CAPTAIN:Choroidal Neovascularization Assessment by Pattern Electroretinography

1. Background 1.1 Pathophysiology Age-related macular degeneration (AMD) is a progressive
disease that causes irreversible visual impairment and blindness in nearly 50 million
people globally 1. 2. Current estimates of patients affected with AMD are higher than
those affected by Alzheimer's disease 1.3 Although geographic atrophy and
neovascularization represent the advanced forms of AMD, neovascular AMD is the more
aggressive form and accounts for almost 90% of blindness from this disease. It is
characterized by choroidal neovascularization (CNV) which is the development of abnormal
blood vessels underneath the retina. Current treatments such as photodynamic therapy
(PDT) and intravitreal pegaptanib are designed to limit further visual loss, but these
are only marginally effective 4-6.

1.2 Treatment of on-label naive AMD patients Recent randomized clinical trials (Marina,
Anchor) have conclusively demonstrated that continued intravitreal therapy with
ranibizumab in patients with subfoveal CNV from AMD leads to stabilization of vision in
over 90% of patients and improvement in vision in at least a third of the patients and
has led to the approval of ranibizumab (0.5 mg) for the treatment of neovascular AMD.
Naive patients will be used in this study to determine if an improvement by ERG can be
determined in those without prior therapy.

1.3 Electroretinography(ERG) Effects Of Ranibizumab Therapy AMD trials are typically
designed to address visual acuity outcomes but not designed to evaluate retinal function
outcomes. Global and macular retinal indices as measured by electroretinography (ERG)
are key indicators of retinal health which have largely been ignored in clinical trials.

1.4 Non-Clinical Experience With Ranibizumab 1.4.1 Nonclinical Pharmacokinetics The
pharmacokinetics of ranibizumab have been investigated in rabbits and cynomolgus monkeys
following intravitreal and intravenous administration. In both species, following
intravitreal administration, ranibizumab was cleared from the vitreous humor with a half
life of 2-3 days. Following single intravitreal administration to cynomolgus monkeys,
retinal concentrations of ranibizumab were approximately one third of vitreous
concentrations and declined in parallel with vitreous concentrations. In humans, the
intravitreal half-life of ranibizumab is estimated to be 7-8 days. Repeated intravitreal
injections of ranibizumab can lead to detectable antibodies in serum in rabbits and
cynomolgus monkeys.

1.4.2 Nonclinical Toxicology A series of nonclinical studies of ranibizumab administered
by intravitreal injection to cynomolgus monkeys have been performed (details regarding
study design and results can be found in the Investigator Brochure).

1.4.3 Stability Studies The stability of ranibizumab alone and in combination with
verteporfin was assessed in vitro. The combination of ranibizumab and verteporfin in a
5% dextrose solution at concentrations of 500 mg/mL and 1.4 mg/mL, respectively,
resulted in ranibizumab degradation and a decrease in ranibizumab capacity to bind VEGF.
The ranibizumab degradation products have not been fully characterized. Although it is
currently unknown if such degradation also occurs in vivo, sequential administration of
verteporfin followed by ranibizumab with an intervening washout period will decrease the
likelihood of loss of ranibizumab activity and degradation.

1.5 Clinical Experience With Ranibizumab Ranibizumab has been or is being clinically
evaluated in nine studies (additional details regarding study design and results can be
found in the Investigator Brochure).

The first clinical trial with ranibizumab, Study FVF1770g was a Phase Ia study of the
molecule given as a single intravitreal injection to subjects with neovascular AMD. The
goals of the study were to investigate safety and tolerability and to define the
maximally tolerated dose (MTD). The single intravitreal MTD was determined to be 0.5 mg
(limited by ocular inflammation).

The Phase I/II study FVF2128g was the first clinical trial of multiple-dose regimens of
intravitreally administered ranibizumab. Sixty-four subjects were enrolled in the study.
Data show that ranibizumab was safe and potentially efficacious in subjects with
subfoveal choroidal neovascularization due to AMD.

Study FVF2425g was a Phase I, open-label, randomized study of three escalating multiple
dose regimens of intravitreally administered ranibizumab. Data show that doses of
ranibizumab up to 2 mg could be safely given as part of an escalating dose regimen to
subjects with subfoveal choroidal neovascularization due to AMD.

Study FVF2428g was a Phase I/II, single masked, multicenter study of the safety,
tolerability, and efficacy of multiple dose intravitreal injections of ranibizumab in
combination with verteporfin PDT in subjects with neovascular AMD. Data show that the
combination of ranibizumab and verteporfin PDT had a good safety profile in the study
population, and the efficacy of ranibizumab and verteporfin PDT was better than that of
verteporfin PDT alone.

Preliminary findings from Study FVF2428g suggest that administration of ranibizumab
injections 7 days (plus/minus 2 days) after treatment with verteporfin PDT in the same
eye may result in a decrease in visual acuity of 30 letters due to temporary intraocular
inflammation (uveitis).

Study FVF2508g is an ongoing Phase I extension study designed to assess the safety and
tolerability of multiple-dose intravitreal injections of ranibizumab administered
monthly in subjects who have completed the treatment phase of a Genentech-sponsored
Phase I study.

Study FVF2587g is an ongoing Phase III active treatment-controlled study designed to
assess the efficacy and safety of intravitreal administered ranibizumab compared with
verteporfin in subjects with angiographically determined, predominantly classic
subfoveal neovascular AMD.

Study FVF2598g was an ongoing Phase III study designed to assess the efficacy and safety
of intravitreal injections of ranibizumab administered monthly compared with sham
injections administered monthly in subjects with angiographically determined, minimally
classic or occult subfoveal neovascular AMD. Data show that ranibizumab was safe and
efficacious in subjects with subfoveal CNV due to AMD.

Study FVF3192g is an ongoing Phase IIIb study designed to assess the efficacy and safety
of intravitreal injections of ranibizumab administered as three monthly injections
followed by quarterly injections for a total duration of 24 months, in subjects with
angiographically determined subfoveal neovascular AMD with or without classic CNV.

Study 3426g is an ongoing open-label extension study designed to assess the safety and
tolerability of intravitreal injections of ranibizumab in subjects who have completed
the treatment phase of a Genentech-sponsored ranibizumab study.

Study 3689g is an ongoing Phase IIIb, 1 year multicenter study of the safety and
tolerability of intravitreally administered ranibizumab at two different doses (0.3mg
and 0.5mg) to subjects with active subfoveal CNV secondary to AMD, administered once a
month for 3 months and thereafter as needed, based on criteria-based re-treatment
options.

2. Objectives

2.1 Primary Objective To determine if there is an improvement in retinal function
determined by the pattern and full-field ERG following treatment with ranibizumab for
AMD

2.2 Secondary Objectives To determine if there is a correlation between improvement in
visual acuity and retinal function as determined by the ERG Visual acuity at 6 months

3. Study Design 3.1 Description Of The Study This is an open-label, Phase I single arm
study of intravitreally administered ranibizumab in on-label treatment naive patients
following by an assessment of retinal function using the ERG.

Consented, enrolled subjects will receive monthly open-label intravitreal injections of 0.5
mg ranibizumab administered every month for 6 months. ERG will be performed at baseline, 1
month, 3 months and 6 months.

Electroretinograms will be recorded using DTL fiber electrodes moistened with
carboxymethyl-cellulose sodium 1% lying in the inferior fornix of each eye. Each DTL fiber
will be laid along the top of the lower eyelids so that it contacts the inferior cornea.
Fibers will be anchored with small adhesive pads near the inner and outer canthi. A reference
electrode will be applied with adhesive paste lateral to the outer canthi. An adhesive
electrode placed on the forehead will serve as the ground. Prior to pupil dilation, PERG
responses will be recorded, including P50 (derived from macular photoreceptors) and N95
(post-photoreceptor, including optic nerve), in response to an alternating checkerboard
pattern. Pupils will then be dilated with tropicamide 1% and phenylephrine hydrochloride 2.5%
for the full-field ERG and PhNR recordings. The patient will be dark-adapted for 30 minutes.
For full-field recordings, stimuli will be brief white flashes presented by a Ganzfeld
integrating sphere. Responses to dim and bright flashes will be recorded under scotopic
conditions, and a- and b-wave amplitudes will be noted. Patients will then be light adapted
for ten minutes. Responses to bright flash and 30 Hz flicker responses will then be recorded
under photopic conditions. A- and b-wave amplitudes and implicit times will be noted.
Finally, the photopic negative response (PhNR) will be recorded with a red flash on a blue
background.

3.2 Rationale For Study Design Per the package insert, naive AMD patients will receive
monthly injections of Lucentis as part of their usual care.

3.3 Outcome Measures 3.3.1 Primary Outcome Measures Percent of patients with Improvement in
ERG from baseline to 6 months based on international standards (determined by expert reader).

3.3.2 Secondary Outcome Measures

Percent of patients with Improvement in ERG from baseline to 3 months based on international
standards (determined by expert reader) Correlation between change in PERG and mean change in
VA at 6 months Mean change in VA from baseline to 3 months and 6 months.

3.4 Safety Plan There are no safety issues associated with the ERG. All safety monitoring
will be as in standard care with the use of on-label ranibizumab. ERG testing is
non-invasive.

3.5 Compliance With Laws And Regulations This study will be conducted in accordance with
current U.S. Food and Drug Administration (FDA) Good Clinical Practices (GCPs), and local
ethical and legal requirements.

Inclusion Criteria:

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

- Age ≥ 50 years

- Treatment naive AMD patients that are determined to be candidates for ranibizumab

- Visual acuity 20/40 to 20/320

Exclusion Criteria:

- Pregnancy

- Prior enrollment in the study

- Previous therapy for AMD or other retinal diseases which may be used in the treatment
of AMD

- Any other condition that the investigator believes would pose a significant hazard to
the subject if on-label ranibizumab were prescribed

- Any condition that would interfere with the ERG recording (such as media opacities
including lens or corneal opacity)

- Concurrent eye disease in the study eye that could compromise visual acuity (such as
diabetic retinopathy, advanced glaucoma)

- Any condition causing the patient to have a significant tremor that would interfere
with the patient's ability to remain still during the ERG (such as Parkinson's
disease)

- Participation in another simultaneous medical investigation or trial