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Background
Vitreo-macular adhesion (VMA) is a condition in which the vitreous gel of the eye adheres to the retina in an abnormally strong manner. As the eye ages, it is common for the vitreous gel to separate from the retina. However, if this separation is incomplete (i.e., there is still an adhesion), this can create pulling forces on the retina, which may result in subsequent loss or distortion of vision. Vitreo-macular adhesion by itself is not dangerous, but the resulting vitreo-macular traction can result in macular damage. The current treatment for VMA is vitrectomy that entails the surgical removal of the vitreous gel from the eye. More recently, agents such as plasmin and microplasmin (also known as ocriplasmin), administered as a single intra-vitreal injection, have been employed as non-invasive treatment of VMA.
Ocriplasmin (molecular weight of 27.2 kDa), a recombinant protease, is a truncated form of human plasmin obtained from microplasminogen produced in a Pichia pastoris expression system by recombinant DNA. Ocriplasmin is purported to exert proteolytic effects on fibrinogen, fibronectin and, to a lesser extent, laminin and collagen, each of which is a component of VMA. The safety and effectiveness of ocriplasmin for the treatment of patients with VMA has been evaluated in several clinical trials.
In a multi-center, prospective, uncontrolled, dose-escalation, phase I/II clinical trial, de Smet et al (2009) evaluated the safety and preliminary efficacy of 4 doses and several exposure times of intra-vitreal microplasmin given before pars plana vitrectomy (PPV) for vitreo-macular traction maculopathy. A total of 60 patients were enrolled into 6 successive cohorts. A single intra-vitreal injection of microplasmin at 1 of 4 doses (25, 50, 75, or 125 microg in 100 microl) was administered 1 to 2 hours, 24 hours, or 7 days before planned PPV. For safety, a complete ophthalmologic examination, fundus photography, fluorescein angiography, Humphrey visual fields, and electrophysiology were carried out; for efficacy, PVD induction as assessed by B-scan ultrasound and ease of PVD induction at the time of vitrectomy were performed. The use of microplasmin led to a progressively higher incidence of PVD induction on ultrasonography with increasing time exposure. A PVD before surgery was observed with 25 microg microplasmin in 0, 2, and 5 patients with increasing exposures (2 hours, 24 hours, 7 days). With increasing dose, a PVD before surgery was observed by ultrasound as follows: 25 microg, n = 0; 50 microg, n = 1; 75 microg, n = 2; 125 microg, n = 3. However, at surgery, with a 125-microg dose, these patients had a discontinuous layer of vitreous present on the retinal surface resulting from the induction of an anomalous PVD in the form of vitreoschisis. One retinal detachment developed shortly after administration of microplasmin; 2 developed after surgery. There were no other safety concerns. The authors concluded that results from this initial clinical trial evaluating intra-vitreal microplasmin showed the drug to be well-tolerated and capable of inducing a pharmacologic PVD in some patients.
In a randomized, double-masked, phase II clinical trial, Stalmans et al (2010) evaluated the ability of a single or repeated injection of microplasmin to release vitreo-macular traction (n = 6). Patients in each of the 4 cohorts were randomized (4:1) to active treatment or sham injection. In the first 3 cohorts, increasing doses of microplasmin (75, 125, and 175 microg) were administered. In the 4th cohort, an initial injection of 125 microg microplasmin or sham was administered followed 1 month later by an injection of 125 microg microplasmin if no release of adhesion occurred. A 3rd dose was injected 4 weeks later if there was still no release of adhesion. Within 28 days of sham, 75, 125, and 175 microg microplasmin administrations, non-surgical resolution of VMA was observed in 8, 25, 44, and 27 % of the patients, respectively. When the 125-microg dose was repeated up to 3 times, adhesion release was observed in 58 % of patients 28 days after the final injection. The authors concluded that these findings provided support for the potential of microplasmin as a non-surgical treatment for VMA.
In a phase II, multi-center, placebo-controlled, double-masked, parallel-group, dose-ranging clinical trial, Benz et al (2010) evaluated the safety and effectiveness of a pre-operative intra-vitreal injection of microplasmin in patients scheduled for vitrectomy. A total of 125 patients scheduled for PPV, primarily for treatment of either vitreo-macular traction or macular hole were included in this study. A single intra-vitreal injection of either microplasmin at 1 of 3 doses (25 microg, 75 microg, or 125 microg in 100 microl) or placebo injection was administered 7 days before PPV. Main outcome measures included presence or absence of PVD at the time of PPV, progression of PVD, and resolution of vitreo-macular interface abnormality precluding the need for PPV. Rates of total PVD at the time of surgery were 10 %, 14 %, 18 %, and 31 % in the placebo group (n = 30), 25-microg (n = 29), 75-microg (n = 33), and 125-microg microplasmin groups (n = 32), respectively. The secondary end point resolution of vitreo-macular interface abnormality precluding the need for vitrectomy at the 35-day time point was observed at rates of 3 %, 10 %, 15 %, and 31 % in the placebo, and the 25-microg, the 75-microg, and the 125-microg microplasmin groups, respectively. At the 180-day time point, the equivalent rates were 3 %, 7 %, 15 %, and 28 %, respectively. The authors concluded that microplasmin injection at a dose of 125 microg led to a greater likelihood of induction and progression of PVD than placebo injection. Patients receiving microplasmin were significantly more likely not to require vitrectomy.
In 2 multi-center, randomized, double-blind, phase III clinical trials, Stalmans et al (2012) compared a single intra-vitreal injection of ocriplasmin (125 microg) with a placebo injection in patients with symptomatic VMA. The primary end point was resolution of VMA at day 28. Secondary end points were total PVD and non-surgical closure of a macular hole at 28 days, avoidance of vitrectomy, and change in best-corrected visual acuity (BCVA). Overall, 652 eyes were treated: 464 with ocriplasmin and 188 with placebo. Vitreo-macular adhesion was resolved in 26.5 % of ocriplasmin-injected eyes; and in 10.1 % of placebo-injected eyes (p < 0.001). Total PVD was more prevalent among the eyes treated with ocriplasmin than among those injected with placebo (13.4 % versus 3.7 %, p < 0.001). Non-surgical 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 BCVA was more likely to improve by a gain of at least 3 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 2 groups (p = 0.26). The authors concluded that intra-vitreal injection of ocriplasmin resolved vitreo-macular 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.
On October 18, 2012, the Food and Drug Administration (FDA) approved ocriplasmin (Jetrea) for the treatment of symptomatic VMA. The recommended dosage of ocriplasmin is 0.125 mg (0.1 ml of the diluted solution) administered by intra-vitreal injection to the affected eye once as a single dose. The most commonly reported adverse reactions (greater than or equal to 5 %) in patients treated with ocriplasmin were blurred vision, conjunctival hemorrhage, eye pain, macular hole, photopsia, reduced visual acuity, retinal edema, visual impairment, and vitreous floaters.
Ocriplasmin has also been investigated for other uses in laboratory and clinical studies, including mobilization of hematopoietic progenitor cells, as a surgical adjunct to vitrectomy, as well as treatment of catheter-related thrombosis, coronary artery thrombosis, exudative age-related macular degeneration, peripheral arterial occlusion, ischemic stroke, and vitreous hemorrhage. However, there is currently insufficient evidence to support the use of ocriplasmin for these indications.
Tjwa et al (2008) stated that the role of proteinases in the mobilization of hematopoietic progenitor cells (HPCs) after granulocyte colony-stimulating factor (G-CSF) remains unclear. These researchers reported that genetic loss of the plasminogen activator inhibitor Pai-1 or of the plasmin inhibitor alpha2-antiplasmin increases HPC mobilization in response to G-CSF. Moreover, thrombolytic agents (e.g., microplasmin and tenecteplase) enhance HPC mobilization in mice as well as humans. The authors concluded that these findings identified a novel role for plasmin in augmenting HPC mobilization in response to G-CSF. Well-designed studies are needed to ascertain the clinical value of microplasmin in the mobilization of HPCs.
In an open-label, ascending-dose, pilot study, Verhamme et al (2009) examined the safety and effectiveness of intra-catheter microplasmin bolus administration for the restoration of catheter function in long-term venous access catheter thrombosis. This study enrolled 31 subjects. Two doses of microplasmin were evaluated: 5 mg and 8 mg administered via a 2-ml intra-catheter bolus injection in 10 and 21 patients, respectively. Catheter function was evaluated 30 minutes after the first bolus administration. In case of incomplete catheter function restoration, a second bolus was administered with re-assessment of catheter function 30 minutes thereafter. After the first bolus, complete restoration of catheter withdrawal function was observed in 5 out of 10 (50 %) and 14 of out 21 (66 %) subjects treated with 5-mg and 8-mg of microplasmin, respectively; and in 8 out of 10 (80 %) and 18 out of 21 (86 %) subjects after a second administration of microplasmin. No bleeding complications, nor other adverse events, were related to microplasmin. The authors concluded that in this pilot trial, microplasmin restored catheter function in a safe and effective way. These preliminary findings need to be validated by well-designed studies.
In a multi-center, double-blind, randomized, placebo-controlled phase II clinical trial, Thijs and colleagues (2009) tested the tolerability of microplasmin in patients with acute ischemic stroke. A total of 40 patients with ischemic stroke were treated with either placebo or microplasmin between 3 and 12 hours after symptom onset in a dose-finding design. Ten patients received placebo, 6 patients received a total dose of 2 mg/kg body weight, 12 patients received a total dose of 3 mg/kg, and 12 patients received a total dose of 4 mg/kg. These investigators studied the pharmacodynamics of microplasmin and its effect on the clinical and hemodynamic parameters of the patients. Magnetic resonance imaging was used as a surrogate marker and matrix metalloproteinases serum concentrations were used as markers of neurovascular integrity. The study was under-powered to detect clinical efficacy. Microplasmin induced reversible effects on markers of systemic thrombolysis and neutralized alpha(2)-antiplasmin by up to 80 %. It was well-tolerated with 1 of 30 treated patients developing a fatal symptomatic intra-cerebral hemorrhage. No significant effect on re-perfusion rate or on clinical outcome was observed. Matrix metalloproteinase-2 levels were reduced in microplasmin-treated patients. The authors concluded that microplasmin was well-tolerated and achieved neutralization of alpha(2)-antiplasmin. Moreover, they stated that further studies are needed to determine whether microplasmin is an effective therapeutic agent for ischemic stroke.
Dommke et al (2010) examined the in-vitro fibrinolytic properties of microplasmin and its thrombolytic efficacy in a canine model of coronary artery thrombosis. The amidolytic and fibrinolytic activity of recombinant microplasmin was compared with natural human plasmin. Animals were randomly assigned to 1 of 6 treatment regimens, each with 5 animals per cohort. Four treatment groups received an intravenous bolus of microplasmin followed by an intravenous infusion of microplasmin for 1 hour (1 mg/kg + 1.5 mg/kg/hr with or without abciximab or 2 mg/kg + 3 mg/kg/hr). In 2 treatment groups, microplasmin was administered via an intra-coronary route. Bolus administration was followed by a 1-hour infusion if coronary flow was incompletely restored after the initial bolus administration (1 mg/kg + 1.5 mg/kg/hr or 2 mg/kg + 3 mg/kg/hr, respectively). The thrombolytic efficacy was documented by repeated angiographies and the coronary perfusion was assessed with the Thrombolysis in Myocardial Infarction (TIMI) grading. No significant differences between plasmin and microplasmin were observed with respect to the catalytic efficiencies towards the synthetic chromogenic substrates S-2403 or S-2444. The concentration required for 50 % lysis of purified fibrin clots in 3 hours, was approximately 100 nM for microplasmin compared to 20 nM for natural plasmin. Intravenous bolus administration of microplasmin restored TIMI 3 coronary flow in 0/5, 0/5, 1/5 and 2/5, respectively, whereas intra-coronary bolus administration restored TIMI 3 coronary flow in 1/5 and 4/5 (1 mg/kg and 2 mg/kg, respectively) (ANOVA p < 0.05). Thrombolysis in Myocardial Infarction 3 coronary flow was obtained in 0/5, 2/5, 2/5 and 3/5, respectively, during subsequent intravenous administration and in 5/5 and 4/5 in case of intra-coronary administration (ANOVA p < 0.05). When compared to natural plasmin, the catalytic efficiency of microplasmin towards chromogenic substrates was similar, but the fibrinolytic potency of microplasmin towards fibrin clots was lower.
In an open-label, dose-ascending, single-center, phase IIa study, Verhamme et al (2012) examined the safety and effectiveness of catheter-directed thrombolysis with microplasmin for infra-inguinal arterial or bypass occlusions. Patients who presented with acute occlusions were subsequently treated with an intra-thrombus infusion of 5 ascending doses of microplasmin: 0.3 mg/kg/hr for 4 hours; 0.45 mg/kg/hr for 4 hours; 0.6 mg/kg/hr for 4 hours; 0.9 mg/kg/hr for 4 hours or 0.6 mg/kg/hr for 6 hours. Repeat angiograms were obtained to assess the degree of clot lysis. The primary outcome was complete thrombolysis defined as greater than 95 % thrombus volume reduction at the end of the microplasmin infusion. Safety evaluation included bleedings, adverse events and coagulation biomarkers. Complete thrombolysis was obtained in 3 of the 19 treated patients at the end of microplasmin infusion. Thrombus volume reduction between 50 % and 95 % was achieved with all dosing regimens. Clinically significant distal embolization occurred in 8 patients; 1 major and 2 non-major bleedings occurred. Microplasmin depleted alpha 2-anti-plasmin and decreased fibrinogen. The authors concluded that intra-thrombus infusion of microplasmin for 4 or 6 hours resulted in significant clot lysis. Distal embolization appeared the most important limitation.
Tsui et al (2012) noted that fibronectin and laminin are clinically relevant plasmin receptors in the eye. Located at the vitreo-retinal interface, they are cleaved by ocriplasmin. A series of clinical trials to study ocriplasmin for the treatment of vitreo-retinal diseases including exudative age-related macular degeneration are underway. The results are promising and may impact patient care.
Gad Elkareem and de Smet (2014) stated that microplasmin is known to alter the structure of the vitreous gel. These researchers evaluated its ability to enhance clearance of an experimentally-induced vitreous hemorrhage, and compared it to ovine hyaluronidase. In this animal study, a total of 25 rabbits were divided into 5 groups: rabbits in groups 1 to 3 were treated with 25, 75 and 125 microg microplasmin, respectively; rabbits in group 4 were treated with 55 IU of hyaluronidase, while rabbits in group 5 were treated with normal saline (control). Eyes were injected in the mid-vitreous with 0.05 ml of autologous blood obtained from the marginal ear vein. One week later, all the groups were injected with the test solution injected in mid-vitreous as stated above. Clearance of the vitreous hemorrhage was assessed weekly by indirect ophthalmoscopy for 8 weeks. Microplasmin-treated eyes showed a significant clearance of the vitreous hemorrhage in a dose-dependent fashion, where group 3 (125 microg) had the highest clearance rate in comparison with control eyes. Hyaluronidase-treated eyes showed a similar clearance rate as group 3. In addition, group 3 showed a complete PVD, which did not develop in hyaluronidase-treated eyes. The authors concluded that microplasmin may be a useful agent to accelerate the clearance of vitreous hemorrhage.
Wong and Capone (2013) discussed the potential role of ocriplasmin as a surgical adjunct to vitrectomy in pediatric vitreo-retinopathies. These investigators performed a literature review of the laboratory and clinical evidence to-date for the use of both autologous plasmin enzyme as an adjunct to vitrectomy and more recently recombinant ocriplasmin as monotherapy for focal vitreo-macular traction in adults. Autologous plasmin enzyme is currently being used as a surgical adjunct to vitrectomy, with supporting levels 2 and 3 published evidence in a range of pediatric vitreo-retinopathies including stage-5 retinopathy of prematurity and congenital X-linked retinoschisis. The availability of autologous plasmin enzyme is limited. In recent phase III clinical trials, intra-vitreal ocriplasmin versus sham injection resulted in resolution of focal vitreo-macular traction in 27 % versus 10 % (p < 0.001, n = 652). The authors concluded that ocriplasmin may potentially be used as a surgical adjunct to vitrectomy in place of autologous plasmin enzyme. A phase II, randomized, placebo-controlled surgical trial is underway to assess this.
Jackson et al (2013) noted that symptomatic VMA describes symptomatic loss of visual function as a result of vitreous traction at the macula. Symptomatic VMA (sVMA) can occur in isolation as vitreo-macular traction, which may lead to the development of a macular hole, or it may occur alongside epiretinal membrane. It is likely to be associated with age-related macular degeneration and possibly diabetic maculopathy, although this is less certain. The treatment depends largely on the cause, but options include observation, vitrectomy, and pharmacologic vitreolysis. Small uncontrolled trials have also explored the use of an intra-vitreal gas bubble as a means of releasing VMA. If all cases of sVMA are considered together, then the burden of illness is substantial, with a prevalence of approximately 0.35 per 100 population (excluding epiretinal membrane). Furthermore, there may be many more cases of undiagnosed sVMA. The authors concluded that the recent introduction of ocriplasmin is likely to increase interest in sVMA. The authors concluded that clinical trials suggested that it has a role in the treatment of vitreo-macular traction and Stages 1 to 3 macular holes; but not primarily as a treatment of epiretinal membrane. Moreover, they stated that its role in other diseases associated with VMA remains to be determined.
de Smet and Castilla (2013) noted that diabetic retinopathy (DR) is a serious public health concern. Vision impairment follows from intra-ocular vascular proliferation known as proliferative DR (PDR) and/or from diabetic macular edema (DME). Clinical acumen and a recent meta-analysis of published studies suggested that the presence of a posterior vitreous detachment (PVD) reduces the risk of developing PDR, and has a favorable impact on DME. Pharmacologic vitreolysis by ocriplasmin or other agents may provide a minimally invasive method of achieving a PVD. If demonstrated in appropriate clinical studies including randomized trials, it would provide an interesting approach to prevent advanced and blinding stages of DR, particularly in areas where access to care is limited. These investigators reviewed the current epidemiology of DR as well as the role of the vitreous and its separation from the retina known as a PVD in DR based on a recent meta-analysis of published literature regarding the contribution of complete, partial or absent PVD to PDR and DME. The principles underlying vitreolysis and the induction of PVD were reviewed as well as the challenges faced by a pharmacologic approach. The results of clinical trials on the use of ocriplasmin were analyzed regarding its possible use in DR. They stated that ocriplasmin has the ability to liquefy the vitreous and induce a PVD in a statistically significant number of patients. However, current studies on patients with vitreo-macular adhesion and traction suggested that the majority of patients would not achieve a PVD with a single injection. As shown in the meta-analysis, a complete PVD is needed to significantly reduce the risk of PDR, while a partial PVD may worsen the prognosis. If a strategy can be developed that insures a complete PVD within an appropriate time interval, the prevention of PDR might become a realistic target for ocriplasmin or other vitreolytic agents. In DME, release of traction, whether complete or partial, is associated with a reduction in DME, which in several cases has resulted in improved vision. While no studies have been conducted on the use of ocriplasmin or other vitreolytic agents in DR, a few studies using plasmin indicated that it is likely to have a beneficial effect in DME. The authors concluded that based on the information available, randomized clinical trials would be needed to evaluate the clinical relevance of ocriplasmin and other potential vitreolytic agents in both forms of DR. Such trials could determine the effectiveness of this strategy as compared to prophylactic laser particularly in high-risk populations. Moreover, they noted that new follow-up and treatment strategies would also be needed should initial studies be encouraging.
The prescribing information for Jetrea states that “Repeated administration of Jetrea in the same eye is not recommended”. The prescribing information also notes that a second intra-vitreal administration of ocriplasmin (28 days apart) in monkeys at doses of 75 ug/eye (41 mcg/ml vitreous) or 125 ug/eye (68 mcg/ml vitreous) was associated with lens subluxation in all ocriplasmin treated eyes. Sustained increases in IOP occurred in two animals with lens subluxation. Microscopic findings in the eye included vitreous liquefaction, degeneration/disruption of the hyaloideocapsular ligament (with loss of ciliary zonular fibers), lens degeneration, mononuclear cell infiltration of the vitreous, and vacuolation of the retinal inner nuclear cell layer. These doses are 1.4-fold and 2.3-fold the intended clinical concentration in the vitreous of 29 ug/ml, respectively.
Appendix
The prescribing information of Jetrea notes the following regarding its dosage and administration:
- Must dilute before use.
- For single use ophthalmic intra-vitreal injection only.
- The recommended dose is 0.125 mg (0.1 mL of the diluted solution) administered by intra-vitreal injection to the affected eye once as a single dose.
The prescribing information states that repeated administration of Jetrea in the same eye is not recommended.
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