained, on average, 1.6 letters from months six to 12, and 1.8 letters from months six to 24.
• Both three- and six-month switcher groups experienced significant CFT reductions over 24 months.
Researchers found that month-three hypothetical switchers achieved vision and anatomic improvement while remaining on their original ranibizumab treatment. They added that month-six switcher outcomes replicated those commonly reported in published anti-VEGF switching studies: stable vision or nominal improvements in vision with continued substantial anatomic improvement.
SOURCE: Zarbin M, Tsuboi M, Hill LF, et al. Simulating an anti-vascular endothelial growth factor switch in neovascular age-related macular degeneration: A HARBOR subanalysis. Ophthalmology 2019; Jan 11. [Epub ahead of print].
Rates of Exudative Recurrence for Inactivated Wet AMD Eyes on Interval Dosing With Bevacizumab
Investigators determined the recurrence rate of exudative age-related macular degeneration in individuals on a 12-week dosing interval of anti-vascular endothelial growth factor bevacizumab therapy.
The retrospective chart review was performed on wet AMD patients treated with anti-VEGF therapy using a “treat-and-extend” methodology at one physician's practice over two years (2012 to 2014). Charts were evaluated for visual acuity, anti-VEGF agent used, treatment interval and duration, participation in trials while off of anti-VEGF therapy, evidence of exudation and wet AMD recurrence characteristics. The following were some of the results:
• Of 321 wet AMD patients treated, 57 eyes were without active exudation by clinical exam or optical coherence tomography and were maintained on 12-week interval suppressive anti-VEGF therapy.
• Sixteen percent (8/49) showed exudation recurrence, with an average 10 percent cumulative recurrence rate per year for eyes on bevacizumab.
• Eight eyes without active exudation were discontinued off of bevacizumab therapy.
• Sixty-three percent (5/8) of eyes discontinuing therapy demonstrated recurrence on average four months after stopping therapy.
Investigators wrote that the findings suggested that patients who were extended to 12-week interval bevacizumab therapy had on average a 10-percent chance of recurrence with each successive year. They added that discontinuing anti-VEGF therapy increased the chance of recurrence by four months.
SOURCE: Hwang RY, Santos D, Oliver SCN, et al. Rates of exudative recurrence for eyes with inactivated wet age-related macular degeneration on 12-week interval dosing with bevacizumab therapy. Retina 2018; Jan. 14. [Epub ahead of print].
Age-related Differences in Prevalence of nAMD Subtypes in the First Diagnosed Eye
Researchers evaluated age-related differences in the prevalence of subtypes of neovascular age-related macular degeneration in the first diagnosed eye, as part of a retrospective, observational study of 1,099 cases diagnosed with neovascular AMD.
The neovascular AMD cases were classified into three subtypes: typical neovascular AMD; polypoidal choroidal vasculopathy; and type 3 neovascularization. Subjects were divided into four groups, according to age: >50 and <60 years; ≥60 and <70 years; ≥70 and <80 years; and ≥80 years. Difference in the prevalence of three AMD subtypes was evaluated among the four age groups. Here are some of the findings:
• In the >50 and <60 years age group, 34 (25 percent) subjects were diagnosed with typical nAMD and 102 individuals (75 percent) were diagnosed with PCV.
• In the ≥60 and <70 years age group, 90 (28.1 percent) were diagnosed with typical nAMD, 206 (64.4 percent) were diagnosed with PCV and 24 individuals (7.5 percent) were diagnosed with type 3 neovascularization.
• In the ≥70 and <80 years age group, 200 (41.9 percent) were diagnosed with typical nAMD, 197 (41.3 percent) were diagnosed with PCV and 80 (16.8 percent) were diagnosed with type 3 neovascularization.
• In the ≥80 years age group, 83 (50 percent) were diagnosed with typical nAMD, 39 (23.5 percent) were diagnosed with PCV and 44 (26.5 percent) were diagnosed with type 3 neovascularization.
• A significant difference was observed in the prevalence of the subtypes of neovascular AMD among the four age groups (chi-square test, p<0.001).
Researchers concluded that subtype prevalence in newly diagnosed neovascular AMD differed significantly according to age. They added that this suggested that different pathophysiology might be involved in the development of neovascular AMD subtypes.
SOURCE: Kim JH, Chang YS, Kim JW, et al. Age-related differences in the prevalence of subtypes of neovascular age-related macular degeneration in the first diagnosed eye. Graefes Arch Clin Exp Ophthalmol 2019; Jan. 7. [Epub ahead of print].
Imaging Characteristics of CNV Lesions in AREDS2-HOME Study
Researchers characterized choroidal neovascular lesions and the corresponding change in visual acuity in eyes that converted to neovascular age-related macular degeneration in the AREDS2-HOME Study, as part of a cohort study. The study is sponsored by Notal Vision, maker of the ForeseeHome Monitoring Program.
A total of 1,520 participants at risk of developing CNV were enrolled, each of whom contributed >1 study eye(s) that had best-corrected VA letter score of >54 letters (Snellen equivalent 20/60) and >1 large (>125 um) macular druse in the absence of neovascular AMD or central geographic atrophy.
Using a multicenter clinical trial comparing standard care (SC) vs. SC plus ForeseeHome (FH) monitoring strategy in the detection of neovascular AMD, independent reading centers (RCs) evaluated fluorescein angiograms and optical coherence tomography from the visit in which the ophthalmologist identified progression to CNV (n=82 eyes). Main outcome measures were development of CNV on OCT or FA, or both OCT and FA. Here were some of the findings:
• The reading center confirmed CNV in 67 out of 82 eyes (82 percent); lesions were confirmed in 42/70 eyes (60 percent) with FA, 59/72 eyes (82 percent) with OCT and on both images in 34/67 eyes (51 percent).
• Among FA confirmed cases, median lesion size was 0.82 disc area (DA); lesions were subfoveal in 40.5 percent; occult CNV composition was present in 54.8 percent and associated hemorrhage was present in 50 percent.
• Median (IQR) lesion size on FA was 0.23 (0.0, 0.91) DA in FH eyes vs. 0.70 (0.0, 1.50) DA in SC eyes, (p=0.051).
• Among the OCT confirmed cases, center point thickness was: median 209 μm (175 μm, 274 μm interquartile range), with retinal pigment epithelial lesion complex present in 86.4 percent, and subretinal fluid present in 76.3 percent.
• Median change in VA from baseline was -4 letters in FH eyes and -10 letters in SC eyes (p=0.008) confirmed as CNV at the RC.
Researchers reported that incident CNV lesions were more prevalent on OCT images than FA; however, they added that use of both OCT and FA enhanced detection of incident lesions. Researchers wrote further that lesions were smaller and associated with less vision loss among eyes in the FH group.
SOURCE: Domalpally A, Clemons TE, Bressler SB, et al. Imaging characteristics of choroidal neovascular lesions in the AREDS2- HOME Study: The HOME Study, Report Number 4. Ophthalmology Retina 2019; Jan. 10. [Epub ahead of print].
Choroidal Thickness Changes in Wet AMD
Scientists assessed choroidal thickness changes during an exudative recurrence of age-related macular degeneration as part of a prospective, non-interventional study conducted between November 2016 and July 2017 in consecutive patients with exudative AMD.
CT was measured manually in both eyes based on enhanced-depth imaging spectral-domain optical coherence tomography at follow-up visits scheduled in the morning. A total of 134 individuals were included. Ninety-five patients presented with at least one episode, defined by a follow-up visit under controlled conditions (dry retina) followed by a visit for exudative recurrence. A total of 119 episodes were analyzed.
The mean CT change in the treated eye was +8.45 ±13.52 μm (p<0.001) in the subfoveal area and +5.62 ±14.77 μm (p=0.009) in the nasal area. No significant changes in CT were observed in the fellow eyes. No significant associations between CT changes and treatments, number of intravitreal injections and blood pressure were observed.
Scientists wrote that CT increased mildly, but significantly in cases of exudative recurrence of neovascular AMD. Thus, they suggested, CT could be used as a monitoring criterion, similar to central retinal thickness in AMD management.
SOURCE: Bouteleux V, Kodjikian L, Mendes M, et al. Increased choroidal thickness: a new feature to monitor age-related macular degeneration recurrence. Graefes Arch Clin Exp Ophthalmol 2018; Dec. 16. [Epub ahead of print].
Macular Atrophy in nAMD
Scientists determined optical coherence tomography signs associated with macular atrophy in eyes with neovascular age-related macular degeneration and pigment epithelial detachments treated with vascular endothelial growth factor inhibitors.
They analyzed OCT scans from a subgroup of the PED cohort of the HARBOR study for MA. Two groups were formed based on MA presence/absence at month 24. Then, scientists graded OCT scans from each baseline visit with standard reading center grading parameters including ellipsoid zone disruption, intraretinal cysts, subretinal fluid, and MA or nascent MA in study and fellow eyes. Twenty-eight eyes were included in the analysis. The following are some of the results:
• Fourteen eyes had OCT-based MA at month 24 and 14 did not.
• Macular atrophy at month 24 was significantly associated with MA/nascent MA at baseline (p=0.0136); intraretinal cysts at baseline (p=0.0048); and collapse of PEDs in study eyes (p=0.0025).
• Macular atrophy wasn’t associated with ellipsoid zone disruption or subretinal fluid in the study eye at baseline.
Scientists determined that some OCT findings in eyes of individuals with nAMD were present before the start of anti-vascular endothelial growth factor therapy and might predict the development of MA.
SOURCE: Rebhun CB, Moreira-Neto C, Gune S, et al. Macular atrophy in neovascular age-related macular degeneration: A pilot post hoc analysis of patients with pigment epithelial detachments. Retina 2018; Dec 24. [Epub ahead of print].
En Face OCTA Averaging vs. Single-image Quantitative Measurements for RVO Visual Outcomes
Investigators demonstrated the effect of averaging multiple en face optical coherence tomography angiography images on the correlation between retinal microvasculature quantitative metrics and best-corrected visual acuity in eyes with retinal vein occlusion.
A cross-sectional cohort with unilateral retinal vein occlusion in both eyes was imaged. Investigators averaged five 3 mm × 3 mm spectral-domain OCTA images, and correlated quantitative parameters from averaged vs. single images with logMAR BCVA. They performed regression analyses to correlate quantitative metrics with BCVA. Ten individuals (five males; average age: 64.3 years) were included. The following were some of the results:
• Among retinal vein occlusion eyes, vessel length density was significantly less in averaged vs. single images for the superficial retinal layer (15.5 ±2.5/mm vs. 17.8 ±2.4/mm; p=0.05) and deep retinal layer (16.2 ±1.4/mm vs. 18.5 ±1.6/mm; p=0.003).
• Multivariate linear regression showed an increased R2 value with averaging (0.93 for single and 0.95 for averaged groups).
• Foveal avascular zone circularity was associated with BCVA on single images (coefficient=-0.96; p=0.002), but not with averaged images (p=0.063).
Investigators concluded that scan averaging of en face OCTA images improved the clarity of vessels and might allow for more accurate quantification of vessel metrics. They added that quantitative metrics were significantly associated with BCVA, and averaging didn’t further improve this association compared with single-scan analysis.
SOURCE: Jung JJ, Chen MH, Shi Y, et al. Correlation of en face optical coherence tomography angiography averaging versus single-image quantitative measurements with retinal vein occlusion visual outcomes. Retina 2018; Jan. 22. [Epub ahead of print].
Vessel Density Measurements Using OCTA
Researchers analyzed the values of retinal vessel density (VD) in the three retinal capillary plexuses, the foveal avascular zone area and retinal layer thickness in a cohort of healthy subjects. They analyzed the optical coherence tomography angiography maps of 148 eyes of 84 healthy subjects, ages 22 to 76 years, to measure VD of the retinal capillary plexuses using a projection artifact removal algorithm. In addition, they evaluated foveal avascular zone metrics, and studied the relationship between OCTA findings and age, sex and image quality.
The deep capillary plexus showed the lowest VDs (31.6 ± 4.4 percent) in all macular areas and age groups compared with the superficial vascular plexus (47.8 ±2.8 percent) and intermediate capillary plexus (45.4 ±4.2 percent).
The mean VDs decreased yearly by 0.06 percent in the superficial vascular plexus, 0.06 in the intermediate capillary plexus and 0.08 percent in the deep capillary plexus.
The mean FAZ area density was 0.25 ±0.1 mm2, the FAZ acircularity index was 1.1 ±0.05 and the capillary density in a 300-µm area around the FAZ was 50.8 ±3.4 percent.
The yearly increase in FAZ area was 0.003 mm2 (p<0.001).
Researchers determined that the deep capillary plexus had the lowest VD, which they wrote was a significant finding that might be used to evaluate retinal vascular diseases. They added that VD decreased with age in the three capillary plexuses.
SOURCE: Lavia C, Bonnin S, Maule M, et al. Vessel density of superficial, intermediate, and deep capillary plexuses using optical coherence tomography angiography. Retina 2018; Dec. 6. [Epub ahead of print].
AERPIO COMPLETES PATIENT DOSING IN TIME-IIB STUDY OF AKB-9778 IN DR
Aerpio Pharmaceuticals finished patient dosing in the company’s TIME-IIb study, a clinical trial designed to assess the efficacy and safety of the company’s lead candidate, AKB-9778, for individuals with moderate to severe non-proliferative diabetic retinopathy. The double-masked, placebo-controlled, multicenter trial is evaluating the effect of AKB-9778 in 167 subjects with moderate to severe NPDR. Individuals were randomized to receive 48 weeks of treatment with AKB-9778 15 mg subcutaneously once daily (and placebo subcutaneously once daily), AKB-9778 15 mg subcutaneously twice daily or placebo subcutaneously twice daily. The primary endpoint is the percentage of individuals who improve by two or more steps in diabetic retinopathy severity score in the study eye. Read more.
SOURCE: Aerpio Pharmaceuticals, January 2019
AERIE TO INITIATE PHASE II CLINICAL STUDY IN FIRST QUARTER 2019
Aerie Pharmaceuticals announced that the FDA reviewed its Investigational New Drug Application for AR-1105 (dexamethasone intravitreal implant), and authorized the company to initiate human studies in the treatment of macular edema due to retinal vein occlusion. Aerie expects to initiate a Phase II clinical study later in the first quarter of 2019. AR-1105 is a bio-erodible implant designed to release the steroid dexamethasone over a six-month period. The method of administration is intravitreal injection. Read more.
SOURCE: Aerie Pharmaceuticals, January 2019
Olix Announces Clinical Candidate Nomination for GA Treatment
Olix Pharmaceuticals, a developer of RNAi therapeutics, announced the nomination of OLX10020 as a clinical candidate for the treatment of geographic atrophy. OLX10020 targets an undruggable gene involved in GA. Results from animal studies support that OLX10020 can specifically target patients with GA among dry age-related macular degeneration patients. An IND application is expected to be submitted to the FDA to initiate a Phase I within the year. Read more.
Source: Olix Pharmaceuticals, January 2019
GEMINI INITIATES CLARITY DISEASE REGISTRY & NATURAL HISTORY STUDY OF DRY AMD SUBJECTS
Gemini Therapeutics announced the initiation of CLARITY, a disease registry and natural history study designed to identify and characterize disease progression in subjects with non-central geographic atrophy secondary to dry AMD, who are carriers of high-risk genetic variants. CLARITY will genetically screen thousands of subjects and enroll hundreds based on genetic criteria. Subjects will be separated into one of two studies. Read more.
SOURCE: Gemini Therapeutics, January 2019
ComfortPack Designed to Enhance Patient Experience With Intravitreal Injections
American Surgical Company recently partnered with ophthalmologists to develop patent-pending ComfortPack, a needle-free solution for anesthetizing the eye prior to intravitreal injections such as those used to administer Eylea, Lucentis and Avastin. The ComfortPack includes a 4% lidocaine solution to directly numb the injection site and reduce discomfort and the feeling of pressure for the patient. Read more.
Source: American Surgical Company, January 2019
BioTime Enters Into Agreement With Orbit for Subretinal Delivery of OpRegen Cells to Treat Dry AMD
BioTime entered into a research and option agreement with Orbit Biomedical to collaborate on the use of Orbit’s proprietary injection technology to deliver OpRegen for the treatment of dry age-related macular degeneration. Traditionally, the subretinal space is accessed via vitrectomy, followed by an injection into the eye and through the retina. Orbit’s injection system is designed to precisely and consistently deliver therapeutics to the subretinal space via a suprachoroidal route, avoiding the need for a vitrectomy and perforation of the retina, the company says. Read more.
SOURCE: BioTime, January 2019
PROQR RECEIVES FDA FAST TRACK DESIGNATION FOR QR-421A
ProQR Therapeutics received the FDA’s Fast Track designation for QR-421a, a first-in-class, investigational, RNA-based oligonucleotide designed to address the underlying cause of vision loss associated with Usher syndrome type 2 and non-syndromic retinitis pigmentosa due to mutations in exon 13 of the USH2A gene. Fast Track designation is granted by the FDA to drugs that are under development for serious conditions and have the potential to fulfill an unmet medical need. Read more.
SOURCE: ProQR Therapeutics, January 2019
CLEARSIDE SUBMITS NEW DRUG APPLICATION FOR XIPERE
Clearside Biomedical submitted a New Drug Application for Xipere to the FDA for the treatment of macular edema associated with uveitis. Macular edema is the leading cause of vision loss and blindness in uveitis patients and can occur from uveitis affecting any anatomic location—anterior, intermediate, posterior or pan. If approved, Xipere would be the first therapy for macular edema associated with uveitis. Read more.
SOURCE: Clearside Biomedical, December 2018
OcuSciences Says Flavoprotein Fluorescence Might Yield Helpful Information in DME Cases
OcuSciences, which is developing a device to monitor retinal flavoprotein fluorescence (FPF) called the OcuMet Beacon, says the machine may be able to help monitor diabetic macular edema patients undergoing anti-VEGF therapy. The company states that FPF can detect improvement in metabolic function that more directly correlates to vision improvement than improvements in macular thickness as measured by optical coherence tomography in DME patients. It adds that FPF may be able to detect metabolic improvements that precede structural improvements in DME patients benefiting from anti-VEGF injections. Read more.
SOURCE: OcuSciences, January 2019
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