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.

Heterogeneity in disease activity, frequency of treatments, and visual outcomes among patients with retinal vein occlusion: relationship between injection need and vision with as-needed ranibizumab.

BACKGROUND/AIMS: We characterised the relationships between monitoring frequency, ranibizumab injection need and vision in patients receiving as-needed (pro re nata; PRN) ranibizumab for macular oedema due to branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO) in this post-hoc analysis of SHORE and HORIZON. METHODS: Patients aged 18 years and older with macular oedema due to BRVO/CRVO were included in this analysis. Injection frequency and best-corrected visual acuity (BCVA) were evaluated by PRN injection frequency in the PRN dosing phase (months (M) 7-15) of SHORE and through 12 months of HORIZON. Prespecified PRN re-treatment criteria for each trial were based on protocol-prespecified BCVA and optical coherence tomography outcomes. RESULTS: After the initial 7 monthly ranibizumab injections, patients in SHORE gained a mean of 18.3 letters from baseline. Patients randomised to PRN, on average, maintained these gains. However, some patients experienced additional mean gains, whereas others suffered losses (range 4.0 (95% CI 0.7 to 7.3) to -4.6 (95% CI -11.8 to 2.6) letters in patients who received 0 and 6-7 PRN injections, respectively). In BRAVO and CRUISE (lead-in trials), patients experienced mean gains from baseline to M6 (monthly dosing) of 19.3 and 15.0 letters, respectively, with gains maintained with PRN from M6 to M12. However, mean BCVA changes from baseline to M12 varied in HORIZON (range -0.4 (95% CI -2.5 to 1.6) to -3.6 (95% CI -6.2 to -1.0) letters in patients who received zero and six injections, respectively, during the preceding PRN phase of BRAVO and CRUISE). CONCLUSION: The BRVO/CRVO population is heterogenous with a varied response to ranibizumab treatment.

Faricimab Treat-and-Extend for Diabetic Macular Edema: Two-Year Results from the Randomized Phase 3 YOSEMITE and RHINE Trials.

PURPOSE: To evaluate the 2-year efficacy, durability, and safety of dual angiopoietin-2 and vascular endothelial growth factor (VEGF) A pathway inhibition with intravitreal faricimab according to a personalized treat-and-extend (T&E)-based regimen with up to every-16-week dosing in the YOSEMITE and RHINE (ClinicalTrials.gov identifiers, NCT03622580 and NCT03622593, respectively) phase 3 trials of diabetic macular edema (DME). DESIGN: Randomized, double-masked, noninferiority phase 3 trials. PARTICIPANTS: Adults with visual acuity loss (best-corrected visual acuity [BCVA] of 25-73 letters) due to center-involving DME. METHODS: Patients were randomized 1:1:1 to faricimab 6.0 mg every 8 weeks, faricimab 6.0 mg T&E (previously referred to as personalized treatment interval), or aflibercept 2.0 mg every 8 weeks. The T&E up to every-16-week dosing regimen was based on central subfield thickness (CST) and BCVA change. MAIN OUTCOME MEASURES: Included changes from baseline in BCVA and CST, number of injections, durability, absence of fluid, and safety through week 100. RESULTS: In YOSEMITE and RHINE (n = 940 and 951, respectively), noninferior year 1 visual acuity gains were maintained through year 2; mean BCVA change from baseline at 2 years (weeks 92, 96, and 100 average) with faricimab every 8 weeks (YOSEMITE and RHINE, +10.7 letters and +10.9 letters, respectively) or T&E (+10.7 letters and +10.1 letters, respectively) were comparable with aflibercept every 8 weeks (+11.4 letters and +9.4 letters, respectively). The median number of study drug injections was lower with faricimab T&E (YOSEMITE and RHINE, 10 and 11 injections, respectively) versus faricimab every 8 weeks (15 injections) and aflibercept every 8 weeks (14 injections) across both trials during the entire study. In the faricimab T&E arms, durability was improved further during year 2, with > 60% of patients receiving every-16-week dosing and approximately 80% receiving every-12-week or longer dosing at week 96. Almost 80% of patients who achieved every-16-week dosing at week 52 maintained every-16-week dosing without an interval reduction through week 96. Mean CST reductions were greater (YOSEMITE/RHINE weeks 92/96/100 average: faricimab every 8 weeks -216.0/-202.6 µm, faricimab T&E -204.5/-197.1 µm, aflibercept every 8 weeks -196.3/-185.6 µm), and more patients achieved absence of DME (CST < 325 µm; YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 87%-92%/88%-93%, faricimab T&E 78%-86%/85%-88%, aflibercept every 8 weeks 77%-81%/80%-84%) and absence of intraretinal fluid (YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 59%-63%/56%-62%, faricimab T&E 43%-48%/45%-52%, aflibercept every 8 weeks 33%-38%/39%-45%) with faricimab every 8 weeks or T&E versus aflibercept every 8 weeks through year 2. Overall, faricimab was well tolerated, with a safety profile comparable with that of aflibercept. CONCLUSIONS: Clinically meaningful visual acuity gains from baseline, anatomic improvements, and extended durability with intravitreal faricimab up to every 16 weeks were maintained through year 2. Faricimab given as a personalized T&E-based dosing regimen supports the role of dual angiopoietin-2 and VEGF-A inhibition to promote vascular stability and to provide durable efficacy for patients with DME. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Efficacy, Durability, and Safety of Faricimab in Patients From Asian Countries With Diabetic Macular Edema: 1-Year Subgroup Analysis of the Phase III YOSEMITE and RHINE Trials.

PURPOSE: To assess the 1-year efficacy, durability, and safety of faricimab in patients with diabetic macular edema from Asian and non-Asian countries. DESIGN: Global, multicenter, randomized, double-masked, active comparator-controlled, phase III trials. METHODS: Subgroup analysis of patients from Asian (N=144) and non-Asian (N=1747) countries randomized to faricimab 6.0 mg every 8 weeks (Q8W), faricimab per personalized treatment interval (PTI), or aflibercept 2.0 mg Q8W in the YOSEMITE/RHINE (NCT03622580/NCT03622593) trials. Primary endpoint: best-corrected visual acuity (BCVA) changes from baseline at 1 year, averaged over weeks 48, 52, and 56. RESULTS: Mean BCVA change from baseline at 1 year in the Asian country subgroup was similar between arms: faricimab Q8W (n=50), +10.9 (95% CI: 8.6-13.2); faricimab PTI (n=48) +10.0 (7.7-12.4) letters; aflibercept Q8W (n=46) +9.0 (6.6-11.4) letters. BCVA gains in the non-Asian country subgroup (n=582, 584, 581) were +11.3 (10.5-12.1), +11.2 (10.5-12.0), and +10.7 (9.9-11.5) letters, respectively. At 1 year, 49% of Asian country patients in the faricimab PTI arm achieved Q16W dosing (vs. 52% non-Asian) and 78% achieved ≥Q12W dosing (vs. 72% non-Asian). Anatomic improvementswere generally greater with faricimab versus aflibercept and similar between the Asian and non-Asian country subgroups. Faricimab was well tolerated, with no new safety signals. CONCLUSIONS: Vision, durability, anatomic, and safety outcomes were generally similar between the Asian and non-Asian country subgroups, suggesting that global YOSEMITE/RHINE results may be generalized to the Asian population. These data support the benefit-risk profile of faricimab for treating Asian patients with diabetic macular edema.

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.

Predictors of As-Needed Ranibizumab Injection Frequency in Patients With Macular Edema Following Retinal Vein Occlusion.

PURPOSE: To evaluate spectral-domain optical coherence tomography (SD-OCT) biomarkers associated with ranibizumab injection frequency after 7 monthly doses in the prospective, multicenter SHORE study for macular edema due to retinal vein occlusion (RVO). DESIGN: Prospective phase IV clinical trial data. METHODS: Post hoc analysis of 95 patients who received 7 monthly doses of ranibizumab followed by either pro re nata (PRN) or nonrandomized monthly injections from months 7-15 in eyes with macular edema secondary to RVO. Baseline SD-OCT biomarkers assessed include central subfield thickness (CST), epiretinal membrane presence, intraretinal and subretinal fluid, hyperreflective foci, disorganization of retinal inner layers (DRIL), and disruption of the external limiting membrane, ellipsoid zone, or interdigitation zone. Univariate and multivariable regression analyses evaluated the association between SD-OCT biomarkers and ranibizumab injection frequency. RESULTS: Mean age of patients was 65.3 (SD, 12.7) years. Overall, 57.9% had BRVO/HRVO and 42.1% of eyes had CRVO. Mean BCVA improved (+17.5 [SD, 1.2] Early Treatment of Diabetic Retinopathy Study [ETDRS] letters) during the 7-month fixed dosing period, remaining stable from baseline (+20.1 [SD, 1.5] ETDRS letters) during the PRN phase from months 7-15. The mean number of PRN injections was 4.32 (SD, 2.35). On multivariate regression, greater baseline DRIL (ß = 0.021, P = .0275) and higher CST at month 3 (ß = 0.01, P < .001) were associated with a higher total number of PRN injections. CONCLUSION: Greater baseline DRIL and higher CST at 3 months after starting ranibizumab treatment are associated with more frequent ranibizumab injections in PRN-treated patients with macular edema due to RVO.

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.

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.

Author Correction: Deep learning algorithm predicts diabetic retinopathy progression in individual patients.

A Correction to this paper has been published: https://doi.org/10.1038/s41746-020-00365-5.

Predictors of Early Diabetic Retinopathy Regression with Ranibizumab in the RIDE and RISE Clinical Trials.

PURPOSE: To investigate the predictors of early diabetic retinopathy (DR) improvement in the RIDE/RISE (NCT00473382/NCT00473330) clinical trials. PATIENTS AND METHODS: In RIDE/RISE, adult patients with vision loss due to diabetic macular edema (DME) were randomized to monthly intravitreal ranibizumab 0.3 or 0.5 mg (n=502 total) or sham (n=257). DR severity was graded (using the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale). In this post hoc analysis of RIDE/RISE, eyes with baseline DR score ≥35 were evaluated for ≥2-step improvements, and eyes with baseline DR score ≥43 were evaluated for ≥3-step improvements. The characteristics associated with ≥2- or ≥3-step DR improvement at months 3 or 6 were assessed using univariate and/or multivariable analyses. RESULTS: The percentage of eyes with a ≥2- or ≥3-step DR improvement was 20.1% and 3.7% at month 3 and 31.2% and 5.8% at month 6. Odds of ≥2-step DR improvement at months 3 or 6 were significantly greater in eyes with moderately severe to severe nonproliferative DR (NPDR) at baseline versus less severe or more severe DR (both P<0.0001). At month 6, odds of ≥2-step DR improvement were significantly greater in eyes with no DME at month 3 (P=0.008). Most patients with ≥3-step DR improvement at months 3 or 6 had proliferative DR (PDR) at baseline (83.3% and 66.7%). CONCLUSION: The strongest predictors of DR response to ranibizumab at month 6 were baseline DR severity and DME quiescence at month 3. Eyes with the most robust early improvements had moderately severe or severe NPDR or PDR at baseline.

Efficacy of Every Four Monthly and Quarterly Dosing of Faricimab vs Ranibizumab in Neovascular Age-Related Macular Degeneration: The STAIRWAY Phase 2 Randomized Clinical Trial.

Importance: Faricimab neutralizes angiopoietin-2 and vascular endothelial growth factor A via both simultaneous and independent binding. Objective: To evaluate extended dosing with faricimab, the first bispecific antibody designed for intraocular use, in patients with neovascular age-related macular degeneration. Design, Setting, and Participants: This phase 2 randomized clinical trial was a 52-week multicenter, active comparator-controlled, parallel-group study. Study participants were enrolled in 25 sites in the US from January and March 2017 with treatment-naive choroidal neovascularization secondary to neovascular age-related macular degeneration and best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study letter score of 73 (approximate Snellen equivalent, 20/40) to 24 (approximate Snellen equivalent, 20/320). Analysis began January 2017 and ended March 2018. Interventions: Participants were randomized 1:2:2 to receive intravitreal ranibizumab, 0.5 mg, every 4 weeks or faricimab, 6.0 mg, every 12 or 16 weeks. Participants in the faricimab arms initially received 4 monthly injections of faricimab. No rescue injections were allowed. Participants randomized to dosing every 16 weeks were assessed for disease activity at week 24 using prespecified criteria. Those with no active disease continued dosing every 16 weeks through trial end; participants with disease activity continued received dosing every 12 weeks. Main Outcomes and Measures: Mean change in BCVA from baseline at week 40. Results: Of 76 participants enrolled (mean [SD] age, 78.5 [8.5] years; age range, 56-94 years; 41 women [58%]; 69 white [97%]), 16 (21.0%) were randomized to ranibizumab every 4 weeks, 29 (38.2%) to faricimab every 12 weeks, and 31 (40.8%) to faricimab every 16 weeks. At week 24, 12 weeks after their last initiation injection, 65% (36 of 55) of all faricimab-treated participants had no disease activity. At week 40, adjusted mean BCVA gains from baseline (Early Treatment Diabetic Retinopathy Study letters) were +11.4 (80% CI, 7.8-15.0), +9.3 (80% CI, 6.4-12.3), and +12.5 (80% CI, 9.9-15.1) for the ranibizumab every 4 weeks, faricimab every 12 weeks, and faricimab every 16 weeks arms, respectively. Participants received a mean (SD) total of 12.9 (0.25), 6.7 (0.91), and 6.2 (0.93) injections, for the ranibizumab every 4 weeks, faricimab every 12 weeks, and faricimab every 16 weeks arms, respectively, through week 52. The secondary BCVA and anatomical imaging end points supported the primary end point and were comparable with ranibizumab every 4 weeks. No new or unexpected safety signals were identified. Conclusions and Relevance: At week 52, faricimab dosing every 16 weeks and every 12 weeks resulted in maintenance of initial vision and anatomic improvements comparable with monthly ranibizumab. These results suggest a role for simultaneous neutralization of angiopoietin-2 and vascular endothelial growth factor A in providing sustained efficacy through extended durability, warranting further investigation. Trial Registration: ClinicalTrials.gov Identifier: NCT03038880.

Spectral-Domain OCT Predictors of Visual Outcomes after Ranibizumab Treatment for Macular Edema Resulting from Retinal Vein Occlusion.

PURPOSE: To evaluate spectral-domain (SD)-OCT features associated with baseline vision and visual outcomes in the prospective, multicenter Study Evaluating Dosing Regimens for Treatment with Intravitreal Ranibizumab Injections in Subjects with Macular Edema following Retinal Vein Occlusion (SHORE). DESIGN: Post hoc analysis of prospective clinical trial data. PARTICIPANTS: Two hundred two participants in the 15-month, phase 4 SHORE study comparing monthly versus pro re nata ranibizumab after 7 monthly doses in eyes with retinal vein occlusion (RVO) with macular edema. METHODS: Baseline SD-OCT images were assessed for (1) central subfield thickness (CST); (2) presence of vitreomacular adhesion, vitreomacular traction, or epiretinal membrane; (3) presence, location, and amount of intraretinal fluid or subretinal fluid (SRF); (4) presence, location, and amount of hyperreflective foci (HF); (5) disorganization of retinal inner layers (DRIL); and (6) disruption of external limiting membrane (ELM), ellipsoid zone (EZ), and interdigitation zone (IZ). Univariate and multivariate regression analyses were performed to evaluate the association of these features with baseline best-corrected visual acuity (BCVA) and change in BCVA after 7 monthly ranibizumab injections. MAIN OUTCOME MEASURES: Association of SD-OCT features with baseline BCVA and change in BCVA after 7 monthly ranibizumab injections. RESULTS: Before therapy, worse baseline BCVA was associated with ERM presence (P = 0.0045), thicker SRF (P = 0.0006), larger intraretinal cysts (P = 0.0015), and higher percentage of DRIL (P < 0.0001), percentage of ELM disruption (P < 0.0001), percentage of EZ disruption (P = 0.0003), and percentage of IZ disruption (P = 0.0018). In multivariate models, only percentage of ELM disruption independently impacted baseline BCVA (P < 0.0001). After 7 monthly ranibizumab injections, mean BCVA improved by 18.3±12.6 Early Treatment Diabetic Retinopathy Study letters in treated eyes. The only factors independently associated with BCVA gain after 7 monthly ranibizumab treatments were younger age (P < 0.0001) and worse baseline BCVA (P < 0.0001). CONCLUSIONS: Although SD-OCT features may be associated with presenting vision in eyes with macular edema and RVO, most eyes treated with ranibizumab achieve substantial vision gains, and only older age and better baseline BCVA limited visual improvements.

Deep learning algorithm predicts diabetic retinopathy progression in individual patients.

The global burden of diabetic retinopathy (DR) continues to worsen and DR remains a leading cause of vision loss worldwide. Here, we describe an algorithm to predict DR progression by means of deep learning (DL), using as input color fundus photographs (CFPs) acquired at a single visit from a patient with DR. The proposed DL models were designed to predict future DR progression, defined as 2-step worsening on the Early Treatment Diabetic Retinopathy Diabetic Retinopathy Severity Scale, and were trained against DR severity scores assessed after 6, 12, and 24 months from the baseline visit by masked, well-trained, human reading center graders. The performance of one of these models (prediction at month 12) resulted in an area under the curve equal to 0.79. Interestingly, our results highlight the importance of the predictive signal located in the peripheral retinal fields, not routinely collected for DR assessments, and the importance of microvascular abnormalities. Our findings show the feasibility of predicting future DR progression by leveraging CFPs of a patient acquired at a single visit. Upon further development on larger and more diverse datasets, such an algorithm could enable early diagnosis and referral to a retina specialist for more frequent monitoring and even consideration of early intervention. Moreover, it could also improve patient recruitment for clinical trials targeting DR.

Calcineurin inhibitors augment endothelial-to-mesenchymal transition by enhancing proliferation in association with cytokine-mediated activation.

Calcineurin Inhibitors (CNIs) are routinely used for immunosuppression following solid organ transplantation. However, the prolonged use of these agents lead to organ fibrosis which limits their efficacy. CNIs induce TGFß expression, which is reported to augment endothelial-to-mesenchymal transition (EndMT), but their role in this process is not known. In these studies, we find that the CNIs FK506 and cyclosporine (CsA) are potent to increase endothelial cell (EC) proliferation using established in vitro assays (P < 0.05). Furthermore, using phosphokinase arrays, we find that each CNI activates the MAPK and Akt/mTOR signaling pathways, and that pharmacological inhibition of each pathway targets CNI-induced proliferative responses (P < 0.001). EndMT was evaluated by FACS for N-cadherin and CD31 expression and by qPCR for the expression of α-smooth muscle actin, N-cadherin and Snail. We find that CNIs do not directly induce dedifferentiation, while TGFß and hypoxia induce EndMT in small numbers of EC. In contrast, the treatment of EC with the inflammatory cytokine TNFα was potent to elicit an EndMT response, and its effects were most notably in EC following proliferation/doubling. Taken together, these observations suggest that CNIs elicit proliferative responses, which enhance EndMT in association with local inflammation. The clinical implications of these findings are that anti-proliferative therapeutics have high potential to target the initiation of this EndMT response.

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.

Baseline characteristics associated with early visual acuity gains after ranibizumab treatment for retinal vein occlusion.

BACKGROUND: To identify baseline patient characteristics associated with early clinically significant visual acuity (VA) improvements within 3 months of treatment initiation in ranibizumab-treated patients with retinal vein occlusion (RVO) in the SHORE study. METHODS: Post hoc analysis of baseline patient characteristics in the randomized, open-label, vision examiner-masked SHORE phase 4 study that compared monthly versus pro re nata dosing of ranibizumab in patients with branch and central RVO. Patients who enrolled in SHORE fulfilled eligibility criteria per protocol (N = 202). SHORE data were retrospectively analyzed to identify baseline patient characteristics associated with early clinically significant improvements in VA, defined as improvement to a Snellen equivalent of 20/40 or better vision (≥ 69 Early Treatment Diabetic Retinopathy Study [ETDRS] letters) or an increase in best-corrected VA (BCVA) of 15 or more ETDRS letters from baseline within 3 months of treatment initiation. Main outcome measures were BCVA gain of 15 or more ETDRS letters from baseline, Snellen equivalent of 20/40 or better vision, and baseline factors associated with early clinically significant improvement in BCVA. RESULTS: The median time for patients to achieve a BCVA of 20/40 or better was 59 days and the median time for patients to gain 15 or more ETDRS letters was 63 days. Better baseline BCVA (> 50 ETDRS letters/Snellen equivalent ≥ 20/100), greater baseline total macular volume (> 9.99 mm3), and presence of subretinal fluid at baseline were all associated with early improvement to 20/40 or better vision (ETDRS equivalent ≥ 69 letters; P < .0001, P = .02, and P = .03, respectively). CONCLUSIONS: This retrospective analysis found that better BCVA, greater total macular volume, and presence of subretinal fluid at baseline were associated with more rapid vision gains. Clinicians may find these helpful when considering the likelihood of achieving early clinically significant VA improvements with ranibizumab in patients with RVO. TRIAL REGISTRATION: ClinicalTrials.gov NCT01277302 .

Durability of Diabetic Retinopathy Improvement with As-Needed Ranibizumab: Open-Label Extension of RIDE and RISE Studies.

PURPOSE: To evaluate the durability of diabetic retinopathy (DR) improvements after a change in ranibizumab dosing from monthly to individualized pro re nata (PRN) therapy. DESIGN: Pooled analysis of the open-label extension (OLE) of RIDE and RISE (clinicaltrials.gov identifiers, NCT00473382 and NCT00473330) patients with DR and diabetic macular edema (DME). PARTICIPANTS: Patients who completed 36-month participation in RIDE and RISE and entered the OLE. METHODS: In RIDE and RISE, patients (n = 759) were randomized 1:1:1 to ranibizumab 0.3 mg monthly, 0.5 mg monthly, or monthly sham injections with rescue macular laser available after 6 months, per protocol-specified criteria. After 24 months, sham patients crossed over to ranibizumab 0.5 mg monthly. After 36 months in the core studies, patients in the OLE (n = 500) could receive ranibizumab 0.5 mg PRN based on predefined DME re-treatment criteria. Diabetic retinopathy severity was evaluated photographically using the Early Treatment Diabetic Retinopathy Study DR severity scale. MAIN OUTCOME MEASURES: Change in DR severity from months 36 to 48 by re-treatment status. RESULTS: Among patients who entered the OLE, 121 of 500 (24%) did not require additional ranibizumab injections. Overall, 367 patients had evaluable DR at months 36 and 48. Among patients not requiring ranibizumab re-treatment from months 36 to 48 (88/367), 57% to 78%, 0% to 7%, and 22% to 36% experienced DR severity stability, 2-step or more improvement, and 2-step or more worsening, respectively. Among patients requiring ranibizumab re-treatment (279/367), 84% to 94%, 2%, and 3% to 14% experienced DR severity stability, 2-step or more improvement, and 2-step or more worsening, respectively. On average, vision improvements were maintained during the OLE regardless of change in DR severity. CONCLUSIONS: Diabetic retinopathy severity improvements with ranibizumab were maintained in over 70% of OLE patients after switching from ranibizumab monthly to an individualized ranibizumab 0.5 mg PRN dosing regimen. Because approximately one third of OLE patients experienced DR worsening, careful monitoring should be part of the long-term management of patients with DR.

Usability of the Ranibizumab 0.5 mg Prefilled Syringe: Human Factors Studies to Evaluate Critical Task Completion by Healthcare Professionals.

PURPOSE: A ranibizumab prefilled syringe (PFS) has been approved by the U.S. Food and Drug Administration. Here we evaluate the use of the ranibizumab PFS for intravitreal injection by assessing whether the PFS enables healthcare providers to successfully prepare and administer an injection without prior training. DESIGN: Simulated-use and actual-use human factors usability studies. PARTICIPANTS: Retina specialists and ophthalmic medical personnel. METHODS: In a simulated-use summative usability study, retina specialists (n = 15) and ophthalmic medical personnel (n = 15) prepared the ranibizumab PFS and performed injections into a model eye. In an actual-use formative usability study (ClinicalTrials.gov identifier: NCT02698566), three assistants and three retina specialists prepared the PFS and performed intravitreal injections, respectively, in study eyes of patients with retinal diseases (n = 35). MAIN OUTCOME MEASURES: Twelve tasks specific to the unpacking, preparing, and properly administering the PFS for intravitreal injection were evaluated by a study assessor. Task performances were evaluated for use errors, close calls, and operational difficulties. Post-injection subjective user evaluations were performed to assess ease of use. RESULTS: All participants successfully performed all essential and safety-critical tasks without use error in both the simulated-use and actual-use human factors usability studies. The majority of participants rated the tasks required to use the ranibizumab PFS as "Easy" or "Very Easy." CONCLUSIONS: Both the simulated-use and actual-use usability studies yielded consistent data, showing that healthcare professionals are able to use the ranibizumab PFS by successfully performing all critical tasks involved in preparing and delivering an intravitreal injection. The simulated-use usability testing was sufficiently realistic and representative of real-world use, and was appropriate and preferred over actual-use usability testing for proper evaluation of the product user interface.LAY ABSTRACT: Ranibizumab is approved in the United States to treat various eye conditions, including neovascular (wet) age-related macular degeneration, macular edema following retinal vein occlusion, diabetic macular edema, diabetic retinopathy, and myopic choroidal neovascularization. It is administered as an injection into the eye once a month, and is available in a vial from which medication needs to be withdrawn using a standard syringe with a 19-gauge filter needle. The filter needle is then replaced by a smaller gauge needle for the intravitreal injection. The recent U.S. Food and Drug Administration approval of a 0.5 mg ranibizumab prefilled syringe eliminates the need for withdrawing medication from a vial and changing needles prior to use. The studies described in this report assessed the usability of the ranibizumab prefilled syringe by retina specialists and ophthalmic medical personnel in simulated- and actual-use settings. Twelve tasks that included unpacking, preparing, and properly administering the prefilled syringe for intravitreal injection were evaluated by a study assessor. Task performances were evaluated for use errors, close calls, and operational difficulties. Participants successfully performed all the tasks without any critical errors in both simulated-use and actual-use human factors usability studies, and most participants found the syringe to be "Easy" or "Very Easy" to use.

Self-reported healthcare utilization by adults with diabetic retinopathy in the United States.

PURPOSE: To assess healthcare utilization patterns across diabetic retinopathy (DR) severity levels in the United States (US). DESIGN: Cross-sectional study of 699 adults, participating in the 2005-2008 National Health and Nutritional Examination Surveys. METHODS: Diagnosis of DR was based on fundus photographs and categorized as: (1) no DR; (2) mild/moderate nonproliferative DR (NPDR); and (3) severe NPDR/proliferative DR (PDR). Healthcare utilization patterns were assessed during a household questionnaire where survey participants self-reported: (1) awareness that diabetes had affected their eyes; (2) pupil-dilation during the past year; and (3) visits to a diabetes education/nutrition specialist during the past year. RESULTS: Among adults with self-reported diabetes, the proportion of those that were aware that diabetes had affected their eye was 15.3% [95% confidence interval (C.I.)] 10.9-19.6%), 21.7% (95% C.I. 14.6-28.7%), and 81.5% (95% C.I. 66.5-96.5%) across those with no retinopathy, mild/moderate NPDR, and severe NPDR/PDR, respectively (p < 0.01). The utilization of a diabetic education/nutrition specialist during the past year was 30.4% (95% C.I. 24.8-36.0%), 31.8% (95% C.I 23.4-40.2%), and 55.9% (95% C.I. 32.3-79.6%) across those with no retinopathy, mild/moderate NPDR, and severe NPDR/PDR, respectively (p = 0.13). Pupil dilation within the past year was 62.2% (95% C.I. 56.3-68.1%), 62.1% (95% C.I. 53.4-70.8%), and 93.8% (95% C.I. 87.3-100.0%) across those with no DR, mild/moderate NPDR, and severe NPDR/PDR, respectively (p = 0.01). CONCLUSIONS: Adults with diabetes in the United States, even those with the most severe forms of DR, do not fully utilize healthcare services for diabetic eye disease. Future studies should aim to address barriers to appropriate diabetes care.