Volume 10, Number 8
August 2014


WELCOME to Review of Ophthalmology's Retina Online e-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.

Supplemental Biologics License Application Submitted to FDA for Lucentis Indication in Diabetic Retinopathy
Genentech has submitted a supplemental Biologics License Application for Lucentis (ranibizumab injection) to the FDA for the treatment of diabetic retinopathy...

Phase II Clinical Data Supports Use of Squalamine Eye Drops (OHR-102) in RVO
Ohr Pharmaceutical Inc. has announced data supporting the use of squalamine eye drops (OHR-102) in the treatment of macular edema...

And More...

Initial Use of Aflibercept in Exudative AMD

Intravitreal aflibercept, a fusion protein with high affinity for vascular endothelial growth factor, offers an alternative treatment for exudative age-related macular degeneration. Preclinical studies and early- and late-phase clinical trials suggest that aflibercept's high-binding affinity may impart greater durability of activity and increased efficacy compared to ranibizumab or bevacizumab.

The authors of the following retrospective review included 266 eyes of 249 patients with exudative AMD who received aflibercept after treatment with bevacizumab and/or ranibizumab. They calculated mean central subfoveal thickness on spectral-domain optical coherence tomography and mean logarithm of the minimal angle of resolution visual acuity at one, three, six and 12 months after the first aflibercept injection. They also performed subgroup analyses in eyes receiving at least five bevacizumab and/or ranibizumab injections in the six months prior to aflibercept and in eyes receiving at least 10 injections in the 12 months prior to aflibercept.

Eyes received an average of 14.7 (range one to 43) ranibizumab and/or bevacizumab treatments prior to initiation of aflibercept therapy, the authors reported. They also noted that mean central subfoveal thickness decreased from 300 to 275 µm at one month (p<0.001) and was maintained at six months. Mean logMAR visual acuity improved from 0.60 (Snellen equivalent 20/80) to 0.54 (20/70, p=0.01) at one month and was stable at 0.55 at six months (Snellen equivalent 20/70, p=0.11, n=251). In 82 eyes receiving at least five injections in the six months prior to aflibercept treatment (average of 18.1 injections total), the central subfoveal thickness improved from 296 to 279 µm at one month (p<0.0001) and was maintained at six months (p<0.0001). Visual acuity did not change (0.48 [20/61] at one month compared to baseline, 0.49 [20/62], p=0.634, and at six months 0.51 [20/65], p=0.601). In 50 eyes receiving at least 10 injections in the 12 months prior to aflibercept treatment (average of 21.8 injections total), the mean central subfoveal thickness decreased by 17 µm at one month (p=0.0007) and was maintained at six months (p=0.013). Again, VA did not change (0.46 [20/56] at one month; baseline 0.44 [20/56], p=0.547; and 0.50 [20/63] at six months, p=0.2445).

Aflibercept is a valuable treatment alternative in patients previously treated with bevacizumab and/or ranibizumab injections. The authors of the study observed stability of VA and anatomic improvement on spectral-domain optical coherence tomography after initiation of aflibercept treatment in those preciously treated with ranibizumab and/or bevacizumab injections every four to six weeks.

Source: Cho H, Weber ML, Shah CP, Heier JS. Initial utilization of aflibercept in exudative age-related macular degeneration. Eur J Ophthalmol. 2014;24(4):576–581.

Anti-VEGF Treatment's Affect on Choroidal Thickness Over Time in Patients With Wet AMD

The study below evaluated change in subfoveal choroidal thickness as measured by spectral-domain optical coherence tomography in patients with wet age-related macular degeneration undergoing anti-vascular endothelial growth factor therapy.

Patients with a diagnosis of wet AMD were retrospectively reviewed to identify those who had at least 12 months of follow-up. The subfoveal choroidal thickness was manually measured from Bruch's membrane to the choroid-sclera junction at baseline and last follow-up. Only cases in which the choroid was fully visible were included in quantitative analyses. The SCT measurements were correlated with other characteristics including number and duration of treatments.

A total of 60 eyes of 47 patients with a follow-up of 23.8 months (SD 7.3) met study inclusion criteria, and 49 eyes of 40 patients received anti-VEGF treatment. Mean age was 83.7 years, and 52% were female. Treated eyes received a mean of 7.8 (SD 7.3) intravitreal anti-VEGF injections. The subfoveal choroidal thickness at baseline was 126.7 µm (SD 50.6) for untreated and 136.2 µm (SD 57.6) for treated eyes. The SCT showed a decrease over time in both groups, with a mean rate of reduction of 6.0 µm (p<0.0002) in treated eyes and 3.6 µm (p=0.3741) in untreated eyes. However, the change in subfoveal choroidal thickness did not differ between the groups (p=0.5113), and did not correlate with the number of re-treatments (p=0.552), visual acuity at baseline (p=0.618), or change in visual acuity over time (p=0.429).

Although choroidal thickness decreased over time in eyes with wet AMD, anti-VEGF therapy did not appear to accelerate or otherwise alter this decline.

Source: McDonnell EC, Heussen FM, Ruiz-Garcia H, et al. Effect of anti-VEGF treatment on choroidal thickness over time in patients with neovascular age-related macular degeneration. Eur J Ophthalmol. 2014; Jul 18. [Epub ahead of print]. DOI: 10.5301/ejo.5000509.

Short-Term IOP Trends Following Intravitreal Ranibizumab Injections for Wet AMD

In this open-label, parallel, randomized, controlled trial (EudraCT Number: 2010-023037-35), researchers aimed to determine the effect of oral acetazolamide on lowering the peak and duration of intraocular pressure rise in glaucoma and glaucoma suspect patients, following intravitreal injection of ranibizumab for wet age-related macular degeneration.

Twenty-four glaucoma or glaucoma suspect patients received either 500 mg acetazolamide or no treatment 60 to 90 minutes before 0.5 mg ranibizumab. The primary outcome measure was the difference in IOP immediately after injection (T0) and five, 10 and 30 min following injection. The researchers used analysis of covariance to compare groups, adjusting for baseline IOP, and the study was powered to detect a 9-mmHg difference at T0.

According to the researchers, the IOP at T0 was 2.3 mmHg higher in the non-treated group (mean 44.5 mmHg, range [19 mmHg to 86 mmHg]) compared with the treated group (mean 42.2 mmHg, range [25 mmHg to 58 mmHg]), but was not statistically significant after adjusting for baseline IOP (p=0.440). They observed that at 30 minutes, IOP was 4.9 mmHg higher in the non-treated group (mean 20.6 mmHg, range [11 mmHg to 46 mmHg]) compared with the treated group (mean 15.7 mmHg, range (8 mmHg to 21 mmHg]). This was statistically significant after adjusting for baseline IOP (p=0.013).

Although the primary endpoints were not reached, the study researchers concluded that 500 mg oral acetazolamide, 60 to 90 minutes before intravitreal injection, results in a statistically significant reduction in IOP at 30 minutes post injection. Prophylactic treatment may be considered as an option to minimize neuroretinal rim damage in high-risk glaucoma patients who are most vulnerable to IOP spikes and undergoing repeated intravitreal injections of ranibizumab.

Source: Murray CD, Wood D, Allgar V, et al. Short-term intraocular pressure trends following intravitreal ranibizumab injections for neovascular age-related macular degeneration—the role of oral acetazolamide in protecting glaucoma patients. Eye. 2014;Aug 1. [Epub ahead of print]. DOI: 10.1038/eye.2014.180.

Switching to Intravitreal Aflibercept Injection for Treatment of PCV Refractory to Ranibizumab

To clarify the efficacy of switching to intravitreal aflibercept injection to treat polypoidal choroidal vasculopathy refractory to ranibizumab, this retrospective study examined 43 eyes of 42 patients (mean age, 76.5 years) with PCV treated with aflibercept (2 mg/0.05 mL).

A treatment history of three consecutive monthly intravitreal injections of ranibizumab as an induction phase followed by a pro re nata maintenance phase over 12 months was seen for all patients. All patients were refractory to ranibizumab (defined as having persistent subretinal or intraretinal fluid by optical coherence tomography and unchanged or decreased visual acuity compared with the time of the first ranibizumab injection, despite receiving the last three consecutive monthly intravitreal ranibizumab injections after 12 months).

The mean logarithm of the minimum angle of resolution best-corrected visual acuity levels (Snellen equivalent) improved significantly (p=0.0074) from 0.38 (20/48) at baseline to 0.34 (20/43) three months after switching to aflibercept (Month Three) (mean BCVA improvement, 0.47 line). The central retinal thickness decreased significantly (p<0.0001) from 245 µm at baseline to 131 µm at Month Three. Of 30 eyes with polypoidal lesions at baseline, the polypoidal lesions regressed completely in 15 eyes (50%) at Month Three.

It was concluded that administering intravitreal aflibercept injection for patients with PCV refractory to ranibizumab maintained or improved visual acuity and reduced or eliminated exudative lesions and occluding polypoidal lesions without adverse events with short-term follow-up.

Source: Saito M, Kano M, Itagaki K, et al. Switching to intravitreal aflibercept injection for polypoidal choroidal vasculopathy refractory to ranibizumab. Retina. 2014;Jul 30. [Epub ahead of print]. DOI: 10.1097/IAE.0000000000000236.

Low-Luminance Visual Acuity and Microperimetry in AMD

Investigators in Australia sought to compare the effectiveness of low-luminance visual acuity and microperimetry as functional measures in early stages of age-related macular degeneration in this prospective, cross-sectional study.

Participants consisted of 179 subjects with a clinical spectrum of non-neovascular AMD and 26 control participants. The investigators measured best-corrected visual acuity, LLVA and microperimetric retinal sensitivity on one eye of all participants. They calculated low-luminance deficit as the difference between LLVA and BCVA. They also compared functional parameters between six clinical severity groups (from controls to non-foveal geographic atrophy), and determined and compared the relationships and magnitude of these parameters. Main outcome measures were visual acuity parameters (BCVA, LLVA and LLD) and central retinal sensitivity.

Best-corrected visual acuity, LLVA and central retinal sensitivity were reduced significantly for all AMD clinical severity groups when compared with control participants (p≤0.002), except for those with drusen between 63 and 125 µm (p≥0.107). However, LLD was not significantly different from control participants in all groups (p≥0.073), except in the non-foveal GA group (p=0.008). According to the investigators, a significant positive relationship between central retinal sensitivity and LLD (r=0.613; p<0.001), but not BCVA, suggests that there is a trend for LLVA to detect a greater extent of functional deficit than BCVA in eyes with increasingly poorer retinal sensitivity. However, the results of the linear regression models estimated central retinal sensitivity to be 6.1, 3.7 and 5.1 standard deviations less than normal by the time BCVA, LLVA and LLD, respectively, were two SDs less than normal.

To conclude, in early stages of AMD, LLVA did not detect a greater extent of functional deficit than BCVA when compared with control participants. Although there was a trend for LLVA to be more effective at detecting foveal deficits than BCVA in eyes with increasingly poorer retinal sensitivity, both visual acuity measures were much less sensitive compared with microperimetry.

Source: Wu Z, Ayton LN, Guymer RH, Luu CD. Low-luminance visual acuity and microperimetry in age-related macular degeneration. Ophthalmology. 2014;121(8):612–1619.

Link Between Vasodilators, Blood Pressure-Lowering Medications and AMD

Scientists examined the association of vasodilator and anti-hypertensive medication use with the incidence of age-related macular degeneration in this longitudinal population-based study that included persons aged 43 to 86 years living in Beaver Dam, Wisc., from 1988 through 1990.

They performed examinations every five years over a 20-year period. There were 9,676 total person-visits over the course of the study. Status of AMD was determined from grading retinal photographs and the incidence of AMD was the main outcome measure.

The scientists reported that the five-year incidence of early AMD over the 20-year period was 8.4%; for late AMD, it was 1.4%; for pure geographic atrophy, it was 0.6%; for exudative AMD, it was 0.9%; and for progression of AMD, it was 24.9%. While adjusting for age, gender and other factors, using a vasodilator (hazard ratio [HR], 1.72; 95% confidence interval [CI], 1.25 to 2.38), particularly oral nitroglycerin (HR, 1.81; 95% CI, 1.14 to 2.90), was associated with an increased risk of early AMD. Using an oral beta-blocker was associated with an increased hazard of incident exudative AMD (HR, 1.71; 95% CI, 1.04 to 2.82), but not pure GA (HR, 0.51; 95% CI, 0.20 to 1.29) or progression of AMD (HR, 0.92; 95% CI, 0.67 to 1.28) over the 20-year period.

To conclude, use of vasodilators is associated with a 72% increase in the hazard of incidence of early AMD, and use of oral beta-blockers is associated with a 71% increase in the hazard of incident exudative AMD. If these findings are replicated, it may have implications for care of older adults because vasodilators and oral beta-blockers are drugs that are used commonly by older persons.

Source: Klein R, Myers CE, Klein BE. Vasodilators, blood pressure-lowering medications, and age-related macular degeneration. Ophthalmology. 2014;121(8): 1604–1611.

Photoreceptor Layer Changes Overlying Drusen in Eyes With AMD Associated With VMT

To investigate by spectral-domain optical coherence tomography changes of photoreceptor layers over drusen in cases of dry age-related macular degeneration associated with vitreomacular traction, clinical examination, fluorescein angiography, fundus photography and SD-OCT data were retrospectively studied for a consecutive series of 27 patients with drusen, pseudodrusen and VMT. Control groups of 32 patients with VMT without drusen and 34 patients with drusen and pseudodrusen without VMT were also studied.

The examination revealed disruption of the line corresponding to the inner segment ellipsoid (ISel), previously called inner segment/outer segment junction, of photoreceptor layer, and development of cystoid edema in significantly higher incidence in VMT associated with drusen group. It was noted that 22 out of 32 eyes with VMT and drusen (68.75%) had disrupted ISel, compared to eight out of 37 (21.6%) control eyes with drusen only and to 12 out of 37 (32.4%) control eyes with VMT only. Chi-square analysis showed significant association between drusen and pseudodrusen on fovea, VMT and localization of ISel disruption. The changes of the ISel were mainly found in the area that corresponded to VMT. The SD-OCT revealed drusen throughout the macula and discontinuation of ISel only in the fovea in four of 32 (12.5%) eyes with VMT, whereas none of 37 control eyes with drusen only had similar appearance.

The drusen in association with the cystoid macular edema induced by vitreous traction contribute to the photoreceptor layer defect overlying drusen in the fovea. In addition, the number of drusen and pseudodrusen was increased in the area of the vitreous traction compared to the peripheral retina.

Source: Theodossiadis PG, Theodoropoulou S, Stamatiou P, et al. Photoreceptor layer changes overlying drusen in eyes with age-related macular degeneration associated with vitreomacular traction. Eur J Ophthalmol. 2014;24(4):582–592.

Pseudodrusen and Choroidal Thickness

The authors of the study below sought to determine the relationship between pseudodrusen as evidenced by the presence of subretinal drusenoid deposits and choroidal thickness using a multimodal imaging approach.

They analyzed two sets of data. The first set was composed of consecutive patients older than 60 years with either high myopia or pseudodrusen. The authors calculated correlations between the subfoveal choroidal thickness and the presence of pseudodrusen. They obtained the second set of data from previously published data examining 90 consecutive eyes with dry age-related macular degeneration so they could analyze the relationship between pseudodrusen and subfoveal choroidal thickness.

According to the study authors, there were 96 eyes of 53 patients in the first data set, 36 (67.9%) were female and 17 (32.1%) were male. There were 34 patients (61 eyes) in the high myopia group and 19 patients (35 eyes) in the primary pseudodrusen group. The authors noted that the mean age of the primary pseudodrusen group was 83.7 years and that of the high myopia group was 74.9 years—a difference that was significant (p<0.001). Of the 61 eyes in the high myopia group, they determined that only three (4.9%) had pseudodrusen and zero had conventional drusen. In the primary pseudodrusen group, all had pseudodrusen by definition, but 28 (80%) also had conventional drusen. Moreover, the mean subfoveal choroidal thickness was 181.7 µm (median, 147; interquartile range, 65 µm to 225 µm) in the primary pseudodrusen group and 59 µm (median, 36; interquartile range, 21 µm to 90 µm) in the myopic group. Generalized estimating equation analysis showed that eyes with pseudodrusen had thicker subfoveal choroidal thickness than eyes without, a result driven by the high myopia group. In the second set of data, while the absolute number of eyes with pseudodrusen had a choroidal thickness between 201 µm and 250 µm, the proportion with pseudodrusen was higher in eyes with thinner choroids, with a broad peak between 50 µm and 100 µm.

The authors concluded that their results are not consistent with a simple cause or consequence relationship between pseudodrusen and choroidal thinning, but rather with a third yet unknown factor impacting both the pseudodrusen appearance and the choroidal thinning in susceptible populations. The reasons for the relative lack of drusen and pseudodrusen formation in high myopes need to be ascertained.

Source: Mrejen S, Spaide RF. The relationship between pseudodrusen and choroidal thickness. Retina. 2014;34(8):1560–1566.

Change in Subfoveal Choroidal Thickness Following Intravitreal Ranibizumb for Idiopathic CNV

Researchers investigated changes in subfoveal choroidal thickness after intravitreal injections of ranibizumab for idiopathic subfoveal choroidal neovascularization in the following prospective, consecutive case series study.

They included 16 patients with unilateral idiopathic subfoveal CNV and treated all eyes with a single intravitreal injection of 0.5 mg ranibizumab, followed by as-needed dosing. They also measured subfoveal choroidal thickness using enhanced-depth imaging optical coherence tomography.

The mean total follow-up time was 4.9 ± 1.5 months, and the follow-up after the last intravitreal ranibizumab injection was 4.4 ± 1.3 months, the researchers reported. In the treated eyes, they found that the subfoveal choroidal thickness decreased significantly from 354 ± 84 µm at baseline to 328 ± 79 µm at one month later (p<0.001) and reincreased (p=0.02) to 342 ± 75 µm at the final visit (p=0.15 versus baseline value). Change in subfoveal choroidal thickness was marginally (p=0.11) associated with the change in retinal foveal thickness. In the contralateral unaffected eyes, the subfoveal choroidal thickness did not change significantly during follow-up (p=0.76).

In patients with unilateral idiopathic subfoveal CNV, the study researchers found that intravitreal ranibizumab therapy was associated with a thinning of an abnormally thick subfoveal choroid, marginally in association with a parallel decrease in retinal foveal thickness. It remained elusive whether the choroidal thinning was due to a direct pharmacological effect of ranibizumab or whether it was secondary due to the foveal retinal thinning. In view of the significant differences in subfoveal choroidal thickness between affected eyes and unaffected contralateral eyes at baseline and in view of the significant therapy-associated decrease in subfoveal choroidal thickness, the potential role of subfoveal choroidal thickness as an additional marker for the diagnosis and follow-up of idiopathic subfoveal CNV and other neovascular maculopathies may be examined in future studies.

Source: Cao XS, Peng XY, You QS, et al. Subfoveal choroidal thickness change after intravitreal ranibizumab for idiopathic choroidal neovascularization. Retina. 2014;34(8):1554–1559.

Retinal Sensitivity Assessed by Microperimetry and Corresponding Retinal Structure and Thickness in Resolved CSC

In Korea, investigators examined the relationship between retinal sensitivity assessed by microperimetry and retinal structural changes in patients with resolved central serous chorioretinopathy. They found that retinal sensitivity was dependent on the status of the ellipsoid portion of the inner segments (EPIS) in patients with resolved CSC and determined that the correlation between mean retinal sensitivity and mean central retinal thickness was compatible with the point-to-point correlation between retinal sensitivity and the corresponding retinal point thickness.

The investigators performed spectral domain optical coherence tomography examination and MP tests in patients with resolved CSC. They also performed point-to-point correlation between retinal sensitivity and corresponding retinal structural changes using Pearson's correlation analysis. In addition, in a 1-mm zone in the central fovea, a correlation was calculated between the mean retinal sensitivity and the mean CRT.

A total of 84 eyes were analyzed, the investigators reported. They noted that the total number of microperimetry test points was 1,092 (84 eyes x 13 points). The mean retinal sensitivity and RPT of all test points were 13.53 ± 3.84 dB and 208.6 ± 48.0 µm, respectively. The investigators also found that the retinal sensitivity and RPT were significantly decreased in the test points with loss of the EPIS (p<0.0001). Furthermore, within the 1-mm foveal center zone, they found a significant correlation between mean retinal sensitivity and mean CRT (r=0.432, p<0.0001) and between retinal sensitivity and the corresponding RPT (r=0.339, p<0.0001).

Retinal sensitivity was dependent on the status of the EPIS in patients with resolved CSC, the investigators concluded. The correlation between mean retinal sensitivity and mean CRT was compatible with the point-to-point correlation between retinal sensitivity and the corresponding RPT.

Source: Chung HW, Yung CM, Kim JT, et al. Retinal sensitivity assessed by microperimetry and corresponding retinal structure and thickness in resolved central serous chorioretinopathy. Eye. 2014;Aug 1. [Epub ahead of print]. DOI: 10.1038/eye.2014.185.

Relationship Between Epiretinal Proliferation and Lamellar Macular Holes

Researchers in this retrospective observational case review aimed to describe the prevalence and imaging characteristics of a distinct entity of epiretinal proliferation seen predominantly in association with lamellar macular holes, termed lamellar hole-associated epiretinal proliferation (LHEP).

They reviewed 2,030 eyes of 1,104 patients with diagnoses including lamellar macular holes, full-thickness macular hole and epiretinal membrane imaged with spectral domain optical coherence tomography from 2008 to 2013. The researchers identified LHEP, defined on SD-OCT imaging as an epiretinal material of homogenous medium reflectivity, and they qualitatively compared its features against conventional ERM using the SD-OCT data.

They found LHEP in 68 of 2,030 eyes (3.3%), of which 88.2% had lamellar macular holes and 11.8% had full-thickness macular hole. They found LHEP in 60 of 197 eyes (30.5%) with lamellar macular holes and eight of 99 eyes (8.0%) with full-thickness macular hole. They did not detect LHEP in 1,734 eyes with ERM, which had no inner retinal defects detectable on SD-OCT; however, LHEP appeared as a substantial material of homogenous medium reflectivity on the epiretinal surface that demonstrated contiguity with the middle retinal layers and conformed to the adjacent retinal anatomy. Of the eyes with LHEP and lamellar macular holes, 98% had splitting of the retina in the region of Henle's fiber layer in the area immediately around the partial thickness hole, whereas 88% had visible connecting tissue from the base of the lamellar hole to the proliferating epiretinal tissue. In contrast to ERM, LHEP did not induce tractional effects such as distortion or edema of the underlying normal retinal tissue. Morphologic stability was demonstrated in 97% of eyes containing LHEP in serial eye-tracked SD-OCT images for up to 63 months of retrospective follow-up.

According to the study researchers, SD-OCT imaging showed that a subset of patients with lamellar macular holes had an epiretinal proliferation with medium reflectivity and no evidence of contractile properties that was contiguous with layers of the mid-retina. This phenotype differs from conventionally described ERMs in appearance and induced changes of the underlying retina. Given these distinct anatomical relationships, the presence of LHEP could affect surgical outcomes.

Source: Pang CE, Spaide RF, Freund KB. Epiretinal proliferation seen in association with lamellar macular holes: a distinct clinical entity. Retina. 2014;34(8):1513–1523.

Impact of Exome Sequencing on the Phenotypic Spectrum for ABHD12 Mutations

The authors of this case series sought to identify the genetic causes underlying autosomal recessive retinitis pigmentosa (arRP) and to describe the associated phenotype. Participants consisted of 347 unrelated families affected by arRP and 33 unrelated families affected by retinitis pigmentosa plus noncongenital and progressive hearing loss, ataxia or both, respectively.

The study authors performed a whole exome sequencing (WES) analysis in two families segregating arRP. A mutational screening was performed in 378 additional unrelated families for the exon–intron boundaries of the ABHD12 gene. To establish a genotype–phenotype correlation, individuals who were homozygous or compound heterozygotes of mutations in ABHD12 underwent exhaustive clinical examinations by ophthalmologists, neurologists and otologists. DNA sequence variants, best-corrected visual acuity, visual field assessments, electroretinogram responses, magnetic resonance imaging and audiography were the main outcome measures.

After a WES analysis, the authors identified four new mutations: p.Arg107Glufs*8; p.Trp159*; p.Arg186Pro; and p.Thr202Ile in ABHD12 in two families (RP-1292 and W08-1833) previously diagnosed with nonsyndromic arRP, which co-segregated with the disease among the family members. They detected another homozygous mutation (p.His372Gln) in one affected individual (RP-1487) from a cohort of 378 unrelated arRP and syndromic RP patients. After exhaustive clinical examinations by neurologists and otologists, the four affected members of the RP-1292 had no polyneuropathy or ataxia, and the sensorineural hearing loss and cataract were attributed to age or the normal course of the RP, whereas the affected members of the families W08-1833 and RP-1487 showed clearly symptoms associated with polyneuropathy, hearing loss, cerebellar ataxia, RP and early-onset cataract (PHARC) syndrome.

In conclusion, null mutations in the ABHD12 gene lead to PHARC syndrome, a neurodegenerative disease including polyneuropathy, hearing loss, cerebellar ataxia, RP and early-onset cataract. This study allowed the authors to report five new mutations in ABHD12. This is the first time missense mutations have been described for this gene. Furthermore, these findings are expanding the spectrum of phenotypes associated with ABHD12 mutations ranging from PHARC syndrome to a nonsyndromic form of retinal degeneration.

Source: Nishiguchi KM, Avila-Fernandez A, van Huet RA, et al. Exome sequencing extends the phenotypic spectrum for ABHD12 mutations. Ophthalmology. 2014;121(8):1620–1627.

Retinal Blood Flow's Impact on OAG Patients With and Without Diabetes

To evaluate the impact of retinal blood flow on optic nerve head morphology in patients with open-angle glaucoma with and without diabetes mellitus, 66 patients with OAG (14 with DM, 52 without DM) were assessed at baseline and at three-year follow-up for retinal capillary blood flow using confocal scanning laser Doppler and ocular structure using Heidelberg retinal tomography and optical coherence tomography.

Change in retinal tissue with zero blood flow in the superior and inferior retina was found to have a strong correlation with ONH changes in diabetic patients (r≥0.90, p≤0.03); however, no relation was found in the nondiabetic cohort. There were also significant changes in inferior mean flow that strongly correlated with changes in cup area (r=0.97, p=0.0029), cup/disc area ratio (r=0.96, p=0.0070), linear cup/disc ratio (r=0.93, p=0.0172), rim area (r=−0.97, p=0.0036) and rim volume (r=–0.95, p=0.0084) in diabetic patients only, while changes in the superior mean flow were only significantly associated with cup area (r=–0.30, p=0.0498), cup volume (r=–0.36, p=0.0178) and rim volume (r=0.35, p=0.0193) in nondiabetic patients.

In this cohort of patients with OAG, changes in retinal capillary blood flow correlated more strongly with changes in ONH morphology in patients with DM than in those without DM. These data suggest that changes in retinal blood flow may play a larger role in glaucomatous ONH progression in patients with OAG with DM.

Source: Lee E, Harris A, Siesky B, et al. The influence of retinal blood flow on open-angle glaucoma patients with and without diabetes. Eur J Ophthalmol. 2014;24(4):542–549.


Supplemental Biologics License Application Submitted to FDA for Lucentis Indication in Diabetic Retinopathy

Genentech has submitted a supplemental Biologics License Application for Lucentis (ranibizumab injection) to the FDA for the treatment of diabetic retinopathy. According to a press release, the submission is based on results of the RISE and RIDE Phase III clinical trials demonstrating the safety and efficacy of Lucentis for the disease. During these trials, a clinically significant proportion of DR patients treated with Lucentis showed meaningful improvements in their disease at two years compared to patients treated with sham injections (control group). The benefits of Lucentis on the signs of DR were maintained during the third year of treatment.

Source: Genentech, August 2014.

Phase II Clinical Data Supports Use of Squalamine Eye Drops (OHR-102) in RVO

Ohr Pharmaceutical Inc. has announced data supporting the use of squalamine eye drops (OHR-102) in the treatment of macular edema secondary to branch retinal vein occlusion or central retinal vein occlusion. Ohr says the data demonstrated that the combination of topical squalamine eye drops and intravitreal Lucentis led to a mean gain in visual acuity of 20.3 letters and resolution of the foveal edema in 95% of the patients at week 10. The investigator-sponsored study is a single-site, prospective clinical trial in which 20 treatment-naïve patients with macular edema due to RVO (nine with non-ischemic CRVO, eight with BRVO and three with hemi-central RVO) received OHR-102 for the first 10 weeks of treatment, with two injections of Lucentis given at week two and week six.

Source: Ohr Pharmaceutical Inc., August 2014.

Two New Vitrectomy Technologies Now Offered by Alcon

Alcon recently unveiled two vitrectomy technologies designed to help surgeons deliver a higher level of precision and efficiency during retina surgery. The Ultravit High Speed Vitrectomy Probe operates at an ultrahigh-speed of 7,500 cpm, which helps reduce traction that can cause iatrogenic tears and postoperative complications. The probe also features a dual-pneumatic drive that helps enable efficient flow and precise sharing, even at higher cut rates. Alcon also introduced a new portfolio of 27+ series instruments and accessories that are designed to allow surgeons to reduce incision size as well as provide access to small tissue planes with a stiffness experience similar to 25+ instrumentation. Both technologies are available in the United States. Read more here.

Source: Alcon, August 2014.

Eylea Now Approved by FDA and European Commission for Treatment of DME

In two recent press releases, Regeneron Pharmaceuticals Inc. announced that both the FDA and the European Commission have approved EYLEA (aflibercept) Injection for the treatment of diabetic macular edema. The recommended dosage of EYLEA in patients with DME is 2 mg every two months following five initial monthly injections.

Source: Regeneron Pharmaceuticals Inc., 2014.

Phase II Clinical Trial Initiated to Evaluate LE-MPP in RVO, DME and MGD

Kala Pharmaceuticals Inc. has initiated a Phase II clinical trial (KPI-121-C-004) to evaluate its loteprednol etabonate Mucus Penetrating Particle (LE-MPP) drug product, KP-121, in patients with intraretinal or subretinal fluid secondary to retinal vein occlusion or diabetic macular edema. The single-masked, randomized trial will investigate the efficacy and safety of 1% LE-MPP and 0.25% LE-MPP dosed q.i.d. in patients having measurable intraretinal or subretinal fluid secondary to RVO or DME. Kala aims to enroll up to 20 patients at two U.S. centers. The company has also initiated a Phase II clinical trial (KPI-121-C-003) of LE-MPP, in which it will study the safety and efficacy of 0.25% LE-MPP compared to vehicle dosed q.i.d. in subjects with meibomian gland disease. Kala aims to enroll roughly 150 patients in up to 10 U.S. centers in this double-masked, randomized trial. Find out more by visiting www.kalarx.com.

Source: Kala Pharmaceuticals Inc., July 2014.

Zebrafish May Hold Key to Retinal Regeneration in Humans

Ann Morris, a biologist at the University of Kentucky, is studying retinal regeneration in zebrafish to find ways to combat human eye diseases. The small, tropical freshwater fish belong to the minnow family and have eyes that develop similar to human eyes; however, they also have the ability to regenerate retinal cells following an injury. She will study the process of the development of eyes under a light microscope in a dish in to determine whether mammals once had the ability to regenerate neurons and lost that ability as they evolved (in which case perhaps there is a way to reactive it), or that certain vertebrates evolved that ability and others didn't. The ultimate goal is to open a pathway to therapeutic approaches of treating retinal degenerative diseases in humans. Learn more here.

Source: University of Kentucky, July 2014.

Ophthotech Initiates Expansion Studies to Further Evaluate Fovista Therapy in Wet AMD Patients

Ophthotech Corp. has initiated the first of several planned expansion trials, in addition to the ongoing Fovista combination therapy Phase III clinical program. Ophthotech says these trials will investigate the potential role of Fovista combination therapy in reducing subretinal fibrosis, addressing suboptimal treatment response and reducing treatment burden in wet age-related macular degeneration patients receiving anti-vascular endothelial growth factor monotherapy. The first expansion trial is a Phase IIa open-label study investigating the potential role of anti-platelet derived growth factor therapy in combination with anti-VEGF therapy in reducing subretinal fibrosis in wet AMD patients. For further information, click here.

Source: Ophthotech Corp., August 2014.

NIH Awards Oraya Therapeutics With Small Business Technology Transfer Grant for Gold Nanoparticles Development

In a recent press release, Oraya Therapeutics Inc. reported that it has been awarded a $215,500 Small Business Technology Transfer Grant from the National Institutes of Health to investigate how Oraya Therapy, a low-voltage stereotactic radiotherapy, and gold nanoparticles can further enhance the treatment of wet age-related macular degeneration. Under the grant, scientists at Oraya will collaborate with scientists at Dana-Farber Cancer Institute to develop a novel approach to treating wet AMD that utilizes the intravenous delivery of gold nanoparticles to target neovascular endothelial cells, the key therapeutic target associated with wet AMD.

Source: Oraya Therapeutics Inc., August 2014.

Iluvien Receives Marketing Authorization in Norway and Denmark for the Treatment of Chronic DME

Alimera Sciences Inc. announced this past week that the Norwegian Medicines Evaluation Board and the Danish Health and Medicines Authority have granted marketing authorization to Iluvien for the treatment of vision impairment associated with chronic diabetic macular edema considered insufficiently responsive to available therapies. Norway is the first country (and Denmark the second) to grant national marketing authorization following the positive outcome in June of the Repeat-Use Procedure application. The sustained-release intravitreal implant is now also approved for marketing in Austria, France, Germany, Italy, Portugal, Spain and the United Kingdom, and is commercially available in the United Kingdom and Germany.

Source: Alimera Sciences Inc., July 2014.


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