Pharmacokinetic-Pharmacodynamic Modelling in Hemophilia A: Relating Thrombin and Plasmin Generation to Factor VIII Activity After Administration of a VWF/FVIII Concentrate.

BACKGROUND: Hemophilia A patients are treated with factor (F) VIII prophylactically to prevent bleeding. In general, dosage and frequency are based on pharmacokinetic measurements. Ideally, an alternative dose adjustment can be based on the hemostatic potential, measured with a thrombin generation assay (TGA), like the Nijmegen hemostasis assay. OBJECTIVE: The objective of this study was to investigate the predicted performance of a previously developed pharmacokinetic-pharmacodynamic model for FVIII replacement therapy, relating FVIII dose and FVIII activity levels with thrombin and plasmin generation parameters. METHODS: Pharmacokinetic and pharmacodynamic measurements were obtained from 29 severe hemophilia A patients treated with pdVWF/FVIII concentrate (Haemate P®). The predictive performance of the previously developed pharmacokinetic-pharmacodynamic model was evaluated using nonlinear mixed-effects modeling (NONMEM). When predictions of FVIII activity or TGA parameters were inadequate [median prediction error (MPE) > 20%], a new model was developed. RESULTS: The original pharmacokinetic model underestimated clearance and was refined based on a two-compartment model. The pharmacodynamic model displays no bias in the observed normalized thrombin peak height and normalized thrombin potential (MPE of 6.83% and 7.46%). After re-estimating pharmacodynamic parameters, EC50 and Emax values were relatively comparable between the original model and this group. Prediction of normalized plasmin peak height was inaccurate (MPE 58.9%). CONCLUSION: Our predictive performance displayed adequate thrombin pharmacodynamic predictions of the original model, but a new pharmacokinetic model was required. The pharmacodynamic model is not factor specific and applicable to multiple factor concentrates. A prospective study is needed to validate the impact of the FVIII dosing pharmacodynamic model on bleeding reduction in patients.

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.

O2L-001, an innovative thrombolytic to evacuate intracerebral haematoma.

Intracerebral haemorrhage is an unmet medical need affecting more than 3 million people worldwide every year and leading to the formation of an intracerebral haematoma. Updated guidelines (2022) for the management of intracerebral haemorrhage patients recognize that minimally invasive approaches for the evacuation of supratentorial intracerebral haemorrhage have demonstrated reductions in mortality compared with medical management alone. However, improvement of functional outcome with a procedure involving thrombolytic therapy was neutral in the last large phase 3 clinical trial and requires a more effective and safer thrombolytic agent than those currently available. Here, we demonstrate that O2L-001 allows for the extended release of W253R/R275S recombinant tissue-type plasminogen activator (rtPA). A new rtPA variant, called optimized tPA (OptPA), offers improved efficacy for haematoma evacuation as well as improved safety. OptPA was produced in a Chinese hamster ovary cell line before purification, nanoprecipitation using the NANOp2Lysis® technological platform followed by suspension in a solution of 17% poloxamer 407 to obtain O2L-001. Plasmin generation assays were performed to demonstrate O2L-001 safety. Ex vivo haematoma models using human blood were used to demonstrate O2L-001 thrombolysis properties and efficacy. For the best translational significance, a clinical sized haematoma was used to ensure catheter placement and to allow administration of the thrombolytic agent into the core of the haematoma via a minimally invasive procedure. The capacity of OptPA to convert plasminogen into plasmin is strongly decreased compared to rtPA, thereby reducing potential bleeding events. However, a clot lysis assay showed that OptPA had the same fibrinolytic activity as rtPA. We demonstrated that long-term exposure to a thrombolytic agent was essential to achieve high thrombolysis efficacy. Indeed, 24 h continuous exposure to 0.1 µg/ml rtPA had similar efficacy than repeated short exposure to 30 µg/ml rtPA. This finding led to the development of O2L-001, allowing the extended release of OptPA in the first 6 h following injection. An ex vivo model using human blood was used to demonstrate O2L-001 efficacy. Interestingly, unlike rtPA, O2L-001 was able to induce the complete lysis of the 5 ml haematoma. In clinical sized haematomas (obtained from 30 ml of human blood), a single injection of O2L-001 at 1 mg/ml into the core of the haematoma led to a 44% increase in thrombolysis compared to rtPA. Taken together, these results demonstrate that O2L-001 provides new hope for haematoma evacuation and the treatment of patients with intracerebral haemorrhage.

Resolution of outer retinal abnormalities in eyes with vitreomacular traction without macular hole in the OASIS trial.

BACKGROUND/AIMS: To describe the clinical impact of external limiting membrane (ELM) disruption, ellipsoid zone (EZ) disruption and subretinal fluid (SRF) seen on optical coherence tomography (OCT) in eyes with vitreomacular traction (VMT) without macular hole (MH) in the Ocriplasmin for Treatment for Symptomatic Vitreomacular Adhesion Including Macular Hole study. METHODS: Phase 3b randomised double-blind sham-controlled multicentre study including 144 eyes with VMT without MH. Eyes were randomised to receive a single intravitreal injection of ocriplasmin or sham injection and were followed for 24 months. Eyes were analysed for presence, course and clinical impact of ELM disruption, EZ disruption and SRF on OCT. RESULTS: ELM disruption, EZ disruption and SRF were present in 32.6%, 52.2% and 45.8% of ocriplasmin-treated eyes and 39.6%, 42.6% and 37.5% of sham-treated eyes at baseline. VMT resolution was associated with resolution of ELM and EZ disruption and SRF. A small number of eyes had persistent ELM disruption, EZ disruption and/or SRF at the seventh visit or later (17 months or later) following medical or surgical VMT resolution. Resolution of ELM disruption, EZ disruption and/or SRF was associated with an improvement of visual acuity from baseline. Following VMT resolution, ELM recovery usually preceded EZ recovery and SRF resolution. CONCLUSIONS: ELM disruption, EZ disruption and/or SRF are present in a significant percentage of eyes with VMT without MH. Release of VMT is usually associated with outer retinal recovery and an associated improvement in visual acuity. ELM recovery typically precedes EZ recovery and SRF resolution following VMT release.

The serine protease plasmin plays detrimental roles in epithelial sodium channel activation and podocyte injury in Dahl salt-sensitive rats.

Salt-sensitive hypertension is associated with poor clinical outcomes. The epithelial sodium channel (ENaC) in the kidney plays pivotal roles in sodium reabsorption and blood pressure regulation, in which its γ subunit is activated by extracellular serine proteases. In proteinuric nephropathies, plasmin filtered through injured glomeruli reportedly activates γENaC in the distal nephron and causes podocyte injury. We previously reported that Dahl salt-sensitive (DS) rats fed a high-salt (HS) diet developed hypertension and proteinuria along with γENaC activation and that a synthetic serine protease inhibitor, camostat mesilate, mitigated these changes. However, the role of plasmin in DS rats remained unclear. In this study, we evaluated the relationship between plasmin and hypertension as well as podocyte injury and the effects of plasmin inhibitors in DS rats. Five-week-old DS rats were divided into normal-salt diet, HS diet, and HS+plasmin inhibitor (either tranexamic acid [TA] or synthetic plasmin inhibitor YO-2) groups. After blood pressure measurement and 24 h urine collection over 5 weeks, rats were sacrificed for biochemical analyses. The HS group displayed severe hypertension and proteinuria together with activation of plasmin in urine and γENaC in the kidney, which was significantly attenuated by YO-2 but not TA. YO-2 inhibited the attachment of plasmin(ogen) to podocytes and alleviated podocyte injury by inhibiting apoptosis and inflammatory/profibrotic cytokines. YO-2 also suppressed upregulation of protease-activated receptor-1 and phosphorylated ERK1/2. These results indicate an important role of plasmin in the development of salt-sensitive hypertension and related podocyte injury, suggesting plasmin inhibition as a potential therapeutic strategy.

Calculating the individual probability of successful ocriplasmin treatment in eyes with vitreomacular traction-Validation and refinement of a multivariable prediction model.

PURPOSE: To evaluate a multivariable model predicting the individual probability of successful intravitreal ocriplasmin (IVO) treatment in eyes with vitreomacular traction (VMT). METHODS: Data from three prospective, multicenter IVO studies (OASIS, ORBIT, and INJECT) were pooled. Patients were included if they were treated for a symptomatic VMT without a full-thickness macular hole. A prediction model for VMT resolution using the factors 'age' and 'horizontal VMT diameter' was validated by receiver operating characteristic analysis and according to grouped prediction after calibration. Multivariable regression analysis was performed to check robustness and explore further improvements. RESULTS: Data from 591 eyes was included. In the univariate analysis all key factors (age, gender, VMT diameter, lens status, ERM) significantly correlated to treatment success. The prediction model was robust and clinically applicable to estimate the success rate of IVO treatment (AUC of ROC: 0.70). A refinement of the model was achieved through a calibration process. CONCLUSION: The developed multivariable model using 'horizontal VMT diameter' and 'age' is a valid tool for prediction of VMT resolution upon IVO treatment.

Tranexamic acid: Beyond antifibrinolysis.

Tranexamic acid (TXA) is a popular antifibrinolytic drug widely used in hemorrhagic trauma patients and cardiovascular, orthopedic, and gynecological surgical patients. TXA binds plasminogen and prevents its maturation to the fibrinolytic enzyme plasmin. A number of studies have demonstrated the broad life-saving effects of TXA in trauma, superior to those of other antifibrinolytic agents. Besides preventing fibrinolysis and blood loss, TXA has been reported to suppress posttraumatic inflammation and edema. Although the efficiency of TXA transcends simple inhibition of fibrinolysis, little is known about its mechanisms of action besides the suppression of plasmin maturation. Understanding the broader effects of TXA at the cell, organ, and organism levels are required to elucidate its potential mechanisms of action transcending antifibrinolytic activity. In this article, we provide a brief review of the current clinical use of TXA and then focus on the effects of TXA beyond antifibrinolytics such as its anti-inflammatory activity, protection of the endothelial and epithelial monolayers, stimulation of mitochondrial respiration, and suppression of melanogenesis.

COMBINED PNEUMATIC AND ENZYMATIC VITREOLYSIS FOR SEVERE CASES OF VITREOMACULAR TRACTION.

PURPOSE: To evaluate the efficacy of combined pneumatic and enzymatic vitreolysis for treatment of severe cases of vitreomacular traction (VMT). METHODS: We analyzed a retrospective, consecutive series of five patients diagnosed with severe VMT refractory to pneumatic vitreolysis who then received an additional ocriplasmin injection while their gas bubble from pneumatic vitreolysis was still present between February 2015 and February 2019. Vitreomacular traction release was confirmed using spectral-domain optical coherence tomography. RESULTS: Four of the five patients treated with combined pneumatic and enzymatic vitreolysis achieved VMT release by Day 28, and all cases eventually achieved complete VMT release. In addition to having VMT refractory to pneumatic vitreolysis, patient characteristics included broad adhesion diameter (>1,500 µ m, n = 1), presence of epiretinal membrane (n = 2), age >65 years (n = 4), and pseudophakia (n = 1). The visual acuity improved by three or more lines at 6 months in both of the patients with initial vision worse than 20/50 on an Early Treatment Diabetic Retinopathy Study chart but not in those whose vision was already fairly good (i.e., visual acuity >20/60). None of the patients experienced the following complications after receiving this combined treatment: retinal tears or detachments, vitreous floaters, and ellipsoid zone changes. CONCLUSION: Sequential, combined pneumatic and enzymatic vitreolysis resulted in VMT release in all 5 cases (4 cases by 28 days) and may be a potentially useful alternative to surgical intervention for refractory VMT cases.

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.

Morphological Reconstitution and Persistent Changes After Intravitreal Ocriplasmin for Vitreomacular Traction and Macular Hole.

Purpose: To assess the long-term anatomical and functional findings in patients with symptomatic vitreomacular traction (VMT), with or without full thickness macular hole (FTMH), after eye treatment with intravitreal ocriplasmin injection (IOI). Methods: This longitudinal case series includes 51 eyes from 51 symptomatic patients with VMT (<800 µm) who received a single IOI (Jetrea® 0.125 mg); 21 cases with an FTMH (<400 µm) were included. Best-corrected visual acuity (BCVA) and optical coherence tomography findings were recorded before IOI, and 1 day to 24 months thereafter. Data are presented as mean ± standard deviation. Results: Mean adhesion size before injection was 345 ± 146 µm. In 34 eyes (67%), complete release of VMT was observed; whereas VMT persisted in 17 eyes (33%). The latter included 15 of the 21 eyes (71%) with FTMH, 15 of which underwent pars plana vitrectomy and inner limiting membrane peeling. BCVA improved from (logarithm of the minimal angle of resolution [logMAR]) 0.41 ± 0.03 before injection to 0.32 ± 0.03 after 1 month and 0.23 ± 0.05 after 6 months and remained stable thereafter (0.24 ± 0.06 after 24 months of follow-up). Forty-five percent of the eyes presented submacular deposits soon after IOI that were not functionally relevant; 61% completely resolved by 12 months. Except floaters that disappeared within 48 h, no other adverse events were reported during follow-up. Conclusions: Treatment with ocriplasmin in a real-life setting showed an overall efficacy of 67% in patients with symptomatic VMT, with better results evident in the absence of an FTMH (70% vs. 62% VMT release) and a visual gain for over 2 years.

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.