Dorzolamide-timolol in Combination With Anti-vascular Endothelial Growth Factor Injections for Wet Age-related Macular Degeneration

Intravitreal anti-vascular endothelial growth factor (VEGF) agents, including ranibizumab and
aflibercept, remain the standard of care treatment for neovascular age-related macular
degeneration (AMD). Various treatment modalities using these agents have been proposed,
including monthly, pro re nata, and treat-and-extend regimens. Despite frequent and
consistent treatment with anti-VEGF therapy, there is a subset of patients who are incomplete
responders and have persistent exudation, including intraretinal edema, subretinal fluid
(SRF), and/or retinal pigment epithelial detachment (PED) on spectral-domain optical
coherence tomography (SD-OCT). While clearance of intravitreal anti-VEGF drugs is not
completely understood, some studies have suggested that outflow through the anterior chamber
may play a role. We hypothesized that by decreasing aqueous production, outflow may also be
reduced which could subsequently slow the clearance of intravitreal drugs. In a prior pilot
study with 10 eyes of 10 patients who were incomplete responders with neovascular AMD, the
effect of topical dorzolamide-timolol in combination with continued intravitreal anti-VEGF
injections was explored. Patients were kept on the same anti-VEGF drug as well as the same
interval between injections for the 2 visits before enrollment and through the course of the
pilot study in order to minimize the chances that any changes noted might be the result of
altering one of these variables. The mean central subfield thickness (CST) decreased from
419.7 μm at enrollment to 334.1 μm at the final visit (p=0.012). Mean maximum subretinal
fluid (SRF) height decreased from 126.6 μm at enrollment to 56.5 μm at the final visit
(p=0.020). This decrease in mean CST and SRF was significant beginning at the first visit
after initiation of the drops. Based on this initial pilot data, dorzolamide-timolol appears
to be a promising adjuvant treatment in combination with anti-VEGF injections for incomplete
anti-VEGF responders with neovascular AMD. However, since there was no control group in the
pilot study, it is possible that the decreased exudation seen was a result of the continued
anti-VEGF therapy alone rather than an effect of the topical therapy. As a result, a
randomized, placebo-controlled clinical trial will be better able to assess the efficacy of
dorzolamide-timolol in this setting.

Inclusion Criteria:

1. Active choroidal neovascularization (CNV) due to AMD.

2. Prior treatment with at least 4 injections of anti-VEGF agents in the past 6 months
and persistent intraretinal and/or subretinal fluid on SD-OCT at each visit during
this period.

3. Baseline CST ≥ 270 µm on SD-OCT automated retinal thickness map.

4. Injection of the same anti-VEGF agent at each of the two visits immediately preceding
study enrollment.

5. Time interval of 5 weeks (± 1 week) between visits for at least two visits immediately
preceding study enrollment.

6. Subjects of either gender aged ≥ 45 years.

7. Provide written informed consent

8. Ability to comply with study and follow-up procedures and return for study visits.

Exclusion Criteria:

1. History of uveitis.

2. Presence of intraocular inflammation, significant epiretinal membrane (causing
distortion of macular anatomy per investigator discretion), significant vitreomacular
traction (per investigator discretion), macular hole, or vitreous hemorrhage.

3. Any ophthalmic surgery within previous 6 months, including cataract extraction.

4. Any history of vitrectomy or glaucoma surgery (e.g., trabeculectomy, tube shunt).

5. Current prescription eye drop usage (e.g., glaucoma drops, corticosteroid drops,
etc.).

6. Any contraindication for topical use of a beta-blocker (e.g., bradycardia,
decompensated heart failure, chronic obstructive pulmonary disease, reactive airway
disease, asthma, etc.).

7. Any history of sulfonamide allergy.