Assessment of Anatomical and Functional Outcomes in Patients Treated with Ocriplasmin for Vitreomacular Traction/Symptomatic Vitreomacular Adhesion (VMT/sVMA)

Under normal physiologic conditions, the vitreous maintains a gel-like
consistency and adheres completely to the entire surface of the retina. The
consistency of the vitreous and the adhesion to the retina are maintained by a
matrix of proteins including collagen, laminin, and fibronectin.
As part of the normal aging process, the protein structure of the vitreous
progressively liquefies and the vitreoretinal adhesions weaken. This leads to
separation of the posterior vitreous cortex from the retinal internal limiting
membrane * a process called posterior vitreous detachment (PVD).

Two related processes contribute to PVD: synchysis and syneresis. Synchysis
occurs when pockets of liquefaction form within the vitreous and increase in
number and size with increasing age. As liquefaction progresses, the collagen
fibrillar component collapses and the individual collagen fibers aggregate to
form parallel bundles and, subsequently, the vitreous shrinks and separates
from the retina; this is known as syneresis. Conjunctive weakening of the
vitreoretinal adhesion leads to eventual separation of the vitreous from the
posterior retina. If liquefaction occurs concurrently with, and to a similar
degree as, the weakening at the vitreoretinal interface, PVD will generally
occur after a critical amount of liquefaction. However, if the extent of
liquefaction outweighs the degree of dehiscence at the vitreoretinal interface,
areas of adhesion between the posterior vitreous cortex and the macular remain,
leading to what is considered *abnormal* PVD. Typically, the adhesion remains
at sites where
the bonds between the vitreous and retina are strongest, including the macula
(the primary area of the retina responsible for central vision) and optic nerve
head. Adhesion at the macula is known as vitreomacular adhesion (VMA). VMA may
be asymptomatic where the persistent attachment of the posterior vitreous to
the macula does not cause functional impairment, but can also be symptomatic
due to tractional effects on the retina and the surrounding area. Vitreomacular
traction (VMT), one of the deleterious effects of VMA, is an abnormal traction
or *pulling force* localized at the site of the VMA. VMT can result in macular
deformation and macular hole (MH), an opening in the retina that develops at
the fovea. Other deleterious effects of VMT at the vitreoretinal interface are
hemorrhage, retinal tears and detachments, and macular edema. By definition,
VMT is always pathologic. Therefore, the term *symptomatic VMA* (sVMA) can be
equated to VMT, with or without concurrent MH. Symptoms
commonly associated with VMT (including when associated to a macular hole)
include metamorphopsia, reduced visual acuity, micropsia, scotoma, and
difficulties with daily visionrelated tasks such as reading.

Until recently, vitrectomy was the only treatment for VMT/VMA and MH.Because of
the risks associated with vitrectomy (including retinal detachment, hemorrhage,
and cataract), vitrectomy is usually only performed once the loss of vision has
become clinically significant.
Attempts at developing enzymes for vitreolysis against the substrates
responsible for VMA have been generally unsuccessful. However, ocriplasmin has
been developed and is approved by the European Medicines Agency (EMA) for
treatment of VMT in adults, including when
associated with macular hole of diameter less than or equal to 400 microns
under the trade name JETREA®. In Canada, JETREA is indicated for the treatment
of symptomatic vitreomacular adhesion (VMA). Ocriplasmin is a recombinant
truncated form of human plasmin that exerts enzymatic activity on proteins,
including collagens, fibronectin, and laminin. The mechanism of action of
ocriplasmin is to dissolve the protein matrix responsible for the VMA.
Ocriplasmin consists of two polypeptide chains containing 19 and 230 amino
acids, linked together by two disulfide bonds. Four other disulfide bonds are
also present. Ocriplasmin does not contain O or N-glycosylation residues or
other post-translational
modifications. Ocriplasmin is obtained from microplasminogen and produced in a
Pichia pastoris expression system by recombinant DNA technology. Ocriplasmin is
administered by intravitreal injection of a single 0.125 mg dose in 0.1 mL. In
dose-finding studies, ocriplasmin 0.125 mg in 0.1 mL is associated with
improved efficacy relative to that observed with other doses, with similar
safety profiles. This dose was taken
forward into Phase 3, randomized, vehicle injection-controlled studies.

The objective of this study is to observe the anatomical and functional
outcomes of ocriplasmin over a 6-month follow-up period.

About 6 months (180 days + time between screening and injection), single arm,
single dose, no masking, no randomization multicentre study.

single intravitreal injection with ocriplasmin 0,1mL (0,125mg)

In a period of about 6 months, the patients need to come to the hospital 6
times for an ophthalmic examination. Each visit will take between 2 and 3 hours
of their time. None of the tests are experimental. After screening and approval
of the central reading center the patients will receive a single injection with
ocriplamsin.

The examinations that will be conducted during the study may cause some
discomfort:

Dilating eye drops will be put in the eye for the eye examinations which could
make the patient sensitive to light and cause temporary blurry vision while the
pupils are dilated.

Administration of the dilating eye drops, like any medication, may cause an
allergic reaction. Allergic reactions may be mild (rash, hives) to severe
(difficulty breathing, or a collapse of blood circulation and breathing
systems). A severe allergic reaction would require immediate medical treatment
and could result in permanent disability or death.

Side effects associated with the ocriplasmin injection including intraocular
inflammation/infection, intraocular bleeding, retinal detachment, and increased
intraocular pressure (IOP) may be experienced. Most of the adverse reactions
occurred within the first week after the injection. The majority of these
reactions was non-serious, mild in intensity and resolved within 2 to 3 weeks.

Other side effects commonly reported with the use of ocriplasmin were increased
sensitivity to light, increased number of dark floating spots in the field of
vision (floaters), eye pain, flashes of light, blurry vision and redness of the
eye.