Monoclonal enolase-1 blocking antibody ameliorates pulmonary inflammation and fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic fatal disease with limited therapeutic options. The infiltration of monocytes and fibroblasts into the injured lungs is implicated in IPF. Enolase-1 (ENO1) is a cytosolic glycolytic enzyme which could translocate onto the cell surface and act as a plasminogen receptor to facilitate cell migration via plasmin activation. Our proprietary ENO1 antibody, HL217, was screened for its specific binding to ENO1 and significant inhibition of cell migration and plasmin activation (patent: US9382331B2). METHODS: In this study, effects of HL217 were evaluated in vivo and in vitro for treating lung fibrosis. RESULTS: Elevated ENO1 expression was found in fibrotic lungs in human and in bleomycin-treated mice. In the mouse model, HL217 reduced bleomycin-induced lung fibrosis, inflammation, body weight loss, lung weight gain, TGF-ß upregulation in bronchial alveolar lavage fluid (BALF), and collagen deposition in lung. Moreover, HL217 reduced the migration of peripheral blood mononuclear cells (PBMC) and the recruitment of myeloid cells into the lungs. In vitro, HL217 significantly reduced cell-associated plasmin activation and cytokines secretion from primary human PBMC and endothelial cells. In primary human lung fibroblasts, HL217 also reduced cell migration and collagen secretion. CONCLUSIONS: These findings suggest multi-faceted roles of cell surface ENO1 and a potential therapeutic approach for pulmonary fibrosis.

The Effect of Intravitreal Ocriplasmin on Hue Discrimination.

SIGNIFICANCE: We report 13 patients who received ocriplasmin for symptomatic vitreomacular adhesion. Farnsworth-Munsell 100 (FM 100) hue test total error score (TES) increased from baseline to month 1, before recovering at year 1. Ocriplasmin may alter hue discrimination. PURPOSE: This study aimed to determine whether intravitreal ocriplasmin affects hue discrimination. METHODS: Thirteen patients with symptomatic vitreomacular adhesion received intravitreal ocriplasmin 125 µg. Patients underwent full ocular examination, optical coherence tomography, and FM 100 hue test at baseline, 1 week, 1 month, and 1 year. RESULTS: Mean age was 74.8 years. The median baseline FM 100 TES was similar in the injected and fellow eyes (272 vs. 252, respectively). Median TES in the injected eye increased from 272 to 348 at 1 week (median difference compared with baseline, +52.0; 98.8% confidence interval of difference, -64.0 to 184.0; P = .29), decreased to 324 at 1 month (median difference compared with baseline, -4.0; 98.8% confidence interval of difference, -44.0 to 256.0; P = .40), and decreased to 268 at 1 year (median difference compared with baseline, -108.0; 93.8% confidence interval of difference, -200.0 to 52.0; P = .19). Two patients (15.4%) had anatomic release of vitreomacular adhesion, occurring within 1 month of injection. CONCLUSIONS: Ocriplasmin may alter hue discrimination, but larger studies are required to provide sufficient power to detect or exclude a statistically significant effect. Longer follow-up is needed to determine the duration of any effect.

REVISED PREDICTIVE BIOMARKER FOR OCRIPLASMIN THERAPY IN VITREOMACULAR TRACTION DISORDERS.

PURPOSE: To determine a statistically optimal limit of adhesion size in vitreomacular traction (VMT) syndrome for ocriplasmin treatment. METHODS: In this retrospective, consecutive, interventional study, we included 106 patients treated with ocriplasmin injection because of VMT between July 2013 and January 2018. A univariate and multivariate risk analysis was performed with grouped factors and continuous factors. We used a receiver operating characteristic curve to measure the prognostic relevance of each continuous factor for therapy success and determined the statistically optimal cutoff value at which specificity and sensitivity are simultaneously maximized. RESULTS: Among the grouped factors, only a phakic lens status showed a highly significant positive influence on the resolution of the VMT. For the continuous factors, only the adhesion diameter before injection was a good predictor of anatomical success. The statistically optimal threshold value for the adhesion size was calculated to be 480 µm. Eyes below this limit had a 6.84-fold better chance of VMT resolution compared with eyes with a larger adhesion diameter. CONCLUSION: The threshold value of the VMT diameter for ocriplasmin therapy could be statistically defined as 480 µm and may thus be a new quantitative biomarker to predict treatment success.

The effectiveness of ocriplasmin versus surgery for the treatment of macular holes: A systematic review and meta-analysis.

OBJECTIVE: To conduct a systematic review looking at the effects of ocriplasmin compared to pars plana vitrectomy on macular holes to assess the effectiveness of the treatment options. METHODS: Literature was searched through MEDLINE, EMBASE, CINAHL, Clinical Trials.gov, and ProQuest Dissertations and Theses until June 12, 2018. Conferences held through Association for Research in Vision and Ophthalmology, Canadian Society of Ophthalmology, and American Academy of Ophthalmology were searched until June 18, 2018. A total of 208 records were screened leaving 26. One author independently reviewed them for quality and extracted data. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines were followed. The adverse events, MH closure rate, change in MH size, and the extent to which the patients' visual acuity is restored by each treatment option; ocriplasmin and vitrectomy. RESULTS: Twenty-six articles were included for qualitative and quantitative analysis. Meta-analysis results showed a 34% closure of macular holes after ocriplasmin treatment compared to 92% after vitrectomy. A significant improvement in visual acuity was seen after vitrectomy (SMD = -1.42; CI: [-1.98, -0.86]) as well as the ocriplasmin treatment (SMD = -0.73; CI: [-0.98, -0.48]). CONCLUSIONS: Results suggested 92% macular hole closure after vitrectomy compared to 34% after ocriplasmin. A significant improvement in visual acuity of patients was seen after both treatments. More good quality randomized controlled trials are required to make strong conclusions.

Cost-effectiveness analysis of ocriplasmin versus watchful waiting for treatment of symptomatic vitreomacular adhesion in the US.

Aim: Evaluate the cost-effectiveness of ocriplasmin in symptomatic vitreomacular adhesion (VMA) with or without full-thickness macular hole ≤400 µm versus standard of care. Methods: A state-transition model simulated a cohort through disease health states; assignment of utilities to health states reflected the distribution of visual acuity. Efficacy of ocriplasmin was derived from logistic regression models using Ocriplasmin for Treatment for Symptomatic Vitreomacular Adhesion Including Macular Hole trial data. Model inputs were extracted from Phase III trials and published literature. The analysis was conducted from a US Medicare perspective. Results: Lifetime incremental cost-effectiveness ratio was US$4887 per quality-adjusted life year gained in the total population, US$4255 and US$10,167 in VMA subgroups without and with full-thickness macular hole, respectively. Conclusion: Ocriplasmin was cost effective compared with standard of care in symptomatic VMA.

BASELINE CHARACTERISTICS OF VITREOMACULAR TRACTION PROGRESSING TO FULL-THICKNESS MACULAR OR LAMELLAR HOLES IN THE PHASE III TRIALS OF ENZYMATIC VITREOLYSIS.

PURPOSE: To identify characteristics associated with progression from vitreomacular traction (VMT) to a full-thickness macular hole (FTMH) or lamellar hole (LH). METHODS: Post-hoc analysis of the Phase III clinical trial comparing ocriplasmin with placebo for treatment of vitreomacular adhesion (MIVI-TRUST). Exact logistic regression analyses were used to identify baseline characteristics significantly associated with progression from vitreomacular traction to FTMH or LH over the 6-month study period. RESULTS: Twenty eyes (4.5%) developed an FTMH and 38 (9.7%) developed an LH during the study period. The rate of progression to FTMH or LH did not differ significantly between ocriplasmin- and saline-treated eyes (P = 0.090 for FTMH, P = 0.369 for LH). On univariate analysis, the presence of subretinal fluid (adjusted odds ratio 5.64, 95% confidence interval 2.02-17.17, P < 0.001) and mean subretinal fluid thickness (adjusted odds ratio 1.10, 95% confidence interval 1.04-1.16, P = 0.003) were associated with FTMH development. Both remained significantly associated with FTMH development on multivariate testing. On univariate analysis, the presence of macular schisis (adjusted odds ratio 2.26, 95% confidence interval 1.30-3.82, P = 0.004) and mean retinal thickness (adjusted odds ratio 1.06, 95% confidence interval 1.01-1.10, P = 0.010) were associated with LH development. Schisis remained a significant predictor of LH formation on multivariate testing. CONCLUSION: Vitreomacular traction is more likely to progress to FTMH when associated with subretinal fluid, but when associated with intraretinal changes (such as schisis), vitreomacular traction appears more likely to progress to a LH after a single intravitreal injection of ocriplasmin or saline.

EXPERIENCE WITH OCRIPLASMIN IN PATIENTS WITH VITREOMACULAR TRACTION SYNDROME: A RETROSPECTIVE STUDY OF 10 PATIENTS.

PURPOSE: To assess the efficacy of ocriplasmin in patients with vitreomacular traction (VMT) syndrome <1,500 µm with or without a full-thickness macular holes of <400 µm. METHODS: In this study, a retrospective analysis of 10 eyes of 10 patients with VMT who were treated with ocriplasmin between December 2014 and January 2016 was performed. Ocriplasmin 0.125 mg was injected only once in all cases. Outcome measures included the detachment of VMT, best-corrected visual acuity, the evaluation of optical coherence tomography, including the closure of full-thickness macular holes, and the reduction of macular edema (if present) and the decrease of metamorphopsia if present. RESULTS: Ten patients (7 women and 3 men) with an average age of 75.1 years (range, 63-84 years) were treated with ocriplasmin with a follow-up period of 8 weeks. All patients were treated for VMT syndrome, and 5 patients (50.0%) showed an additional macular hole. An absolute detachment of VMT was seen in 3 patients (30.0%) and partially in 4 patients (40.0%). In three of the five patients, a complete closure of the full-thickness macular holes was seen. The two other patients needed an additional pars plana vitrectomy as a result of the persistent macular hole. An improvement of visual acuity was seen in 6 out of 10 patients (60.0%), a reduction of macular edema in 8 out of 9 patients (88.9%), and a decrease of metamorphopsia in 6 out of 7 patients (85.7%). CONCLUSION: In this retrospective analysis, the treatment with ocriplasmin showed a resolution of VMT in 7 of 10 patients (70.0%) after a follow-up period of 8 weeks.

[Efficacy and Safety Profile of Ocriplasmin Treatment - an Update]. / Wirkungen und Nebenwirkungen von Ocriplasmin ­ ein Update.

Pharmacological vitreolysis with ocriplasmin is an effective treatment option for eyes with vitreomacular traction. Pre-marketing and post-marketing clinical studies revealed an improvement of visual function in ocriplasmin treated eyes and showed a release of traction in up to 78% of cases. Treatment success is related to patient selection based on positive predictive factors. Adverse events, such as visual acuity loss, dyschromatopsia or photopsia are known to be self-limited in the majority of eyes. Structural outer retinal layer changes, such as ellipsoid zone disturbances or subretinal fluid accumulation on SD-OCT analysis, as well as ERG abnormalities, are transient and correlated to VMT release. Surgical outcomes in patients with a prior history of ocriplasmin injection have been shown to be comparable with patients who proceeded directly to surgery without ocriplasmin treatment.

Ocriplasmin retinopathy: Possible cause of macular hole closure failure. / Retinopatía asociada a ocriplasmina: posible causa de fracaso de cierre de agujero macular.

CASE REPORT: A 53 year-old woman with a stage 2 macular hole received ocriplasmin injection as a first approach. She subsequently underwent pars plana vitrectomy due to enlargement of the hole post-injection. The visual gain following the surgery was minimal despite closure of the hole. This could be explained by outer retina atrophy as a consequence of potential toxic mechanisms related to ocriplasmin. DISCUSSION: Further studies may be warranted to fully understand the impact of ocriplasmin on long-term visual function.

[Initial Clinical Experiences Using Ocriplasmin for the Treatment of Vitreomacular Traction with or without a Macular Hole]. / Stellenwert von Ocriplasmin bei der Therapie der vitreomakulären Traktion mit und ohne Makulaforamen ­ erste klinische Erfahrungen.

PURPOSE: In vitreomacular traction (VMT), there is abnormal adhesion between the vitreous cortex and the retina, especially in the fovea. Symptoms of VMT include metamorphopsia and a decrease in visual acuity. Since 2013, ocriplasmin (Jetrea®) has been approved for treatment of symptomatic vitreomacular traction with or without macular holes (≤ 400 µm). METHODS: We retrospectively examined twenty-three eyes of twenty-one patients who underwent intravitreal ocriplasmin treatment for symptomatic vitreomacular traction with or without macular holes. Best corrected visual acuity and central retinal thickness (CRT) were measured in advance and after ocriplasmin treatment. The numbers of resolved vitreomacular traction and closed macular holes were documented. RESULTS: Vitreomacular traction was resolved in eight of twenty-three eyes (34.8 %); in fifteen eyes (65.2 %) it was persistent and two of four macular holes were found closed. The average best corrected visual acuity was 0.39 ± 0.25 logMAR at baseline and 0.41 ± 0.24 logMAR at the first follow-up visit after injection (p = 0.613). The average CRT was 453.3 ± 172.7 µm at baseline, with a slight decrease to 412.0 ± 212 µm (p = 0.124). CONCLUSION: Intravitreal injection of ocriplasmin appears is an experimental therapy in patients with symptomatic vitreomacular traction. Patient selection seems to be critically important for the therapeutic outcome, whereas greater age, specific VMT morphology and missing chromatopsia seem to be negative predictors.

Visual Function Response to Ocriplasmin for the Treatment of Vitreomacular Traction and Macular Hole: The OASIS Study.

Purpose: To assess the effect of ocriplasmin on visual function response (VFR) measured using visual acuity (VA) and vision-related quality of life, and to quantify the association between release of vitreomacular adhesion (VMA) at day 28 and VFR. Methods: Prespecified analysis of secondary endpoints from a randomized controlled trial. Of 220 participants with symptomatic VMA/vitreomacular traction (VMT), including VMT associated with a macular hole up to 400 µm, 146 received a single intravitreal injection of 125 µg ocriplasmin and 74 a sham injection. Based on principal components analysis results, a VFR was defined as either a VA improvement of ≥2 lines or an improvement exceeding the minimal clinically important difference (MCID) in the composite or the mental health subscale scores of the Visual Function Questionnaire (VFQ-25). The MCID was estimated using the standard error of measurement approach. The main outcome measure was the VFR at month 6, with further assessments at months 12 and 24. Results: The MCID was estimated at 3.71 points for the VFQ-25 composite score and 10.71 for the VFQ-25 mental health subscale score. A VFR occurred in 51.0% of ocriplasmin versus 23.3% of sham participants (P = 0.0001). The VFR was maintained through months 12 and 24: 53.1% and 50.3% in ocriplasmin versus 21.9% and 20.5% in sham participants, respectively (P < 0.0001). Resolution of VMA at day 28 significantly increased the odds of a VFR at each assessment period. Conclusions: Treatment with ocriplasmin compared with sham resulted in a significant improvement in VFR. The 6-month treatment effect was sustained at months 12 and 24.

Intravitreal ocriplasmin: A breakthrough in the treatment of vitreomacular traction?

Vitreoretinal interface pathologies, such as vitreomacular traction syndrome, epiretinal membranes and macular holes are sight-threatening conditions and one of the important causes of vision defects and vision loss. To this date, vigilance with observation of how the vitreomacular traction resolves, or vitreoretinal surgery in more severe cases, were the only treatment options. Recent rapid progress in ophthalmology, especially in diagnostic and visualization techniques, provided better insight into the mechanisms taking place on the vitreoretinal surface, which enabled a more accurate selection of treatment options. Development of ophthalmic pharmacological procedures, such as treatment of vitreomacular traction syndrome with ocriplasmin, constitutes an innovative breakthrough in ophthalmology. The enzyme is a genetically engineered form of human plasmin, a component of blood coagulation cascade that has been envisioned for human therapy since 1950s. It has never been used for vitreolysis in ophthalmology before. The aim of this review is to analyze and compare therapeutic options for symptomatic vitreomacular adhesion and vitreoretinal traction, with particular emphasis on microplasmin. We reviewed the results of recent studies comparing ocriplasmin to other widespread treatment options, such as pars plana vitrectomy.

PROPORTION OF PATIENTS WITH MACULAR HOLE SURGERY WHO WOULD HAVE BEEN FAVORABLE OCRIPLASMIN CANDIDATES: A Retrospective Analysis.

PURPOSE: To identify favorable ocriplasmin candidates from a cohort of idiopathic full thickness macular hole surgery patients. METHODS: The records of patients with full thickness macular hole who underwent pars plana vitrectomy surgery between 2011 and 2015 were reviewed. Clinical data collected included patient demographics, pre- and post-operative Snellen visual acuity, optical coherence tomography findings, and lens status. The authors defined "favorable" ocriplasmin candidates as patients with focal vitreomacular traction, no epiretinal membrane, and hole size ≤400 µm. The authors further categorized "optimal" candidates as age ≤65, phakic, no epiretinal membrane, with focal vitreomacular traction, and hole size ≤400 µm. RESULTS: The records of 238 patients were assessed; 30.7% were male while mean age was 68.6 ± 8.3 years. The mean logMAR acuity was 1.2 (Snellen 20/317) preoperatively and 0.90 (Snellen 20/159) postoperatively. Optical coherence tomography findings indicated that 46.5% of the macular holes studied were less than ≤400 µm in size, 14.8% had an epiretinal membrane, and 25.3% had vitreomacular traction. A total of 17.7% of study patients were found to be favorable candidates, whereas 3.8% were optimal ocriplasmin candidates. CONCLUSION: Only a minority of full thickness macular hole surgical candidates in this cohort would be considered favorable ocriplasmin candidates.

The Efficacy and Safety Profile of Ocriplasmin in Vitreomacular Interface Disorders.

Vitreomacular adhesion (VMA) describes the adhesion of the posterior hyaloid face to the inner retina in any part of the macula. This can arise after incomplete separation of the posterior vitreous cortex from the macula during vitreous liquefaction. While the VMA may resolve spontaneously, a strong and persistent adhesion can lead to a variety of anatomical changes, including vitreomacular traction (VMT) and macular hole (MH). Both conditions can present with metamorphopsia and decreased vision. In cases of symptomatic VMT and full-thickness macular hole, pars plana vitrectomy has long been the standard of care. However, due to the possible surgical complications and need for postoperative care, many have searched for non-surgical options via pharmacologic vitreolysis. Ocriplasmin (Jetrea, Thrombogenics USA, Alcon/Novartis EU) is a recombinant protease approved in October 2012 for the treatment of symptomatic vitreomacular adhesion (VMA). There have been conflicting views on the safety of Ocriplasmin with changes in the ellipsoid zone seen on OCT and changes seen on ERG indicating photoreceptor damage. This publication reviews the efficacy and safety of ocriplasmin injection for VMA based on previously published data.

From the analysis of pharmacologic vitreolysis to the comprehension of ocriplasmin safety.

INTRODUCTION: Pharmacologic vitreolysis is a strategy used to treat anomalous posterior vitreous detachment, by weakening vitreoretinal adhesion with an intravitreal drug. Pharmacologic vitreolysis facilitates surgery, and abnormalities of the vitreoretinal interface including vitreomacular traction (VMT) and early stage macular hole (MH) could be resolved. Ocriplasmin is a recombinant protease, active against fibronectin and laminin, which are important components of the vitreoretinal interface. Ocriplasmin has been approved for symptomatic treatment of VMT and MH with visible traction, and it functions by dissolving the proteins that link the vitreous to the macula, thereby creating a complete posterior vitreous detachment (PVD). AREAS COVERED: This paper reviews the current knowledge and status of investigations regarding the use of ocriplasmin for pharmacologic vitreolysis and its safety. EXPERT OPINION: Ocriplasmin is a non-specific enzyme; therefore, it dissolves vitreal proteins as well as possibly proteins associated with visual function in the retina, choroid, and lens. Ocular adverse events (OAEs) of ocriplasmin include transient visual loss, intraocular inflammation, vitreous floaters, lens opacification, zonular instability of the lens, and intraocular hemorrhage. The prevalence of the OAEs is very low; however, on rare occasions, they can result in widespread retinal dysfunction. Research into the acute and long-term safety of ocriplasmin is required.