Faricimab for neovascular age-related macular degeneration and diabetic macular edema: from preclinical studies to phase 3 outcomes.

Intravitreal anti-vascular endothelial growth factor (VEGF) therapy is the standard of care for diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD); however, vision gains and anatomical improvements are not sustained over longer periods of treatment, suggesting other relevant targets may be needed to optimize treatments. Additionally, frequent intravitreal injections can prove a burden for patients and caregivers. Angiopoietin-2 (Ang-2) has been explored as an additional therapeutic target, due to the involvement of Ang-2 in DME and nAMD pathogenesis. Recent evidence supports the hypothesis that targeting both VEGF and Ang-2 may improve clinical outcomes in DME and nAMD compared with targeting VEGF alone by enhancing vascular stability, resulting in reduced macular leakage, prevention of neovascularization, and diminished inflammation. Faricimab, a novel bispecific antibody that targets VEGF-A and Ang-2, has been evaluated in clinical trials for DME (YOSEMITE/RHINE) and nAMD (TENAYA/LUCERNE). These trials evaluated faricimab against the anti-VEGFA/B and anti-placental growth factor fusion protein aflibercept, both administered by intravitreal injection. In addition to faricimab efficacy, safety, and pharmacokinetics, durability was evaluated during the trials using a treat-and-extend regimen. At 1 year, faricimab demonstrated non-inferior vision gains versus aflibercept across YOSEMITE/RHINE and TENAYA/LUCERNE. In YOSEMITE/RHINE, faricimab improved anatomic parameters versus aflibercept. Reduction of central subfield thickness (CST), and absence of both DME and intraretinal fluid were greater in faricimab- versus aflibercept-treated eyes. In TENAYA/LUCERNE, CST reductions were greater for faricimab than aflibercept at the end of the head-to-head phase (0-12 weeks), and were comparable with aflibercept at year 1, but with less frequent dosing. CST and vision gains were maintained during year 2 of both YOSEMITE/RHINE and TENAYA/LUCERNE. These findings suggest that dual Ang-2/VEGF-A pathway inhibition may result in greater disease control versus anti-VEGF alone, potentially addressing the unmet needs and reducing treatment burden, and improving real-world outcomes and compliance in retinal vascular diseases. Long-term extension studies (RHONE-X, AVONELLE-X) are ongoing. Current evidence suggests that dual inhibition with faricimab heralds the beginning of multitargeted treatment strategies inhibiting multiple, independent components of retinal pathology, with faricimab providing opportunities to reduce treatment burden and improve outcomes compared with anti-VEGF monotherapy.

Intraretinal Hyper-Reflective Foci Are Almost Universally Present and Co-Localize With Intraretinal Fluid in Diabetic Macular Edema.

Purpose: In diabetic macular edema (DME), hyper-reflective foci (HRF) has been linked to disease severity and progression. Using an automated approach, we aimed to investigate the baseline distribution of HRF in DME and their co-localization with cystoid intraretinal fluid (IRF). Methods: Baseline spectral-domain optical coherence tomography (SD-OCT) volume scans (N = 1527) from phase III clinical trials YOSEMITE (NCT03622580) and RHINE (NCT03622593) were segmented using a deep-learning-based algorithm (developed using B-scans from BOULEVARD NCT02699450) to detect HRF. The HRF count and volume were assessed. HRF distributions were analyzed in relation to best-corrected visual acuity (BCVA), central subfield thickness (CST), and IRF volume in quartiles, and Diabetic Retinopathy Severity Scores (DRSS) in groups. Co-localization of HRF with IRF was calculated in the central 3-mm diameter using the en face projection. Results: HRF were present in most patients (up to 99.7%). Median (interquartile range [IQR]) HRF volume within the 3-mm diameter Early Treatment Diabetic Retinopathy Study ring was 1964.3 (3325.2) pL, and median count was 64.0 (IQR = 96.0). Median HRF volumes were greater with decreasing BCVA (nominal P = 0.0109), and increasing CST (nominal P < 0.0001), IRF (nominal P < 0.0001), and DRSS up to very severe nonproliferative diabetic retinopathy (nominal P < 0.0001). HRF co-localized with IRF in the en face projection. Conclusions: Using automated HRF segmentation of full SD-OCT volumes, we observed that HRF are a ubiquitous feature in DME and exhibit relationships with BCVA, CST, IRF, and DRSS, supporting a potential link to disease severity. The spatial distribution of HRF closely followed that of IRF.

TENAYA and LUCERNE: Two-Year Results from the Phase 3 Neovascular Age-Related Macular Degeneration Trials of Faricimab with Treat-and-Extend Dosing in Year 2.

PURPOSE: To evaluate 2-year efficacy, durability, and safety of the bispecific antibody faricimab, which inhibits both angiopoietin-2 and VEGF-A. DESIGN: TENAYA (ClinicalTrials.gov identifier, NCT03823287) and LUCERNE (ClinicalTrials.gov identifier, NCT03823300) were identically designed, randomized, double-masked, active comparator-controlled phase 3 noninferiority trials. PARTICIPANTS: Treatment-naive patients with neovascular age-related macular degeneration (nAMD) 50 years of age or older. METHODS: Patients were randomized (1:1) to intravitreal faricimab 6.0 mg up to every 16 weeks (Q16W) or aflibercept 2.0 mg every 8 weeks (Q8W). Faricimab fixed dosing based on protocol-defined disease activity at weeks 20 and 24 up to week 60, followed up to week 108 by a treat-and-extend personalized treatment interval regimen. MAIN OUTCOME MEASURES: Efficacy analyses included change in best-corrected visual acuity (BCVA) from baseline at 2 years (averaged over weeks 104, 108, and 112) and proportion of patients receiving Q16W, every 12 weeks (Q12W), and Q8W dosing at week 112 in the intention-to-treat population. Safety analyses included ocular adverse events (AEs) in the study eye through study end at week 112. RESULTS: Of 1326 patients treated across TENAYA/LUCERNE, 1113 (83.9%) completed treatment (n = 555 faricimab; n = 558 aflibercept). The BCVA change from baseline at 2 years was comparable between faricimab and aflibercept groups in TENAYA (adjusted mean change, +3.7 letters [95% confidence interval (CI), +2.1 to +5.4] and +3.3 letters [95% CI, +1.7 to +4.9], respectively; mean difference, +0.4 letters [95% CI, -1.9 to +2.8]) and LUCERNE (adjusted mean change, +5.0 letters [95% CI, +3.4 to +6.6] and +5.2 letters [95% CI, +3.6 to +6.8], respectively; mean difference, -0.2 letters [95% CI, -2.4 to +2.1]). At week 112 in TENAYA and LUCERNE, 59.0% and 66.9%, respectively, achieved Q16W faricimab dosing, increasing from year 1, and 74.1% and 81.2%, achieved Q12W or longer dosing. Ocular AEs in the study eye were comparable between faricimab and aflibercept groups in TENAYA (55.0% and 56.5% of patients, respectively) and LUCERNE (52.9% and 47.5% of patients, respectively) through week 112. CONCLUSIONS: Treat-and-extend faricimab treatment based on nAMD disease activity maintained vision gains through year 2, with most patients achieving extended dosing intervals. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Efficacy and Safety of Faricimab for Macular Edema due to Retinal Vein Occlusion: 24-Week Results from the BALATON and COMINO Trials.

PURPOSE: To evaluate the 24-week efficacy and safety of the dual angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF)-A inhibitor faricimab versus aflibercept in patients with vein occlusion. DESIGN: Phase 3, global, randomized, double-masked, active comparator-controlled trials: BALATON/COMINO (ClincalTrials.gov identifiers: NCT04740905/NCT04740931; sites: 149/192). PARTICIPANTS: Patients with treatment-naïve foveal center-involved macular edema resulting from branch (BALATON) or central or hemiretinal (COMINO) RVO. METHODS: Patients were randomized 1:1 to faricimab 6.0 mg or aflibercept 2.0 mg every 4 weeks for 24 weeks. MAIN OUTCOME MEASURES: Primary end point: change in best-corrected visual acuity (BCVA) from baseline to week 24. Efficacy analyses included patients in the intention-to-treat population. Safety analyses included patients who received ≥ 1 doses of study drug. RESULTS: Enrollment: BALATON, n = 553; COMINO, n = 729. The BCVA gains from the baseline to week 24 with faricimab were noninferior versus aflibercept in BALATON (adjusted mean change, +16.9 letters [95.03% confidence interval (CI), 15.7-18.1 letters] vs. +17.5 letters [95.03% CI, 16.3-18.6 letters]) and COMINO (+16.9 letters [95.03% CI, 15.4-18.3 letters] vs. +17.3 letters [95.03% CI, 15.9-18.8 letters]). Adjusted mean central subfield thickness reductions from the baseline were comparable for faricimab and aflibercept at week 24 in BALATON (-311.4 µm [95.03% CI, -316.4 to -306.4 µm] and -304.4 µm [95.03% CI, -309.3 to -299.4 µm]) and COMINO (-461.6 µm [95.03% CI, -471.4 to -451.9 µm] and -448.8 µm [95.03% CI, -458.6 to -439.0 µm]). A greater proportion of patients in the faricimab versus aflibercept arm achieved absence of fluorescein angiography-based macular leakage at week 24 in BALATON (33.6% vs. 21.0%; nominal P = 0.0023) and COMINO (44.4% vs. 30.0%; nominal P = 0.0002). Faricimab was well tolerated, with an acceptable safety profile comparable with aflibercept. The incidence of ocular adverse events was similar between patients receiving faricimab (16.3% [n = 45] and 23.0% [n = 84] in BALATON and COMINO, respectively) and aflibercept (20.4% [n = 56] and 27.7% [n = 100], respectively). CONCLUSIONS: These findings demonstrate the efficacy and safety of faricimab, a dual Ang-2/VEGF-A inhibitor, in patients with macular edema secondary to retinal vein occlusion. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

BALATON and COMINO: Phase III Randomized Clinical Trials of Faricimab for Retinal Vein Occlusion: Study Design and Rationale.

Purpose: Dual inhibition of angiopoietin-2 and VEGF-A with faricimab (Vabysmo) offers excellent visual acuity gains with strong durability in patients with diabetic macular edema (ME) and neovascular age-related macular degeneration. The phase III BALATON/COMINO (NCT04740905/NCT04740931) trials will investigate the efficacy, safety, and durability of faricimab in patients with ME due to retinal vein occlusion (RVO). Design: Two identically designed global, randomized, double-masked, active comparator-controlled studies. Participants: Anti-VEGF treatment-naive patients with branch, central, or hemiretinal RVO. Methods: Patients were randomized to 6 monthly injections of faricimab 6.0 mg or aflibercept 2.0 mg. From weeks 24 to 72, all patients received faricimab 6.0 mg administered in up to 16-week intervals using an automated treatment algorithm to generate a treat-and-extend-based personalized treatment interval dosing regimen. Personalized treatment interval adjustments were based on changes in central subfield thickness (CST) and best-corrected visual acuity (BCVA). Main Outcome Measures: Primary end point was noninferiority of faricimab versus aflibercept in mean change from baseline in BCVA (week 24; noninferiority margin: 4 letters). Secondary end points (weeks 0-24) were mean change from baseline in BCVA, CST, and National Eye Institute Visual Function Questionnaire 25 composite score; proportion of patients gaining or avoiding loss of ≥ 15/≥ 10/≥ 5/> 0 letters. Secondary end points (weeks 24-72) were treatment durability (week 68); continuation of weeks 0 to 24 end points. Ocular/nonocular adverse events will be assessed. Results: In total, 1282 patients across 22 countries were enrolled (BALATON, 553 patients, 149 centers; COMINO, 729 patients, 193 centers). Conclusions: Using a novel automated interval algorithm, BALATON/COMINO will evaluate the efficacy and safety of faricimab for ME secondary to RVO and provide key insights into how to personalize treatment. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Population Pharmacokinetics of Ranibizumab Delivered via the Port Delivery System Implanted in the Eye in Patients with Neovascular Age-Related Macular Degeneration.

The port delivery system with ranibizumab (PDS) is designed to continuously deliver ranibizumab to maintain therapeutic drug concentrations in the vitreous of the eye for an extended duration. The PDS has been evaluated for the treatment of neovascular age-related macular degeneration in the Ladder (PDS 10, 40, and 100 mg/mL, with refill exchanges as needed, versus monthly intravitreal ranibizumab 0.5 mg), Archway (PDS 100 mg/mL with 24-week refill exchanges, versus monthly intravitreal ranibizumab 0.5 mg), and ongoing Portal (PDS 100 mg/mL with 24-week refill exchanges) clinical trials. Data from Ladder, Archway, and Portal were used to develop a population pharmacokinetics (PK) model to estimate the ranibizumab release rate from the PDS implant, describe ranibizumab PK in serum and aqueous humor, and predict the concentration in vitreous humor. A model was developed to adequately describe the serum and aqueous humor PK data, as suggested by goodness-of-fit plots as well as visual predictive checks. In the final model, the first-order implant release rate was estimated to be 0.00654 (1/day), corresponding to a half-life of 106 days, consistent with the implant release rate determined in vitro. The model-predicted vitreous concentrations achieved with PDS 100 mg/mL given every 24 weeks were below the intravitreal peak concentration and above the intravitreal trough concentration of ranibizumab over the entire 24-week refill interval. The results demonstrate a durable release of ranibizumab from the PDS with a half-life of 106 days, providing vitreous exposure to ranibizumab for at least 24 weeks that is within the range of exposure for monthly intravitreal treatment.

Archway Phase 3 Trial of the Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration 2-Year Results.

PURPOSE: To report 2-year results from the Archway clinical trial of the Port Delivery System with ranibizumab (PDS) for treatment of neovascular age-related macular degeneration (nAMD). DESIGN: Phase 3, randomized, multicenter, open-label, active-comparator-controlled trial. PARTICIPANTS: Patients with previously treated nAMD diagnosed within 9 months of screening and responsive to anti-vascular endothelial growth factor therapy. METHODS: Patients were randomized 3:2 to PDS with ranibizumab 100 mg/ml with fixed refill-exchanges every 24 weeks (PDS Q24W) or intravitreal ranibizumab 0.5 mg injections every 4 weeks (monthly ranibizumab). Patients were followed through 4 complete refill-exchange intervals (∼2 years). MAIN OUTCOME MEASURES: Change in best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score from baseline averaged over weeks 44 and 48, weeks 60 and 64, and weeks 88 and 92 (noninferiority margin, -3.9 ETDRS letters). RESULTS: The PDS Q24W was noninferior to monthly ranibizumab, with differences in adjusted mean change in BCVA score from baseline averaged over weeks 44/48, 60/64 and 88/92 of -0.2 (95% confidence interval [CI], -1.8 to +1.3), +0.4 (95% CI, -1.4 to +2.1) and -0.6 ETDRS letters (95% CI, -2.5 to +1.3), respectively. Anatomic outcomes were generally comparable between arms through week 96. Through each of 4 PDS refill-exchange intervals, 98.4%, 94.6%, 94.8%, and 94.7% of PDS Q24W patients assessed did not receive supplemental ranibizumab treatment. The PDS ocular safety profile was generally unchanged from primary analysis. Prespecified ocular adverse events of special interest (AESI) were reported in 59 (23.8%) PDS and 17 (10.2%) monthly ranibizumab patients. The most common AESI reported in both arms was cataract (PDS Q24W, 22 [8.9%]; monthly ranibizumab, 10 [6.0%]). Events in the PDS Q24W arm included (patient incidence) 10 (4.0%) conjunctival erosions, 6 (2.4%) conjunctival retractions, 4 (1.6%) endophthalmitis cases, and 4 (1.6%) implant dislocations. Serum ranibizumab sampling showed that the PDS continuously released ranibizumab over the 24-week refill-exchange interval and ranibizumab serum concentrations were within the range experienced with monthly ranibizumab. CONCLUSIONS: The PDS Q24W showed noninferior efficacy to monthly ranibizumab through approximately 2 years, with approximately 95% of PDS Q24W patients not receiving supplemental ranibizumab treatment in each refill-exchange interval. The AESIs were generally manageable, with learnings continually implemented to minimize PDS-related AEs. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Physical Activity in Functionally Monocular Persons in the United States, 2003-2006.

Purpose: Real-world physical activity patterns in monocular persons have not been previously characterized. This study uses a nationally representative sample to compare the physical activity levels of functionally monocular to binocularly sighted persons in the United States. Methods: This cross-sectional study uses data from the 2003-2004 and 2005-2006 National Health and Nutrition Examination Survey (NHANES) to compare differences in physical activity between functionally monocular and binocular participants. The main outcome measures were accelerometer-measured mean steps per day and mean daily minutes of moderate or vigorous physical activity (MVPA). Statistical analysis was conducted using multivariable negative binomial regression models adjusted for age. Results: In total, 7967 NHANES participants had complete visual acuity and accelerometer data. The mean age at baseline was 44.5 years, and a majority were Caucasian (73%) and female (51%). In models adjusted for age only, functionally monocular participants (n = 172) took fewer steps (9277 with 95% confidence interval [CI], 8800-9753 vs. 10,057 with 95% CI, 9832-10,281) and engaged in similar minutes of MVPA (26.75 with 95% CI, 22.0-31.5 vs. 26.70 with 95% CI, 25.6-27.7) per day compared to binocularly sighted participants (n = 7758). In our final model, functionally monocular participants took 16% fewer steps per day (P < 0.01) and engaged in 26% fewer minutes per day of MVPA (P = 0.01). Poorer visual acuity, older age, female gender, obesity, congestive heart failure, and arthritis were also associated with a statistically significant decrease in physical activity in both models. Conclusions: Functionally monocular persons have lower physical activity levels compared to those with binocular eyesight in the United States, even after adjusting for better-eye visual acuity. Translational Relevance: Our translational study provides insight into the epidemiology of physical activity and its impact on population health. We quantify real-world physical activity in two at-risk populations, monocular and blind individuals.

YOSEMITE and RHINE: Phase 3 Randomized Clinical Trials of Faricimab for Diabetic Macular Edema: Study Design and Rationale.

Purpose: Faricimab is a novel anti-angiopoietin-2 and anti-vascular endothelial growth factor (VEGF) bispecific antibody with high affinities and specificities for both VEGF and angiopoietin-2. It is postulated that targeting angiogenic factors and inflammatory pathways in addition to the VEGF pathway will increase treatment durability and improve outcomes. The phase 3 YOSEMITE (ClinicalTrials.gov identifier, NCT03622580) and RHINE (ClinicalTrials.gov identifier, NCT03622593) trials are designed to assess efficacy, safety, and durability of faricimab compared with aflibercept in patients with diabetic macular edema (DME). The trials evaluate a personalized treatment interval (PTI) approach to address heterogeneity in treatment response among patients with DME. Design: Two identically designed, global, double-masked, randomized, controlled phase 3 trials (YOSEMITE and RHINE). Participants: Adults with center-involving DME secondary to type 1 or 2 diabetes mellitus. Methods: These studies were designed to evaluate 3 treatment groups: faricimab 6.0 mg dosed either at fixed dosing every 8 weeks after initial treatment with 6 intravitreal doses at 4-week intervals, or faricimab 6.0 mg dosed according to PTI after initial treatment with 4 every-4-week doses, compared with aflibercept 2.0 mg dosed every 8 weeks after 5 initial every-4-week doses. The primary end point of the studies was change from baseline in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Secondary end points included anatomic, durability, and patient-reported outcomes. Safety outcomes included incidence and severity of ocular and nonocular adverse events. The PTI is a protocol-defined flexible regimen based on the treat-and-extend concept, which allowed up to every-16-week adjustable dosing based on objective and standardized criteria. The PTI design aimed to maximize therapeutic results while minimizing treatment burden. Main Outcome Measures: We describe the rationale for the study design and the novel PTI (up to every-16-week adjustable dosing) approach for treatment with faricimab. Results: YOSEMITE and RHINE enrolled 940 and 951 patients, respectively. Results from each study will be reported separately. Conclusions: YOSEMITE and RHINE were the first registrational trials in retinal disease to incorporate an objective PTI regimen, allowing for up to every-16-week adjustable dosing with a dual angiopoietin-2 and VEGF-A inhibitor, faricimab 6.0 mg, for treatment of DME.

Management of Key Ocular Adverse Events in Patients Implanted with the Port Delivery System with Ranibizumab.

PURPOSE: To provide strategies for the management of key ocular adverse events (AEs) that may be encountered with the Port Delivery System with ranibizumab (PDS) in practice and provide recommendations that may mitigate such AEs based on clinical trial experiences and considerations from experts in the field. DESIGN: Safety evaluation based on the phase 2 Ladder (NCT02510794) and phase 3 Archway (NCT03677934) trials of the PDS. METHODS: The PDS implant is a permanent, indwelling, and refillable ocular drug delivery system that requires standardized procedural steps for its insertion and refill-exchange procedures, which evolved during the PDS clinical program. We described identified AEs that may arise after implant insertion or refill-exchange procedures, including conjunctival retraction, conjunctival erosion, endophthalmitis, implant dislocation, conjunctival blebs or conjunctival filtering bleb leaks, wound leaks, hypotony, choroidal detachment, vitreous hemorrhage, rhegmatogenous retinal detachment, cataract, and septum dislodgement. RESULTS: Adverse events related to the PDS were well understood, were manageable by trial investigators, and did not prevent patients from achieving optimal outcomes in most cases. CONCLUSIONS: Surgeons using the PDS should be aware of potential ocular AEs and identify them early for optimal management. As with any new surgical procedure, it is important to provide surgeons with appropriate training, ensure adherence to optimal surgical techniques, and continually refine the procedure to mitigate complications and improve outcomes.

Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE): two randomised, double-masked, phase 3 trials.

BACKGROUND: To reduce treatment burden and optimise patient outcomes in diabetic macular oedema, we present 1-year results from two phase 3 trials of faricimab, a novel angiopoietin-2 and vascular endothelial growth factor-A bispecific antibody. METHODS: YOSEMITE and RHINE were randomised, double-masked, non-inferiority trials across 353 sites worldwide. Adults with vision loss due to centre-involving diabetic macular oedema were randomly assigned (1:1:1) to intravitreal faricimab 6·0 mg every 8 weeks, faricimab 6·0 mg per personalised treatment interval (PTI), or aflibercept 2·0 mg every 8 weeks up to week 100. PTI dosing intervals were extended, maintained, or reduced (every 4 weeks up to every 16 weeks) based on disease activity at active dosing visits. The primary endpoint was mean change in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Efficacy analyses included the intention-to-treat population (non-inferiority margin 4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); safety analyses included patients with at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (YOSEMITE NCT03622580 and RHINE NCT03622593). FINDINGS: 3247 patients were screened for eligibility in YOSEMITE (n=1532) and RHINE (n=1715). After exclusions, 940 patients were enrolled into YOSEMITE between Sept 5, 2018, and Sept 19, 2019, and 951 patients were enrolled into RHINE between Oct 9, 2018, and Sept 20, 2019. These 1891 patients were randomly assigned to faricimab every 8 weeks (YOSEMITE n=315, RHINE n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Non-inferiority for the primary endpoint was achieved with faricimab every 8 weeks (adjusted mean vs aflibercept every 8 weeks in YOSEMITE 10·7 ETDRS letters [97·52% CI 9·4 to 12·0] vs 10·9 ETDRS letters [9·6 to 12·2], difference -0·2 ETDRS letters [-2·0 to 1·6]; RHINE 11·8 ETDRS letters [10·6 to 13·0] vs 10·3 ETDRS letters [9·1 to 11·4] letters, difference 1·5 ETDRS letters [-0·1 to 3·2]) and faricimab PTI (YOSEMITE 11·6 ETDRS letters [10·3 to 12·9], difference 0·7 ETDRS letters [-1·1 to 2·5]; RHINE 10·8 ETDRS letters [9·6 to 11·9], difference 0·5 ETDRS letters [-1·1 to 2·1]). Incidence of ocular adverse events was comparable between faricimab every 8 weeks (YOSEMITE n=98 [31%], RHINE n=137 [43%]), faricimab PTI (n=106 [34%], n=119 [37%]), and aflibercept every 8 weeks (n=102 [33%], n=113 [36%]). INTERPRETATION: Robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for faricimab to extend the durability of treatment for patients with diabetic macular oedema. FUNDING: F Hoffmann-La Roche.

Feasibility Study of a Multimodal, Cloud-Based, Diabetic Retinal Screening Program in a Workplace Environment.

Purpose: To evaluate the feasibility of capturing and interpreting retinal images in a workplace environment using a multimodal, cloud-based, diabetic retinal screening program combined with electronic self-reported questionnaires. The burden of diabetic retinopathy (DR) and other retinal conditions, healthcare utilization, and visual function were also assessed. Methods: A cross-sectional feasibility study was conducted at the Genentech, Inc., Campus Health Center. Eyes of participants were imaged using ultra-widefield (UWF) color fundus photography (CFP) and spectral-domain optical coherence tomography (SD-OCT). A cloud-based platform was used for the automated, seamless transfer of images to a remote reading center for evaluation for DR and other retinal pathologies. Electronic surveys collected participants' self-reported medical histories, healthcare utilization, and visual function data. Results: Among 100 participants (mean age, 43.9 years; 44% male), 33% of them self-reported diabetes. Eye examinations within the past 12 months were reported by 71% of all participants (n = 71/100) and by 85% (n = 28/33) of those with self-reported diabetes. Among participants with complete screening images from both UWF-CFP and SD-OCT, 20% (n = 6/30) of those with self-reported diabetes and 8.5% (n = 5/59) of participants with no history of diabetes were unaware they had mild/moderate nonproliferative DR. Among all participants, 20% (20/100) had a retinal finding, on either UWF-CFP or SD-OCT, or both, which prompted a referral for further evaluation. Conclusions: A retinal screening program deployed via a secure, scalable, and interoperable cloud-based platform was feasible and conveniently integrated into the workplace. Translational Relevance: Cloud-based platforms could be used to promote a secure, scalable, and interoperable system for retinal screening in nontraditional environments.

TENAYA and LUCERNE: Rationale and Design for the Phase 3 Clinical Trials of Faricimab for Neovascular Age-Related Macular Degeneration.

Purpose: To describe the design and rationale of the phase 3 TENAYA (ClinicalTrials.gov identifier, NCT03823287) and LUCERNE (ClinicalTrials.gov identifier, NCT03823300) trials that aimed to assess efficacy, safety, and durability of faricimab, the first bispecific antibody for intraocular use, which independently binds and neutralizes both angiopoietin-2 and vascular endothelial growth factor-A (VEGF-A) versus aflibercept in patients with neovascular age-related macular degeneration (nAMD). Design: Identical, global, double-masked, randomized, controlled, phase 3 clinical trials. Participants: Adults with treatment-naïve nAMD. Methods: These trials were designed to evaluate patients randomized to receive faricimab 6.0 mg up to every 16 weeks after 4 initial every-4-week doses or aflibercept 2.0 mg every 8 weeks after 3 initial every-4-week doses. The initial doses in the faricimab arm were followed by individualized fixed treatment intervals up to week 60, based on disease activity assessment at weeks 20 and 24, guided by central subfield thickness, best-corrected visual acuity (BCVA), and investigator assessment. The primary efficacy end point was BCVA change from baseline averaged over weeks 40, 44, and 48. Secondary end points included the proportion of patients receiving every-8-week, every-12-week, and every-16-week faricimab and anatomic outcomes. Safety outcomes included incidence and severity of ocular and nonocular adverse events. From week 60, faricimab-treated patients followed a personalized treatment interval (PTI), a novel protocol-driven treat-and-extend regimen with interval adjustment from every 8 weeks to every 16 weeks based on individualized treatment response measured by anatomic criteria, functional criteria, and investigator assessment of patients' disease activity. Main Outcome Measures: Rationale for trial design and PTI approach. Results: The TENAYA and LUCERNE trials were the first registrational trials in nAMD to test fixed dosing regimens up to every 16 weeks based on patients' disease activity in year 1 and incorporate a PTI paradigm during year 2. The PTI approach was designed to tailor treatment intervals to individual patient needs, to reflect clinical practice treatment practice, and to reduce treatment burden. Conclusions: The innovative trial design rationale for the TENAYA and LUCERNE trials included maximizing the benefits of angiopoietin-2 blockade through dosing up to every 16 weeks and PTI regimens based on patients' disease activity while fulfilling health authority requirements for potential registrational efforts.

Comparative Analysis of Biofilm Formation on Materials Used for the Fabrication of Implant-Supported Prostheses.

The purpose of this study was to compare biofilm formation on materials used for the fabrication of implant-supported dental prostheses. Twenty discs (D=15 mm, H=3 mm) were fabricated from one of the following restorative materials: yttria tetragonal zirconia polycrystal (Y-TZP); commercially pure titanium (CP-Ti); or heat-cured polymethyl methacrylate (PMMA). Specimens were polished following standard protocols. A non-contact profilometer (NPFLEX, Bruker, UK) was used to assess the surface roughness of each disk; results were reported as Ra (µm). Five strains of Gram-negative bacteria frequently associated with peri-implantitis, Aggregatibacter actinomycetemcomitans, Candida. albicans, Porphyromonas gingivalis, Prevotella intermedia, and Tannerella forsythia, were cultured on hand-polished discs fabricated from heat-cured PMMA, Y-TZP, or CP-Ti to compare biofilm formation on each type of material. The results were reported as colony-forming units per milliliter (CFU/mL). One-way ANOVA and post hoc tests were used to compare surface roughness and bacterial colonization on the respective materials. Statistical significance was set at a = 0.05. Discs fabricated from Y-TZP had a significantly higher Ra value (350 ± 30 µm) than either PMMA, or CP-Ti discs. Discs fabricated from either Y-TZP and CP-Ti may exhibit less colonization by bacteria associated with peri-mucositis and peri-implantitis. Y-TZP and CP-Ti are suggested materials for fabrication of implant-supported prostheses, considering biofilm formation.

Development of Deep Learning Models to Predict Best-Corrected Visual Acuity from Optical Coherence Tomography.

Purpose: To develop deep learning (DL) models to predict best-corrected visual acuity (BCVA) from optical coherence tomography (OCT) images from patients with neovascular age-related macular degeneration (nAMD). Methods: Retrospective analysis of OCT images and associated BCVA measurements from the phase 3 HARBOR trial (NCT00891735). DL regression models were developed to predict BCVA at the concurrent visit and 12 months from baseline using OCT images. Binary classification models were developed to predict BCVA of Snellen equivalent of <20/40, <20/60, and ≤20/200 at the concurrent visit and 12 months from baseline. Results: The regression model to predict BCVA at the concurrent visit had R2 = 0.67 (root-mean-square error [RMSE] = 8.60) in study eyes and R2 = 0.84 (RMSE = 9.01) in fellow eyes. The best classification model to predict BCVA at the concurrent visit had an area under the receiver operating characteristic curve (AUC) of 0.92 in study eyes and 0.98 in fellow eyes. The regression model to predict BCVA at month 12 using baseline OCT had R2 = 0.33 (RMSE = 14.16) in study eyes and R2 = 0.75 (RMSE = 11.27) in fellow eyes. The best classification model to predict BCVA at month 12 had AUC = 0.84 in study eyes and AUC = 0.96 in fellow eyes. Conclusions: DL shows promise in predicting BCVA from OCTs in nAMD. Further research should elucidate the utility of models in clinical settings. Translational Relevance: DL models predicting BCVA could be used to enhance understanding of structure-function relationships and develop more efficient clinical trials.

Comparative analysis of biofilm formation on materials used for the fabrication of implant-supported prostheses

Abstract The purpose of this study was to compare biofilm formation on materials used for the fabrication of implant-supported dental prostheses. Twenty discs (D=15 mm, H=3 mm) were fabricated from one of the following restorative materials: yttria tetragonal zirconia polycrystal (Y-TZP); commercially pure titanium (CP-Ti); or heat-cured polymethyl methacrylate (PMMA). Specimens were polished following standard protocols. A non-contact profilometer (NPFLEX, Bruker, UK) was used to assess the surface roughness of each disk; results were reported as Ra (µm). Five strains of Gram-negative bacteria frequently associated with peri-implantitis, Aggregatibacter actinomycetemcomitans, Candida. albicans, Porphyromonas gingivalis, Prevotella intermedia, and Tannerella forsythia, were cultured on hand-polished discs fabricated from heat-cured PMMA, Y-TZP, or CP-Ti to compare biofilm formation on each type of material. The results were reported as colony-forming units per milliliter (CFU/mL). One-way ANOVA and post hoc tests were used to compare surface roughness and bacterial colonization on the respective materials. Statistical significance was set at a = 0.05. Discs fabricated from Y-TZP had a significantly higher Ra value (350 ± 30 µm) than either PMMA, or CP-Ti discs. Discs fabricated from either Y-TZP and CP-Ti may exhibit less colonization by bacteria associated with peri-mucositis and peri-implantitis. Y-TZP and CP-Ti are suggested materials for fabrication of implant-supported prostheses, considering biofilm formation.

Resumo O objetivo deste estudo foi comparar a formação de biofilme em materiais utilizados na confecção de próteses dentárias implantossuportadas. Vinte discos (D = 15 mm, H = 3 mm) foram confeccionados com um dos seguintes materiais restauradores: zircônia tetragonal policristalina estabilizada por ítrio (Y-TZP); titânio comercialmente puro (CP-Ti); ou polimetilmetacrilato (PMMA). As amostras foram polidas seguindo protocolos padrão. Um perfilômetro sem contato (NPFLEX, Bruker, UK) foi usado para avaliar a rugosidade da superfície de cada disco; os resultados foram relatados como Ra (µm). Cinco cepas de bactérias Gram-negativas freqüentemente associadas a peri-implantite, Aggregatibacter actinomycetemcomitans, Candida. albicans, Porphyromonas gingivalis, Prevotella intermedia e Tannerella forsythia, foram cultivadas em discos polidos à mão feitos de PMMA, Y-TZP ou CP-Ti para comparar a formação de biofilme em cada tipo de material. Os resultados foram relatados como unidades formadoras de colônias por mililitro (UFC/mL). Análise de variância a um fator e testes post hoc foram usados ​​para comparar a rugosidade da superfície e a colonização bacteriana nos respectivos materiais. A significância estatística foi estabelecida em a=0,05. Os discos feitos de Y-TZP tiveram um valor Ra significativamente mais alto (350 ± 30 µm) do que os discos de PMMA ou CP-Ti. Os discos fabricados com Y-TZP e CP-Ti podem apresentar menor colonização por bactérias associadas à perimucosite e peri-implantite. Considerando O Y-TZP e CP-Ti são materiais indicados para a confecção de próteses implantossuportadas, considerando a formação de biofilme

Progression from Early/Intermediate to Advanced Forms of Age-Related Macular Degeneration in a Large UK Cohort: Rates and Risk Factors.

PURPOSE: To estimate rates and risk factors for progression to geographic atrophy (GA) or choroidal neovascularization (CNV) among eyes diagnosed with early or intermediate age-related macular degeneration (AMD) in clinical practice. DESIGN: Retrospective cohort analysis of a multicenter electronic medical record (EMR) database from the United Kingdom. PARTICIPANTS: Patients aged 50 years or more with diagnosis of early/intermediate AMD in at least 1 eye (the study eye) and no evidence of CNV or GA in the study eye, from 10 clinical sites using the EMR. METHODS: Anonymized data for 40 543 patients with a diagnosis of early/intermediate AMD were extracted between October 2000 and February 2016 from EMR database records held in the 10 sites. A sample of records randomly selected from each center was used to validate disease definitions. Records were analyzed by subgroup, based on the AMD status of the fellow eye. Multivariate Cox regression models identified other predictors of disease progression. MAIN OUTCOME MEASURES: Progression rate (per 100 person-years) to GA or CNV in study eyes with early/intermediate AMD by fellow eye status and identified risk factors for progression. RESULTS: Study eyes with early/intermediate AMD and a diagnosis of CNV in the fellow eye progressed to CNV fastest (at a rate of 15.2 per 100 person-years), and those with a diagnosis of GA in the fellow eye progressed to GA fastest (11.2 per 100 person-years), compared with the rates per 100 person-years of progression to CNV (3.2-11.9) or GA (2.0-7.8) in the other subgroups. In individuals with bilateral early/intermediate AMD, rates of progression to GA or CNV were 2.0 and 3.2 per 100 person-years, respectively. In the multivariate model, age, female sex, and cardiovascular disease were associated with an increased risk for progression to advanced AMD, whereas diabetes and glaucoma were associated with a decreased rate of progression (hazard ratios, 0.45 and 0.64, respectively). CONCLUSIONS: Progression to GA or CNV was observed frequently in eyes with early/intermediate AMD, with the status of the fellow eye affecting the rate of progression. Novel associations with risk factors were observed and require replication in other cohorts.

Direct Ophthalmic Healthcare Resource Use among Patients with Geographic Atrophy in a Large Cohort from the United Kingdom.

PURPOSE: To estimate the direct ophthalmic healthcare resource use in patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD). DESIGN: Retrospective analysis of anonymized data derived from electronic medical records (EMRs) acquired at 10 clinical sites in the United Kingdom. PARTICIPANTS: Patients aged ≥50 years with ≥1 eye with a clinical record of GA or, for comparison, bilateral early/intermediate AMD. Four subgroups were identified: GA in both eyes (GA:GA); GA in 1 eye, choroidal neovascularization (CNV) in the fellow eye (GA:CNV); GA in 1 eye with early or intermediate AMD in the fellow eye (GA:E); and early/intermediate AMD in both eyes (E:E). METHODS: The EMRs were analyzed to derive the median number of visits over the first 2 years after diagnosis of GA or early/intermediate AMD. Clinical tests recorded at visits were used to calculate estimated costs (payer perspective) of monitoring. Analyses were restricted to patients with an initial diagnosis on or after January 1, 2011, to represent present day monitoring and costs associated with AMD. MAIN OUTCOME MEASURES: Median number of visits and estimated monitoring costs per patient (in £) over the first 2 years among patients with ≥2 years of follow-up and in the individual subgroups. Intravitreal treatment costs in the GA:CNV group were excluded. RESULTS: For all 3 GA subgroups (n = 1080), the median number of visits over the first 2 years was 5, and monitoring costs were £460.80 per patient. The GA:CNV subgroup (n = 355) had the highest number of visits (median, 15), with a cost of £1581, compared with the GA:E subgroup (n = 283; median 4 visits; cost ∼£369) and the GA:GA subgroup (n = 442; median 3 visits; cost ∼£277). Ophthalmic tests were conducted most frequently in the GA:CNV subgroup. Visits and costs in the E:E subgroup (n = 6079) were lower. CONCLUSIONS: Resource use in patients with GA varies considerably and is strongly influenced by the concomitant presence of CNV and lack of monitoring strategies for GA.

Deep Learning Predicts OCT Measures of Diabetic Macular Thickening From Color Fundus Photographs.

Purpose: To develop deep learning (DL) models for the automatic detection of optical coherence tomography (OCT) measures of diabetic macular thickening (MT) from color fundus photographs (CFPs). Methods: Retrospective analysis on 17,997 CFPs and their associated OCT measurements from the phase 3 RIDE/RISE diabetic macular edema (DME) studies. DL with transfer-learning cascade was applied on CFPs to predict time-domain OCT (TD-OCT)-equivalent measures of MT, including central subfield thickness (CST) and central foveal thickness (CFT). MT was defined by using two OCT cutoff points: 250 µm and 400 µm. A DL regression model was developed to directly quantify the actual CFT and CST from CFPs. Results: The best DL model was able to predict CST ≥ 250 µm and CFT ≥ 250 µm with an area under the curve (AUC) of 0.97 (95% confidence interval [CI], 0.89-1.00) and 0.91 (95% CI, 0.76-0.99), respectively. To predict CST ≥ 400 µm and CFT ≥ 400 µm, the best DL model had an AUC of 0.94 (95% CI, 0.82-1.00) and 0.96 (95% CI, 0.88-1.00), respectively. The best deep convolutional neural network regression model to quantify CST and CFT had an R2 of 0.74 (95% CI, 0.49-0.91) and 0.54 (95% CI, 0.20-0.87), respectively. The performance of the DL models declined when the CFPs were of poor quality or contained laser scars. Conclusions: DL is capable of predicting key quantitative TD-OCT measurements related to MT from CFPs. The DL models presented here could enhance the efficiency of DME diagnosis in tele-ophthalmology programs, promoting better visual outcomes. Future research is needed to validate DL algorithms for MT in the real-world.