Aniz Girach

Enzymatic Vitreolysis with Ocriplasmin for Vitreomacular Traction and Macular Holes

BACKGROUND Vitreomacular adhesion can lead to pathologic traction and macular hole. The standard treatment for severe, symptomatic vitreomacular adhesion is vitrectomy. Ocriplasmin is a recombinant protease with activity against fibronectin and laminin, components of the vitreoretinal interface. METHODS We conducted two multicenter, randomized, double-blind, phase 3 clinical trials to compare a single intravitreal injection of ocriplasmin (125 μg) with a placebo injection in patients with symptomatic vitreomacular adhesion. The primary end point was resolution of vitreomacular adhesion at day 28. Secondary end points were total posterior vitreous detachment and nonsurgical closure of a macular hole at 28 days, avoidance of vitrectomy, and change in best-corrected visual acuity. RESULTS Overall, 652 eyes were treated: 464 with ocriplasmin and 188 with placebo. Vitreomacular adhesion resolved in 26.5% of ocriplasmin-injected eyes and in 10.1% of placebo-injected eyes (P<0.001). Total posterior vitreous detachment was more prevalent among the eyes treated with ocriplasmin than among those injected with placebo (13.4% vs. 3.7%, P<0.001). Nonsurgical closure of macular holes was achieved in 40.6% of ocriplasmin-injected eyes, as compared with 10.6% of placebo-injected eyes (P<0.001). The best-corrected visual acuity was more likely to improve by a gain of at least three lines on the eye chart with ocriplasmin than with placebo. Ocular adverse events (e.g., vitreous floaters, photopsia, or injection-related eye pain--all self-reported--or conjunctival hemorrhage) occurred in 68.4% of ocriplasmin-injected eyes and in 53.5% of placebo-injected eyes (P<0.001), and the incidence of serious ocular adverse events was similar in the two groups (P=0.26). CONCLUSIONS Intravitreal injection of the vitreolytic agent ocriplasmin resolved vitreomacular traction and closed macular holes in significantly more patients than did injection of placebo and was associated with a higher incidence of ocular adverse events, which were mainly transient. (Funded by ThromboGenics; ClinicalTrials.gov numbers, NCT00781859 and NCT00798317.).

Visual Side Effects Of Successful Scatter Laser Photocoagulation Surgery For Proliferative Diabetic Retinopathy: A Literature Review

Purpose: To review the literature on limitations and adverse effects associated with scatter or panretinal laser photocoagulation (PRP) for diabetic retinopathy (DR). Design: Literature review. Results: Scatter laser photocoagulation is associated with moderate visual loss, some diminished visual field, reduced color vision, and reduced contrast sensitivity. Conclusions: Scatter laser photocoagulation has been shown to reduce the risk of severe visual loss from proliferative DR. However, scatter treatment is associated with some decline in visual function. These effects should be studied more extensively and should be considered when comparing pharmacologic treatments for proliferative DR.

Efficacy of Intravitreal Ocriplasmin for Treatment of Vitreomacular Adhesion: Subgroup Analyses from Two Randomized Trials

PURPOSE To evaluate the efficacy of a single intravitreal injection of ocriplasmin 125 μg across relevant subpopulations of patients with symptomatic vitreomacular adhesion (VMA)/vitreomacular traction (VMT), including when associated with macular hole. DESIGN Two multicenter, randomized, placebo-controlled, double-masked, 6-month studies. PARTICIPANTS A total of 652 randomized patients (464 receiving ocriplasmin; 188 receiving placebo). METHODS A single intravitreal injection of ocriplasmin 125 μg or placebo in the study eye. MAIN OUTCOME MEASURES Prespecified subgroup analyses were conducted to evaluate the effects on the proportion of patients with nonsurgical resolution of focal VMA at day 28, nonsurgical full-thickness macular hole (FTMH) closure at month 6, and categoric improvement in best-corrected visual acuity (BCVA) at month 6. RESULTS Resolution of VMA at day 28 was achieved more often in younger patients (<65 years), eyes without epiretinal membrane, eyes with FTMH, phakic eyes, and eyes with a focal VMA ≤ 1500 μm. Eyes with FTMH width ≤ 250 μm were more likely to achieve nonsurgical FTMH closure. Categoric ≥ 2-line and ≥ 3-line improvement in BCVA occurred more often in younger patients (<65 years) and in patients with a lower baseline BCVA (<65 letters). Treatment differences in favor of ocriplasmin were generally observed across each subgroup of subpopulations studied. CONCLUSIONS Subgroup analyses confirmed the positive effect of ocriplasmin across relevant subpopulations.

Effect of Ruboxistaurin on the Visual Acuity Decline Associated with Long-standing Diabetic Macular Edema

PURPOSE To compare relationships between severity and duration of diabetic macular edema (DME) and visual acuity (VA) observed in the PKC-DRS2 with those from the Early Treatment Diabetic Retinopathy Study (ETDRS) and to assess the effect of the orally administered PKC beta inhibitor ruboxistaurin (RBX) on these parameters. METHODS In the PKC-DRS2, patients with moderately severe to very severe nonproliferative diabetic retinopathy (n = 685) were randomly assigned to 32 mg/d RBX or placebo and followed up for 36 months with ETDRS VA measurements and fundus photographs (FP) every 3 to 6 months. Mean VA was calculated across all FP visits for eyes in each level of the ETDRS DME severity scale at those visits. For eyes with baseline VA > or = 20/40, relationships between change in VA from baseline to last visit and duration of severe DME were analyzed with linear regression. RESULTS Mean VA decreased by approximately 22 letters between the mildest and most severe levels of the DME scale in the PKC-DRS2, compared with 27 letters in the ETDRS. In the placebo group, the rate of decrease in VA over time associated with duration of severe DME was 0.67 letters per month (24 letters over 36 months, compared with 20 letters over 28-36 months in the ETDRS). This rate was 30% less in the RBX group (0.47 letter per month, P = 0.022). CONCLUSIONS The VA decrease in the PKC-DRS2 associated with long-standing DME agrees well with estimates from the ETDRS. RBX appears to ameliorate this decrease, an effect that could be important clinically. (ClinicalTrials.gov number, NCT00604383.).

Association between anatomical resolution and functional outcomes in the mivi-trust studies using ocriplasmin to treat symptomatic vitreomacular adhesion/vitreomacular traction, including when associated with macular hole.

Purpose: To evaluate visual function in patients with symptomatic vitreomacular adhesion (VMA)/vitreomacular traction including when associated with macular hole after ocriplasmin treatment, and the association between resolution of the underlying condition and improvement in visual function. Methods: Six hundred and fifty-two patients from 2 Phase 3 trials received a single intravitreal injection of ocriplasmin 125 &mgr;g (n = 464) or placebo (n = 188). Mean and categorical changes from baseline in best-corrected visual acuity and 25-item Visual Function Questionnaire scores were used to evaluate visual function. Subgroups with VMA resolution and full-thickness macular hole closure were compared. Results: Overall, 42% of patients who achieved VMA resolution at Day 28 had a ≥2-line improvement in best-corrected visual acuity at Month 6, and 20% had a ≥3-line improvement. Likewise, 69% of patients with nonsurgical full-thickness macular hole closure at Day 28 had a ≥2-line improvement at Month 6, and 48% had a ≥3-line best-corrected visual acuity improvement. Mean improvements in 25-item Visual Function Questionnaire scores were associated with achieving VMA resolution and nonsurgical full-thickness macular hole closure. Conclusion: In patients with symptomatic VMA/vitreomacular traction, VMA resolution and nonsurgical full-thickness macular hole closure were each associated with improvements in visual function. Resolving the underlying anatomical condition in symptomatic VMA/vitreomacular traction will increase the probability of achieving a clinically meaningful improvement in visual function.

Vitreous Levels of Active Ocriplasmin Following Intravitreal Injection: Results of an Ascending Exposure Trial

PURPOSE To characterize the levels of active ocriplasmin over a period of ascending time points (range, 5 minutes to 7 days) from intravitreal injection of a 125-μg dose to sampling. METHODS During this 7-week controlled, open-label, phase 2 study, a single intravitreal (125 μg) dose of ocriplasmin was injected into the midvitreous of one eye of each of 34 patients prior to their scheduled primary pars plana vitrectomy. Patients were allocated to vitreous sampling at the beginning of the surgery, which occurred 5 to 30 minutes, 31 to 60 minutes, 2 to 4 hours, 24 ± 2 hours, or 7 ± 1 days after ocriplasmin injection, or to the control group, who received no ocriplasmin injection. RESULTS With increasing time from ocriplasmin injection to vitreous sampling, mean active ocriplasmin concentration decreased. While at 5 to 30 minutes postinjection, mean active ocriplasmin concentration was 11,597.7 ng/mL, within 31 to 60 minutes from injection the mean active ocriplasmin concentration had reduced to 8108.7 ng/mL; and by 24 hours after injection, half of the patients (2/4) had active ocriplasmin concentrations below the lower limit of quantification (LLQ; <272.4 ng/mL), as did all samples from the day 7 and control groups. No ocular serious adverse events (SAEs) were reported in patients who received ocriplasmin, while three ocular SAEs occurred in the study eye of one patient in the control group (1/38; 2.6%). CONCLUSIONS Active ocriplasmin concentrations in vitreous samples decreased with increasing time from injection to sample, with enzyme levels in all of the patients in the day 7 group being comparable to those in the control group. (ClinicalTrials.gov number, NCT01159665.).

Vitreomacular interface diseases: pathophysiology, diagnosis and future treatment options

Over the past two decades, the role of vitreomacular adhesion in vitreomacular interface pathologies, such as vitreomacular traction syndrome, epiretinal membrane and macular hole, has been increasingly recognized. Abnormalities of the vitreoretinal interface may contribute to important retinal pathologies such as diabetic retinopathy, diabetic macular edema and age-related macular degeneration. The prevalence of many of these serious disorders is rising. Eyes with vitreomacular adhesion-related disorders can experience rapid deterioration of vision and function if not managed in a timely and effective manner. The only treatment option currently available is vitrectomy. Pharmacologic treatment options have advanced over the past decade, and the current strategy of ‘watchful waiting’ until symptoms worsen may not be acceptable in the future. This article reviews vitreomacular interface disorders, and explores the evidence of experimental agents that can potentially treat these conditions.

A RANDOMIZED, PLACEBO-CONTROLLED STUDY OF INTRAVITREAL OCRIPLASMIN IN PEDIATRIC PATIENTS SCHEDULED FOR VITRECTOMY.

Purpose: To evaluate safety and preliminary efficacy of 175 &mgr;g of intravitreal ocriplasmin in pediatric patients scheduled for vitrectomy. Methods: Based on a single-center, prospective, randomized, placebo-controlled, and double-masked Phase 2 study, 22 pediatric patients scheduled for vitrectomy were randomized 2:1 to 175-&mgr;g ocriplasmin injection or placebo. Treatment was administered midvitreous 30 minutes to 60 minutes before vitrectomy. Safety was assessed by reported adverse events (AEs), ophthalmologic examinations, fundus photography, and fluorescein angiography. The primary efficacy endpoint was the proportion of eyes with total macular posterior vitreous detachment before vitrectomy or after application of suction. Secondary endpoints included vitreous liquefaction assessment before vitrectomy and immediate postoperative retinal reattachment. Results: All patients experienced at least 1 AE. Most AEs were ocular and occurred in the study eye. Serious AEs were reported for 2 of 16 eyes (3.4%) in the ocriplasmin group and 2 of 8 eyes (11.1%) in the placebo group. One case of lens subluxation due to zonular disruption was observed in the ocriplasmin group. A clear efficacy signal was not observed. Conclusion: Intravitreal injection of 175 &mgr;g of ocriplasmin was tolerated in pediatric patients before vitrectomy; however, the small sample size in this study precluded adequate efficacy comparisons. AEs reported were consistent with those anticipated in pediatric patients.

Sustained moderate visual loss as a predictive end point for visual loss in non-proliferative diabetic retinopathy.

PurposeIn PKC-DRS2, the efficacy of the oral PKC-β inhibitor, ruboxistaurin 32 mg/day, was measured by the primary end point of sustained moderate visual loss (SMVL: a ⩾15 letter decrease from baseline on the ETDRS (Early Treatment Diabetic Retinopathy Study) chart sustained at least for the last 6 months of study participation). We now evaluate whether SMVL is more accurate than moderate visual loss (MVL: a single occurrence of a decrease from baseline of ⩾15 ETDRS letters) for predicting future visual loss.MethodsStudy eyes with moderately severe to very-severe non-proliferative diabetic retinopathy, best-corrected visual acuity of at least 45 letters on the ETDRS chart (∼Snellen 20/125), and no prior pan retinal photocoagulation were evaluated in 506 patients (869 eyes) who completed 36 months of treatment.ResultsSixty-five percentage (26/40) of study eyes with the onset of SMVL within 24 months of enrolment still had SMVL at study completion (36 months). In comparison, only 24% (30/126) with MVL within 24 months had SMVL at study completion. Analyses based on data from 6, 12, and 18 months of treatment were similar.ConclusionsSMVL is a more predictable measure of subsequent visual loss than is a single time point measure of MVL.