The SARS-CoV-2 Virus and the Cholinergic System: Spike Protein Interaction with Human Nicotinic Acetylcholine Receptors and the Nicotinic Agonist Varenicline.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the worldwide coronavirus disease 2019 (COVID-19) pandemic. Although the pathophysiology of SARS-CoV-2 infection is still being elucidated, the nicotinic cholinergic system may play a role. To evaluate the interaction of the SARS-CoV-2 virus with human nicotinic acetylcholine receptors (nAChRs), we assessed the in vitro interaction of the spike protein of the SARS-CoV-2 virus with various subunits of nAChRs. Electrophysiology recordings were conducted at α4ß2, α3ß4, α3α5ß4, α4α6ß2, and α7 neuronal nAChRs expressed in Xenopus oocytes. In cells expressing the α4ß2 or α4α6ß2 nAChRs, exposure to the 1 µg/mL Spike-RBD protein caused a marked reduction of the current amplitude; effects at the α3α5ß4 receptor were equivocal and effects at the α3ß4 and α7 receptors were absent. Overall, the spike protein of the SARS-CoV-2 virus can interact with select nAChRs, namely the α4ß2 and/or α4α6ß2 subtypes, likely at an allosteric binding site. The nAChR agonist varenicline has the potential to interact with Spike-RBD and form a complex that may interfere with spike function, although this effect appears to have been lost with the omicron mutation. These results help understand nAChR's involvement with acute and long-term sequelae associated with COVID-19, especially within the central nervous system.

OC-01 (Varenicline Solution) Nasal Spray for the Treatment of Dry Eye Disease Signs and Symptoms in Subjects with Autoimmune Disease: Integrated Data from ONSET-1 and ONSET-2.

Purpose: We evaluate the treatment effect of OC-01 (varenicline solution) nasal spray (VNS) in dry eye disease (DED) subjects from two randomized trials who self-reported autoimmune disease (AID). Patients and Methods: Post hoc subgroup analysis of subjects reporting a history of AID from the integrated OC-01 VNS 0.03 or 0.06 mg and vehicle control (VC) treatment groups of the ONSET-1 and ONSET-2 trials. Mean change in Schirmer test with anesthesia score (STS, mm) and Eye Dryness Score (EDS) from baseline to 28 days was compared between OC-01 VNS and VC groups. Consistency of treatment effect in subjects with and without AID was evaluated using treatment-subgroup interaction terms in ANCOVA models for mean changes from baseline STS and EDS, and in a logistic regression model for proportion achieving ≥10 mm STS improvement. Results: Of the 891 participants, 31 reported comorbid AID. In all models, the treatment-subgroup interaction terms were not significant (p>0.05), indicating consistency of therapeutic effect of OC-01 VNS in subjects with and without AID. In subjects with AID, the treatment difference for STS was 11.8 mm and -9.3 for EDS and difference for proportion of subjects with ≥10 mm STS improvement was 61.1%. The most common adverse event was sneeze (82-84%), graded as mild by 98% of subjects. Conclusion: OC-01 VNS demonstrated consistency in improving both tear production and patient-reported symptoms in subjects with AID, consistent with pivotal ONSET-1 and 2 trial results. Further investigation is warranted, and results may further support use of OC-01 VNS for DED in AID patients.

ONSET-1 Phase 2b Randomized Trial to Evaluate the Safety and Efficacy of OC-01 (Varenicline Solution) Nasal Spray on Signs and Symptoms of Dry Eye Disease.

PURPOSE: The purpose of this trial was to evaluate the safety and efficacy of OC-01 (varenicline solution), a nicotinic acetylcholine receptor agonist nasal spray, on signs and symptoms of dry eye disease. METHODS: A phase 2b, multicenter, randomized, double-masked, vehicle-controlled trial (ONSET-1; NCT03636061) was performed. Patients were aged 22 years or older with a physician's diagnosis of dry eye disease and previous use of artificial tears were randomized 1:1:1:1 to control (vehicle nasal spray twice daily [BID]), OC-01 0.006 mg BID, OC-01 0.03 mg BID, and OC-01 0.06 mg BID. The primary end point was the change in the anesthetized Schirmer test score from baseline to day 28 in the study eye. The secondary end points included the change in the eye dryness score from baseline to day 28. RESULTS: One hundred eighty-two patients were randomized. After 28 days, patients who received OC-01 0.03 or 0.06 mg showed a statistically significant improvement in tear film production relative to vehicle, with least squares mean differences from vehicle of 7.7 mm [95% confidence interval, 3.8-11.7; P < 0.001] with OC-01 0.03 mg and 7.5 mm (95% confidence interval, 3.4-11.6; P < 0.001) with OC-01 0.06 mg. Patients receiving OC-01 0.03 mg showed a significant reduction in the eye dryness score by day 28 versus vehicle (P = 0.021); those receiving the OC-01 0.06 mg dose showed a nonsignificant reduction versus vehicle. OC-01 administration was associated with sneezing (62%-84%) and cough (9%-25%); these were transient and predominantly mild in severity. CONCLUSIONS: OC-01 nasal spray administered BID at 0.03 and 0.06 mg resulted in significant improvements in signs and symptoms of dry eye disease, was well tolerated, and warrants further clinical investigation.

Efficacy and Safety of Single-dose OC-02 (Simpinicline Solution) Nasal Spray on Signs and Symptoms of Dry Eye Disease: The PEARL Phase II Randomized Trial.

PURPOSE: Dry eye disease is a multifactorial disorder that affects the ocular surface, with symptoms including ocular irritation, impaired vision, and pain. Nicotinic acetylcholine receptor (nAChR) agonists are novel treatments for dry eye disease; this study investigates the nAChR agonist OC-02 (simpinicline solution) as an aqueous nasal spray. METHODS: PEARL (Clinical Trial to Evaluate the Efficacy of OC-02 Nasal Spray on Signs and Symptoms of Dry Eye Disease) was a Phase II study that evaluated the efficacy and safety of OC-02 (simpinicline solution) nasal spray (OC-02 SNS) in adult patients with dry eye disease. Patients ≥22 years of age were eligible if they had an Ocular Surface Disease Index score ≥23, corneal fluorescein staining score ≥2 in >1 region or ≥4 for all regions, or Schirmer test score (STS) ≤10 mm; there were no restrictions on eye dryness score (EDS). Patients (N = 165) were randomly assigned 1:1:1:1 to vehicle (control; n = 42) or OC-02 SNS (0.11 mg, 0.55 mg, or 1.1 mg; n = 41 per group) and received a single dose of study drug (100 µL using a nasal spray atomizer) at visit 1 and visit 2 (15-19 days after visit 1). Primary efficacy outcomes were change in the STS from baseline to immediately after treatment administration (visit 1) and change in the EDS from before to 5 minutes after treatment during controlled adverse environment exposure (visit 2). FINDINGS: Baseline demographic and ocular clinical characteristics were similar across all groups. Single-dose OC-02 SNS improved the signs and symptoms of dry eye disease. For the STS, statistically significant and dose-dependent improvements were found from before to after treatment with OC-02 SNS versus vehicle (least-squares mean change from baseline: vehicle, 3.0 mm; 0.11 mg OC-02 SNS, 9.0 mm; 0.55 mg, 17.5 mm; and 1.1 mg, 19.6 mm). For EDS, statistically significant and dose-dependent improvements were found from before to 5 minutes after treatment with higher doses of OC-02 SNS versus vehicle (least-squares mean change from baseline: vehicle, -6.5; 0.11 mg OC-02 SNS, -9.4; 0.55 mg, -17.4; and 1.1 mg, -20.7). OC-02 SNS was well tolerated: only 2 ocular adverse events were reported (eye pruritis and keratitis), and the most common nonocular events were cough and throat irritation. IMPLICATIONS: Single-dose OC-02 SNS over a range of doses immediately and significantly increased tear production and improved eye dryness. Together with previous studies of OC-01 (varenicline solution) nasal spray, our findings suggest that agonist stimulation of nAChRs in the nasal cavity is a valid and effective mechanism to elicit natural tear production in patients with dry eye disease. CLINICALTRIALS: gov identifier: NCT03452397.

A Single Administration of OC-01 (Varenicline Solution) Nasal Spray Induces Short-Term Alterations in Conjunctival Goblet Cells in Patients with Dry Eye Disease.

INTRODUCTION: Dry eye disease is characterized by a persistently unstable or deficient tear film causing discomfort or visual impairment. Varenicline is a small-molecule nicotinic acetylcholine receptor agonist recently approved for use as a preservative-free nasal spray (OC-01 [varenicline solution] nasal spray [OC-01 VNS]) to treat signs and symptoms of dry eye disease, but its effect on conjunctival goblet cells has not been studied. METHODS: In this phase 2, single-center, vehicle-controlled study, patients aged 18 years or more with a diagnosis of dry eye disease and Ocular Surface Disease Index© score of at least 23 were randomized 2:1 to receive a 50-µL single dose of OC-01 0.06 mg VNS or vehicle nasal spray in each nostril. Image assessments for area and perimeter were performed pre and 10 min post treatment for goblet cells by in vivo confocal microscopy and for meibomian glands by infrared meibography. Non-parametric Wilcoxon signed-rank test compared pre- and post-treatment measurements for each treatment group. Treatment-emergent adverse events (TEAEs) were assessed. RESULTS: The study randomized 18 patients (mean age 61 years); 6 received vehicle (3/6 [50%] female) and 12 patients received OC-01 VNS (11/12 [92%] female). OC-01 VNS treatment decreased mean goblet cell area (pre-treatment, 106.4 µm2; post-treatment, 67.6 µm2; p = 0.02) and perimeter (pre-treatment, 38.9 µm; post-treatment, 31.2 µm; p = 0.03) but not vehicle did not (p = 0.25). There were no significant changes in mean meibomian gland area with either treatment (p ≥ 0.05). All TEAEs were non-ocular, non-serious, and mild. CONCLUSIONS: This study demonstrated that a single administration of OC-01 0.06 mg VNS in patients with dry eye disease reduced conjunctival goblet cell area and perimeter, suggesting goblet cell degranulation and associated release of lubricating mucin. By activating the natural tear film, OC-01 VNS may provide benefits over topical medications. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03688802.

Efficacy and Safety of OC-01 (Varenicline Solution) Nasal Spray on Signs and Symptoms of Dry Eye Disease: The ONSET-2 Phase 3 Randomized Trial.

PURPOSE: To evaluate the efficacy and safety of OC-01 (varenicline solution) nasal spray for treatment of patients with dry eye disease. DESIGN: Randomized, multicenter, double-masked, vehicle-controlled, phase 3 study. PARTICIPANTS: Adults 22 years of age or older with a diagnosis of dry eye disease, artificial tear use, Ocular Surface Disease Index score of 23 or more, and Schirmer test score (STS) of 10 mm or less. Eligibility was not restricted by eye dryness score (EDS). METHODS: Patients (N = 758) were randomized in a 1:1:1 ratio to twice-daily treatment with 50-µl intranasal spray in each nostril of OC-01 0.03 mg (n = 260), OC-01 0.06 mg (n = 246), or vehicle (control; n = 252) for 4 weeks (ClinicalTrials.gov identifier, NCT04036292). MAIN OUTCOME MEASURES: The primary efficacy end point was the percentage of patients achieving a 10-mm improvement or more in STS at week 4. Secondary end points included change from baseline to week 4 in STS and EDS in a controlled adverse environment (CAE) chamber and in the clinic. Treatment-emergent adverse events (TEAEs) were assessed. RESULTS: A statistically significantly greater percentage of patients achieved the primary end point in both OC-01 treatment groups compared with the vehicle group (OC-01 0.03 mg, 47.3%; OC-01 0.06 mg, 49.2%; vehicle, 27.8%; P < 0.0001 for both doses). Change from baseline in STS at week 4 was statistically significantly greater for patients receiving OC-01 than vehicle (P < 0.0001 for both doses). Eye dryness score assessed at week 4 improved with OC-01 treatment compared with vehicle, although the difference was not significant for EDS measured in the CAE chamber and showed (nominal) significance in the clinic. Overall, 86.5% of patients (654/756) reported at least 1 TEAE during the treatment period; most were mild, nonocular (sneezing, cough, throat irritation, and instillation site irritation) and were reported by fewer patients in the vehicle group than in the OC-01 treatment groups (OC-01 0.03 mg, 97.3%; OC-01 0.06 mg, 99.2%; vehicle, 57%). CONCLUSIONS: OC-01 nasal spray was well tolerated and showed a clinically meaningful effect on signs and symptoms of dry eye disease.

A phase II randomized trial to evaluate the long-term (12-week) efficacy and safety of OC-01 (varenicline solution) nasal spray for dry eye disease: The MYSTIC study.

PURPOSE: Dry eye disease is characterized by loss of tear film stability. OC-01 (varenicline solution) is a small-molecule nicotinic acetylcholine receptor agonist administered as a nasal spray that stimulates tear production. METHODS: In MYSTIC (NCT03873246) patients aged ≥22 years with dry eye disease were randomized 1:1:1 to OC-01 0.03 mg, OC-01 0.06 mg, or vehicle (n = 41 per group), administered twice daily via intranasal spray, for 12 weeks (84 days). Primary efficacy endpoint was mean change from baseline in anesthetized Schirmer's test score (STS) in study eye at day (D) 84. RESULTS: Patients receiving OC-01 0.03 and 0.06 mg had statistically significantly increased tear production at D84 versus vehicle; least squares mean changes from baseline in STS were 10.8 mm and 11.0 mm for OC-01 0.03 and 0.06 mg, respectively. A trend toward a higher proportion of patients experiencing ≥10-mm improvement in STS from baseline was observed with OC-01 0.03 mg (36.6%; p > 0.05), and was significant for OC-01 0.06 mg (48.8%; p = 0.024), versus vehicle (24.4%). Non-ocular treatment-emergent adverse events (TEAEs) were reported by 21 patients; the most common was sneezing (OC-01 0.03 mg, 2 [4.9%]; OC-01 0.06 mg, 3 [7.3%]), with similar frequencies between treatment groups. No severe or serious TEAEs were reported. CONCLUSIONS: OC-01 (varenicline solution) nasal spray improved tear production in patients with dry eye disease over a long-term (12-week) period, and represents a receptor neuro-activator with a nasal route of administration that spares the ocular surface to stimulate tear production.

A Phase I, Open-label, Randomized, 2-Way Crossover Study to Evaluate the Relative Bioavailability of Intranasal and Oral Varenicline.

PURPOSE: To estimate the systemic bioavailability of OC-01 (varenicline) nasal spray, an investigational treatment for dry eye disease, relative to oral varenicline approved for smoking cessation. METHODS: The Study to Evaluate the Relative Bioavailability of Varenicline Administered as OC-01 (Varenicline) Nasal Spray as Compared to Varenicline Administered Orally as Chantix (ZEN study) was a Phase I, open-label, randomized, single-center, 2-way crossover study. On day 1, 22 healthy participants were randomized 1:1 to a single intranasal dose of varenicline 0.12 mg in OC-01 nasal spray or a single oral dose of varenicline 1 mg. On day 15, all participants crossed over to receive a single dose of the alternate treatment. Plasma samples were collected for 6 days after each dose, and pharmacokinetic parameters were estimated using noncompartmental analysis. Tolerability was monitored throughout. FINDINGS: After a single dose of intranasal varenicline 0.12 mg in OC-01 nasal spray, peak systemic exposure (mean plasma Cmax) was 0.34 ng/mL, which occurred at a median Tmax of 2.0 hours. In comparison, mean plasma Cmax after oral varenicline 1 mg was 4.63 ng/mL at a median Tmax of 3.0 hours. On the basis of geometric mean ratio point estimates, peak exposure (Cmax) and total exposure (AUC0-∞) after intranasal varenicline 0.12 mg were 7.0% and 7.5%, respectively, of the systemic exposure associated with oral varenicline 1 mg. Dose-normalized Cmax and AUC0-∞ for intranasal varenicline remained 39% and 33% lower versus oral varenicline, respectively. No new or unexpected tolerability signals were detected. IMPLICATIONS: At its highest intended single dose in OC-01 nasal spray, intranasal varenicline delivered less drug to the systemic circulation than oral varenicline at its highest approved single dose. ClinicalTrials.gov identifier: NCT04072146.

Macular epiretinal brachytherapy in treated age-related macular degeneration (MERITAGE): month 24 safety and efficacy results.

PURPOSE: To evaluate the safety and efficacy of epimacular brachytherapy for the treatment of chronic, active neovascular age-related macular degeneration. METHODS: A prospective, multicenter, interventional noncontrolled clinical trial recruited 53 participants with previously treated neovascular age-related macular degeneration. Participants underwent pars plana vitrectomy with a single 24 Gray dose of epimacular brachytherapy, delivered using an intraocular cannula containing a Strontium 90/Yttrium 90 source that was positioned over the active lesion. Participants were retreated with ranibizumab, administered monthly as needed, using predefined retreatment criteria. Coprimary outcomes at 24 months were the proportion of participants losing <15 Early Treatment of Diabetic Retinopathy Study letters and mean number of ranibizumab retreatments. RESULTS: Over 24 months, 68.1% lost <15 letters with a mean of 8.7 ranibizumab retreatments. Mean change in visual acuity was -6.3 (standard deviation, 18.9) letters. There was one case of nonproliferative radiation retinopathy. CONCLUSION: The apparent reduction in ranibizumab retreatment was less evident in Year 2 than Year 1, with the moderate reduction in visual acuity extending into the second year. Although radiation retinopathy occurred in one case, it was not vision threatening and safety remained acceptable.

Safety testing of epimacular brachytherapy with microperimetry and indocyanine green angiography: 12-month results.

PURPOSE: To determine if epimacular brachytherapy is associated with reduced retinal sensitivity or choroidal nonperfusion. METHODS: A prospective intervention case series of 12 participants with neovascular age-related macular degeneration requiring frequent ranibizumab underwent vitrectomy and epimacular brachytherapy. The Strontium 90/Yttrium 90 source delivered a single 24-Gy dose at the center of the treatment zone. The dose attenuated with increasing distance from the source. Microperimetry and indocyanine green angiography were performed at baseline and 12 months. The main outcome measures were mean sensitivity and choroidal nonperfusion. A linear mixed model was used to assess the association between the dose of radiation and the change in mean sensitivity. RESULTS: Mean visual acuity remained within 1 letter of baseline at 12 months (-0.33 ± 13.2 letters). There was no statistically significant change in mean sensitivity within the neovascular age-related macular degeneration lesion area (gain of 0.94 ± 3.25 dB; P = 0.339) or in neighboring unaffected retina (0.66 ± 4.14 dB; P = 0.594), defined using fluorescein angiography. Within the lesion area, mean sensitivity improved by an average of 0.23 ± 0.16 dB (P = 0.006) for every additional gray of radiation received. Indocyanine green angiography failed to demonstrate any choroidal nonperfusion or radiation damage at 12 months after the treatment. CONCLUSION: Stable retinal sensitivity in areas not manifestly affected by neovascular age-related macular degeneration suggests that epimacular brachytherapy does not damage retinal function. The presence of a dose response suggests that the positive effect of epimacular brachytherapy relates more to beta irradiation than vitrectomy.

Epimacular brachytherapy for neovascular age-related macular degeneration (CABERNET): fluorescein angiography and optical coherence tomography.

PURPOSE: To report the fluorescein angiography (FA) and optical coherence tomography (OCT) results of a clinical trial of epimacular brachytherapy (EMBT) used for the treatment of neovascular age-related macular degeneration (AMD). DESIGN: Pivotal multicenter, active-controlled, randomized clinical trial. PARTICIPANTS: A total of 494 participants with treatment-naïve, neovascular AMD. METHODS: Participants with classic, minimally classic, and occult lesions were randomized to receive (a) EMBT and 2 mandated monthly ranibizumab injections followed by pro re nata (PRN) ranibizumab or (b) 3 mandated monthly ranibizumab injections followed by mandated quarterly plus PRN ranibizumab. Participants underwent FA at screening and at months 1, 6, 12, 18, and 24. Optical coherence tomography scans were undertaken monthly for 24 months. The FA and OCT images were analyzed at respective independent reading centers. MAIN OUTCOME MEASURES: Change at 24 months in mean FA total lesion size and choroidal neovascularization (CNV) size and change in mean OCT centerpoint thickness. RESULTS: The mean (standard deviation) changes in FA total lesion size in the EMBT and control arms were +1.9 (8.7) and -3.0 (7.2) mm(2), respectively, with a mean change in total CNV size of +0.4 (8.4) and -4.7 (6.5) mm(2), respectively. Mean (standard deviation) changes in OCT centerpoint thickness were -144 (246) and -221 (185) µm, respectively. Retrospective subgroup analyses showed no significant difference between treatment arms in mean centerpoint thickness in some subgroups, including eyes with classic lesions. The control arm showed a significantly larger reduction in mean total lesion size and mean CNV size than the EMBT arm in all subgroups analyzed. Nine eyes in the EMBT arm showed features consistent with mild, nonproliferative radiation retinopathy, but with a mean gain of 5.0 Early Treatment Diabetic Retinopathy Study letters. CONCLUSIONS: Both FA and OCT suggest that EMBT with PRN ranibizumab results in an inferior structural outcome than quarterly plus PRN ranibizumab. Some subgroup analyses suggest that classic lesions may be more responsive than occult lesions, although generally both subgroups are inferior to ranibizumab. A non-vision-threatening radiation retinopathy occurs in 2.9% of eyes over 24 months, but longer follow-up is needed. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Epimacular brachytherapy for neovascular age-related macular degeneration: a randomized, controlled trial (CABERNET).

PURPOSE: To evaluate the safety and efficacy of epimacular brachytherapy (EMBT) for the treatment of neovascular age-related macular degeneration (AMD). DESIGN: Multicenter, randomized, active-controlled, phase III clinical trial. PARTICIPANTS: Four hundred ninety-four participants with treatment-naïve neovascular AMD. METHODS: Participants with classic, minimally classic, and occult lesions were randomized in a 2:1 ratio to EMBT or a ranibizumab monotherapy control arm. The EMBT arm received 2 mandated, monthly loading injections of 0.5 mg ranibizumab. The control arm received 3 mandated, monthly loading injections of ranibizumab then quarterly injections. Both arms also received monthly as needed (pro re nata) retreatment. MAIN OUTCOME MEASURES: The proportion of participants losing fewer than 15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline visual acuity (VA) and the proportion gaining more than 15 ETDRS letters from baseline VA. RESULTS: At 24 months, 77% of the EMBT group and 90% of the control group lost fewer than 15 letters. This difference did not meet the prespecified 10% noninferiority margin. This end point was noninferior using a 20% margin and a 95% confidence interval for the group as a whole and for classic and minimally classic lesions, but not for occult lesions. The EMBT did not meet the superiority end point for the proportion of participants gaining more than 15 letters (16% for the EMBT group vs. 26% for the control group): this difference was statistically significant (favoring controls) for occult lesions, but not for predominantly classic and minimally classic lesions. Mean VA change was -2.5 letters in the EMBT arm and +4.4 letters in the control arm. Participants in the EMBT arm received a mean of 6.2 ranibizumab injections versus 10.4 in the control arm. At least 1 serious adverse event occurred in 54% of the EMBT arm, most commonly postvitrectomy cataract, versus 18% in the control arm. Mild, nonproliferative radiation retinopathy occurred in 3% of the EMBT participants, but no case was vision threatening. CONCLUSIONS: The 2-year efficacy data do not support the routine use of EMBT for treatment-naïve wet AMD, despite an acceptable safety profile. Further safety review is required.

Macular epiretinal brachytherapy in treated age-related macular degeneration (MERITAGE): month 12 optical coherence tomography and fluorescein angiography.

PURPOSE: To report the optical coherence tomography (OCT) and fundus fluorescein angiography (FFA) results of the Macular Epiretinal Brachytherapy in Treated Age-Related Macular Degeneration study. DESIGN: Prospective, multicenter, interventional, noncontrolled clinical trial. PARTICIPANTS: Fifty-three eyes of 53 participants with chronic, active neovascular age-related macular degeneration (AMD) requiring frequent anti-vascular endothelial growth factor retreatment. METHODS: Participants underwent pars plana vitrectomy with a single 24-gray dose of epimacular brachytherapy (EMB), delivered with an intraocular, handheld, cannula containing a strontium 90/yttrium 90 source positioned over the active lesion. Participants were retreated with ranibizumab administered monthly as needed, using predefined retreatment criteria. Patients underwent FFA at baseline, month 1, and month 12. Patients underwent optical coherence tomography (OCT) at baseline and then monthly for 12 months. The FFA and OCT images were evaluated by independent, central reading facilities. MAIN OUTCOME MEASURES: Change in OCT centerpoint thickness and angiographic lesion size 12 months after EMB. RESULTS: Mean centerpoint thickness increased by 50 µm, from 186 to 236 µm (P = 0.292), but 70% of participants had an increase of less than the mean, with a median increase of only 1.8 µm. The FFA total lesion size increased slightly by 0.79 mm(2), from 14.69 to 15.48 mm(2) (P = 0.710). Total choroidal neovascularization (CNV) area increased by 1.17 mm(2), from 12.94 to 14.12 mm(2) (P = 0.556). The classic CNV area decreased substantially by 3.70 mm(2), from 3.90 to 0.20 mm(2) (P<0.01). Predominantly classic lesions showed the greatest response, with mean Early Treatment Diabetic Retinopathy Study visual acuity improving by 1.5 letters (versus -4.0 for all participants combined); mean centerpoint thickness decreased by 43 µm (P = 0.875). The angiographic and OCT response did not correlate with lesion size at baseline. CONCLUSIONS: In chronic, active, neovascular AMD, EMB is associated with nonsignificant changes in centerpoint thickness and FFA total lesion size over 12 months.

Macular epiretinal brachytherapy in treated age-related macular degeneration: MERITAGE study: twelve-month safety and efficacy results.

PURPOSE: To evaluate the safety and efficacy of epimacular brachytherapy (EMB) for the treatment of chronic, active, neovascular age-related macular degeneration (AMD). DESIGN: Prospective, multicenter, interventional, noncontrolled clinical trial. PARTICIPANTS: Fifty-three eyes of 53 participants with neovascular AMD requiring frequent anti-vascular endothelial growth factor (VEGF) retreatment. METHODS: Participants underwent pars plana vitrectomy with a single 24-Gy dose of EMB delivered using an intraocular, handheld cannula containing a strontium 90/yttrium 90 source positioned over the active lesion. Participants were retreated with ranibizumab administered monthly as needed, using predefined retreatment criteria. Optical coherence tomography (OCT) was undertaken monthly, with images assessed by an independent reading center. MAIN OUTCOME MEASURES: Coprimary outcomes at 12 months were proportion of participants with stable vision (losing <15 Early Treatment Diabetic Retinopathy Study [ETDRS] letters) and mean number of anti-VEGF retreatments. RESULTS: Before enrollment, participants had received an average of 12.5 anti-VEGF injections. After a single treatment with EMB, 81% maintained stable vision, with a mean of 3.49 anti-VEGF retreatments in 12 months. Mean ± standard deviation change in visual acuity was -4.0±15.1 ETDRS letters. Mean ± standard deviation OCT central retinal thickness increased by 50±179 µm. Common adverse events included conjunctival hemorrhage (n = 38), cataract (n = 16), resolving vitreous hemorrhage (n = 6), and eye pain (n = 5). CONCLUSIONS: Epimacular brachytherapy produces stable visual acuity in most participants with previously treated, active disease. Epimacular brachytherapy may reduce the need for frequent anti-VEGF retreatment.

Three-year safety and visual acuity results of epimacular 90 strontium/90 yttrium brachytherapy with bevacizumab for the treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration.

PURPOSE: To evaluate the long-term safety and visual acuity outcomes associated with epimacular strontium 90 brachytherapy combined with intravitreal bevacizumab for the treatment of subfoveal choroidal neovascularization because of age-related macular degeneration. METHODS: Thirty-four treatment-naive patients with predominantly classic, minimally classic, and occult subfoveal choroidal neovascularization lesions participated in this prospective, 2-year, nonrandomized multicenter study. Subjects from 1 center (n = 19) were reconsented and followed-up for 3 years. Each subject received a single 24-Gy beta irradiation treatment via an intraocular delivery device and 2 planned injections of bevacizumab at treatment and 1 month later. Additional bevacizumab therapy was permitted based on prespecified retreatment criteria. Adverse events were observed, and best-corrected visual acuity was measured using Early Treatment Diabetic Retinopathy Study vision charts. Subjects were evaluated every 3 months during the first year of follow-up and every 6 months during Years 2 and 3 of follow-up. RESULTS: All 34 subjects were followed-up for 24 months and 19 were followed-up through 36 months. With up to 24 months of follow-up, 12 of 24 phakic patients (50%) exhibited ≥ 2 grades of progression in Lens Opacification Classification System (LOCS) II lens classification; 5 eyes underwent cataract extraction before the Month 36 visit. There was 1 case of nonproliferative retinopathy identified at 36 months of follow-up that did not have an adverse effect on visual acuity, was stable at 43 months of follow-up, and was isolated to the parafoveal region. Mean best-corrected visual acuity demonstrated an average gain of +15.0 and -4.9 letters at 12 months and 24 months, respectively; the drop in mean gain at Month 24 was largely attributable to cataract formation. At 36 months (n = 19), the mean best-corrected visual acuity was +3.9, 90% (17 of 19) of eyes had lost <15 letters from baseline, 53% (10 of 19) had gained ≥ 1 letter, and 21% (4 of 19) had gained ≥ 15 letters. Through 36 months, 11 eyes required additional bevacizumab retreatment therapy and received a mean of 3.0 injections (range, 2-7 injections). CONCLUSION: Epimacular brachytherapy shows promise as a therapeutic option for subfoveal neovascular age-related macular degeneration. The procedure was safe and well tolerated, with a reasonable risk-benefit profile that warrants further study in larger subject populations. The most common adverse event was cataract progression/formation. Surgical complications are similar to those expected from standard vitrectomy trials. This novel device is currently being evaluated in two prospective, randomized, controlled trials in treatment-naive subjects (CABERNET) and in subjects already treated with anti-vascular endothelial growth factor therapy (MERLOT).

Epimacular brachytherapy for the treatment of retinal angiomatous proliferation.

PURPOSE: The purpose of this study was to present a case of a retinal angiomatous proliferation (RAP) treated with epimacular brachytherapy that was refractory to continued ranibizumab therapy. PATIENTS: An interventional case report of an 89-year-old woman with angiographically confirmed RAP had shown a poor response to 8 anti-vascular endothelial growth factor (anti-vascular endothelial growth factor) retreatment injections over a 10-month period. METHODS: The patient underwent pars plana vitrectomy combined with beta irradiation of the RAP lesion using a Strontium-90 applicator (NeoVista). The device was positioned over the lesion to deliver 24 gray over 4.5 minutes. Early Treatment Diabetic Retinopathy Study best-corrected visual acuity with full refraction was undertaken monthly by trial-certified examiners, independent of the operating surgeon. The main outcome measures were Early Treatment Diabetic Retinopathy Study best-corrected visual acuity, central retinal thickness measured by optical coherence tomography, and the number of anti-vascular endothelial growth factor retreatments. RESULTS: Preoperative best-corrected visual acuity was 53 letters (20/80), improving to 69 letters (20/50) at 12 months and 71 letters (20/40) at 21 months. Only one ranibizumab retreatment was required, at Month 2. Optical coherence tomography central retinal thickness reduced from 312 µm to 224 µm with a return of the normal foveal contour. There was full regression of the RAP lesion on clinical examination, with a reduction in lesion activity demonstrated by fundus fluorescein angiography. CONCLUSION: This is the first reported case of RAP treated with epimacular brachytherapy, with encouraging results. Epimacular brachytherapy may be a new treatment option for refractory RAP lesions requiring frequent intravitreal ranibizumab, but further studies are needed.

Radiation maculopathy after epimacular brachytherapy for the treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration.

PURPOSE: To describe a case of radiation maculopathy after a 24-Gy single-fraction epimacular brachytherapy delivered concomitantly with ranibizumab for the treatment of age-related macular degeneration. METHODS: Case report. RESULTS: An 82-year-old man with neovascular age-related macular degeneration was treated with epiretinal brachytherapy and 2 intraocular injections of ranibizumab with initial good response. Nineteen months after initial treatment, visual acuity decreased and the patient was diagnosed of radiation maculopathy. CONCLUSION: Radiation-related ocular side effects such as maculopathy may become evident several years after the treatment. Thus, vascular abnormalities that may appear in the follow-up of these patients can easily be misdiagnosed as a complication of the previous choroidal neovascularization.

Twelve-month safety and visual acuity results from a feasibility study of intraocular, epiretinal radiation therapy for the treatment of subfoveal CNV secondary to AMD.

PURPOSE: The purpose of this study was to evaluate the short-term safety and feasibility of intraocular, epiretinal delivery of beta radiation for the treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration for 12 months. A 3-year follow-up period is planned to assess the long-term safety of the procedure. METHODS: In this nonrandomized, multicenter feasibility study, 34 treatment-naïve patients with predominantly classic, minimally classic, or occult lesions due to subfoveal choroidal neovascularization secondary to age-related macular degeneration received a single treatment with either 15 Gray (Gy) (8 patients) or 24 Gy (26 patients) beta radiation (strontium-90) using a novel intraocular delivery device. Adverse events and safety endpoints were observed and recorded. Visual acuity was measured preoperatively and postoperatively using standard Early Treatment Diabetic Retinopathy Study vision charts. RESULTS: Twelve months after treatment, no adverse events associated with exposure to radiation were observed. All patients in both 15 Gy (n = 4) and 24 Gy cohorts (n = 17) who met inclusion criteria and were treated according to protocol lost fewer than three lines of vision. Fifty percent (2/4) of the 15 Gy-treated patients and 76% (13/17) of the 24 Gy-treated patients improved or maintained their visual acuity at 12 months. In the 24 Gy group, 29% (5/17) gained three lines or more in visual acuity. The mean change in visual acuity observed at month 12 was +10.3 letters in the 24 Gy study cohort and -1.0 letters in the 15 Gy cohort. CONCLUSION: The short-term safety and efficacy of intraocular, epiretinal delivery of beta radiation for the treatment of subfoveal choroidal neovascularization was promising in this small study group and should be studied in a larger cohort of patients.