Treatment of Exudative and Vasogenic Chorioretinal Diseases Including Variants of Age-Related Macular Degeneration (AMD) and Other Related Maculopathy

Approximately 40 subjects (maximum of 5 subjects per disease category): (Coats’ Disease,
Idiopathic Perifoveal Telangiectasia, Retinal Angiomatous Proliferation, Polypoidal
Vasculopathy, Pseudoxanthoma Elasticum, Pathological Myopia, Multi-focal Choroiditis,
Rubeosis Iridis) will be enrolled. Written informed consent will be obtained prior to any
screening study procedures. Previous treatment related or unrelated to the subjects'
condition of 30 days or more will be screened for eligibility. The screening evaluations may
be performed within 10 days preceding Day 0 (the day of the first injection of ranibizumab).

Subjects will receive 0.5 mg ranibizumab by intravitreal injection monthly for three months
(at Day 0, Month 1 and Month 2). If the physician determines a subject needs re-treatment,
the following re-treatment criteria must be met:

- Presence of intraretinal/subretinal blood and/or fluid (as determined by fluorescein
angiography and OCT); OR

- Central retinal thickness > 225 mm, determined using OCT; OR

- A 5-letter decrease in BCVA (determined using ETDRS chart at a distance of 4 meters).

Concomitant medications are any prescription drugs or over-the-counter preparations other
than protocol-specified procedural medications (e.g. dilating drops, etc) and pre- and
post-injection medications (e.g., proparacaine, antimicrobials, etc.) used by a subject
within 30 days preceding Day 0 until conclusion of study participation (Month 12) or early
termination.

Verteporfin PDT is not allowed in the study eye during the study. If Verteporfin PDT is to
be administered to the study eye, the subject should be discontinued from the study before
receiving Verteporfin PDT. Verteporfin PDT should not be administered in the study eye at
least 21 days following the last ranibizumab injection.

Treatment with pegaptanib sodium injection is not allowed in the study eye during the study.
Subjects will be discontinued from the study if pegaptanib sodium is to be administered in
the study eye. If pegaptanib sodium treatment is deemed necessary, treatment should not be
initiated in the study eye at least 28 days following the last ranibizumab injection.

Subfoveal laser photocoagulation, elective vitrectomy surgery, transpupillary thermotherapy,
external beam radiation therapy, submacular surgery, or other surgical intervention are not
allowed in the study eye during study participation.

Onset of glaucoma during study participation should be treated as clinically indicated.
Cataract surgery in the study eye is allowed provided the next ranibizumab injection can be
held for 30 days following the cataract surgery.

Subjects may continue to receive all medications and standard treatments administered for
their conditions at the discretion of their treating physician.

In subjects where the fellow eye requires treatment for the same condition as in the study
eye, physician can provide treatment with 0.5 mg ranibizumab only. Patients receiving
ranibizumab treatment in the fellow eye should be followed according to study protocol for
both eyes.

Screening assessment - Day –10 to day 0

Type of assessment: Comments

Informed consent: To be obtained prior to any specific protocol investigations

Demographic data: Patient’s initials, date of birth, gender

Medical history/medical condition: Significant medical and surgical events and current
medical condition collected through a careful patient interview

History of ocular disease: Primary diagnosis and any other ocular conditions

Acute illness assessment: If a patient presents with an unexplained acute illness, the study
assessments must be rescheduled to occur after the illness resolves or has been explained.

Pregnancy test: A serum pregnancy test, if applicable

Concomitant treatment: Any ongoing medications and any medications within the last 6 months

Vital signs: Collect the patient’s heart rate, blood pressure (sitting), height, and weight.

Ophthalmic examination: In the following order:

1. Protocol refraction

2. Best corrected visual acuity starting at 4 meters.

3. Ophthalmic examination to include biomicroscopy and indirect ophthalmoscopy

4. Color fundus photography

5. Fluorescein angiography

6. Optical coherence tomography

Inclusion/exclusion review: Before scheduling for the first treatment, each inclusion and
exclusion criterion should be checked. If both the eyes are eligible, the study investigator
will choose with the patient which eye will be the study treated eye.

FIRST TREATMENT – BASELINE/DAY 0

Type of assessment: Comments

Medical history/medical condition: Significant medical and surgical events and current
medical condition collected through a careful patient’s interview

Concomitant treatment: Any ongoing medications and any medications within the last 6 months

Vital signs: Collect the patient’s heart rate and blood pressure (sitting)

Ophthalmic examination: In the following order:

1. Protocol refraction

2. Best corrected visual acuity starting at 4 meters (see the study operations manual)

3. Ophthalmic examination to include biomicroscopy and indirect ophthalmoscopy

FOLLOW UP VISITS

Type of assessment: Comments

Adverse event monitoring: Any change in ongoing symptoms, resolution of symptoms, and
recurrence of symptoms, all adverse experiences, since last visit, are to be recorded. Each
symptom or syndrome will be reported on the adverse event form.

Concomitant treatment: Any changes in medications or in concurrent ocular procedures.

Vital signs: Collect the patient’s heart rate and blood pressure (sitting)

Ophthalmic examination: In the following order:

1. protocol refraction

2. best corrected visual acuity starting at 4 meters

3. ophthalmic examination to include biomicroscopy and indirect ophthalmoscopy

4. color fundus photography

5. fluorescein angiography (at months 3,6, and 9)

6. Optical coherence tomography

POST INJECTION VISIT (2-7 days post first injection)

Type of assessment: Comments

Adverse event monitoring: Any changes in ongoing symptoms, new symptoms, resolution of
symptoms and recurrence of symptoms, all adverse experiences, since last visit are to be
recorded. Each symptom or syndrome will be reported on the adverse event form.

Concomitant treatment: Any changes in medications or in concurrent ocular procedures.

Ophthalmic examination: Best corrected visual acuity starting at 4 meters.

Ophthalmic examination to include biomicroscopy and indirect ophthalmoscopy.

EARLY TERMINATION VISIT and EXIT VISIT

Type of assessment: Comments

Adverse event monitoring: Any changes in ongoing symptoms, new symptoms, resolution of
symptoms and recurrence of symptoms, all adverse experiences, since last visit are to be
recorded. Each symptom or syndrome will be reported on the adverse event form.

Concomitant treatment: Any changes in medications or in concurrent ocular procedures.

Vital signs: Collect the patient’s heart rate and blood pressure (sitting)

Ophthalmic examination: In the following order:

1. Protocol refraction

2. Best corrected visual acuity starting at 4 meters (see the study operations manual).

3. Ophthalmic examination to include biomicroscopy and indirect ophthalmoscopy

4. Color fundus photography

5. Fluorescein angiography

6. Optical coherence tomography

UNSCHEDULED VISIT ASSESSMENTS

Type of assessment: Comments

Adverse event monitoring: Any changes in ongoing symptoms, new symptoms, resolution of
symptoms and recurrence of symptoms, all adverse experiences, since last visit are to be
recorded. Each symptom or syndrome will be reported on the adverse event form.

Concomitant treatment: Any changes in medications or in concurrent ocular procedures.

Ophthalmic examination: In the following order:

1. Protocol refraction

2. Best corrected visual acuity starting at 4 meters (see the study operations manual).

3. Ophthalmic examination to include biomicroscopy and indirect ophthalmoscopy

4. Color fundus photography (As needed)

5. Fluorescein angiography (As needed)

6. Optical coherence tomography (As needed)

Early Termination Assessments:

Subjects who withdraw from the study prior to completion should return for an early
termination evaluation 30 days ( 7 days) following the last injection/study visit for
monitoring of all adverse events (serious and nonserious). The schedule of assessments for
early termination is the same as that for the final visit.

SUBJECT DISCONTINUATION:

Subjects have a right to withdraw from the study at any time. The subject may be withdrawn
from the study for any reasons: if it is in the best interest of the subject, intercurrent
illness, adverse events, or worsening condition. Manhattan Eye, Ear & Throat Hospital may
request the withdrawal of a subject because of protocol violations, administrative reasons,
or any other valid and ethical reasons.

If a subject discontinues from the study, he or she will not be allowed to re enter the
study.

Reasons for subject discontinuation may include, but are not limited to, the following:

- Severe uveitis

- Endophthalmitis

- Sensory rhegmatogenous retinal detachment or Stage 3 or 4 macular hole

- Investigator determination that it is not in the best interest of the subject to
continue participation

- Any other safety concerns. In the event of an adverse event in the study eye that is
considered by the investigator to be severe in intensity, serious consideration should
be given to discontinuing the subject from the study.

STUDY DISCONTINUATION:

This study may be terminated by Manhattan Eye, Ear & Throat Hospital or Genentech at any
time. Reasons for terminating the study may include the following:

- The incidence or severity of adverse events in this or other studies indicates a
potential health hazard to subjects

- Subject enrollment is unsatisfactory

- Data recording is inaccurate or incomplete

Inclusion Criteria:

Subjects will be eligible if the following criteria are met:

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

2. Age > 18 years

3. Clinical diagnosis of the following conditions: Coats’ disease, idiopathic
perifoveal telangiectasia, retinal angiomatous proliferation, polypoidal
vasculopathy, pseudoxanthoma elasticum, pathological myopia, multi-focal choroiditis,
rubeosis iridis.

4. Visual acuity of 20/40 to 20/320 in the study eye on the ETDRS visual acuity chart.

5. Media clarity, pupillary dilation and patient cooperation sufficient to allow OCT
testing and retinal photography

Exclusion Criteria:

Subjects who meet any of the following criteria will be excluded from this study:

1. Any other condition that the investigator believes would pose a significant hazard to
the subject if the investigational therapy is initiated

2. Participation in another simultaneous medical investigation or trial

3. Patient with significantly compromised visual acuity in the study eye due to
concomitant ocular conditions.

4. Patients who have undergone intraocular surgery within the last 2 months.

5. Patient participating in any other investigational drug study.

6. Use of an investigational drug or treatment related or unrelated to the patient's
condition within 30 days prior to receipt of study medication (verteporfin,
pegaptanib, or other AMD therapy in the study eye)

7. Patient treated with systemic anti-VEGF or pro-VEGF agents within 3 months before
enrollment.

8. Previous treatment (in either eye) with intravitreal or intravenously administered
Avastin (bevacizumab).

9. Inability to obtain photographs to document CNV (including difficulty with venous
access).

10. Patient with a known adverse reaction to fluorescein dye.

11. Patient has a history of any medical condition which would preclude scheduled visits
or completion of the study.

12. Patient has had insertion of scleral buckle in the study eye

13. Patient has received radiation treatment.

14. Aphakia or absence of the posterior capsule in the study eye. Previous violation of
the posterior capsule in the study eye is also excluded unless as a result of yttrium
aluminum garnet (YAG) posterior capsulotomy in association with posterior chamber
lens implantation.

15. Pregnancy (positive pregnancy test) or lactation.

16. Premenopausal women not using adequate contraception. The following are considered
effective means of contraception: surgical sterilization or use of oral
contraceptives, barrier contraception with either a condom or diaphragm in
conjunction with spermicidal gel, an intrauterine device (IUD), or contraceptive
hormone implant or patch.

17. History of glaucoma filtering surgery in the study eye.

18. Concurrent use of more than two therapies for glaucoma.

19. Uncontrolled glaucoma in the study eye (defined as intraocular pressure > 30 mm Hg
despite treatment with anti-glaucoma medication)

20. Inability to comply with study or follow-up procedure