Treat & Extend Treatment With 0.5mg Ranibizumab vs Monthly Treatment With 0.5mg Ranibizumab

This trial will compare the results of 2 cohorts, with different treatment intervals, to
assess the safety, tolerability and efficacy of IVT of ranibizumab for the treatment of wet
AMD. Specifically, this trial will evaluate the ability to reduce the amount of visits and
IVT ranibizumab treatments needed all while maintaining an exudation-free macula. Subjects in
both cohorts will be followed for a total of 156 weeks.

Cohort A (control arm, monthly, n=20) Subjects will receive monthly treatment of IVT 0.5 mg
ranibizumab from Day 0 to week 100. Monthly treatment is defined as every 28 days (±7 days).
Dosing should not occur earlier than 21 days after the previous treatment.

Week 104 - Week 156 Starting at week 104 subjects will be seen monthly and treated with IVT
ranibizumab pro re nata (PRN) based on pre-defined re-treatment criteria.

Retreatment criteria for PRN phase

Re-treatment will be initiated if any of the following criteria are meet:

- Presence of any abnormal intraretinal or subretinal fluid on high resolution SD-OCT.

- Presence of new intraretinal or subretinal hemorrhage related to AMD on examination.

- 10 letter loss from previous visit, related to active wet AMD in the opinion of the
treating investigator

Cohort B (comparator arm, TREX, n=40) Subjects will receive a minimum of 3 consecutive IVT
0.5 mg ranibizumab (visits 2, 4 and 5). Starting at week 8, if a subject has achieved a "dry"
macula; signs of active exudation have resolved by both ophthalmic exam and SD-OCT evaluation
they will begin a Treat and Extend protocol.

For a macula to be considered "dry" it must meet both the following criteria:

1. Resolution of intraretinal and subretinal fluid

2. Resolution of all subretinal hemorrhage related to active exudative AMD

Resolution of pigment epithelial detachments (PED) is not required for a macula to be
considered "dry". Small intraretinal cystic areas observed on SD-OCT are acceptable and the
corresponding macula can be considered dry. The criteria for these are specific; see
reference images (Appendix D) for examples of acceptable intraretinal cystic spaces. When
cysts described in Appendix D are present the macula should be considered dry and should be
notated on the SD-OCT interpretation. Also, minimal increased retinal thickening on SD-OCT
without definitive intraretinal or subretinal exudative fluid can be observed and the
corresponding macula will be considered dry.

Once a "dry" macula is achieved the interval between visits is then lengthened by 2-week
increments, at every visit the macula is "dry". IVT ranibizumab will be rendered at every
visit, no earlier than 7 days before the target date and no later than 7 days after the
target date; the interval between visits is individualized based on each patient's response
to treatment. The interval between injections will not exceed 12 weeks

After a subject is extended beyond 4-weeks and develops recurrent exudative disease activity,
the eye is treated and the treatment interval for the next visit is reduced by 2 weeks,
compared to the previous treatment interval. The interval between treatments will be reduced
by 2-week intervals until a dry macula is again established. Once a dry macula is again
achieved, the interval between visits will be extended by 1-week intervals, instead of 2-week
intervals.

For example: If recurrent exudative disease activity is detected after an 8-week interval,
the eye is treated and the interval for the next visit is reduced to 6 weeks; if the macula
is then dry after the 6-week interval, the interval is increased to 7 weeks. If the macula is
then dry after the 7-week interval, the interval is increased to 8 weeks, etc.

Once an eye is extended by 1-week intervals, if recurrent exudative disease is detected
again, the treatment interval for the next visit is reduced by 1 week, compared to the
previous treatment interval, and will continue to be decreased by 1-week intervals until dry
or the 4-week interval is reached. Once a dry macula is again established, the most recent
interval between treatments is maintained for one additional visit; if the macula remains dry
at this time, the interval will then be extended by 1-week increments.

If an eye exhibits recurrent exudative disease activity 3 times at a given interval and is
unable to extend beyond that interval, the eye will continue treatment at the next shorter
interval for 3 consecutive visits. After these 3 visits, the interval between visits will
again be extended by 1-week intervals, while the macula remains "dry". If the eye exhibits
recurrent exudative disease activity, the interval will be decreased by 1-week intervals
until the macula is again "dry." The eye will then continue treatment at this interval for 3
consecutive visits before extending by 1-week again. This pattern of repeating 3 visits at
the same "dry" interval will be repeated each time after the eye becomes "wet" before again
attempting another 1-week extension.

Evidence of recurrent exudative activity

Clinical evidence of recurrent exudative disease activity requiring reducing the interval
between treatments includes any of the following:

1. Evidence of subretinal or intraretinal fluid on SD-OCT which is not classified as small
intraretinal cystic areas unrelated to active exudative AMD (Appendix D) or minimal
increased retinal thickening by SD-OCT without definitive intraretinal or subretinal
fluid

2. New macular hemorrhage related to active exudative AMD.

3. ETDRS VA loss of 5 letters from the previous measurement due to neovascular AMD disease
process with corresponding SD-OCT evidence of fluid in the macula.

4. Increase in CRT of 50 microns due to active exudative AMD.

The isolated presence of a PED, or enlargement of a PED, does not constitute evidence of
exudative disease activity.

If an eye has an ETDRS VA decrease of ≥ 4 lines (20 letters) or a subretinal macular
hemorrhage of 1DD or larger, at any point during the trial, the subject will subsequently be
treated with ranibizumab every 4 weeks.

Week 104 - Week 156 Starting at Week 104 subjects who have achieved a "dry" macula, at the 12
week interval will be seen monthly and treated pro re nata (PRN) based on pre-defined
re-treatment criteria. Study visits should be scheduled to occur every 28 (±7) days relative
to the date of week 104 visit.

Retreatment criteria for PRN phase

Re-treatment will be initiated if any of the following criteria are met:

- Presence of any abnormal intraretinal or subretinal fluid on high resolution SD- OCT.

- Presence of new intraretinal or subretinal hemorrhage related to AMD on examination.

- 10 letter loss from previous visit, related to active wet AMD in the opinion of the
treating investigator

Starting at Week 104, subjects who have NOT achieved extension to the 12-week treatment
interval will continue with the treat and extend protocol. At any time during weeks 104 to
156 if a subject achieves a "dry" macula, at the 12-week interval, they will immediately
begin monthly PRN treatment based on pre-defined re-treatment criteria. Study visits should
be scheduled to occur every 28 (±7) days, relative to the date the 12-week interval is
achieved. Subjects will not be treated at the visit they achieve the 12 week interval (this
is the date PRN treatment will begin).

Inclusion Criteria:

- Ability to provide written informed consent and comply with study assessments for the
full duration of the study

- Age > 50 years

- Ability and willingness to return for all scheduled visits and assessments

- Any CNVM lesion (Occult, Minimally Classic or Classic) (i.e., leakage on fluorescein
angiography or subretinal, intraretinal activity on SDOCT) secondary to age-related
macular degeneration.

Best corrected visual acuity in the study eye, using ETDRS testing, between 20/32 and
20/400 (Snellen equivalent), inclusive.

-The total area of subretinal hemorrhage and fibrosis must comprise less than 50% of the
total lesion. Clear ocular media and adequate pupillary dilation to permit good quality
fundus imaging.

Exclusion Criteria:

- Subretinal hemorrhage in the study eye that involves the center of the fovea, if the
size of the hemorrhage is either > 50% of the total area of the lesion or > 1 disc
area (2.54 mm2) in size

- Subfoveal fibrosis or atrophy in the study eye

- CNV in either eye due to other causes, such as ocular histoplasmosis, trauma, or
pathologic myopia