Long-Term Efficacy & Safety of Aflibercept IVT for the Treatment of DME in Subjects Who Completed the VISTA-DME Trial

The investigational product is aflibercept, which will be supplied by Regeneron
Pharmaceuticals, Inc. in sterile vials for intravitreal (IVT) injection. Vials must be used
(defined as entered with needle) only once. All drug supplies are to be kept under
recommended storage conditions.

The injection volume will be 50μL (0.05 mL) and will be administered to the subjects by IVT
injection.

Throughout the trial, subjects will be treated with intravitreal aflibercept injections PRN
in the presence of CR-DME; this is defined as DME that the treating investigator believes is
limiting visual function.

All subjects will initially be evaluated every 4 weeks (28 days) for CR-DME and treated PRN.
If CR-DME is present the subject will receive IVT aflibercept injection. If CR-DME is not
present the subject will not receive an IVT aflibercept injection and will be observed.

At any point throughout the study, once a subject has been evaluated and observed (with no
IVT aflibercept) for a total of 8 weeks (3 consecutive monthly visits), the interval between
visits will be increased to 8 weeks.

After an additional 24 weeks (3 consecutive visits, every 8 weeks) without an IVT aflibercept
injection, the interval between visits will be increased to 12 weeks.

If a subject has recurrent CR-DME they will receive an IVT aflibercept injection and the
interval between visits will reduce back to 4 weeks. Subjects can again extend the interval
between visits to 8 weeks once they have not received an IVT aflibercept injection for a
total of 8 weeks (3 consecutive visits) as described above. Extension to 12 weeks is then
performed as above.

Starting at week 52, once a subject has extended to a 12 week interval, if CR-DME is not
present the subject will not receive an IVT aflibercept injection and will be extended to a
16 week interval. Once at a 16 week interval, if CR-DME is not present the subject will not
receive an IVT aflibercept injection and will be extended to a 20 week interval. At any point
past a 12 week interval extension, if a subject has recurrent CR-DME they will receive an IVT
aflibercept injection and the interval for the next visit will be reduced at investigator
discretion to be either 12 or 16 weeks. If the interval is needed to be reduced to below 12
weeks, the subject will return to a 4 or 8 week interval, at investigator discretion and
return to the protocol above.

All subjects receiving PRN IVT aflibercept injections will be evaluated for focal laser
treatment beginning at week 12 through the end of the study. If the subject meets any of the
criteria for focal laser treatment (FLT), fluorescein angiography (FA) will be performed to
guide the focal laser treatment. Focal laser treatment and focal laser re-treatment will be
administered no more than once every 90 days.

When a subject receives ≥ 2 IVT aflibercept injections in ≤ 24 weeks FLT will be applied.
Once the initial session of FLT is applied subjects are eligible for FLT re-treatment after
90 days, when they have received ≥ 2 IVT aflibercept injections within the prior 90 day
period.

FLT will be applied to:

1. All leaking microaneurysms.

2. Grid to all areas of diffuse leakage.

3. Grid to all areas of retinal ischemia outside of the FAZ (once ischemic areas are
treated once with grid FLT, these same areas should not be treated again).

4. Laser will not be applied within the capillaries of the FAZ.

FLT will not be applied if any of the following apply and are identified:

1. Significant macular ischemia involving the foveal avascular zone (once this has been
determine additional fluorescein angiography for FLT planning should not be performed
and subjects will not longer be eligible for rescue FLT).

2. Treatment would be too close to the foveal avascular zone.

3. Macular edema is not related to DME (eg: postoperative CME, etc).

Inclusion Criteria:

- A subject must meet the following criteria to be eligible for inclusion in the study:

1. Enrolled and Completed VISTA DME (VGFT-OD-1009) clinical trial

2. Willing and able to comply with clinic visits and study-related procedures

3. Provide signed informed consent

4. Enrollment in the trial within 12 weeks of trial activation.

Exclusion Criteria:

- A subject who meets any of the following criteria will be excluded from the study:

1. Prior treatment with anti-VEGF therapy in the study eye within 28 days of
baseline

2. Pregnant or breast-feeding women

3. Sexually active men* or women of childbearing potential** who are unwilling to
practice adequate contraception during the study (adequate contraceptive measures
include stable use of oral contraceptives or other prescription pharmaceutical
contraceptives for 2 or more menstrual cycles prior to screening; intrauterine
device [IUD]; bilateral tubal ligation; vasectomy; condom plus contraceptive
sponge, foam, or jelly, or diaphragm plus contraceptive sponge, foam, or jelly).

- Contraception is not required for men with documented vasectomy.
**Postmenopausal women must be amenorrheic for at least 12 months in order
not to be considered of child bearing potential. Pregnancy testing and
contraception are not required for women with documented hysterectomy or
tubal ligation.