Adjunctive Photodynamic Therapy + Aflibercept vs. Afilbercept Alone for PDA in NV AMD

Neovascular age-related macular degeneration (NV AMD) remains the leading cause of vision
loss among people over 65. Intravitreal injections with drugs that block vascular endothelial
growth factor (VEGF), a major protein mediator of angiogenesis and vascular leakage, have
revolutionized treatment of NV AMD. This class of drugs includes the FDA-approved medications
ranibizumab (Lucentis ®, Genentech) and aflibercept (Eylea ®, Regeneron), as well as
bevacizumab (Avastin ®, Genentech), which is not FDA-approved for the treatment of NV AMD but
is used off-label with demonstrated clinical efficacy. However, these therapies are not a
cure. Even when effective, the vast majority of NV AMD patients require continued treatment
with anti-VEGF drugs indefinitely for the rest of their lives, to sustain stable visual
acuity. Further, in spite of continuous monthly anti-VEGF therapy, up to 40-50% of patients
demonstrate persistent disease activity (PDA). Patients with persistent disease activity in
spite of ongoing anti-VEGF therapy remain at increased risk for long-term vision loss.
Persistent disease activity is defined as (1) unresolved intraretinal, subretinal, or
sub-retinal pigment epithelium (RPE) fluid or exudation; (2) progressive lesion enlargement
and fibrosis; and/or (3) persistent or new hemorrhage. Several large, multicenter,
prospective clinical trials have demonstrated ~75% rate of PDA following loading dose therapy
(i.e. three consecutive monthly injections), and ~ 40-50% PDA following one year of continued
anti-VEGF therapy.

The treatment burden to sustain visual acuity for patients with PDA is especially high, since
undertreatment or cessation of therapy assures visual decline. The PIER study assessed the
efficacy of quarterly (i.e. every-three-months) anti-VEGF therapy with ranibizumab, following
initiation with loading dose therapy. Patients who had resolution of disease activity
following loading dose maintained visual acuity gains with subsequent quarterly therapy. In
contrast, patients with PDA following loading dose had progressive loss of visual acuity
gains when switched to subsequent quarterly therapy. Several subsequent clinical trials
(CATT, IVAN, others) have demonstrated that patients with PDA typically require continued
monthly therapy to sustain improved visual acuity. Though "do-able" in the short term,
indefinite long-term therapy with monthly injections is often impractical for patients and
for retina physicians, and as a result, undertreatment occurs with high frequency.

Verteporfin (Visudyne ®, Bausch + Lomb) PDT is an FDA-approved treatment for NV AMD that was
initially approved over 10 years ago, prior to the advent of anti-VEGF therapy. As a
first-line therapy, verteporfin PDT is much less effective than anti-VEGF therapy in
improving vision for NV AMD patients. PDT has been studied as an adjunctive therapy in
previously treatment-naïve patients receiving anti-VEGF therapy. It was not found to offer
significant visual acuity benefit over anti-VEGF therapy alone, in this population. However,
it is unknown whether adjunctive PDT may be effective in improving treatment response in
patients with PDA in spite of anti-VEGF therapy. The investigators have performed several
retrospective studies of NV AMD patients in the Duke Medical Retina practice to assess the
role of adjunctive PDT in cases of PDA. Preliminary results indicate that adjunctive
verteporfin PDT reduces disease activity (i.e. decreased fluid and exudation) in patients
with PDA, facilitates treatment with fewer anti-VEGF injections (i.e. reduces treatment
burden), and reduces risk of subsequent vision loss. However, no studies have prospectively
evaluated the efficacy of adjunctive PDT in patients with PDA in spite of anti-VEGF therapy.
The present study will assess the efficacy of adjunctive PDT for the treatment of PDA in NV
AMD. The investigators will compare administration of anti-VEGF therapy with adjunctive PDT
to the standard-of-care treatment approach, anti-VEGF monotherapy administered according to a
"treat-and-extend" approach, where the interval between intravitreal injections is as short
as every 1 month (approximately 4 weeks) but can be gradually lengthened to the longest
interval between treatments that ensures disease quiescence.

Inclusion Criteria:

- Clinical diagnosis of either 1) NV AMD with PDA in spite of standard-of-care
intravitreal anti-VEGF therapy, either loading dose or maintenance therapy or 2)
Clinical diagnosis of NV AMD with Progressive Disease in spite of standard-of-care
intravitreal anti-VEGF therapy, either loading dose or maintenance therapy

- Best-corrected visual acuity equivalent of 20/25-20/320

- Able to provide written informed consent

- Presence of discernible choroidal neovascular lesion by ICG angiography

Exclusion Criteria:

- History of porphyria or sensitivity to any component of verteporfin preparation

- Presence of systemic fungal infection or sensitivity to any component of triamcinolone
acetonide preparation

- Presence of ocular or periocular infection or sensitivity to any component to
aflibercept

- Prior vitrectomy surgery

- Prior thermal laser for macular photocoagulation

- Inability to avoid exposure of skin or eyes to direct sunlight or bright indoor light
for 5 days following verteporfin PDT treatment sessions

- Presence of large submacular hemorrhage in association with choroidal neovascular
lesion

- Known or suspected allergy to fluorescein and/or indocyanine green

- Known history of open angle glaucoma

- Known history of diabetic macular edema or macular edema attributable to central
retinal vein occlusion

- Recent history (within prior 6 months) of cerebrovascular accident (i.e. stroke) or
myocardial infarction.