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STOP-Uveitis Study: Evaluating Tocilizumab in Non-Infectious Uveitis

STOP-Uveitis, a randomized, controlled, multicenter clinical trial, analyzed the safety and efficacy of two different doses of intravenous infusions of tocilizumab (TCZ), an IL-6 inhibitor, in eyes with non-infectious intermediate, posterior or pan-uveitis.

STOP-Uveitis was conducted at five clinical centers across the United States. Thirty-seven individuals with non-infectious uveitis (NIU) were randomized into one of two treatment groups in a ratio of 1:1. Group one received IV infusions of 4 mg/kg TCZ, and group two received IV infusions of 8 mg/kg TCZ. Infusions were given every four weeks in both groups until month six (primary endpoint). The primary outcome measure was incidence and severity of systemic and ocular adverse events through month six. Secondary outcome measures included mean change in visual acuity (VA), vitreous haze (VH) and central macular thickness (CMT) at month six.

At month six, 43.5 percent of individuals who had the potential for a two-step decrease in VH demonstrated a two-step decrease (40 percent in group one and 46.1 percent in group two). Mean change in CMT was -83.88 ±136.1 μm at month six (-131.5 ±41.56 μm in group one and -38.92 ±13.7 μm in group two). Mean change in VA was +8.22 ±11.83 ETDRS letters at month six (10.9 ±14.6 in group one and 5.5 ±7.8 in group two). Repeated infusions of TCZ were well tolerated.

Repeated IV administrations of TCZ were well tolerated, the researchers concluded, and TCZ (both four and eight mg/kg) was effective in improving VA and reducing VH and CMT in eyes with non-infectious intermediate, posterior and pan-uveitis.

SOURCE: Sepah YJ, Sadiq MA, Chu DS, et al. Primary (month-six) outcomes of the STOP-uveitis study: Evaluating the safety, tolerability, and efficacy of tocilizumab in patients with non-infectious uveitis. Am J Ophthalmol 2017; Sep 5. [Epub ahed of print].

Sustained Benefits from Ranibizumab for CRVO with Macular Edema: CRYSTAL Study

Researchers evaluated the efficacy and safety profile of an individualized, stabilization criteria-driven regimen of ranibizumab 0.5 mg in individuals with visual impairment due to macular edema secondary to central retinal vein occlusion. The 24-month, prospective, open-label, single-arm, multicenter study included a total of 357 individuals.

Participants received monthly ranibizumab 0.5 mg injections (minimum, three injections) until stable visual acuity was maintained for three consecutive months. Individuals with lower baseline BCVA had larger mean BCVA gains at month 24 (≤39 letters at baseline; mean gain: 18.5 letters) than those with higher baseline BCVA (40 to 59/≥60 letters at baseline; mean gain: 13.9/7.2 letters), although the absolute BCVA values at month 24 were higher in individuals with higher baseline BCVA.

The main secondary outcome measures included mean change from baseline at months one through 24 in best-corrected VA in the overall population and in subgroups categorized according to baseline BCVA, CRVO duration or presence of macular ischemia.

The baseline mean BCVA was 53 letters, and baseline mean CRVO duration was 8.9 months (median, 2.4 months). The mean gain in BCVA from baseline with ranibizumab 0.5 mg at month 24 was 12.1 ±18.60 letters (p<0.0001). BCVA gains at month 24 were similar in individuals with or without baseline macular ischemia (mean change, 11.1 and 12.9 letters, respectively). The mean BCVA gain at month 24 was higher in people with CRVO duration less than three months (13.2 letters) compared with that in those with CRVO duration greater than nine months (10.5 letters). Individuals with lower baseline BCVA had larger mean BCVA gains at month 24 (≤39 letters at baseline [mean]; mean gain: 18.5 letters [SD]) than those with higher baseline BCVA (40 to 59/≥60 letters at baseline; mean gain: 13.9/7.2 letters), although the absolute BCVA values at month 24 were higher in individuals with higher baseline BCVA. The mean and median number of ranibizumab injections up to month 23 were 13.1 ±6.39 and 15 injections, respectively. No new ocular or nonocular safety events were reported.

An individualized, criteria-driven dosing regimen of ranibizumab 0.5 mg led to sustained BCVA gains for up to 24 months in individuals with CRVO. The presence of macular ischemia at baseline didn’t influence VA gains. Researchers determined that shorter duration of CRVO at baseline was associated with better VA gains. Safety findings were consistent with those reported in previous ranibizumab studies in individuals with CRVO.

SOURCE: Larsen M, Waldstein SM, Priglinger S, et al. Sustained benefits from ranibizumab for central retinal vein occlusion with macular edema: 24-month results of the CRYSTAL study. Ophthalmology Retina 2017; Sept. 9. [Epub ahead of print].

Using OCTA to Assess Retinal Microvasculature & VA After IAI in CRVO

Investigators looked at vascular perfusion and the foveal avascular zone area in the superficial and deep capillary plexuses after intravitreal aflibercept therapy in central retinal vein occlusion eyes and the association with best-corrected visual acuity.

Thirty-five subjects with CRVO and macular edema were evaluated. After ME resolution following intravitreal aflibercept, subjects underwent optical coherence tomography angiography to measure SCP and DCP perfusion and the FAZ within a 3- x 3-mm area. Investigators examined correlations between BCVA and OCTA measurements.

After intravitreal aflibercept therapy, the mean retinal vascular area was 3.41 ±0.74 mm² in the SCP and 3.25 ±0.91 mm² in the DCP. FAZ area was 1.03 ±1.04 mm² in the SCP and 1.78 ±1.73 mm² in the DCP. Improved BCVA was significantly associated with better SCP and DCP perfusion (both p<0.001) and with smaller SCP and DCP FAZ areas (both p<0.001). Additionally, SCP and DCP perfusion were negatively correlated with ME before treatment (p<0.05) and ischemia (determined via pretreatment fluorescein angiography, p<0.05), and positively correlated with photoreceptor integrity (p<0.001).

Investigators determined that individuals with better retinal perfusion and less retinal ischemia were associated with better visual outcomes after aflibercept in eyes with CRVO.

Source: Winegarner A, Wakabayashi T, Hara-Ueno C, et al. Retinal microvasculature and visual acuity after intravitreal aflibercept in eyes with central retinal vein occlusion: an optical coherence tomography angiography study. Retina 2017; Sep 7. [Epub ahead of print].

Endovascular Surgery Using Tissue Plasminogen Activator Injection for CRVO

Investigators examined the effects of retinal endovascular surgery with tissue plasminogen activator injections into the retinal vein in central retinal vein occlusion eyes. Sixteen consecutive individuals with CRVO with macular edema and decreased visual acuity who were referred to Japan’s Toyama University Hospital between March 2014 and February 2016 were included in the study.

Investigators evaluated changes in visual acuity and central retinal thickness up to six months after REVS. They graded staining and leakage of the retinal veins in fluorescein angiography in nine individuals.

Ten of 16 eyes were determined to be non-ischemic, while the remaining six were ischemic. The mean logarithm of the minimum angle of resolution of VA was significantly improved from 0.98 ±0.58 (mean ±standard deviation) at baseline to 0.78 ±0.61 at three months (p=0.002), and 0.64 ±0.60 at six months (p=0.003) after REVS. At six months, VA improved in eight eyes (50 percent), while the other eight (50 percent) showed no change and none showed worsening. In the 10 eyes with non-ischemic CRVO, the mean VA was significantly improved at six months (p=0.002) whereas no improvement was found in the six eyes with ischemic CRVO. In all eyes, the mean CRT significantly improved from 804 ±343 μm at baseline to 506 ±304 μm at two months (p=0.014), 332 ±229 μm at three months (p=0.0001) and 305 ±235 μm at six months (p=0.00001). Postoperative complications included: prolonged vitreous hemorrhage in one eye and neovascular glaucoma in two eyes. Five eyes received sub-Tenon’s injection of triamcinolone acetonide, and five eyes received intravitreal injection of an anti-VEGF agent for postoperative recurrence of macular edema. Six eyes with ischemic CRVO received panretinal photocoagulation. The FA score was significantly improved after REVS (p=0.018).

Investigators concluded that REVS using a specially made micro-needle might be a surgical treatment option for non-ischemic CRVO, although they added that didn‘t appear to be effective for ischemic CRVO.

SOURCE: Ishida M, Abe S, Nakagawa T, et al. Short-term results of endovascular surgery with tissue plasminogen activator injection for central retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol 2017; Aug 12. [Epub ahead of print].

Retinal Layer Thickness & Diabetic Peripheral Neuropathy Associations

Researchers determined clinical correlations between the thicknesses of individual retinal layers in the foveal area of diabetics and the presence of diabetic peripheral neuropathy, as part of a retrospective, observational, cross-sectional study.

A total of 120 eyes from 120 individuals were enrolled. The eyes were divided into three groups: normal controls (n=42 eyes); individuals with diabetes mellitus (n=42 eyes) but no DPN; and people with DM and DPN (n=36 eyes). The primary outcome measures were the thickness of all retinal layers in the central 1-mm zone measured using the segmentation analysis of spectral-domain optical coherence tomography. Correlations between the thicknesses of the individual retinal layers and the presence of DPN were also analyzed. Logistic regression analyses helped to determine which change in layer thickness had the most significant association with the presence of DPN.

The mean thicknesses and ratios of retinal nerve fiber layers to total retina thicknesses in the DPN group were 10.77 ±1.79 µm and 4.10 ±0.55 percent, which was significantly lower than those in normal controls and the DM with no DPN group (p=0.014 and p=0.001, respectively). Logistic regression analyses also showed that the decrease in thicknesses of the RNFLs and the inner nuclear layer were significant factors for predicting a higher risk for DPN development (OR=7.407 and 1.757; p<0.001 and p=0.001, respectively).

Researchers concluded that a decrease in the RNFL and the inner nuclear layer thickness was significantly associated with the presence of DPN.

Source: Kim JH, Lee MW, Byeon SH, et al. Associations between individual retinal layer thicknesses and diabetic peripheral neuropathy using retinal layer segmentation analysis. Retina 2017; Sep 7. [Epub ahead of print].

Treat-and-Extend Vs. Monthly Regimen in Neovascular AMD

Researchers evaluated the efficacy and safety of ranibizumab 0.5 mg treat-and-extend versus monthly regimens in individuals with neovascular age-related macular degeneration from the TReat and extEND (TREND) study.

The 12-month Phase IIIb visual acuity assessor-masked, multicenter, randomized interventional study involving 650 individuals included those with treatment-naïve nAMD (age ≥50 years), randomized 1:1 to receive either a ranibizumab 0.5 mg T&E (n=323) or monthly (n=327) regimen. The primary objective was to show non-inferiority of ranibizumab 0.5 mg T&E versus monthly regimen, as assessed by the change in best-corrected VA from baseline to the end of the study. Secondary objectives included change in retinal central subfield thickness (CSFT) from baseline to the end of study, treatment exposure and safety.

Overall, 89.8 percent (T&E) and 90.2 percent (monthly) of individuals completed the study. Participant demographic and baseline characteristics were well balanced between the two treatment groups. The T&E regimen was noninferior (p<0.001) to the monthly regimen, with a least squares mean BCVA change from baseline of 6.2 versus 8.1 letters to the end of study, respectively. In both treatment groups, most BCVA improvements occurred during the first six months and were maintained until the end of the study. The mean change in CSFT from baseline to the end of study was -169.2 μm and -173.3 μm in the T&E and monthly groups, respectively. Fewer injections were required in those receiving the T&E (8.7) versus monthly (11.1) regimen, with mean number of post-baseline visits of 8.9 and 11.2, respectively. Types and rates of adverse events were comparable between the treatment groups.

Researchers concluded ranibizumab 0.5 mg administered according to a T&E regimen was statistically non-inferior and clinically comparable with a monthly regimen in improving VA from baseline to the end of study. No new safety signals for ranibizumab were identified.

SOURCE: Silva R, Berta A, Larsen M, et al. Treat-and-extend versus monthly regimen in neovascular age-related macular degeneration. Ophthalmology 2017; Sept. 8 [Epub ahead of print].

OCT Predictors of Progression to Non-neovascular Atrophic AMD

Researchers wrote that the appearance of geographic atrophy on color photography is preceded by specific features on spectral-domain optical coherence tomography. They aimed to build SD-OCT-based risk assessment models for five-year new onset of GA and central GA on color photos (CP), as part of a prospective, longitudinal study.

Age-Related Eye Disease Study 2 Ancillary SD-OCT study participants with age-related macular degeneration with bilateral, large drusen or noncentral GA and at least one eye without advanced disease (n=317) participated in the study.

Researchers derived qualitative and quantitative SD-OCT variables from standardized grading and semi-automated segmentation at baseline. They extracted annual outcomes and analyzed them to fit multivariate logistic regression models, and built a risk calculator up to seven years later. The main outcome measures included the new onset of CP-visible GA and central GA.

Over four-year median follow-up and among 292 AMD eyes (without advanced disease at baseline), 46 (15.8 percent) developed central GA. Among 265 eyes without any GA on baseline CP, 70 (26.4 percent) developed CP-visible GA. Final multivariate models were adjusted for age. In the GA model, the independent predicting SD-OCT factors (p<0.001 to 0.03) were: hyperreflective foci and retinal pigment epithelium layer atrophy or absence; followed by choroid thickness in absence of subretinal drusenoid deposits; photoreceptor outer segment loss; RPE drusen complex volume; and abnormal thinning volume. For central GA, the factors (p<0.001) were RPE drusen complex abnormal thinning volume, intraretinal fluid or cystoid spaces, hyperreflective foci and RPE layer atrophy or absence. The models yielded a calculator that computed the probabilities of CP-visible, new-onset GA and central GA after one to five years.

Researchers suggested that, for AMD eyes with large drusen and no advanced disease, the novel risk-assessment model might simplify SD-OCT grading and could have a promising role as a clinical prognostic tool, with future validation.

Source: Sleiman K, Veerappan M, Winter KP, et al. Optical coherence tomography predictors of risk for progression to non-neovascular atrophic age-related macular degeneration. Ophthalmology 2017; Aug 25. [Epub ahead of print].

Choroidal Thinning Associated With Hydroxychloroquine Retinopathy

Investigators assessed choroidal thickness in individuals using hydroxychloroquine, and compared choroidal thickness between eyes with and without HCQ retinopathy, as part of a retrospective case series.

They included 124 individuals with systemic lupus erythematosus or rheumatoid arthritis who were treated with HCQ. Participants were divided into an HCQ retinopathy group and a control group.

Two independent investigators manually measured total choroidal thickness and choriocapillaris-equivalent thickness using swept-source optical coherence tomography (DRI-OCT, Topcon) at the fovea, and at nasal and temporal locations 0.5 mm, 1.5 mm and 3 mm from the fovea. They calculated medium-to-large vessel layer thicknesses, compared the HCQ retinopathy group and controls, and performed correlation analyses for choroidal thicknesses and data points regarding HCQ use. Main outcome measures included total choroidal thickness and choriocapillaris-equivalent thickness

Choroidal thicknesses were significantly decreased (p<0.05) in the HCQ retinopathy group compared with controls except at the temporal choroid 1.5 mm from the fovea. Choriocapillaris-equivalent thicknesses were significantly different in all choroidal locations between the groups. In contrast, medium-to-large vessel layer thickness was only significantly different at a few locations. The cumulative dose/body weight was significantly correlated with subfoveal choroidal and choriocapillaris-equivalent thicknesses (both p=0.001). The association of HCQ retinopathy presence and choroidal thicknesses was also statistically significant after adjusting for age, diagnosis for HCQ use, refractive errors and duration of HCQ use (p=0.001 and 0.003 for subfoveal choroidal and choriocapillaris-equivalent thickness, respectively).

Investigators wrote that the results suggested that HCQ retinopathy was associated with choroidal thinning, especially in the choriocapillaris. As well, they added, the findings might suggest choroidal involvement of HCQ toxicity.

Source: Ahn SJ, Ryu SJ, Joung JY, et al. Choroidal thinning associated with hydroxychloroquine retinopathy. Am J Ophthalmol 2017; Sep 7. [Epub ahead of print].

Infusion Misdirection in Microincisional Vitrectomy Surgery

Scientists reviewed the incidence and mechanisms of two problems caused by infusion misdirection during microincisional vitrectomy in one physician’s practice, and determined the broader occurrence among other physicians, as part of an observational series of one surgeon’s cases over two study periods. They included findings from a survey sent to other retinal specialists.

Participants included individuals undergoing microincisional vitrectomy. The physician tracked the occurrence of intraoperative hypotony and unintentional anterior chamber air infusion in his practice. In addition, 2,000 members of the American Society of Retina Specialists and the Retina Society completed a survey.

Main outcome measures included the primary outcome measure of incidence of hypotony during microincisional vitrectomy, defined as softening of the globe to the point of corneal or scleral infolding or both, which resolved with repositioning of the infusion cannula. The secondary outcome measure was incidence of unplanned air flow into the anterior chamber. Survey questions included frequency of observed infusion interruption and incidence of inadvertent anterior chamber air infusion.

In an earlier series, of 232 vitrectomies, 37 (16 percent) showed signs of episodic hypotony after infusion blockage. Seven cases (3 percent) showed inadvertent air flow into the anterior chamber. A total of 152 physicians responded to the survey; 57 percent reported infusion blockage and hypotony in 1 percent to 5 percent of cases. Fifty-nine percent reported air flow into the anterior chamber in some cases. In the later series, 12 instances of infusion blockage were noted in 118 cases. Awareness of the issue and additional attention to the infusion line taping didn’t prevent the problem from occurring. In the survey, most respondents reported observing infusion interruption and inadvertent anterior chamber air infusion on occasion.

Scientists found that infusion misdirection resulting in hypotony or air flow into the anterior chamber appeared to be infrequent but remained a risk. Awareness of the problem reduced the incidence but didn’t eliminate it. As well, scientists found that the potential to inadvertently touch the retina, choroid or lens increased when such events occurred. They suggested that infusion misdirection could be avoided by maintaining the correct position of the cannula, which might be facilitated by an external support to the tubing.

SOURCE: Ryan EH, Halperin LS, Mittra RA, et al. Infusion misdirection in microincisional vitrectomy surgery. Ophthalmology Retina 2017; Sept. 1. [Epub ahead of print].

Microstructural Changes of the Retina in Infants With Congenital Zika Syndrome

Researchers sought a better pathophysiologic understanding of the neurodevelopmental abnormalities observed in neonates exposed in utero to the Zika virus (ZIKV) in order to develop new treatments. They also sought to quantify the microstructural changes of the retina in CZS and compare these changes with those of cobalamin C (cblC) deficiency, a disease involving potential retinal maldevelopment.

This case series included eight infants with CZS and eight infants with cblC deficiency. All participants underwent ophthalmologic evaluation at two university teaching hospitals and SD-OCT imaging in at least one eye. Those with cblC deficiency were homozygous or compound heterozygotes for mutations in the methylmalonic aciduria and homocystinuria type C (MMACHC) gene. Data was collected from January 1 to March 17, 2016, for individuals with CZS and from May 4, 2015, to April 23, 2016, for infants with cblC deficiency. The SD-OCT cross-sections were segmented using automatic segmentation algorithms embedded in the SD-OCT systems. Each retinal layer thickness was measured at critical eccentricities using the position of the signal peaks and troughs on longitudinal reflectivity profiles.

Eight infants with CZS (five girls and three boys ranging in age from 3 to 5 months) and eight with cblC deficiency (three girls and five boys, ranging in age from 4 months to 15 years) were included in the analysis. All eight infants with CZS had foveal abnormalities in the analyzed eyes (eight eyes), including discontinuities of the ellipsoid zone, thinning of the central retina with increased backscatter, and severe structural disorganization, with three eyes showing macular pseudocolobomas. Pericentral retina with normal lamination showed a thinned (<30 percent of normal thickness) ganglion cell layer that colocalized in seven of eight eyes with a normal photoreceptor layer. The inner nuclear layer was normal or had borderline thinning. The central retinal degeneration was similar to that of cblC deficiency.

Congenital Zika syndrome showed a central retinal degeneration with severe GCL loss, borderline inner nuclear layer thinning, and less prominent photoreceptor loss. The findings provide the first, to date, in vivo evidence in humans for possible retinal maldevelopment with a predilection for retinal GCL loss in CZS, consistent with a murine model of the disease and suggestive of in utero depletion of this neuronal population as a consequence of Zika virus infection, researchers concluded.

SOURCE: Aleman TS, Ventura CV, Cavalcanti MM, et al. Quantitative assessment of microstructural changes of the retina in infants with congenital Zika syndrome. JAMA Ophthalmol 2017; Sep 7. [Epub ahead of print].