AN OPEN-LABEL MULTICENTER PHASE 2 CLINICAL SAFETY INVESTIGATION OF THE ENDOART® IMPLANTATION IN SUBJECTS WITH CHRONIC CORNEAL EDEMA

The cornea is a clear, transparent, dome-shaped structure that covers the front
portion of the eyes. An adult cornea is about 0.5 millimeters thick at its
center. It comprises five major layers, namely, the epithelium, Bowman's
membrane, stroma, Descemet's membrane, and endothelium.
The cornea maintains a fluid equilibrium which ensures optimal light
transmission in order to facilitate visual acuity. This is achieved through the
active pumping of fluid by the corneal endothelium layer. When endothelial
cells are injured, fluid begins to accumulate within the corneal stroma
resulting in corneal edema leading to vision impairment and if left untreated,
bullous keratopathy and pain.
Causes of corneal edema include Iatrogenic intraoperative damage to the
endothelial layer most commonly due to cataract surgery, Fuchs' dystrophy,
corneal infection, glaucoma with significant raised IOP, and trauma.
A primary symptom of corneal edema is blurred vision. The individual with
corneal edema may also see halos or rainbows around streetlights, headlights,
and other bright lights at night. As corneal edema progresses, it may affect
the epithelial corneal layer resulting in bullae. These can rupture and become
painful, cause sensitivity to light, and increase the risk for
sight-threatening infections.
Corneal blindness is a leading cause of vision loss worldwide, often requiring
a corneal transplant (keratoplasty) for treatment. In developed countries,
partial thickness corneal transplants have now become the most often performed
corneal transplants with endothelial keratoplasty being the most common.
Although advances have been made over the past two decades in the field of
endothelial keratoplasty there are still several issues that must be overcome.
EyeYon medical has developed the EndoArt® (Artificial Endothelial Layer)
implant which is a permanent implant. The EndoArt® device is indicated for use
as an endothelial keratoprosthesis device and is designed specifically for the
replacement of the endothelial cell layer of the cornea that has become
dysfunctional. With the development of endothelial keratoplasty techniques,
surgeons are now able to remove only the diseased endothelial layer of the
cornea and replace the layer with donor tissue, leaving the healthy areas of
the cornea intact. The most common types of endothelial keratoplasty procedures
are Descemet's Stripping Endothelial Keratoplasty (DSEK) and Descemet's
Membrane Endothelial Keratoplasty (DMEK).
The EndoArt® device is attached to the posterior corneal surface thereby
impeding the transfer of aqueous humor into the cornea and decreasing chronic
corneal edema. The device is designed to serve as an alternative to posterior
lamellar keratoplasty (PLK) in providing alleviation of corneal edema and
improving corneal clarity. As is done in PLK, a portion of the posterior cornea
may be removed prior to insertion of the implant to the tissue as in DSEK or
DMEK. EndoArt® is implanted using a single suture for better positioning with
or without a Descemetorhexis.
EndoArt® is intended to treat vision loss related to corneal decompensation
secondary to endothelial damage and dysfunction. Furthermore, the technology is
designed to treat intractable corneal edema in a more effective manner than the
current standard of care (*SOC*), which involves the use of donor tissue.
The rationale for blocking the posterior surface of the cornea came from
clinical observation and sporadic literature data demonstrating that corneas of
eyes with silicone oil in the anterior chamber are usually transparent, despite
very low endothelial count. In addition to these observations, in 1967 Dolman
C conducted a successful clinical study in 22 patients with chronic corneal
edema. In this study, the endothelium was replaced with an alloplastic material
(silicon layer) and attached with sutures to address the intractable corneal
edema. However, sutures were found to be very challenging in adhering to
corneal implants.
According to a JAMA report, there are approximately 13 million people in the
world currently waiting for corneal tissue. The process of harvesting the
tissue and processing it to fit endothelial keratoplasty is complicated. The
harvested tissue needs to be prepared and stored in special conditions and
needs to be implanted within14 days. The EndoArt® as a synthetic,
non-immunogenic device, has a longer shelf life than donor tissue and will not
require special storage or transportation conditions. Thus, the treatment will
be readily available to patients without waiting for donor tissue. The
estimated waiting time is 6.5 months in countries that are considered
self-sufficient. For the other countries with an imbalance between supply and
demand for corneal transplants, most patients never receive a graft, thus
preventing a calculation of waiting time.9 In addition, EndoArt® eliminates the
inherent variability, as well as the susceptibility of native tissue to damage
or deterioration during harvesting and transfer. A synthetic product may
improve effectiveness both by expanding the population who can be effectively
treated and by providing a reproducible, stable product that is not subject to
degradation in transport prior to implantation.
EndoArt®, a synthetic implant, has the potential to substantially reduce or
eliminate the implant rejection rate and simplify the post-operative follow-up
care required, compared to both endothelial grafting and full-thickness corneal
transplant. According to several reports, 10-30% of DMEK cases result in
detachment of the graft in the early postoperative phase. In addition, in case
of 2-3 times, donor endothelium rejection additional implantation is most
likely to fail again. EndoArt®, as a synthetic device, can be reattached with a
minor anterior chamber re-bubbling procedure and in the event of failure for
any reason the implant is relatively uncomplicated to remove. Furthermore, if
desired, replacement with a new device can be achieved at any time the surgeon
feels replacement should occur.
One of the most disruptive aspects of EndoArt® is its off-the-shelf
availability since it is a synthetic, non-immunogenic device. It has a 5-year
shelf life and does not require special storage or transportation conditions.
Moreover, the EndoArt® is implanted in a manner familiar to the majority of
ophthalmic surgeons (i.e., small incision cataract surgery) and utilizes a
relatively non-complicated procedure to explant and replace should the need
arise.
The above potential benefits justify the proposed investigation focusing on the
clinical safety and efficacy of the EndoArt®. The EndoArt® implant, as an
alternative to the dysfunctional human corneal endothelium, represents a major
advance ineffectiveness for the treatment of resultant corneal edema.
This post-market study is designed to collect and evaluate data based on the
use of the EndoArt® with the aim of confirming the safety and performance,
including the clinical benefit, of the EndoArt® throughout its expected
lifetime; identifying unknown side-effects and monitor the identified
side-effects and contraindications, and ensuring the continued acceptability of
the benefit-risk ratio.
Bibliography in paragraph 17 of the CIP.
*
Evaluation of the Results of Preclinical Testing
The EndoArt® has undergone pre-clinical testing in order to assure the
performance of the device according to published standards and guidelines where
available. These tests include mechanical evaluation of the device,
biocompatibility, and optical testing. The device passed these tests
successfully. The tests performed on the EndoArt® are described in detail in
the Investigator*s Brochure accompanying this clinical investigational plan.

Evaluation of the Animal Studies
The company has also conducted in-vivo testing in animals to further
characterize the safety and performance of EndoArt®.
Up to date, 17 animals (rabbits and pigs) have been implanted with EndoArt® for
different follow-up periods (up to 12 months). The procedure in all cases was
successful with no procedure-related adverse event.
The adverse events that occurred during the follow-up period were either
non-device related or following re-bubbling probably due to animal model
limitation. It can be concluded that the EndoArt® is safe following
implantation onto the cornea of rabbits or pigs. Safety was demonstrated by the
absence of inflammatory reaction or other tissue response to the implanted
device at both clinical and histopathological examinations. There was no major
adverse event.
Detailed studies results are presented in the accompanied IB.

Evaluation of Interim Clinical Study Results
Up to date, the EndoArt® was implanted during a worldwide multisite clinical
study in 24 subjects (20 under the FIH study, 1 under the FIH study in India,
and 3 under compassionate treatment ).
Procedure Results
In all 24 subjects implanted with EndoArt®, the procedure was completed
smoothly with no complications. According to participated physicians, the
EndoArt® implantation procedure is easier than the DSAEK procedure; there were
no issues of graft handling or concern about endothelial cell damage.
In all cases, the device was inserted through a 2-3 mm incision in the cornea.
The endothelial cell layer was left untouched in 5 cases and removed in the
other 19 cases. The device was then attached with an injected air bubble of SF6
gas 20% or C3F8 10%. In 10 cases, the device was sutured. Fixation suture was
found to be beneficial in reducing the re-bubbling rate.
On average, patients underwent 3 re-bubbling procedures up to 2 months
following implantation. Most of the re-bubbling was done mainly in the
first-month post-op. In most cases, the re-bubbling procedure has produced
stable attachment with minimal risk.
Based on the significantly improved attachment results using the suture
technique and the advantage of minimal or no need for re-bubbling, it was
decided to use the suture technique in all future cases.
Results:
Twenty-four (24) subjects were implanted with the EndoArt® with a follow-up of
0.5-24 months (13 subjects with at least 6 months follow-up). No device-related
nor procedure-related serious adverse events (SAE) have been reported to date.
In all cases, no inflammatory reaction was observed in any of the treated eyes
at any of the post-surgical examination time points. All implanted eyes are
quiet, with no evidence of haze, flare, fibrin, cells, or iris
neovascularization. Based on these findings, EndoArt® is demonstrating clinical
parameters supporting its design as a sterile, inert, and biocompatible polymer
implant.
Clinical Results:
In summary, this initial data demonstrates that EndoArt® provides a treatment
option for patients with limited or no other treatment options. Benefits have
been observed even in very challenging cases. Several patients, despite low
visual potential, demonstrated marked reduction in corneal thickness (n=13),
decrease in ocular pain (n=8), and visual improvement (n=7).

To evaluate the safety of EndoArt® in subjects with chronic corneal edema.

Prospective, multicenter, open label, phase 2 clinical safety investigation of
the EndoArt® implantation in subjects with chronic corneal edema assessing
safety of EndoArt.

RISKS AND BENEFITS OF THE INVESTIGATIONAL DEVICE AND CLINICAL INVESTIGATION
Anticipated Clinical Benefit
The purpose of this clinical investigation is to evaluate the safety of
implanting EndoArt® in subjects with corneal edema.
The EndoArt® device is indicated for use as an endothelial keratoprosthesis
device and is designed specifically for replacement of the endothelial cell
layer of the cornea that has become dysfunctional.
The EndoArt® has several advantages in treating corneal edema:
• Rejection of the donor tissue is one of the most serious complication after a
corneal transplant and occurs in 5 - 30 % of patients. EndoArt® eliminates the
need for long term immunosuppression medications to avoid rejection since the
material is inert and non-immunogenic; it thereby eliminates one source of
clinical failure (rejection).
• The corneal incision performed in this procedure is smaller and either
suture-less or requires minimal sutures.
• Decrease the risk of infection as it is sterile as opposed to human tissue
that can*t be sterilized.
• EndoArt® once implanted, is non degradable, while human tissue implantation
and manipulation is associated with cell loss.
• EndoArt® also avoids the possibility of primary donor failure due to damage
to donor tissue during harvesting, storage, insertion or unfolding. Use of a
synthetic material removes the risk of disease transmission from the donor to
the host.
• The procedure can be performed in a much shorter duration than traditional
corneal transplant surgery.
• The waiting list for a donor tissue in most countries is long. Using EndoArt®
will enable availability to everyone in need.
• EndoArt® can be implanted in complex eyes where tissue implantation is not
possible or extremely challenging

Anticipated or Potential Adverse Events
Risks that may be associated with implantation of EndoArt® are similar in
nature to those encountered with other Endothelial keratoplasty e.g. DSEK
(Descemet stripping endothelial keratoplasty) or DMEK (Descemet membrane
endothelial keratoplasty).
The following are possible risks the subject may experience from participation
in this research:
EndoArt® related
• Cornea abrasion, opacity, haze
• Device Detachment and further surgical manipulation
• Worsening of corneal edema
• Cornea thinning and perforation
Operative related
• Anterior or posterior synechiae
• IOP elevation due to procedure or steroids
• Infection
• Inflammation
• Retinal detachment
In the event of complication, the subject will be treated as deemed necessary
by the investigator. This may include DSEK or DMEK procedure.
All adverse events will be collected during the enrollment phase and throughout
the subject participation in the study.

Possible Interactions with Concomitant Medical Treatments
This study protocol includes a careful review of relevant medications taken
retrospectively by the subject to identify any medications that might
reasonably impact the outcome of the procedure. Medications such as topical
antibiotics, NSAID*s and steroids are standard therapies for patients following
ocular implant surgery. All medications subjects are taking prior to surgery
and those administered during the study, will be captured and documented in the
eDC.

Risk Analysis and Risk Mitigation
A risk analysis has been conducted, in accordance with ISO 14971 *Application
of risk management to medical devices.* The risks associated with this
investigational device have been identified and been shown to be minimized
through appropriate design control, by bench testing and by pre-clinical animal
testing presented in the Clinical Investigator*s Brochure.
The warnings and actions to minimize the risk for the patients include (but not
limited to):
• EndoArt® is designed to replace the endothelial cell layer of the cornea that
has become dysfunctional. Preclinical testing has verified that the device is
bio-compatible, minimizing the risk of damage to cornea or any other adverse
tissue response.
• EndoArt® is designed, intended, and distributed for single use only.
• A site qualification will be conducted to ensure the investigators and the
site staff are adequately experienced, an ophthalmology team is in place and
the necessary infrastructure is available.
• Only investigators who are experienced and skilled in ophthalmological
procedures and in corneal/cataract surgery will be selected.
• To ensure adequate EndoArt® implantation the Sponsor or designee will
demonstrate the procedure in a formal training session to the physicians and
site personnel involved in the study. In addition, specific instructions for
use (IFU) will be provided to all study personnel to make sure that handling of
the device and the procedure are perfectly clear.
• Warnings and precautions in the instructions for use including reference to
sterility issues.
• Clearly defined inclusion/exclusion criteria so that only appropriate
subjects are enrolled to the study.
• Ensuring that the treatment and follow-up of the subjects are consistent with
current medical practices.
• Thorough ophthalmic clinical assessment of each subject peri-procedurally.
• Frequent monitoring visits to investigational sites will be conducted.

Risk to Benefit Rationale
The risk analysis for the EndoArt® implant has been performed at the stage of
CE approval in EU and IFU finalization. All applicable risks were identified
and evaluated, and the applicable mitigations defined. The overall residual
risk has been evaluated by the company management and considered acceptable.
Two (2) risks are in AFAP region that are related to the clinical aspects and
are covered by the information supplied to the user in the IFU.
Thereby the company believes that the benefit of the EndoArt® implant to cure
corneal edema was verified through the FIH study interim results and was found
to be safe and effective. Since the EndoArt® is the only solution available
today to treat corneal edema with an artificial implant, the company assesses
that its overall benefit outweighs the risk associated with use of the product.
EndoArt® implantation is designed to replace the need for donor corneal tissue
removing the risk of tissue rejection and disease transmission from the donor
to the host.
Furthermore, EndoArt® fulfils a global unmet need in that the device is readily
available removing the burden associated with a lack of donor tissue.

• Designed to improve safety by:
o Avoiding implant rejection since the material is inert and non-immunogenic
removing the risk of chronic pharmacological immunosuppressive prophylaxis.
o Avoiding the possibility of primary donor failure due to damage to donor
tissue during harvesting, storage, insertion or unfolding.
o Reduced risk of postoperative infection.
• Improved effectiveness by:
o Simplifying the surgical procedure and avoiding the possibility of primary
donor failure.
o Removing the risk of rejection and disease transmission from the donor to the
host
o The procedure can be performed in a much shorter duration than traditional
corneal transplant surgery.
o Reduce the long waiting list for donor tissue in most countries.
o Enables implantation in complex eyes.
Pre-clinical animal studies provided significant data demonstrating the safety
and performance of EndoArt® implantation. Consistent with the preclinical
findings, the initial clinical experience with EndoArt® has demonstrated
efficacy with no significant safety issues.
The EndoArt® implantable device provides potential to treat patients that are
not suitable due to poor prognosis for conventional corneal transplant.
Given these benefits, there is sufficient justification supporting a
prospective investigation focusing on safety and clinical performance of
EndoArt®.
It is reasonable expectation from the current clinical experience, that the
benefits of this therapy will outweigh the risks. This study will collect
clinical information to further confirm the favourable risk-benefit ratio.