Safety and Complications of Ocriplasmin

Abstract

Our ability to examine the vitreoretinal interface has been greatly improved by the invention of spectral-domain optical coherence tomography (OCT). It has allowedearlier andmore accurate diagnosis of abnormalities of vitreomacular adhesion (VMA) that may contribute to vision loss and may benefit fromintervention.While subtle abnormalitiesofVMAmay be observed, symptomatic VMA or that associated with fullthicknessmacularhole (FTMH) requires surgical intervention.1 With improvements in vitreoretinal surgical techniques and better understanding of these conditions, outcomes of surgicalmanagementofVMA-relateddisorders areexcellent.1However, even in thehandsof themost experiencedsurgeon, there are associated surgical risks. There is also expected discomfort to the patient, delay in visual recovery, high cost, and, in cases of surgery for FTMH, postoperative positioning. Furthermore, advanced surgical skills are required for epiretinal membrane or internal limiting membrane peeling. Ocriplasmin (Jetrea) is a recombinant truncated form of human plasminwith amolecularweight of 27.2 kDa. It is a recombinantproteasewithactivity against fibronectinand laminin, which are components of the vitreoretinal interface.2 In 2 phase 3 clinical trials comparing a single intravitreal injection of ocriplasmin (0.125 mg/0.1mL)with aplacebo injection (drug vehicle diluted with saline) inpatientswith symptomaticVMA,where theprimaryendpointwas resolutionofVMAatday28, 26.5%ofocriplasmin-injected eyes had resolution comparedwith 10.1%of placebo-injectedeyes (P < .001).3Nonsurgical closureofmacular holeswas achieved in 40.6%of ocriplasmin-injected eyes, as compared with 10.6% of placebo-injected eyes (P < .001). Consequently, ocriplasminwas approved by the US Food and DrugAdministration (FDA) foruse in symptomaticVMA inOctober 2012. It is notable that ocriplasmin is a first-in-class pharmacologic agent that has been FDA approved to manage symptomatic VMA. Furthermore, the primary end point in the pivotal studieswasbasedonOCTchanges rather thanonvisual acuity improvement, the first time, to my knowledge, that OCT has beenusedas theprimaryoutcomeforaclinical trial inophthalmology. Finally, even when patients do not achieve release of abnormal VMA or closure of FTMH following intravitreal ocriplasmin injection, they can still undergo surgical management.Therefore,ocriplasminofferscliniciansanadditional tool tomanage the anatomical abnormalities of symptomatic VMA in a less invasivemanner thanwith surgery in select cases. However, since the real-worlduseof thedrugbegan, there have been unfavorable anecdotal reports of visual disturbancesafterocriplasmin injection, including transientbutprofound visual decline, raising concerns regarding its safety. While it is not possible to know the frequency of these events in postmarketing surveillance, it is worthwhile to pay attention to safety-related reports. In the report of phase 3 trials of ocriplasmin, ocular adverse events such as vitreous floaters, photopsia, conjunctival hemorrhage, blurred vision, and visual impairment were found to be significantly higher in the treatment group comparedwith theplacebogroup.3However, theauthors state that “most of the adverse events were transient and mild in severity.”3 TheWarnings and Precautions section of the package insert for ocriplasmin4 includesdecreaseof 3ormore lines of best-correctedvisual acuity in 5.6%ofpatients treatedwith ocriplasmin (comparedwith 3.2% in the control group), intravitreal injectionprocedure–associated effects (intraocular inflammation, intraocular hemorrhage, increased intraocular pressure), potential for lens subluxation, retinal breaks, and dyschromatopsia. It states that “dyschromatopsia (generally described as yellowish vision) was reported in 2% of all patients injectedwith Jetrea. In approximatelyhalf of thesedyschromatopsia cases therewerealsoelectroretinographic (ERG) changes reported (aand b-wave amplitude decrease).”4 According to the FDA Advisory Committee briefing document, 9 patients receiving ocriplasmin in various clinical trialswere reportedtohaveexperiencedanacutedecrease invisionwithin 24hours of injection, some to the handmotions level.5 In 8 of 9 patients, vision returned to baseline with a median recovery time of 2 weeks. Dyschromatopsia reportedly resolved within a median time of 3 months. Of the 141 ocriplasmintreatedpatientswhounderwentERGtesting, 11 (7.8%)hadERG changes and 9 of these patients also had dyschromatopsia. Among the 11 patientswithERGchanges, theERGchanges resolved in 6 patients (median time, 6 months), 3 did not have follow-up ERGs, 1 was still undergoing follow-up, and 1 case did not resolve and was thought to be due to concurrent vitelliform dystrophy. Recently, there was a report of a patient with symptomatic VMA, epiretinal membrane, and an impending FTMH who experienced transient vision loss after ocriplasmin injection.6 The patient was found to have disruption of the outer retina, in particular the ellipsoid zone (previously known as the inner segment/outer segment junction), on spectral-domain OCT that partially recovered by 3 weeks along with improvement in visual acuity.6 Two brief reports Related articles pages 484 and 487 Opinion