IMPACT OF FARICIMAB VERSUS AFLIBERCEPT ON EPIRETINAL MEMBRANE FORMATION OVER 2 YEARS IN PATIENTS WITH DIABETIC MACULAR EDEMA IN THE PHASE 3 YOSEMITE AND RHINE TRIALS

Supplemental Digital Content is Available in the Text.

Post hoc analysis of phase 3 YOSEMITE/RHINE trials found that intravitreal faricimab every 8 weeks (Q8W) for 2 years reduced epiretinal membrane (ERM) formation in eyes with diabetic macular edema versus aflibercept Q8W. The findings may inform decision-making when initiating intravitreal therapy and suggest that angiopoietin-2 inhibition may help reduce ERM formation.

Abstract

Background/Purpose:

To assess the effects of faricimab versus aflibercept on epiretinal membrane (ERM) formation in eyes with diabetic macular edema.

Methods:

Post hoc analysis of phase 3 YOSEMITE/RHINE trial data in eyes with diabetic macular edema receiving faricimab every 8 weeks (Q8W), faricimab treat-and-extend (T&E; up to Q16W depending on central subfield thickness and best-corrected visual acuity), or aflibercept Q8W for 100 weeks.

Results:

ERMs developed in 3.8% (23/602) of eyes treated with faricimab Q8W, 5.1% (31/608) with faricimab T&E, and 7.6% (45/590) with aflibercept Q8W at 100 weeks. ERMs were less likely with faricimab Q8W versus aflibercept Q8W (odds ratio [OR] 0.48, 95% confidence interval [CI] 0.29–0.81, P = 0.0055). The mean (SD) best-corrected visual acuity at 100 weeks in eyes with and without ERMs were 69.2 (13.6) letters [20/40 Snellen] versus 73.8 (13.1) [20/40 Snellen], respectively; the mean (SD) CSTs were 315.8 (99.2) versus 274.6 (74.1) µm. Faricimab T&E dosing intervals were extended ≥ Q12W in 79.7% of eyes without ERMs versus 50.0% with ERMs.

Conclusion:

Risk of ERMs was 52% lower with faricimab Q8W versus aflibercept Q8W over 100 weeks in eyes with diabetic macular edema, suggesting a potential role for faricimab in reducing pre-retinal fibrotic proliferation. The results may help inform physician/patient decision-making when initiating intravitreal therapy.

Trial Registration:

NCT03622580 and NCT03622593.

Epiretinal membranes (ERMs) or pre-retinal fibrosis are common findings among patients with diabetic macular edema (DME), occurring in ∼14% of eyes with center-involving disease¹ and 9.5% of eyes treated with intravitreal injections for two years.² Symptomatic ERMs can lead to decreased visual acuity, metamorphopsia, and potentially require surgery.^2–4

The etiology of ERMs is likely multifactorial, with a common phenotype of pre-retinal fibrotic tissue, a potential association with underlying inflammation and poor retinal vasculature control.^3,5 On a pathophysiological level, ERM tissue from eyes with ischemic retinal diseases tends to have increased angiopoietin-2 (Ang-2) and Tie2 expression.⁶ Furthermore, preclinical studies show that Ang-2 promotes inflammation, vascular permeability, and fibrosis.⁶ Under normal conditions, angiopoietin-1 (Ang-1) binds to the Tie2 receptor to activate a cascade of events that stabilizes the vasculature and maintains blood vessels in a quiescent state.^7,8 In disease states, when Ang-2 levels surpass Ang-1, Ang-2 occupies the Tie2 receptor but does not activate it, thereby enhancing vascular endothelial growth factor (VEGF) activity driving excessive permeability, inflammation, pathological angiogenesis, and fibrosis.^9,10 Taken together, these observations suggest that the development of ERMs in DME might be reduced through modulation of the Ang/Tie pathway.

Faricimab is a bispecific anti–Ang-2 and anti–VEGF-A antibody evaluated in the phase 3 YOSEMITE and RHINE trials in eyes with DME.^11,12 Eligible eyes (N = 1,891) received one of three treatment regimens for two years: intravitreal faricimab every eight weeks (Q8W), faricimab Q8W according to a personalized treat-and-extend-based regimen (T&E) with dosing extended up to every 16 weeks (Q16W) based on central subfield thickness (CST) and best-corrected visual acuity (BCVA) criteria, or intravitreal aflibercept Q8W. A major exclusion criterion for the trials was the presence of ERM at baseline.¹¹ Consequently, the trial population can be used to establish whether dual inhibition of Ang-2 and VEGF-A with faricimab decreases ERM formation compared with VEGF inhibition with aflibercept.

The primary objective of this post hoc analysis was to compare the 2-year incidence of ERM formation in eyes with DME treated with faricimab Q8W, faricimab T&E, or aflibercept Q8W. A secondary objective was to conduct a retrospective analysis of baseline factors that may be associated with the development of ERMs among eyes with DME receiving intravitreal injections. Tertiary objectives were to describe the functional and anatomical impact of ERMs in eyes with DME, analyzed in a treatment-agnostic manner, and understand the potential impact of ERMs on treatment burden.

Methods

Study Design

The study design and rationale for the identically designed phase 3 randomized, double-masked, noninferiority YOSEMITE and RHINE trials have previously been described.^11–13 Both trials were conducted in accordance with the International Council for Harmonisation E6 Guideline for Good Clinical Practice, tenets of the Declaration of Helsinki, US Food and Drug Administration regulations, the European Union Clinical Trials Directive (2001/20/EC), as appropriate, and all applicable local, state, and federal laws. Study protocols were approved by applicable institutional review boards and ethics committees before trial commencement.¹² All patients provided written informed consent to participate.

Participants and Randomization

The trials included eyes with center-involving DME secondary to diabetes (Type 1 or 2) (1 eye per patient designated the study eye based on worst BCVA at screening) recruited from 353 sites, worldwide. Key ocular inclusion criteria were CST ≥ 325 µm at screening and BCVA of 73-25 ETDRS letters (∼20/320-20/40 Snellen equivalent). A major exclusion criterion was the presence of an ERM involving the fovea or disrupting the macular architecture in the study eye, as evaluated by a central reading center (CRC; Duke Reading Center, Durham, North Carolina or Vienna Reading Center, Vienna, Austria). Additional key ocular exclusion criteria were anti-VEGF treatment within 3 months (previously treated eyes; capped at 25% enrolment) or any prior anti-VEGF agents to study eye (treatment naïve); any IVT, periocular, or implant corticosteroids within 6 months before day 1, or any use of Iluvien implants; and any cataract surgery within 3 months before day 1, or any other intraocular surgery. Full eligibility criteria are reported in the primary trial publication.¹² Patients with eligible eyes were randomized (1:1:1) to receive six initial doses of intravitreal faricimab 6.0 mg every 4 weeks (Q4W) followed by faricimab 6.0 mg Q8W; four initial doses of intravitreal faricimab 6.0 mg Q4W followed by faricimab 6.0 mg according to a personalized T&E-based regimen; or five initial doses of intravitreal aflibercept 2.0 mg Q4W followed by aflibercept 2.0 mg Q8W. Patients randomized to the faricimab T&E arm initially received faricimab 6.0 mg Q4W until they first reached CST <325 µm, at or after Week 12. Once achieved, treatment intervals were extended to Q8W, then could be maintained, extended by 4 weeks with adjustable dosing up to Q16W, or reduced by 4 weeks or 8 weeks (as low as Q4W) using an automated dosing regimen that was determined based on protocol prespecified CST and BCVA criteria at active dosing visits (see Figure 2, Supplemental Digital Content 2, http://links.lww.com/IAE/C625).^11–13 Each study included a screening period of up to 28 days, a 96-week treatment period, and a final study visit at Week 100 (Year 2).

Assessments

ERMs were prospectively evaluated at baseline, and at Weeks 16, 48, 52, 56, 92, 96, and 100 by CRC assessors who were masked to treatment assignment. An ERM was defined as a membrane on the internal limiting membrane causing significant distortion of the macular architecture in the central 1-mm subfield visualized using optical coherence tomography (OCT). At the beginning of the trials, the two reading centers harmonized their interpretation of ERMs with deformation and showed a high rate of agreement (κ = 0.46–0.77; see Table 1, Supplemental Digital Content 3, http://links.lww.com/IAE/C626).

Best-corrected visual acuity and CST (defined as the distance between the internal limiting membrane and Bruch membrane in the central 1-mm diameter of the Early Treatment Diabetic Retinopathy [ETDRS] grid), and intraretinal fluid (IRF) and subretinal fluid (SRF) were assessed every four weeks through week 100. Macular leakage (6-mm diameter of the ETDRS grid on fundus fluorescein angiography) assessed at baseline and at weeks 16, 52, and 96. The proportion of eyes in the faricimab T&E group receiving treatment Q4W, Q8W, every 12 weeks (Q12W), and Q16W was evaluated through week 96.

Statistical Analysis

Post hoc efficacy analyses were performed on eyes that did not have ERMs at baseline and had baseline/postbaseline ERM assessments grouped according to treatment at randomization. All P-values are nominal and no formal conclusions should be made based on P-values. A descriptive summary of baseline characteristics was provided to evaluate the balance among treatment groups. The cumulative incidence of ERM formation over two years was calculated using the proportions of eyes that developed an ERM over 100 weeks. The denominator is the number of eyes without ERMs at baseline that had ERM status available through the study. The numerator is the number of eyes with ERMs based on the assumption that ERMs remain present throughout the trial once detected. Logistic regression analysis was used to assess the effect of treatment on the risk of developing ERMs after adjusting for stratification factors at randomization. Odds ratios (OR) and the corresponding 95% confidence intervals (CI) were estimated for each of the faricimab treatment arms versus aflibercept.

A retrospective analysis was conducted to explore the relationship between ocular and sociodemographic factors and ERM development. Separate logistic regression analyses were initially conducted on a predefined set of variables along with the treatment group. Variables with a P-value < 0.05 were subsequently included in a multivariable logistic regression model. The final multivariable model included sex, age, lens status, baseline BCVA, baseline macular leakage (mm²), and treatment group as covariates. Adjusted ORs and 95% CI were calculated to determine the potential factors associated with the development of ERMs.

Descriptive analyses were conducted to compare macular leakage area at week 96, and BCVA, CST, and the proportions of eyes with intraretinal fluid (IRF) or SRF on OCT scans at week 100, in eyes that did and did not develop ERMs throughout the study. Data were analyzed in a treatment-agnostic manner due to the small number of eyes that developed ERMs and the associated difficulty conducting meaningful comparisons across treatment arms.

To understand the potential impact of ERMs on treatment durability, descriptive analyses were conducted to evaluate the treatment intervals at week 96 in eyes that did and did not develop ERMs in the faricimab T&E arm. Specifically, the proportion of eyes on Q4W, Q8W, Q12W, and Q16W treatment intervals at week 96 were reported.

Results

Study Population

The YOSEMITE and RHINE trials enrolled 1,891 eyes with DME, 632, 632, and 627, which were randomized to faricimab Q8W, faricimab T&E, and aflibercept Q8W groups, respectively.¹¹ Eligibility for the trials (including ERM status) was assessed at screening, while ERM status at baseline may have been assessed by a different Reader. Inherent variability in the reader assessment of ERMs in borderline cases meant that the study Readers occasionally identified an ERM that was not called an ERM by the eligibility grader. This assessment variability on borderline cases accounts for the small number of enrolled eyes with ERMs, all of which were excluded from the analysis. Overall, 619, 618, and 604 eyes in the faricimab Q8W, faricimab T&E, and aflibercept Q8W groups, respectively, had ERM assessments showing no ERMs at baseline and were included in the post hoc analysis (Figure 1). An example of an OCT scan showing an eye without ERMs is shown in Supplemental Digital Content 1 (see Figure 1A, http://links.lww.com/IAE/C624). Baseline sociodemographic and ocular characteristics were generally balanced across treatment groups (Table 1).

Fig. 1.

Patient flow diagram for the post hoc analysis of ERM formation in the phase 3 YOSEMITE and RHINE trials.

Table 1.

Baseline Sociodemographic and Ocular Characteristics Among Patients With No ERMs at Baseline

Baseline Sociodemographic and Ocular Characteristics	Aflibercept Q8W n = 604	Faricimab T&E n = 618	Faricimab Q8W n = 619
Age, mean (SD) years	62.3 (9.7)	62.2 (10.0)	62.0 (9.8)
Sex, n (%)
Male	349 (57.8)	385 (62.3)	374 (60.4)
Female	255 (42.2)	233 (37.7)	245 (39.6)
Race, n (%)
White	483 (80.0)	476 (77.0)	482 (77.9)
Asian	59 (9.8)	61 (9.9)	63 (10.2)
Black or African American	36 (6.0)	48 (7.8)	39 (6.3)
American Indian or Alaska Native	8 (1.3)	5 (0.8)	5 (0.8)
Native Hawaiian or other Pacific Islander	3 (0.5)	0	4 (0.6)
BMI, mean (SD) kg/m2	30.6 (6.3)	30.4 (6.4)	30.7 (6.5)
Smoking status, n (%)
Never smoked	385 (63.7)	375 (60.7)	356 (57.5)
Previous smoker	168 (27.8)	184 (29.8)	195 (31.5)
Current smoker	51 (8.4)	59 (9.5)	68 (11.0)
HbA1c, mean (SD)	7.6 (1.1)	7.7 (1.1)	7.6 (1.1)
T2DM, n (%)	575 (95.2)	586 (94.8)	577 (93.2)
Time since DME diagnosis, mean (SD) months	18.8 (32.5)	19.3 (35.0)	16.4 (27.5)
BCVA Mean (SD), ETDRS letters, [Snellen equivalent]	62.2 (9.4) [20/63]	62.2 (9.8) [20/63]	62.1 (9.9) [20/63]
CST, mean (SD) µm	478.7 (129.2)	477.8 (129.1)	477.4 (126.9)
IOP, mean (SD) mmHg	15.1 (3.1)	15.2 (3.0)	15.3 (3.1)
Previously treated with anti-VEGF, n (%)	133 (22.0)	130 (21.0)	136 (22.0)
Severe NPDR or worse, n (%)*	134 (22.2)	132 (21.4)	135 (21.8)
Phakic status, n (%)
Phakic	448 (74.2)	461 (74.6)	467 (75.4)
Pseudophakic	151 (25.0)	153 (24.8)	149 (24.1)
Other	5 (0.8)	4 (0.6)	3 (0.5)
Posterior vitreous detachment, n (%)	109 (18.0)	113 (18.3)	101 (16.3)
Macular leakage, mean (SD) mm2	23.0 (12.4)	23.1 (12.3)	23.2 (12.3)

^*Defined as DRS level ≥ 53 excluding level 90 (cannot grade).

BCVA, best-corrected visual acuity; BMI, body mass index; CST, central subfield thickness; DME, diabetic macular edema; DRS, diabetic retinopathy status; ERM, epiretinal membrane; HbA1c, glycated hemoglobin; IOP, intraocular pressure; NPDR, nonproliferative diabetic retinopathy; Q8W, every 8 week; SD, standard deviation; T2DM, type 2 diabetes mellitus; T&E, treat-and-extend; VEGF, vascular endothelial growth factor.

ERM Development Across Intravitreal Therapies

Of the 1,891 study eyes randomized to treatment, 91 either had ERMs at baseline or were not assessed for ERMs at or postbaseline. Thus, 602, 608, and 590 eyes in the faricimab Q8W, faricimab T&E, and aflibercept Q8W groups, respectively, were included in the analysis for incident ERMs (Figure 1). The respective cumulative incidence of ERM formation in eyes that received faricimab Q8W, faricimab T&E, or aflibercept Q8W was 1.5% (9/602), 2.5% (15/608), and 3.9% (23/590) at 1 year, and 3.8% (23/602), 5.1% (31/608), and 7.6% (45/590) at 2 years. The odds of ERM formation over 2 years were reduced by 52% with faricimab Q8W versus aflibercept Q8W (OR 0.48, 95% CI 0.29–0.81, P = 0.0055; Figure 2) with a trend toward reduced odds for faricimab T&E versus aflibercept Q8W (OR 0.65, 95% CI 0.41–1.05, P = 0.0783).

Fig. 2.

Cumulative proportion of eyes without ERMs at baseline that developed ERMs after 1 and 2 years (weeks 52 and 100) (ERM analysis population).

ERM Development: Ocular and Sociodemographic Risk Factors

Retrospective univariate analysis of baseline factors associated with ERM development are summarized in Supplemental Digital Content 4 (see Table 2, http://links.lww.com/IAE/C627). Eyes that developed ERMs had a poorer mean BCVA at baseline (58.8 ETDRS letters [20/80 Snellen] vs. 62.4 letters [20/63 Snellen]; P = 0.0004), were less frequently phakic (63.6% vs. 75.8%; P = 0.0047), had greater baseline macular leakage area (27.5 vs. 22.8 mm², P = 0.0005), and were less likely to be treated with faricimab Q8W (23.3% vs. 34.0%; P = 0.0054) than eyes that did not develop ERMs. In addition, patients with eyes that developed ERMs were older (64.3 years vs. 62.0 years; P = 0.0207) and were more likely to be female (46.5% vs. 39.2%; P = 0.0499). According to univariate analysis, the presence of investigator-reported posterior vitreous detachment was not associated with ERM development (P = 0.6697). Based on multivariable logistic regression analysis, factors associated with reduced ERM development were treatment with faricimab Q8W (OR 0.48, 95% CI 0.28–0.82), and (to a lesser extent) treatment with faricimab T&E (OR 0.67, 95% CI 0.41–1.10), and that associated with increased ERM development was greater baseline macular leakage area (OR for a 10 mm² increase: 1.41, 95% CI 1.16–1.72) (see Table 3, Supplemental Digital Content 5, http://links.lww.com/IAE/C628). Multivariable logistic regression analysis with stratification factors as covariates found that eyes developing ERMs were less likely to have baseline BCVA ≥ 64 EDTRS letters (≥20/50 Snellen) versus < 64 letters (<20/50 Snellen) (OR 0.58, 95% CI 0.38–0.87) (see Table 4, Supplemental Digital Content 6, http://links.lww.com/IAE/C629).

Visual Acuity and Anatomical Outcomes

At 2 years (100 weeks), eyes that developed ERMs across all three treatment groups had poorer BCVA (mean (SD) 69.2 (13.6) ETDRS letters [20/40 Snellen] versus 73.8 (13.1) letters [20/40 Snellen], respectively) and thicker retinas (mean CST (SD) 315.8 (99.2) versus 274.6 (74.1) µm; Figure 3, A and B and see Table 5, Supplemental Digital Content 7, http://links.lww.com/IAE/C630) than eyes that did not develop ERMs. A higher proportion of eyes with versus without ERMs had IRF (75.9% vs. 48.6%) or SRF (10.6% vs. 3.4%) at year 2 (Figure 3C). Eyes that developed ERMs had greater macular leakage area than eyes that did not develop ERMs (14.4 vs. 8.9 mm²) at year 2 (Figure 3D).

Fig. 3.

A. BCVA. B. CST. C. Proportion of eyes with IRF and SRF, and D, macular leakage at baseline and year 2 (week 96 or 100) in eyes with and without ERM formation (ERM analysis population).

Durability Outcomes

Of the 28 eyes treated with faricimab T&E that developed ERMs and completed the study, 14 (50.0%) achieved extended dosing (≥Q12W) at year 2 (96 weeks), with an equal number of eyes receiving treatment Q12W and Q16W (Figure 4). In comparison, dosing in eyes treated with faricimab T&E that did not develop ERMs was extended in 411/516 eyes (79.7%), with 79/516 (15.3%) treated Q12W and 332/516 (63.3%) treated Q16W. Conversely, 8/28 (28.6%) versus 39/516 (7.6%) eyes that did versus did not develop ERMs were treated with faricimab Q4W at year 2, respectively.

Fig. 4.

Proportion of eyes in the faricimab T&E arm on each treatment interval at year 2 (week 96) among eyes with and without ERM formation during the study (ERM analysis population).

Discussion

In this post hoc analysis of phase 3 YOSEMITE/RHINE data in eyes with DME, treatment with faricimab Q8W reduced the risk of ERM formation by 52% versus aflibercept Q8W. Previous studies show that the incidence of ERM formation after injection of intravitreal agents in eyes with DME is 6.5%, 7.1%, and 24%, with either anti-VEGF, triamcinolone, or dexamethasone implant, respectively.² However, the incidence among the general population is approximately 4%–5% over 5 years.^14,15 In our study, the incidence of ERM formation over 2 years was 3.8%, 5.1%, and 7.6% after treatment with faricimab Q8W, faricimab T&E, or aflibercept Q8W, respectively.

The comparatively favorable impact of faricimab versus aflibercept on ERM development may be attributable to faricimab's anti–Ang-2 mechanism of action. Preclinical models of ischemic retinal diseases have demonstrated the potential of Ang-2 inhibition to reduce inflammation, stabilize the vasculature, and limit fibrosis.^6,16,17 While the general etiology of ERM formation is multifactorial, there is strong evidence to suggest that ERMs are associated with inflammation and poor vasculature control.^3,5 Hence, it is plausible from a biological perspective that the effect of faricimab on ERM formation is related to its anti–Ang-2 mechanism, thereby stabilizing vessels and reducing inflammation. Furthermore, the ability of faricimab to reduce IRF levels and CST thickness relative to aflibercept has been previously described,^12,13,18 and this fluid control may contribute to the decreased formation of ERMs among patient eyes treated with faricimab versus aflibercept. Further research is required to understand the exact roles of the VEGF and Ang-2 pathways in ERM formation in patient eyes with DME.

Retrospective multivariate logistic regression analysis showed that faricimab Q8W versus aflibercept Q8W was associated with a reduced risk of ERM development (OR 0.48, 95% CI 0.28–0.82; P = 0.0078) with a trend toward a reduced risk with faricimab T&E versus aflibercept (OR 0.67, 95% CI 0.41–1.10; P = 0.1129). In addition, eyes with greater macular leakage at baseline had an increased risk of ERM development (OR for a 10 mm² increase in area: 1.41, 95% CI 1.16-1.72; P = 0.0007). Such an association is consistent with prior literature citing macular leakage as a risk factor for ERMs.¹⁹ Multivariate logistic regression with stratification factors as covariates showed a BCVA ≥ 64 (20/50 Snellen) versus < 63 ETDRS letters (20/63) and was associated with an decreased risk of ERM formation (OR 0.58, 95% CI 0.38–0.87). The reason for this association is unknown. However, it is possible that eyes with worse BCVA had more severe underlying disease, with greater inflammation and worse vascular stability. Further studies are needed to better understand the relationship between visual acuity and ERM formation. Regardless, this observation may provide useful information for physicians as they counsel their patients about the risk of ERMs after starting intravitreal treatment.

Existing studies comprehensively describe the impact of ERMs on vision and anatomy, and the potential need for surgery.^2–4 Yet there are limited data from large-scale phase 3 trials that assess the detrimental impact of ERMs on visual, anatomical, and durability outcomes. Our study found that eyes that developed ERMs after treatment with faricimab or aflibercept had numerically worse visual acuity and thicker retinas when compared with those that did not develop ERMs at 2 years. Furthermore, a higher proportion of eyes that developed ERMs versus those that did not develop ERMs had IRF (76% vs. 49%) and SRF (11% vs. 3%) at 2 years. IRF is a major negative predictive factor regarding retinal functional and therapeutic outcomes in eyes with neovascular age-related macular degeneration.²⁰ In DME, IRF does not respond as readily to anti-VEGF therapy as is seen in nAMD,^13,21 and persistence of IRF is associated with degenerative alteration of the affected retina.²² The non–VEGF-related mechanism of faricimab may reduce those complications. Future research should investigate how IRF may affect ERM formation and how differential fluid outcomes among patient eyes with ERM and underlying DME affect long-term functional outcomes.

This analysis demonstrated that it was possible to extend the dosing interval to Q16W in only 25% of eyes that developed an ERM in the faricimab T&E arm (n = 31) compared with 64% that did not develop an ERM (n = 577). We speculate that the ERMs prevented resolution of IRF through reduced antibody permeability causing relative anti-VEGF resistance.^23,24 Alternatively, the ERMs could have prevented fluid resolution or the development of degenerative cavitations by a VEGF-independent mechanism. Regardless, persistent IRF, decreased visual acuity, and shorter treatment intervals were all associated with ERMs. Further research is necessary to elucidate how and why ERM formation affects treatment intervals with intravitreal injections^23,24 and whether early treatment with faricimab could help improve overall functional and anatomical outcomes and treatment burden among patient eyes with DME.

A strength of this analysis is the generalizability of the results because the data are from the largest phase 3 trials in eyes with DME to date. In addition, the analyzed population had no ERMs at baseline, allowing for a robust evaluation of the impact of various intravitreal therapies and dosing regimens on ERM development over 2 years. ERMs were also prospectively evaluated by two independent CRCs, who were masked to treatment assignment and harmonized on ERM staging before study initiation. One limitation of this study is that ERMs were not characterized by size and objective quantification. An additional limitation is the subjectivity in the diagnosis of ERMs, especially given the challenges around clearly distinguishing an ERM from a thickened posterior hyaloid. However, the ERM definition was standardized by two professional reading centers and these centers were harmonized in that the membrane needed to have had an impact on macular architecture per OCT scan. Future research should consider quantifying the size of ERMs, as well as prospectively assessing the presence of a PVD on OCTs, to better understand the role of dual VEGF-A/Ang-2 inhibition on ERM development. A further limitation is that the trials only followed patients over 2 years. Thus, there are no data on the role of faricimab and dual inhibition of VEGF-A/Ang-2 on ERM development beyond that time. Although there seem to be lower rates of ERM formation in eyes receiving faricimab Q8W versus aflibercept Q8W and a trend toward lower rates with faricimab T&E versus aflibercept Q8W, this finding needs to be confirmed with longer-term clinical trials. Moreover, as our study results may have been confounded by the T&E algorithm, which assigned more frequent treatment to those with thicker/increasing CST values, there is a need for future trials to investigate the impact of ERMs on T&E treatment intervals. Indeed, it is possible that patient eyes with ERMs and increased retinal thickness may have needed less frequent treatment in a real-world setting. Furthermore, as a proportion of patient eyes in the study had previously received anti-VEGF treatment (capped at 25% enrolment), this could be considered a bias in the analysis of ERM development in this study population. In addition, the impact of treatment with faricimab on other retinal fibrotic outcomes was not evaluated in this study. Given the preclinical evidence of the effect of Ang-2 inhibition on subretinal inflammation,¹⁶ future research should evaluate the potential impact of faricimab on subretinal fibrosis, especially among patients with nAMD, in a clinical trial setting. Such data will be valuable to physicians as they discuss long-term outcomes of various intravitreal therapies with their patients.

Supplementary Material

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