Safety of Intravitreal Ocriplasmin for Focal Vitreomacular Adhesion in Patients with Exudative Age-Related Macular Degeneration Roger L. Novack, MD, PhD,1 Giovanni Staurenghi, MD,2 Aniz Girach, MD,3 Nirodhini Narendran, MD,4 Michael Tolentino, MD5 Purpose: The evaluation of the safety and preliminary efficacy of 125 mg ocriplasmin intravitreal injection in patients with focal vitreomacular adhesion (VMA) and exudative age-related macular degeneration (AMD). Design: Randomized, sham-injection controlled, double-masked, multicenter, phase II trial. Participants: A total of 100 patients with VMA and wet AMD were randomized 3:1 to receive 125 mg ocriplasmin intravitreal injection or sham injection. Methods: Study treatment was administered in the mid-vitreous cavity by injection. Post-treatment safety and efficacy assessments were made at baseline and on days 7, 14, and 28 and months 3, 6, and 12 after injection. Secondary efficacy end points were exploratory in nature. Main Outcome Measures: The safety and tolerability of ocriplasmin were evaluated. The primary efficacy end point was the proportion of patients with VMA release at day 28 after injection. Secondary end points reported included VMA release over time, total posterior vitreous detachment (PVD), change in visual acuity from baseline, and number of antievascular endothelial growth factor (VEGF) injections. Results: The safety of ocriplasmin in patients with VMA and wet AMD was shown to be comparable to the known safety profile, with the majority of adverse events in the study eye occurring in the first 7 days after study treatment. A greater proportion of patients achieved VMA resolution and total PVD at month 12 with ocriplasmin compared with sham treatment. There was a decrease in the number of anti-VEGF injections with ocriplasmin at month 12 compared with the sham group, although no differences in visual acuity were observed. Conclusions: Ocriplasmin treatment in this population seems to be generally safe and well tolerated and resulted in more patients achieving VMA resolution and PVD with less anti-VEGF use compared with sham treatment. Ophthalmology 2015;122:796-802 ª 2015 by the American Academy of Ophthalmology. Supplemental material is available at www.aaojournal.org.
Age-related macular degeneration (AMD) poses significant socioeconomic challenges and is the leading cause of legal blindness in the elderly, affecting 1.75 million people in the United States alone.1 The pathophysiology of and risk factors for AMD are multifactorial, and an understanding of these processes will aid the development of effective treatments and preventative strategies.2,3 Neovascular AMD accounts for 10% to 15% of the overall prevalence of AMD and is characterized by proliferation of abnormal blood vessels in the choroid, which is accompanied by increased vascular permeability.3 Vascular endothelial growth factor (VEGF)-A expression in the retina is a major mediator of angiogenesis and vascular leakage in wet AMD,4 which can result in the loss of central vision. Evidence of the role of VEGF-A in wet AMD has established anti-VEGF agents as the current standard of care.4e6 Despite anti-VEGF treatment, however, more than half of patients do not improve after therapy.4,7 Results from the SUSTAIN study showed that up to 26% of
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2015 by the American Academy of Ophthalmology Published by Elsevier Inc.
patients are nonresponders to therapy with ranibizumab.8 The presence of vitreoretinal adhesions may predict nonresponsiveness to anti-VEGF therapy.9 Published data also indicate that the configuration of the vitreomacular interface may affect treatment outcomes with anti-VEGF therapy in patients with neovascular AMD.10 The relationship between vitreomacular adhesion (VMA) and wet AMD continues to be debated.11 Observational studies show that VMA has been associated with eyes that have wet AMD, with a prevalence of VMA 2.15 times that of control eyes.12,13 Direct tractional force has been suggested as a cause of this association, in particular data from in vivo studies in which mechanical stretch of retinal cells has been shown to induce VEGF expression.14,15 In addition, optical coherence tomography (OCT) images have shown evidence of traction in AMD,16 and sites of vitreous attachment to the macula correspond to areas of choroidal neovascularization, suggesting a direct relationship.17,18
http://dx.doi.org/10.1016/j.ophtha.2014.10.006 ISSN 0161-6420/14
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Vascular endothelial growth factor expression is also stimulated by hypoxia, and an alternative mechanism that may explain this relationship between AMD and posterior vitreous detachment (PVD) includes altered oxygenation of the vitreous cavity after PVD. Furthermore, the viscosity of the liquid in the vitreous cavity has been shown to change after PVD because the vitreous gel is replaced with aqueous humor, which may affect oxygen diffusion rates along with the diffusion coefficients of intravitreal molecules. This in turn may upregulate VEGF expression.7 Current treatments for wet AMD include the need for multiple injections, high financial cost of medication, and a risk of adverse events (AEs) associated with the treatment burden of intraocular administration. The economic strain on the health care system resulting from frequent clinic visits and the expense of medication and imaging studies highlight the need for improved options in the treatment of wet AMD. Current research targeting the angiogenic pathway is pursuing the identification of novel compounds that are less invasive and longer lasting, thus reducing the requirement for multiple injections. In addition, investigation into combination therapy is ongoing, including combining drugs with or without photodynamic therapy or radiation therapies, and numerous clinical trials are analyzing these options.19 Ocriplasmin (JETREA; ThromboGenics, Inc, Iselin, NJ) is a serine protease and a truncated form of plasmin.20e22 Ocriplasmin is active against the substrates fibronectin, laminin, and collagen and is able to cleave the vitreoretinal interface. Results of the 2 phase III MIVI-TRUST studies demonstrated a clinically significant difference in favor of a single ocriplasmin intravitreal injection of 125 mg over placebo for achieving the primary end point, VMA resolution at day 28,23 without the need for surgical intervention. As the interaction between VMA and AMD continues to be explored, it may be that pharmacologic vitreolysis with ocriplasmin could benefit patients with wet AMD. This analysis evaluates the safety and preliminary efficacy of ocriplasmin administered as a single intravitreal injection in patients with symptomatic VMA (synonymous with vitreomacular traction) and concomitant exudative AMD.
Methods Study Design This analysis is based on the results of a global, phase II, randomized, sham-controlled, double-masked, multicenter study assessing the safety and efficacy of 125 mg ocriplasmin intravitreal injection for treatment of patients with symptomatic VMA/vitreomacular traction and exudative AMD.
Inclusion and Exclusion Criteria Patients were eligible for the study if they were at least 50 years old and had focal VMA as measured by OCT, a diagnosis of active primary or recurrent subfoveal choroidal neovascularization secondary to AMD, at least 3 antiangiogenic injections (Lucentis or Avastin; Genentech, Inc, South San Francisco, CA) in the study eye, and a visual acuity of 20/32 to 20/200. For the OCT scan parameters, both the fast macular
thickness acquisition protocol and the 6-mm cross-hair acquisition protocol were used in both eyes. Central fixation was used. Patients were excluded if in the study eye they had evidence of complete macular PVD, vitreous hemorrhage, received more than 9 antiangiogenic injections (Lucentis, Avastin, or other), a history of rhegmatogenous retinal detachment or proliferative vitreoretinopathy, high myopia, or undergone ocular surgery in the past 3 months. Full criteria are listed at www.ClinicalTrials.gov under identifier NCT00913744.
Treatment A total of 100 patients who met all inclusion criteria and none of the exclusion criteria were randomized 3:1 via a telephone-based interactive voice response system to receive a single 125 mg ocriplasmin intravitreal injection or a sham injection. The sham injection was performed by holding a blunt needle to the sclera/ conjunctiva to mimic the study injection procedure. Intraocular pressure (IOP) was measured and an indirect ophthalmoscopic examination was performed immediately afterward to exclude retinal nonperfusion or other complications. To maintain masking of investigators, this examination was performed by the same unmasked investigator who administered the study treatment. Anti-VEGF therapy for treatment of exudative AMD was administered at the clinical discretion of the investigator; therefore, there was no set treatment criterion for use of anti-VEGF medication throughout the study.
Ethical Considerations The study and relevant protocol details are registered at www.ClinicalTrials.gov (identifier NCT00913744). The study was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. Institutional review board/ethics committee approval was obtained. Patients were required to provide written informed consent before enrollment in the study and the conduct of any study-related procedures.
Statistical Analysis Three data sets were considered for analysis in this study: the safety set (consisting of all patients who received the study treatment), the full analysis set (FAS; consisting of all randomized patients who were administered study treatment and for whom data from at least 1 efficacy assessment after baseline were available), and the per-protocol set (PPS; consisting of the FAS excluding patients or data that deviated sufficiently from the protocol). For the statistical analysis of the primary efficacy end point, the number and percentage of patients meeting the end point were tabulated by randomized treatment group. The treatment groups were compared using the Fisher exact test at a 2-sided significance level of 0.05. An exact 2-sided 95% confidence interval (CI) for the difference in proportions of success between the 2 groups was provided. The number of anti-VEGF injections was compared between treatment groups using Wilcoxon rank-sum tests. Any statistical comparisons of the secondary efficacy end points were of a supportive nature only and were interpreted as such, with the strength of association for declaration of a supportive trend set to a nominal 2-sided 0.05 significance level for all comparisons of ocriplasmin with sham. No adjustments were made for multiple comparisons or multiple end points for the secondary end points. The primary end point was evaluated in the FAS, with missing data imputed using the last observation carried forward method. The robustness of the main efficacy analyses was evaluated by performing sensitivity analyses in the FAS and PPS. This study was started before the pivotal phase III studies23 and before the response rate to ocriplasmin was determined. The event
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Results
Safety Measurements
Data from 100 patients were available for analysis. Demographics and baseline characteristics for the FAS are presented in Table 1 (available at www.aaojournal.org). Twenty-five patients were randomized to receive sham injection, and 75 patients were randomized to receive 125 mg ocriplasmin. Of these 100 patients, most (94.0%) completed the study (1/25 patients [4.0%] in the sham group and 5/75 patients [6.7%] in the ocriplasmin group were discontinued from the study). The most common reason for discontinuation was withdrawal of consent (1/1 in the sham group and 2/5 in the ocriplasmin group) and AEs (2/5 in the ocriplasmin group). One patient in the ocriplasmin group died before completing the study. None of the events resulting in discontinuation was related to the study drug. One patient in the ocriplasmin group withdrew consent after receiving study treatment; therefore, the FAS includes 74 of 75 patients (98.7%) in the ocriplasmin group and 25 of 25 patients (100.0%) in the sham group.
An AE was defined as any untoward medical occurrence in a patient who was administered a pharmaceutical product, whether or not it was related to the study treatment. Serious AEs (SAEs) were defined as any AE that resulted in death, was immediately lifethreatening, required inpatient hospitalization, resulted in persistent or significant disability/incapacity, or was a congenital abnormality. The intensity of AEs was characterized as mild, moderate, or severe. The causal relationship to study treatment was assessed as probably related, possibly related, remotely related, or unrelated. An ophthalmologic examination was performed at baseline and on days 7, 14, and 28 and months 3, 6, and 12 after injection on the basis of the investigator’s standard of care. Assessments included IOP measurement, slit-lamp examination, and dilated fundus examination.
Safety Analysis The safety of ocriplasmin injection was assessed by evaluating reported AEs, ophthalmologic examination, fundus photography, and fluorescein angiography. The safety set was used for all analyses of safety data. Summaries of complications after injections included worsening of visual acuity and change from baseline; AEs, with special attention to ophthalmic events (worsening macular edema, vitreous hemorrhage, retinal tear or detachments, inflammation); IOP and change from baseline in IOP; slit-lamp examination findings; retinal examination; and concomitant medication use. Only treatment-emergent AEs, defined as events with an onset on or after the date of study drug injection, were included in the AE summaries and were coded using MedDRA version 14.1 (MedDRA MSSO, McLean, VA).
Efficacy Measurements The primary efficacy end point of the study was the proportion of patients with VMA release at day 28 as measured by time domain OCT (TD-OCT). Secondary end points included the proportion of patients who experienced release of VMA at visits other than day 28 after injection, assessment of PVD status, average macular thickness, visual acuity, central retinal/lesion thickness, classic membrane growth, amount of fluorescein leakage, number of patients requiring additional therapy, number of anti-VEGF injections required during study, initial anti-VEGF-free interval, and 25-item Visual Function Questionnaire (VFQ-25) scores. At the time of study initiation, TD-OCT was the gold standard in retinal imaging technology; therefore, TD-OCT scans were obtained in the study eye at each of the 8 study visits and performed in both eyes at baseline and month 12. Assessments were made after dilating the pupil. All OCT scans were submitted to a central reading center for evaluation. Dynamic B-scan ultrasounds were used to assess the presence and grade of PVD. Best-corrected visual acuity (BCVA) was measured with a backlit Early Treatment Diabetic Retinopathy Study (ETDRS) chart set 4 m from the patient and reported as the number of letters read correctly. The patient-administered VFQ-25 was completed by the patient at baseline, month 6, and month 12, and improvement in VFQ-25 results was evaluated using individual scores, subscale scores, and global composite scores. Fundus photography and fluorescein angiography were conducted at baseline and day 28 and month 12 after injection. All fundus photographs and fluorescein angiograms were assessed by a central reading center.
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Patient Disposition
Overview of Adverse Events An overall summary of AEs is presented in Table 2. The percentage of patients experiencing at least 1 AE was the same (72.0%) in both treatment groups. A larger proportion of patients (36/75 [48.0%]) in the ocriplasmin group experienced a greater number of AEs in the study eye (83 in total) in the first 7 days after injection when compared with the sham group (4/25 [16.0%]; 6 AEs in total).
Ocular Adverse Events The percentage of ocular AEs in the study eye was higher in the ocriplasmin-treated patients than in the sham group (47/75 [62.7%] vs. 13/25 [52.0%], respectively) (Table 3). A total of 131 AEs in the study eye were reported in the ocriplasmin group, and 29 AEs Table 2. Overall Summary of Adverse Events (Safety Set) Sham (n [ 25) Category*
Ocriplasmin (n [ 75)
AEs, n (%) Events (n) AEs, n (%) Events (n)
All AEs Any event 18 (72.0) Any nonocular event 9 (36.0) Any ocular event 15 (60.0) Any study eye event 13 (52.0) Any nonstudy eye event 6 (24.0) Drug-related AEs Any event 5 (20.0) Any nonocular event 0 (0.0) Any ocular event 5 (20.0) Any study eye event 5 (20.0) Any nonstudy eye event 0 (0.0) SAEs Any event 2 (8.0) Any nonocular event 2 (8.0) Any ocular event 0 (0.0) Any study eye event 0 (0.0) Any nonstudy eye event 0 (0.0)
60 25 35 29 11
54 25 48 48 16
(72.0) (33.3) (64.0) (64.0) (21.3)
200 63 137 131 23
5 0 5 5 0
30 0 30 30 3
(40.0) (0.0) (40.0) (40.0) (4.0)
70 0 70 70 3
4 4 0 0 0
18 10 8 8 0
(24.0) (13.3) (10.7) (10.7) (0.0)
24 13 11 11 0
AE ¼ adverse event; SAE ¼ serious adverse event. *Patients may be in >1 category.
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Table 3. Adverse Events in the Study Eye Reported for 5% of Patients (Safety Set)
System Organ Class* Preferred Term
Sham (n [ 25) n (%)
Ocriplasmin (n [ 75)
Events (n)
Eye disorders 13 (52.0) Visual acuity reduced 3 (12.0) Photopsia 2 (8.0) Eye pain 0 (0.0) Conjunctival hemorrhage 2 (8.0) Vitreous floaters 0 (0.0) Retinal hemorrhage 4 (16.0) Blepharitis 0 (0.0) Cataract nuclear 0 (0.0) Corneal edema 0 (0.0) Investigations 0 (0.0) Increased IOP 0 (0.0)
28 5 2 0 3 0 5 0 0 0 0 0
n (%) 47 14 9 10 7 8 2 4 4 4 4 4
Serious Adverse Events
Events (n)
(62.7) (18.7) (12.0) (13.3) (9.3) (10.7) (2.7) (5.3) (5.3) (5.3) (5.3) (5.3)
121 19 10 10 8 8 2 4 4 4 4 4
IOP ¼ intraocular pressure. *Patients could be in multiple categories.
were reported in the sham group (Table 2). The increased frequency of AEs in the ocriplasmin group was predominantly driven by AEs that are known to be associated with the intended action of the drug.22 In the ocriplasmin group, 14 of 75 patients (18.7%) experienced reduced visual acuity, 9 of 75 patients (12.0%) experienced photopsia, and 8 of 75 patients (10.7%) experienced vitreous floaters. Of note, 2 of 75 patients (2.7%) in the ocriplasmin group experienced retinal hemorrhage compared with 4 of 25 patients (16.0%) in the sham group. Table 3 presents study eye AEs that occurred in 5% of patients in either treatment group. Other AEs in the ocriplasmin group were associated with the intravitreal injection procedure itself, including eye pain (10/75 [13.3%]) and conjunctival hemorrhage (7/75 [9.3%]). All drug-related AEs were ocular and more common in ocriplasmin-treated patients than in the sham controls (30 patients of a total of 75 patients treated with ocriplasmin [40.0%] experienced drug-related AEs) (Table 2). A total of 70 AEs in the ocriplasmin group were considered to be drug related, and 5 of 25 patients (20.0%) in the sham group experienced 5 AEs. The majority of drug-related AEs occurred in the study eye, with 3 of 75 patients Table 4. Summary of Serious Adverse Events (Safety Set)
System Organ Class Preferred Term
Sham (n [ 25)
Ocriplasmin (n [ 75)
n (%) Events
Any SAE 2 Any nonocular SAE 2 Any ocular SAE 0 Any study eye SAE 0 Eye disorders (study eye) 0 Retinal detachment 0 Visual acuity reduced 0 Blindness transient 0 Investigations (study eye) 0 Increased IOP 0 Infections and infestations (study eye) 0 Endophthalmitis 0
(8.0) (8.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0)
4 4 0 0 0 0 0 0 0 0 0 0
n (%) 18 10 8 8 7 3 3 2 2 2 1 1
IOP ¼ intraocular pressure; SAE ¼ serious adverse event.
(24.0) (13.3) (10.7) (10.7) (9.3) (4.0) (4.0) (2.7) (2.7) (2.7) (1.3) (1.3)
(4.0%) in the ocriplasmin group, but none of the sham group, reporting drug-related AEs in the nonstudy eye. The 3 nonstudy eye AEs were photopsias, phosphenes, and conjunctivitis.
Events 24 13 11 11 8 3 3 2 2 2 1 1
The frequency of SAEs was higher in the ocriplasmin group (18/75 [24.0%]) than in the sham group (2/25 [8.0%]). Table 4 presents a summary of the SAEs in both treatment groups. Ocular SAEs were experienced by 8 of 75 patients (10.7%) in the ocriplasmin group, all of which occurred in the study eye. No patients in the sham group experienced ocular SAEs. Thirteen nonocular SAEs were reported by 10 of 75 patients (13.3%) in the ocriplasmin group, and 4 nonocular SAEs were reported by 2 of 25 patients (8.0%) in the sham group. Eight SAEs in 6 patients in the ocriplasmin group were considered possibly or probably related to study drug, and all occurred in the study eye. These SAEs are detailed in the following sections. Reduced Visual Acuity. Three patients experienced reduced visual acuity, all within 1 day of study drug injection. The first case was a 64-year-old woman who had a BCVA of 52 ETDRS letters (20/80 Snellen acuity) at baseline. A day after injection with ocriplasmin, her BCVA decreased to hand motion, yet the fundus and OCT examination results were reported as normal. Four days later, she had a “macula-off” rhegmatogenous retinal detachment, which was repaired via vitrectomy but had a poor outcome. The final recorded BCVA was 9 letters (20/800 Snellen acuity). The investigator noted the case as “possibly related to study treatment.” The second case was a 72-year-old woman who had a BCVA of 70 letters (20/40 Snellen acuity) at baseline. She also had some subretinal fluid (SRF) on OCT. The day after injection with ocriplasmin, her BCVA decreased to 38 letters (20/200 Snellen acuity), with increased SRF on OCT. A week later, her BCVA improved to 64 letters (20/50 Snellen acuity), with resolution of the SRF. Her last recorded BCVA was 68 letters (20/40 Snellen acuity), and the investigator noted this case as “probably related to study drug.” The third case was an 80-year-old man who had a BCVA of 76 letters (20/32 Snellen acuity) at baseline. He also had some SRF on OCT at baseline. On the same day as the injection of ocriplasmin, he noticed a decrease in his vision, and his BCVA was 20/200. Four days later, his BCVA had improved to 20/63, with a resolution of the SRF. His last recorded BCVA was 72 letters (20/40 Snellen acuity), and the investigator noted this case as “probably related to study drug.” In accordance with the inclusion/exclusion criteria, all of these cases had VMA and wet AMD at baseline, and in all of them VMA resolved within 1 week of injection of ocriplasmin. Transient Blindness Related to Increased Intraocular Pressure. Two patients experienced transient blindness from baseline visual acuity of 38 and 66 letters to “no light perception” due to increased IOP. Both cases occurred within 5 minutes of injection of the study drug. Both recovered to baseline IOP within 1 hour after treatment with massage and apraclonidine. Both patients recovered their vision to their baseline values. Retinal Detachment. Three cases of retinal detachment were noted in this trial. The 1 patient who experienced a rhegmatogenous retinal detachment associated with visual acuity loss, which was reported as an SAE, has already been noted. The second case was an 80-year-old woman who had a tractional retinal detachment that was unrelated to the study drug, according to the investigator, and occurred 4 months after the injection. This patient had advanced diabetic retinopathy and epiretinal membrane, as well as preretinal macular gliosis. The third case was a 76-year-old man who had a tractional retinal detachment 11 months after the study drug injection, which was deemed to be remotely related to the study drug, according to the investigator.
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Figure 1. Proportion of patients with vitreomacular adhesion (VMA) release and total posterior vitreous detachment (PVD) at day 28.
Figure 2. Mean number of antievascular endothelial growth factor injections at month 12.
Endophthalmitis. One case of endophthalmitis was diagnosed in the study, which involved an 87-year-old man who had endophthalmitis 10 months after the study drug injection and 1 day after an injection of bevacizumab for wet AMD. The investigator confirmed that this case was unrelated to the study drug.
revealed a mean change from baseline of 1.5 letters. A comparison of visual acuity data between treatment groups at each time point did not show clinically relevant differences. The majority of patients in both treatment groups maintained visual acuity at each study visit. The proportion of patients experiencing improvement of at least 1 or 2 lines was slightly greater in the sham group at most visits; however, a greater proportion of patients in the sham group experienced a decline of at least 1 or 2 lines at most visits. Subanalysis was performed to evaluate the change in BCVA by study visit between patients who achieved VMA release by the end of the study and patients who showed no noticeable differences. AntieVascular Endothelial Growth Factor Injections. All patients in both treatment groups were required by the protocol to have received anti-VEGF injections in the study eye before entering the study. During the study, the majority of patients (w91%) in both groups received at least 1 anti-VEGF injection, with a mean of 6.1 injections at month 12 for the sham group and 4.4 injections for the ocriplasmin group (P ¼ 0.069) (Fig 2). Analysis of the cumulative frequency at month 12 and interval frequency of anti-VEGF injections by study visit and treatment showed no notable differences between treatment groups. The 3 anti-VEGF drugs used were ranibizumab (Lucentis), bevacizumab (Avastin), and aflibercept (Eylea; Regeneron Pharmaceuticals, Inc, Tarrytown, NY). No clinically meaningful differences between ocriplasmin and sham were observed in the secondary analysis of average macular thickness, central retinal/lesion thickness, classic membrane growth, amount of fluorescein leakage, changes in visual acuity, or VFQ-25 scores.
Efficacy of Ocriplasmin in Wet Age-Related Macular Degeneration Primary End Point: Vitreomacular Adhesion Release at Day 28. The primary end point of VMA release at day 28 was calculated from the FAS and was achieved in 18 of 74 patients (24.3%) in the ocriplasmin group and 3 of 25 patients (12.0%) in the sham group. The difference between treatment groups was 12.3% (95% CI, 3.7 to 28.4), which was not statistically significant (P ¼ 0.262). Analysis of the primary end point using the PPS revealed similar results. Figure 1 depicts the proportion of patients with VMA release in the study eye at day 28. The mean VMA diameter at baseline was smaller in the ocriplasmin group compared with the sham group; however, the primary end point results were not significant between treatment groups, irrespective of VMA diameter at baseline. Secondary End Points. Secondary end points were designed to be exploratory in nature, support the primary end point, and be evaluated using the FAS and PPS. Because this was a phase II exploratory study, it was not powered to identify significant differences in the secondary end points between the groups. Vitreomacular Adhesion Release over Time and Posterior Vitreous Detachment. The proportion of patients in the ocriplasmin group who experienced VMA release by month 12 was greater than in the sham group (31/74 [41.9%] vs. 6/25 [24.0%], respectively), with a difference of 17.9% (95% CI, 2.3 to 38.1). The proportion of patients experiencing total PVD at day 28 is shown in Figure 1. The proportion of patients experiencing total PVD was greater in the ocriplasmin group at each visit compared with the sham group, with 17 of 74 patients (23.0%) in the ocriplasmin group and 3 of 25 patients (12.0%) in the sham group experiencing total PVD at month 12, a difference of 11.0% (95% CI, 5.0 to 26.9). Subanalysis demonstrated a greater proportion of total PVD observed when VMA release occurred compared with no VMA release. Visual Acuity. The mean change from baseline in the number of ETDRS letters read at month 12 for the sham group was 2.8 letters. By contrast, the mean change from baseline in the ocriplasmin group increased over time up to month 6; however, the month 12 value
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Discussion The analysis of this phase II study of patients with VMA and exudative AMD demonstrated that ocriplasmin was well tolerated by the majority of patients. The majority of AEs in both treatment groups were ocular in nature, and patients in the ocriplasmin group had a higher proportion (64.0%) of study eye AEs than patients in the sham group (52.0%). This was to be expected because the sham injection did not penetrate the globe of the eye. Drug-related AEs were more frequently reported in the ocriplasmin group than in the sham group within the first 7 days of treatment, and the higher
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event rates were likely due to the pharmacologic action of ocriplasmin. By contrast, during the period from day 8 to the end of the study, there was no clinically meaningful difference between the groups. This is consistent with previous studies that showed that the pharmacologic action of ocriplasmin was reduced to below the level of quantification in the vitreous cavity within 7 days compared with concentration immediately after injection.24 In this study, ocriplasmin exhibited a safety profile that was comparable to the results of the 2 phase III trials,23 which had an overall ocular AE rate of 53.5% for placebo (intravitreal vehicle injection) and 68.4% for ocriplasmin-treated patients. A comparison of the drug-related AEs between those in this study and those in the phase III trials again showed similar rates: 20.0% for sham (vs. 21.4% in placebo for phase III) and 40.0% for ocriplasmin in both this study and the phase III trials. The risks of retinal hemorrhage in wet AMD are well documented.25e27 In this study, ocriplasmin did not seem to increase the risk of retinal hemorrhage when compared with the sham group. Efficacy results showed that a greater proportion of patients achieved the primary outcome of VMA resolution by day 28 when treated with ocriplasmin, although this difference was not significant (P ¼ 0.262). In both treatment groups, VMA release increased over time. This study, with a limited sample size of 100 patients, was not sufficiently powered to show statistical significance in VMA resolution between ocriplasmin and sham. It was previously noted that VMA resolution was higher in patients with a smaller VMA diameter at baseline. Although this smaller diameter may have contributed in part to the higher proportion of VMA closures in the ocriplasmin group, it is difficult to conclude this because the results were not statistically significant. However, it is noteworthy that the VMA resolution and total PVD rates at day 28 with ocriplasmin were similar to those in the pivotal phase III trials.23 The VMA resolution and total PVD rates observed in the sham group of this study were also similar to those observed in the placebo group in the pivotal phase III studies; however, the control group in this study may not be a true reflection of the natural history of the disease because patients received concomitant anti-VEGF injections. Secondary efficacy analyses in this study were exploratory only because the study was not powered to identify significant differences between the groups with respect to the secondary end points (release of VMA at visits other than day 28 after injection, assessment of PVD status, average molecular thickness, visual acuity, central retinal/ lesion thickness, classic membrane growth, amount of fluorescein leakage, number of patients requiring additional therapy, number of anti-VEGF injections required during the study, initial anti-VEGF interval, and VFQ-25 scores). Analysis of PVD status showed that a larger event rate was observed in the ocriplasmin group than in the sham group, which was maintained until the end of the study. It has been suggested that VMA can antagonize the effects of anti-VEGF treatment28; however, this was shown in patients without prior anti-VEGF therapy. Despite the study not being powered for significant efficacy values, the mean number of anti-VEGF injections decreased by 28% to 4.4 injections in the ocriplasmin group (which had a higher level of VMA resolution) compared
with 6.1 injections in the sham group. Vitreomacular adhesion resolution may lead to increased oxygenation at the retina. Because hypoxia is a known stimulator of VEGF,7 VMA resolution may lead to decreased VEGF stimulus and production, which may explain the reduced need for anti-VEGF drugs.
Study Limitations In addition to the study not having sufficient power to show the statistical significance of the primary end point, another study limitation included a lack of predefined anti-VEGF treatment criteria. Furthermore, the use of TD-OCT rather than spectral domain (SD)-OCT was considered the gold standard in OCT measurement at the time of study initiation. This has since been generally replaced because SD-OCT allows for a greater resolution and scanning speed of retinal tissue and has been shown to have better reproducibility and reliability of results than TD-OCT.29e31 In conclusion, data from this study add to the total evidence evaluating the safety of ocriplasmin and suggest that ocriplasmin treatment in patients with VMA and wet AMD is generally safe and well tolerated. In addition, ocriplasmin treatment in these patients resulted in greater VMA resolution, total PVD, and a reduced need for anti-VEGF injections compared with sham treatment. Acknowledgments. Medical writing support was provided by Mark Robinson and Diane Kwiatkoski of Quintiles.
References 1. Friedman DS, O’Colmain BJ, Muñoz B, et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 2004;122:564–72. 2. van Lookeren Campagne M, LeCouter J, Yaspan BL, et al. Mechanisms of age-related macular degeneration and therapeutic opportunities. J Pathol 2014;232:151–64. 3. Cheung LK, Eaton A. Age-related macular degeneration. Pharmacotherapy 2013;33:838–55. 4. Tranos P, Vacalis A, Asteriadis S, et al. Resistance to antivascular endothelial growth factor treatment in age-related macular degeneration. Drug Des Devel Ther 2013;7:485–90. 5. Kaiser PK, Cruess AF, Bogaert P, et al. Balancing risk in ophthalmic prescribing: assessing the safety of anti-VEGF therapies and the risks associated with unlicensed medicines. Graefes Arch Clin Exp Ophthalmol 2012;250:1563–71. 6. Stewart MW. The expanding role of vascular endothelial growth factor inhibitors in ophthalmology. Mayo Clin Proc 2012;87:77–88. 7. Simpson AR, Petrarca R, Jackson TL. Vitreomacular adhesion and neovascular age-related macular degeneration. Surv Ophthalmol 2012;57:498–509. 8. Holz FG, Amoaku W, Donate J, et al. Safety and efficacy of a flexible dosing regimen of ranibizumab in neovascular agerelated macular degeneration: the SUSTAIN study. Ophthalmology 2011;118:663–71. 9. Krebs I, Glittenberg C, Ansari-Shahrezaei S, et al. Non-responders to treatment with antagonists of vascular endothelial growth factor in age-related macular degeneration. Br J Ophthalmol 2013;97:1443–6. 10. Mayr-Sponer U, Waldstein SM, Kundi M, et al. Influence of the vitreomacular interface on outcomes of ranibizumab
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11. 12.
13. 14.
15.
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17. 18. 19. 20.
therapy in neovascular age-related macular degeneration. Ophthalmology 2013;120:2620–9. Qian CX, Foster WJ, Rezende FA. Tractional maculopathies in agerelated macular degeneration. US Ophthalmic Rev 2012;5:119–25. Jackson TL, Nicod E, Angelis A, et al. Vitreous attachment in age-related macular degeneration, diabetic macular edema, and retinal vein occlusion: a systematic review and metaanalysis. Retina 2013;33:1099–108. Green-Simms AE, Bakri SJ. Vitreomacular traction and agerelated macular degeneration. Semin Ophthalmol 2011;26:137–8. Suzuma I, Hata Y, Clermont A, et al. Cyclic stretch and hypertension induce retinal expression of vascular endothelial growth factor and vascular endothelial growth factor receptor2: potential mechanisms for exacerbation of diabetic retinopathy by hypertension. Diabetes 2001;50:444–54. Suzuma I, Suzuma K, Ueki K, et al. Stretch-induced retinal vascular endothelial growth factor expression is mediated by phosphatidylinositol 3-kinase and protein kinase C (PKC)-zeta but not by stretch-induced ERK1/2, Akt, Ras, or classical/ novel PKC pathways. J Biol Chem 2002;277:1047–57. Mojana F, Cheng L, Bartsch D-U, et al. The role of abnormal vitreomacular adhesion in age-related macular degeneration: spectral optical coherence tomography and surgical results. Am J Ophthalmol 2008;146:218–27. Sebag J. Anomalous posterior vitreous detachment: a unifying concept in vitreo-retinal disease. Graefes Arch Clin Exp Ophthalmol 2004;242:690–8. Krebs I, Brannath W, Glittenberg C, et al. Posterior vitreomacular adhesion: a potential risk factor for exudative age-related macular degeneration? Am J Ophthalmol 2007;144:741–6. Smith AG, Kaiser PK. Emerging treatments for wet agerelated macular degeneration. Expert Opin Emerg Drugs 2014;19:157–64. Gandorfer A, Rohleder M, Sethi C, et al. Posterior vitreous detachment induced by microplasmin. Invest Ophthalmol Vis Sci 2004;45:641–7.
21. JETREA [package insert]. Iselin, NJ: ThromboGenics, Inc.; 2014. 22. JETREA Summary of Product Characteristics. Leuven, Belgium: ThromboGenics NV; 2013. 23. Stalmans P, Benz MS, Gandorfer A, et al. Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular holes. N Engl J Med 2012;367:606–15. 24. Stalmans P, Girach A. Vitreous levels of active ocriplasmin following intravitreal injection: results of an ascending exposure trial. Invest Ophthalmol Vis Sci 2013;54:6620–7. 25. Scupola A, Coscas G, Soubrane G, Balestrazzi E. Natural history of macular subretinal hemorrhage in age-related macular degeneration. Ophthalmologica 1999;213:97–102. 26. Steel DHW, Sandhu SS. Submacular haemorrhages associated with neovascular age-related macular degeneration. Br J Ophthalmol 2011;95:1051–7. 27. Sunness JS, Gonzalez-Baron J, Bressler NM, et al. The development of choroidal neovascularization in eyes with the geographic atrophy form of age-related macular degeneration. Ophthalmology 1999;106:910–9. 28. Lee SJ, Koh HJ. Effects of vitreomacular adhesion on antivascular endothelial growth factor treatment for exudative agerelated macular degeneration. Ophthalmology 2011;118: 101–10. 29. Forooghian F, Cukras C, Meryerle CB, et al. Evaluation of time domain and spectral domain optical coherence tomography in the measurement of diabetic macular edema. Invest Ophthalmol Vis Sci 2008;49:4290–6. 30. Leung CK, Cheung CY, Weinreb RN, et al. Comparison of macular thickness measurements between time domain and spectral domain optical coherence tomography. Invest Ophthalmol Vis Sci 2008;49:4893–7. 31. Folgar FA, Toth CA, DeCroos FC, et al. Assessment of retinal morphology with spectral and time domain OCT in the phase III trials of enzymatic vitreolysis. Invest Ophthalmol Vis Sci 2012;53:7395–401.
Footnotes and Financial Disclosures Originally received: June 12, 2014. Final revision: October 9, 2014. Accepted: October 13, 2014. Available online: November 27, 2014. Manuscript no. 2014-914. 1 Retina Vitreous Associates, Los Angeles, California.
M.T.: Research grants Aerpio Therapeutics, Alcon, Allegro, Allergan, Bayer, Genentech, GlaxoSmithKline, Notal Vision, Novartis, Pfizer, Roche, ThromboGenics NV; Nonfinancial support and personal fees e Alimera, ThromboGenics NV, Valeant; Grants and Personal fees Regeneron; Personal fees Bausch & Lomb, Notal Vision.
2
Funding for this study was provided by ThromboGenics NV. ThromboGenics NV participated in the design and conduct of the study; collection, management, analysis, and interpretation of data; and preparation, review, and approval of the manuscript.
Department of Biomedical and Clinical Science, Luigi Sacco Hospital, Milan, Italy.
3
NightstaRx Ltd, London, United Kingdom (formerly of ThromboGenics NV).
4
Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, United Kingdom. 5 Center for Retina and Macular Disease, Winter Haven, Florida. Presented at: the American Academy of Ophthalmology Retina 2013 Subspecialty Day, November 15e16, New Orleans, Louisiana. Financial Disclosure(s): The author(s) have made the following disclosure(s): R.L.N.: Nonfinancial support ThromboGenics NV during the conduct of this study; Personal fees Alcon, Clarity Medical, Genentech. G.S.: Nonfinancial support ThromboGenics NV during the conduct of this study; Consultant fees Alcon, Allergan, Bayer, Genentech, GlaxoSmith Kline, Heidelberg Engineering, Novartis, Quantel Medical, Roche, Zeiss. A.G.: Former employee ThromboGenics NV. N.N.: Nonfinancial support ThromboGenics NV during the conduct of this study; Research grant Allergan, Heidelberg Engineering, Novartis; Personal fees Alimera Sciences, Bausch & Lomb.
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Abbreviations and Acronyms: AE ¼ adverse event; AMD ¼ age-related macular degeneration; BCVA ¼ best-corrected visual acuity; CI ¼ confidence interval; ETDRS ¼ Early Treatment Diabetic Retinopathy Study; FAS ¼ full analysis set; IOP ¼ intraocular pressure; OCT ¼ optical coherence tomography; PPS ¼ per-protocol set; PVD ¼ posterior vitreous detachment; SAE ¼ serious adverse event; SD-OCT ¼ spectral domain optical coherence tomography; SRF ¼ subretinal fluid; TD-OCT ¼ time domain optical coherence tomography; VEGF ¼ vascular endothelial growth factor; VFQ25 ¼ 25-item Visual Function Questionnaire; VMA ¼ vitreomacular adhesion. Correspondence: Roger L. Novack, MD, PhD, 1127 Wilshire Boulevard, Suite 1620, Los Angeles, CA 90017. E-mail: [email protected].
Age-related macular degeneration (AMD) poses significant socioeconomic challenges and is the leading cause of legal blindness in the elderly, affecting 1.75 million people in the United States alone.1 The pathophysiology of and risk factors for AMD are multifactorial, and an understanding of these processes will aid the development of effective treatments and preventative strategies.2,3 Neovascular AMD accounts for 10% to 15% of the overall prevalence of AMD and is characterized by proliferation of abnormal blood vessels in the choroid, which is accompanied by increased vascular permeability.3 Vascular endothelial growth factor (VEGF)-A expression in the retina is a major mediator of angiogenesis and vascular leakage in wet AMD,4 which can result in the loss of central vision. Evidence of the role of VEGF-A in wet AMD has established anti-VEGF agents as the current standard of care.4e6 Despite anti-VEGF treatment, however, more than half of patients do not improve after therapy.4,7 Results from the SUSTAIN study showed that up to 26% of
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patients are nonresponders to therapy with ranibizumab.8 The presence of vitreoretinal adhesions may predict nonresponsiveness to anti-VEGF therapy.9 Published data also indicate that the configuration of the vitreomacular interface may affect treatment outcomes with anti-VEGF therapy in patients with neovascular AMD.10 The relationship between vitreomacular adhesion (VMA) and wet AMD continues to be debated.11 Observational studies show that VMA has been associated with eyes that have wet AMD, with a prevalence of VMA 2.15 times that of control eyes.12,13 Direct tractional force has been suggested as a cause of this association, in particular data from in vivo studies in which mechanical stretch of retinal cells has been shown to induce VEGF expression.14,15 In addition, optical coherence tomography (OCT) images have shown evidence of traction in AMD,16 and sites of vitreous attachment to the macula correspond to areas of choroidal neovascularization, suggesting a direct relationship.17,18
http://dx.doi.org/10.1016/j.ophtha.2014.10.006 ISSN 0161-6420/14
Novack et al
Ocriplasmin in Patients with VMA and Wet AMD
Vascular endothelial growth factor expression is also stimulated by hypoxia, and an alternative mechanism that may explain this relationship between AMD and posterior vitreous detachment (PVD) includes altered oxygenation of the vitreous cavity after PVD. Furthermore, the viscosity of the liquid in the vitreous cavity has been shown to change after PVD because the vitreous gel is replaced with aqueous humor, which may affect oxygen diffusion rates along with the diffusion coefficients of intravitreal molecules. This in turn may upregulate VEGF expression.7 Current treatments for wet AMD include the need for multiple injections, high financial cost of medication, and a risk of adverse events (AEs) associated with the treatment burden of intraocular administration. The economic strain on the health care system resulting from frequent clinic visits and the expense of medication and imaging studies highlight the need for improved options in the treatment of wet AMD. Current research targeting the angiogenic pathway is pursuing the identification of novel compounds that are less invasive and longer lasting, thus reducing the requirement for multiple injections. In addition, investigation into combination therapy is ongoing, including combining drugs with or without photodynamic therapy or radiation therapies, and numerous clinical trials are analyzing these options.19 Ocriplasmin (JETREA; ThromboGenics, Inc, Iselin, NJ) is a serine protease and a truncated form of plasmin.20e22 Ocriplasmin is active against the substrates fibronectin, laminin, and collagen and is able to cleave the vitreoretinal interface. Results of the 2 phase III MIVI-TRUST studies demonstrated a clinically significant difference in favor of a single ocriplasmin intravitreal injection of 125 mg over placebo for achieving the primary end point, VMA resolution at day 28,23 without the need for surgical intervention. As the interaction between VMA and AMD continues to be explored, it may be that pharmacologic vitreolysis with ocriplasmin could benefit patients with wet AMD. This analysis evaluates the safety and preliminary efficacy of ocriplasmin administered as a single intravitreal injection in patients with symptomatic VMA (synonymous with vitreomacular traction) and concomitant exudative AMD.
Methods Study Design This analysis is based on the results of a global, phase II, randomized, sham-controlled, double-masked, multicenter study assessing the safety and efficacy of 125 mg ocriplasmin intravitreal injection for treatment of patients with symptomatic VMA/vitreomacular traction and exudative AMD.
Inclusion and Exclusion Criteria Patients were eligible for the study if they were at least 50 years old and had focal VMA as measured by OCT, a diagnosis of active primary or recurrent subfoveal choroidal neovascularization secondary to AMD, at least 3 antiangiogenic injections (Lucentis or Avastin; Genentech, Inc, South San Francisco, CA) in the study eye, and a visual acuity of 20/32 to 20/200. For the OCT scan parameters, both the fast macular
thickness acquisition protocol and the 6-mm cross-hair acquisition protocol were used in both eyes. Central fixation was used. Patients were excluded if in the study eye they had evidence of complete macular PVD, vitreous hemorrhage, received more than 9 antiangiogenic injections (Lucentis, Avastin, or other), a history of rhegmatogenous retinal detachment or proliferative vitreoretinopathy, high myopia, or undergone ocular surgery in the past 3 months. Full criteria are listed at www.ClinicalTrials.gov under identifier NCT00913744.
Treatment A total of 100 patients who met all inclusion criteria and none of the exclusion criteria were randomized 3:1 via a telephone-based interactive voice response system to receive a single 125 mg ocriplasmin intravitreal injection or a sham injection. The sham injection was performed by holding a blunt needle to the sclera/ conjunctiva to mimic the study injection procedure. Intraocular pressure (IOP) was measured and an indirect ophthalmoscopic examination was performed immediately afterward to exclude retinal nonperfusion or other complications. To maintain masking of investigators, this examination was performed by the same unmasked investigator who administered the study treatment. Anti-VEGF therapy for treatment of exudative AMD was administered at the clinical discretion of the investigator; therefore, there was no set treatment criterion for use of anti-VEGF medication throughout the study.
Ethical Considerations The study and relevant protocol details are registered at www.ClinicalTrials.gov (identifier NCT00913744). The study was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. Institutional review board/ethics committee approval was obtained. Patients were required to provide written informed consent before enrollment in the study and the conduct of any study-related procedures.
Statistical Analysis Three data sets were considered for analysis in this study: the safety set (consisting of all patients who received the study treatment), the full analysis set (FAS; consisting of all randomized patients who were administered study treatment and for whom data from at least 1 efficacy assessment after baseline were available), and the per-protocol set (PPS; consisting of the FAS excluding patients or data that deviated sufficiently from the protocol). For the statistical analysis of the primary efficacy end point, the number and percentage of patients meeting the end point were tabulated by randomized treatment group. The treatment groups were compared using the Fisher exact test at a 2-sided significance level of 0.05. An exact 2-sided 95% confidence interval (CI) for the difference in proportions of success between the 2 groups was provided. The number of anti-VEGF injections was compared between treatment groups using Wilcoxon rank-sum tests. Any statistical comparisons of the secondary efficacy end points were of a supportive nature only and were interpreted as such, with the strength of association for declaration of a supportive trend set to a nominal 2-sided 0.05 significance level for all comparisons of ocriplasmin with sham. No adjustments were made for multiple comparisons or multiple end points for the secondary end points. The primary end point was evaluated in the FAS, with missing data imputed using the last observation carried forward method. The robustness of the main efficacy analyses was evaluated by performing sensitivity analyses in the FAS and PPS. This study was started before the pivotal phase III studies23 and before the response rate to ocriplasmin was determined. The event
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Results
Safety Measurements
Data from 100 patients were available for analysis. Demographics and baseline characteristics for the FAS are presented in Table 1 (available at www.aaojournal.org). Twenty-five patients were randomized to receive sham injection, and 75 patients were randomized to receive 125 mg ocriplasmin. Of these 100 patients, most (94.0%) completed the study (1/25 patients [4.0%] in the sham group and 5/75 patients [6.7%] in the ocriplasmin group were discontinued from the study). The most common reason for discontinuation was withdrawal of consent (1/1 in the sham group and 2/5 in the ocriplasmin group) and AEs (2/5 in the ocriplasmin group). One patient in the ocriplasmin group died before completing the study. None of the events resulting in discontinuation was related to the study drug. One patient in the ocriplasmin group withdrew consent after receiving study treatment; therefore, the FAS includes 74 of 75 patients (98.7%) in the ocriplasmin group and 25 of 25 patients (100.0%) in the sham group.
An AE was defined as any untoward medical occurrence in a patient who was administered a pharmaceutical product, whether or not it was related to the study treatment. Serious AEs (SAEs) were defined as any AE that resulted in death, was immediately lifethreatening, required inpatient hospitalization, resulted in persistent or significant disability/incapacity, or was a congenital abnormality. The intensity of AEs was characterized as mild, moderate, or severe. The causal relationship to study treatment was assessed as probably related, possibly related, remotely related, or unrelated. An ophthalmologic examination was performed at baseline and on days 7, 14, and 28 and months 3, 6, and 12 after injection on the basis of the investigator’s standard of care. Assessments included IOP measurement, slit-lamp examination, and dilated fundus examination.
Safety Analysis The safety of ocriplasmin injection was assessed by evaluating reported AEs, ophthalmologic examination, fundus photography, and fluorescein angiography. The safety set was used for all analyses of safety data. Summaries of complications after injections included worsening of visual acuity and change from baseline; AEs, with special attention to ophthalmic events (worsening macular edema, vitreous hemorrhage, retinal tear or detachments, inflammation); IOP and change from baseline in IOP; slit-lamp examination findings; retinal examination; and concomitant medication use. Only treatment-emergent AEs, defined as events with an onset on or after the date of study drug injection, were included in the AE summaries and were coded using MedDRA version 14.1 (MedDRA MSSO, McLean, VA).
Efficacy Measurements The primary efficacy end point of the study was the proportion of patients with VMA release at day 28 as measured by time domain OCT (TD-OCT). Secondary end points included the proportion of patients who experienced release of VMA at visits other than day 28 after injection, assessment of PVD status, average macular thickness, visual acuity, central retinal/lesion thickness, classic membrane growth, amount of fluorescein leakage, number of patients requiring additional therapy, number of anti-VEGF injections required during study, initial anti-VEGF-free interval, and 25-item Visual Function Questionnaire (VFQ-25) scores. At the time of study initiation, TD-OCT was the gold standard in retinal imaging technology; therefore, TD-OCT scans were obtained in the study eye at each of the 8 study visits and performed in both eyes at baseline and month 12. Assessments were made after dilating the pupil. All OCT scans were submitted to a central reading center for evaluation. Dynamic B-scan ultrasounds were used to assess the presence and grade of PVD. Best-corrected visual acuity (BCVA) was measured with a backlit Early Treatment Diabetic Retinopathy Study (ETDRS) chart set 4 m from the patient and reported as the number of letters read correctly. The patient-administered VFQ-25 was completed by the patient at baseline, month 6, and month 12, and improvement in VFQ-25 results was evaluated using individual scores, subscale scores, and global composite scores. Fundus photography and fluorescein angiography were conducted at baseline and day 28 and month 12 after injection. All fundus photographs and fluorescein angiograms were assessed by a central reading center.
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Patient Disposition
Overview of Adverse Events An overall summary of AEs is presented in Table 2. The percentage of patients experiencing at least 1 AE was the same (72.0%) in both treatment groups. A larger proportion of patients (36/75 [48.0%]) in the ocriplasmin group experienced a greater number of AEs in the study eye (83 in total) in the first 7 days after injection when compared with the sham group (4/25 [16.0%]; 6 AEs in total).
Ocular Adverse Events The percentage of ocular AEs in the study eye was higher in the ocriplasmin-treated patients than in the sham group (47/75 [62.7%] vs. 13/25 [52.0%], respectively) (Table 3). A total of 131 AEs in the study eye were reported in the ocriplasmin group, and 29 AEs Table 2. Overall Summary of Adverse Events (Safety Set) Sham (n [ 25) Category*
Ocriplasmin (n [ 75)
AEs, n (%) Events (n) AEs, n (%) Events (n)
All AEs Any event 18 (72.0) Any nonocular event 9 (36.0) Any ocular event 15 (60.0) Any study eye event 13 (52.0) Any nonstudy eye event 6 (24.0) Drug-related AEs Any event 5 (20.0) Any nonocular event 0 (0.0) Any ocular event 5 (20.0) Any study eye event 5 (20.0) Any nonstudy eye event 0 (0.0) SAEs Any event 2 (8.0) Any nonocular event 2 (8.0) Any ocular event 0 (0.0) Any study eye event 0 (0.0) Any nonstudy eye event 0 (0.0)
60 25 35 29 11
54 25 48 48 16
(72.0) (33.3) (64.0) (64.0) (21.3)
200 63 137 131 23
5 0 5 5 0
30 0 30 30 3
(40.0) (0.0) (40.0) (40.0) (4.0)
70 0 70 70 3
4 4 0 0 0
18 10 8 8 0
(24.0) (13.3) (10.7) (10.7) (0.0)
24 13 11 11 0
AE ¼ adverse event; SAE ¼ serious adverse event. *Patients may be in >1 category.
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Ocriplasmin in Patients with VMA and Wet AMD
Table 3. Adverse Events in the Study Eye Reported for 5% of Patients (Safety Set)
System Organ Class* Preferred Term
Sham (n [ 25) n (%)
Ocriplasmin (n [ 75)
Events (n)
Eye disorders 13 (52.0) Visual acuity reduced 3 (12.0) Photopsia 2 (8.0) Eye pain 0 (0.0) Conjunctival hemorrhage 2 (8.0) Vitreous floaters 0 (0.0) Retinal hemorrhage 4 (16.0) Blepharitis 0 (0.0) Cataract nuclear 0 (0.0) Corneal edema 0 (0.0) Investigations 0 (0.0) Increased IOP 0 (0.0)
28 5 2 0 3 0 5 0 0 0 0 0
n (%) 47 14 9 10 7 8 2 4 4 4 4 4
Serious Adverse Events
Events (n)
(62.7) (18.7) (12.0) (13.3) (9.3) (10.7) (2.7) (5.3) (5.3) (5.3) (5.3) (5.3)
121 19 10 10 8 8 2 4 4 4 4 4
IOP ¼ intraocular pressure. *Patients could be in multiple categories.
were reported in the sham group (Table 2). The increased frequency of AEs in the ocriplasmin group was predominantly driven by AEs that are known to be associated with the intended action of the drug.22 In the ocriplasmin group, 14 of 75 patients (18.7%) experienced reduced visual acuity, 9 of 75 patients (12.0%) experienced photopsia, and 8 of 75 patients (10.7%) experienced vitreous floaters. Of note, 2 of 75 patients (2.7%) in the ocriplasmin group experienced retinal hemorrhage compared with 4 of 25 patients (16.0%) in the sham group. Table 3 presents study eye AEs that occurred in 5% of patients in either treatment group. Other AEs in the ocriplasmin group were associated with the intravitreal injection procedure itself, including eye pain (10/75 [13.3%]) and conjunctival hemorrhage (7/75 [9.3%]). All drug-related AEs were ocular and more common in ocriplasmin-treated patients than in the sham controls (30 patients of a total of 75 patients treated with ocriplasmin [40.0%] experienced drug-related AEs) (Table 2). A total of 70 AEs in the ocriplasmin group were considered to be drug related, and 5 of 25 patients (20.0%) in the sham group experienced 5 AEs. The majority of drug-related AEs occurred in the study eye, with 3 of 75 patients Table 4. Summary of Serious Adverse Events (Safety Set)
System Organ Class Preferred Term
Sham (n [ 25)
Ocriplasmin (n [ 75)
n (%) Events
Any SAE 2 Any nonocular SAE 2 Any ocular SAE 0 Any study eye SAE 0 Eye disorders (study eye) 0 Retinal detachment 0 Visual acuity reduced 0 Blindness transient 0 Investigations (study eye) 0 Increased IOP 0 Infections and infestations (study eye) 0 Endophthalmitis 0
(8.0) (8.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0)
4 4 0 0 0 0 0 0 0 0 0 0
n (%) 18 10 8 8 7 3 3 2 2 2 1 1
IOP ¼ intraocular pressure; SAE ¼ serious adverse event.
(24.0) (13.3) (10.7) (10.7) (9.3) (4.0) (4.0) (2.7) (2.7) (2.7) (1.3) (1.3)
(4.0%) in the ocriplasmin group, but none of the sham group, reporting drug-related AEs in the nonstudy eye. The 3 nonstudy eye AEs were photopsias, phosphenes, and conjunctivitis.
Events 24 13 11 11 8 3 3 2 2 2 1 1
The frequency of SAEs was higher in the ocriplasmin group (18/75 [24.0%]) than in the sham group (2/25 [8.0%]). Table 4 presents a summary of the SAEs in both treatment groups. Ocular SAEs were experienced by 8 of 75 patients (10.7%) in the ocriplasmin group, all of which occurred in the study eye. No patients in the sham group experienced ocular SAEs. Thirteen nonocular SAEs were reported by 10 of 75 patients (13.3%) in the ocriplasmin group, and 4 nonocular SAEs were reported by 2 of 25 patients (8.0%) in the sham group. Eight SAEs in 6 patients in the ocriplasmin group were considered possibly or probably related to study drug, and all occurred in the study eye. These SAEs are detailed in the following sections. Reduced Visual Acuity. Three patients experienced reduced visual acuity, all within 1 day of study drug injection. The first case was a 64-year-old woman who had a BCVA of 52 ETDRS letters (20/80 Snellen acuity) at baseline. A day after injection with ocriplasmin, her BCVA decreased to hand motion, yet the fundus and OCT examination results were reported as normal. Four days later, she had a “macula-off” rhegmatogenous retinal detachment, which was repaired via vitrectomy but had a poor outcome. The final recorded BCVA was 9 letters (20/800 Snellen acuity). The investigator noted the case as “possibly related to study treatment.” The second case was a 72-year-old woman who had a BCVA of 70 letters (20/40 Snellen acuity) at baseline. She also had some subretinal fluid (SRF) on OCT. The day after injection with ocriplasmin, her BCVA decreased to 38 letters (20/200 Snellen acuity), with increased SRF on OCT. A week later, her BCVA improved to 64 letters (20/50 Snellen acuity), with resolution of the SRF. Her last recorded BCVA was 68 letters (20/40 Snellen acuity), and the investigator noted this case as “probably related to study drug.” The third case was an 80-year-old man who had a BCVA of 76 letters (20/32 Snellen acuity) at baseline. He also had some SRF on OCT at baseline. On the same day as the injection of ocriplasmin, he noticed a decrease in his vision, and his BCVA was 20/200. Four days later, his BCVA had improved to 20/63, with a resolution of the SRF. His last recorded BCVA was 72 letters (20/40 Snellen acuity), and the investigator noted this case as “probably related to study drug.” In accordance with the inclusion/exclusion criteria, all of these cases had VMA and wet AMD at baseline, and in all of them VMA resolved within 1 week of injection of ocriplasmin. Transient Blindness Related to Increased Intraocular Pressure. Two patients experienced transient blindness from baseline visual acuity of 38 and 66 letters to “no light perception” due to increased IOP. Both cases occurred within 5 minutes of injection of the study drug. Both recovered to baseline IOP within 1 hour after treatment with massage and apraclonidine. Both patients recovered their vision to their baseline values. Retinal Detachment. Three cases of retinal detachment were noted in this trial. The 1 patient who experienced a rhegmatogenous retinal detachment associated with visual acuity loss, which was reported as an SAE, has already been noted. The second case was an 80-year-old woman who had a tractional retinal detachment that was unrelated to the study drug, according to the investigator, and occurred 4 months after the injection. This patient had advanced diabetic retinopathy and epiretinal membrane, as well as preretinal macular gliosis. The third case was a 76-year-old man who had a tractional retinal detachment 11 months after the study drug injection, which was deemed to be remotely related to the study drug, according to the investigator.
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Figure 1. Proportion of patients with vitreomacular adhesion (VMA) release and total posterior vitreous detachment (PVD) at day 28.
Figure 2. Mean number of antievascular endothelial growth factor injections at month 12.
Endophthalmitis. One case of endophthalmitis was diagnosed in the study, which involved an 87-year-old man who had endophthalmitis 10 months after the study drug injection and 1 day after an injection of bevacizumab for wet AMD. The investigator confirmed that this case was unrelated to the study drug.
revealed a mean change from baseline of 1.5 letters. A comparison of visual acuity data between treatment groups at each time point did not show clinically relevant differences. The majority of patients in both treatment groups maintained visual acuity at each study visit. The proportion of patients experiencing improvement of at least 1 or 2 lines was slightly greater in the sham group at most visits; however, a greater proportion of patients in the sham group experienced a decline of at least 1 or 2 lines at most visits. Subanalysis was performed to evaluate the change in BCVA by study visit between patients who achieved VMA release by the end of the study and patients who showed no noticeable differences. AntieVascular Endothelial Growth Factor Injections. All patients in both treatment groups were required by the protocol to have received anti-VEGF injections in the study eye before entering the study. During the study, the majority of patients (w91%) in both groups received at least 1 anti-VEGF injection, with a mean of 6.1 injections at month 12 for the sham group and 4.4 injections for the ocriplasmin group (P ¼ 0.069) (Fig 2). Analysis of the cumulative frequency at month 12 and interval frequency of anti-VEGF injections by study visit and treatment showed no notable differences between treatment groups. The 3 anti-VEGF drugs used were ranibizumab (Lucentis), bevacizumab (Avastin), and aflibercept (Eylea; Regeneron Pharmaceuticals, Inc, Tarrytown, NY). No clinically meaningful differences between ocriplasmin and sham were observed in the secondary analysis of average macular thickness, central retinal/lesion thickness, classic membrane growth, amount of fluorescein leakage, changes in visual acuity, or VFQ-25 scores.
Efficacy of Ocriplasmin in Wet Age-Related Macular Degeneration Primary End Point: Vitreomacular Adhesion Release at Day 28. The primary end point of VMA release at day 28 was calculated from the FAS and was achieved in 18 of 74 patients (24.3%) in the ocriplasmin group and 3 of 25 patients (12.0%) in the sham group. The difference between treatment groups was 12.3% (95% CI, 3.7 to 28.4), which was not statistically significant (P ¼ 0.262). Analysis of the primary end point using the PPS revealed similar results. Figure 1 depicts the proportion of patients with VMA release in the study eye at day 28. The mean VMA diameter at baseline was smaller in the ocriplasmin group compared with the sham group; however, the primary end point results were not significant between treatment groups, irrespective of VMA diameter at baseline. Secondary End Points. Secondary end points were designed to be exploratory in nature, support the primary end point, and be evaluated using the FAS and PPS. Because this was a phase II exploratory study, it was not powered to identify significant differences in the secondary end points between the groups. Vitreomacular Adhesion Release over Time and Posterior Vitreous Detachment. The proportion of patients in the ocriplasmin group who experienced VMA release by month 12 was greater than in the sham group (31/74 [41.9%] vs. 6/25 [24.0%], respectively), with a difference of 17.9% (95% CI, 2.3 to 38.1). The proportion of patients experiencing total PVD at day 28 is shown in Figure 1. The proportion of patients experiencing total PVD was greater in the ocriplasmin group at each visit compared with the sham group, with 17 of 74 patients (23.0%) in the ocriplasmin group and 3 of 25 patients (12.0%) in the sham group experiencing total PVD at month 12, a difference of 11.0% (95% CI, 5.0 to 26.9). Subanalysis demonstrated a greater proportion of total PVD observed when VMA release occurred compared with no VMA release. Visual Acuity. The mean change from baseline in the number of ETDRS letters read at month 12 for the sham group was 2.8 letters. By contrast, the mean change from baseline in the ocriplasmin group increased over time up to month 6; however, the month 12 value
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Discussion The analysis of this phase II study of patients with VMA and exudative AMD demonstrated that ocriplasmin was well tolerated by the majority of patients. The majority of AEs in both treatment groups were ocular in nature, and patients in the ocriplasmin group had a higher proportion (64.0%) of study eye AEs than patients in the sham group (52.0%). This was to be expected because the sham injection did not penetrate the globe of the eye. Drug-related AEs were more frequently reported in the ocriplasmin group than in the sham group within the first 7 days of treatment, and the higher
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Ocriplasmin in Patients with VMA and Wet AMD
event rates were likely due to the pharmacologic action of ocriplasmin. By contrast, during the period from day 8 to the end of the study, there was no clinically meaningful difference between the groups. This is consistent with previous studies that showed that the pharmacologic action of ocriplasmin was reduced to below the level of quantification in the vitreous cavity within 7 days compared with concentration immediately after injection.24 In this study, ocriplasmin exhibited a safety profile that was comparable to the results of the 2 phase III trials,23 which had an overall ocular AE rate of 53.5% for placebo (intravitreal vehicle injection) and 68.4% for ocriplasmin-treated patients. A comparison of the drug-related AEs between those in this study and those in the phase III trials again showed similar rates: 20.0% for sham (vs. 21.4% in placebo for phase III) and 40.0% for ocriplasmin in both this study and the phase III trials. The risks of retinal hemorrhage in wet AMD are well documented.25e27 In this study, ocriplasmin did not seem to increase the risk of retinal hemorrhage when compared with the sham group. Efficacy results showed that a greater proportion of patients achieved the primary outcome of VMA resolution by day 28 when treated with ocriplasmin, although this difference was not significant (P ¼ 0.262). In both treatment groups, VMA release increased over time. This study, with a limited sample size of 100 patients, was not sufficiently powered to show statistical significance in VMA resolution between ocriplasmin and sham. It was previously noted that VMA resolution was higher in patients with a smaller VMA diameter at baseline. Although this smaller diameter may have contributed in part to the higher proportion of VMA closures in the ocriplasmin group, it is difficult to conclude this because the results were not statistically significant. However, it is noteworthy that the VMA resolution and total PVD rates at day 28 with ocriplasmin were similar to those in the pivotal phase III trials.23 The VMA resolution and total PVD rates observed in the sham group of this study were also similar to those observed in the placebo group in the pivotal phase III studies; however, the control group in this study may not be a true reflection of the natural history of the disease because patients received concomitant anti-VEGF injections. Secondary efficacy analyses in this study were exploratory only because the study was not powered to identify significant differences between the groups with respect to the secondary end points (release of VMA at visits other than day 28 after injection, assessment of PVD status, average molecular thickness, visual acuity, central retinal/ lesion thickness, classic membrane growth, amount of fluorescein leakage, number of patients requiring additional therapy, number of anti-VEGF injections required during the study, initial anti-VEGF interval, and VFQ-25 scores). Analysis of PVD status showed that a larger event rate was observed in the ocriplasmin group than in the sham group, which was maintained until the end of the study. It has been suggested that VMA can antagonize the effects of anti-VEGF treatment28; however, this was shown in patients without prior anti-VEGF therapy. Despite the study not being powered for significant efficacy values, the mean number of anti-VEGF injections decreased by 28% to 4.4 injections in the ocriplasmin group (which had a higher level of VMA resolution) compared
with 6.1 injections in the sham group. Vitreomacular adhesion resolution may lead to increased oxygenation at the retina. Because hypoxia is a known stimulator of VEGF,7 VMA resolution may lead to decreased VEGF stimulus and production, which may explain the reduced need for anti-VEGF drugs.
Study Limitations In addition to the study not having sufficient power to show the statistical significance of the primary end point, another study limitation included a lack of predefined anti-VEGF treatment criteria. Furthermore, the use of TD-OCT rather than spectral domain (SD)-OCT was considered the gold standard in OCT measurement at the time of study initiation. This has since been generally replaced because SD-OCT allows for a greater resolution and scanning speed of retinal tissue and has been shown to have better reproducibility and reliability of results than TD-OCT.29e31 In conclusion, data from this study add to the total evidence evaluating the safety of ocriplasmin and suggest that ocriplasmin treatment in patients with VMA and wet AMD is generally safe and well tolerated. In addition, ocriplasmin treatment in these patients resulted in greater VMA resolution, total PVD, and a reduced need for anti-VEGF injections compared with sham treatment. Acknowledgments. Medical writing support was provided by Mark Robinson and Diane Kwiatkoski of Quintiles.
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21. JETREA [package insert]. Iselin, NJ: ThromboGenics, Inc.; 2014. 22. JETREA Summary of Product Characteristics. Leuven, Belgium: ThromboGenics NV; 2013. 23. Stalmans P, Benz MS, Gandorfer A, et al. Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular holes. N Engl J Med 2012;367:606–15. 24. Stalmans P, Girach A. Vitreous levels of active ocriplasmin following intravitreal injection: results of an ascending exposure trial. Invest Ophthalmol Vis Sci 2013;54:6620–7. 25. Scupola A, Coscas G, Soubrane G, Balestrazzi E. Natural history of macular subretinal hemorrhage in age-related macular degeneration. Ophthalmologica 1999;213:97–102. 26. Steel DHW, Sandhu SS. Submacular haemorrhages associated with neovascular age-related macular degeneration. Br J Ophthalmol 2011;95:1051–7. 27. Sunness JS, Gonzalez-Baron J, Bressler NM, et al. The development of choroidal neovascularization in eyes with the geographic atrophy form of age-related macular degeneration. Ophthalmology 1999;106:910–9. 28. Lee SJ, Koh HJ. Effects of vitreomacular adhesion on antivascular endothelial growth factor treatment for exudative agerelated macular degeneration. Ophthalmology 2011;118: 101–10. 29. Forooghian F, Cukras C, Meryerle CB, et al. Evaluation of time domain and spectral domain optical coherence tomography in the measurement of diabetic macular edema. Invest Ophthalmol Vis Sci 2008;49:4290–6. 30. Leung CK, Cheung CY, Weinreb RN, et al. Comparison of macular thickness measurements between time domain and spectral domain optical coherence tomography. Invest Ophthalmol Vis Sci 2008;49:4893–7. 31. Folgar FA, Toth CA, DeCroos FC, et al. Assessment of retinal morphology with spectral and time domain OCT in the phase III trials of enzymatic vitreolysis. Invest Ophthalmol Vis Sci 2012;53:7395–401.
Footnotes and Financial Disclosures Originally received: June 12, 2014. Final revision: October 9, 2014. Accepted: October 13, 2014. Available online: November 27, 2014. Manuscript no. 2014-914. 1 Retina Vitreous Associates, Los Angeles, California.
M.T.: Research grants Aerpio Therapeutics, Alcon, Allegro, Allergan, Bayer, Genentech, GlaxoSmithKline, Notal Vision, Novartis, Pfizer, Roche, ThromboGenics NV; Nonfinancial support and personal fees e Alimera, ThromboGenics NV, Valeant; Grants and Personal fees Regeneron; Personal fees Bausch & Lomb, Notal Vision.
2
Funding for this study was provided by ThromboGenics NV. ThromboGenics NV participated in the design and conduct of the study; collection, management, analysis, and interpretation of data; and preparation, review, and approval of the manuscript.
Department of Biomedical and Clinical Science, Luigi Sacco Hospital, Milan, Italy.
3
NightstaRx Ltd, London, United Kingdom (formerly of ThromboGenics NV).
4
Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, United Kingdom. 5 Center for Retina and Macular Disease, Winter Haven, Florida. Presented at: the American Academy of Ophthalmology Retina 2013 Subspecialty Day, November 15e16, New Orleans, Louisiana. Financial Disclosure(s): The author(s) have made the following disclosure(s): R.L.N.: Nonfinancial support ThromboGenics NV during the conduct of this study; Personal fees Alcon, Clarity Medical, Genentech. G.S.: Nonfinancial support ThromboGenics NV during the conduct of this study; Consultant fees Alcon, Allergan, Bayer, Genentech, GlaxoSmith Kline, Heidelberg Engineering, Novartis, Quantel Medical, Roche, Zeiss. A.G.: Former employee ThromboGenics NV. N.N.: Nonfinancial support ThromboGenics NV during the conduct of this study; Research grant Allergan, Heidelberg Engineering, Novartis; Personal fees Alimera Sciences, Bausch & Lomb.
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Abbreviations and Acronyms: AE ¼ adverse event; AMD ¼ age-related macular degeneration; BCVA ¼ best-corrected visual acuity; CI ¼ confidence interval; ETDRS ¼ Early Treatment Diabetic Retinopathy Study; FAS ¼ full analysis set; IOP ¼ intraocular pressure; OCT ¼ optical coherence tomography; PPS ¼ per-protocol set; PVD ¼ posterior vitreous detachment; SAE ¼ serious adverse event; SD-OCT ¼ spectral domain optical coherence tomography; SRF ¼ subretinal fluid; TD-OCT ¼ time domain optical coherence tomography; VEGF ¼ vascular endothelial growth factor; VFQ25 ¼ 25-item Visual Function Questionnaire; VMA ¼ vitreomacular adhesion. Correspondence: Roger L. Novack, MD, PhD, 1127 Wilshire Boulevard, Suite 1620, Los Angeles, CA 90017. E-mail: [email protected].
